CADTH Reimbursement Review

Ciltacabtagene Autoleucel (Carvykti)

Sponsor: Janssen Inc.

Therapeutic area: Relapsed or refractory multiple myeloma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Ethics Review

Stakeholder Input

Clinical Review

Executive Summary

An overview of the submission details for the drug under review is provided in Table 1.

Table 1: Submitted for Review

CAR = chimeric antigen receptor; NOC/c = Notice of Compliance with Conditions.

Source: Product monograph.¹

Introduction

Multiple myeloma (MM) is a plasma cell cancer caused by the growth of cancer cells in the bone marrow. It was estimated that 4,000 people in Canada would be diagnosed with MM in 2022 and that 1,650 would die from MM, with slightly more cases occurring in males than females.² Although new therapies have been introduced that can improve a patient’s overall survival (OS) and progression-free survival (PFS), MM remains an incurable condition.³ Some estimates suggest that the median survival for patients with MM is just more than 5 years and, during this time, patients can receive 4 lines of therapy or more.^3,4 Patients with MM will ultimately relapse and, according to the clinical experts consulted by CADTH for this review, are usually assessed on a monthly basis following therapy to monitor for relapse. Indications for relapse include a rise in monoclonal (M) protein in the serum or urine or rise in serum free light chain ratio, or development of CRAB symptoms (hypercalcemia, renal insufficiency, anemia, or new bone lesions) or extramedullary plasmacytomas.⁵ The median OS for patients with relapsed or refractory (r/r) MM is approximately 13 months.⁶

The treatment landscape for MM has changed significantly in the past number of years, with the emergence of new therapies in newly diagnosed and r/rMM settings.³ At relapse, the clinical experts consulted by CADTH noted that treatment for patients depends on patient factors, including age, comorbidities, and previous treatments. According to the clinical experts consulted by CADTH as well as the clinical guidelines, regimens containing carfilzomib or pomalidomide are typically reserved for relapse after daratumumab-based regimens in the third line or after.⁷ Other options in the fourth line of therapy and beyond include oral palliative chemotherapy and alkylating drugs, such as cyclophosphamide.⁷ The clinical experts consulted by CADTH noted that belantamab mafodotin is another option available to patients; however, this treatment is available only through special access and is not used frequently. In November 2022, the FDA requested the withdrawal of belantamab mafodotin from US markets based on the outcomes of the pivotal clinical trial (DREAMM-3), which did not meet the requirements of the FDA’s Accelerated Approval regulations.⁸ Selinexor was recommended for reimbursement with conditions by CADTH in July 2022, in combination with bortezomib and dexamethasone for the treatment of adult patients with MM who have received at least 1 prior therapy; however, funding negotiations are still ongoing. Despite an array of therapies, MM remains an incurable disease and patients eventually relapse and their disease becomes refractory to available treatments.⁶

The clinical experts and clinician groups consulted by CADTH agreed there is an unmet need for treatments beyond the third line that prolong survival, delay disease progression, improve quality of life, and minimize side effects. The clinical experts consulted by CADTH also noted there is a need for treatments to be tolerable for patients with comorbidities and that require a shorter treatment duration and lead to a longer treatment-free interval to reduce the treatment burden on this heavily pretreated patient population with a limited lifespan.

The sponsor’s reimbursement request is for the treatment of adult patients with MM who have received at least 3 prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti–cluster of differentiation 38 (CD38) antibody, and whose disease is refractory to their last treatment. Ciltacabtagene autoleucel (cilta-cel) underwent review by Health Canada through advance consideration under its Notice of Compliance with Conditions (NOC/c) and received a NOC/c on February 9, 2023. It has not been previously reviewed by CADTH. It is recommended that cilta-cel be provided as a single-dose infusion at a dose of 0.5 to 1.0 × 10⁶ chimeric antigen receptor (CAR)-positive viable T cells per kg of body weight, with a maximum dose of 1 × 10⁸ CAR-positive viable T cells per single infusion.¹

The objective of this report was to perform a systematic review of the beneficial and harmful effects of cilta-cel for the treatment of adult patients with r/rMM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody. Of note, this CADTH Reimbursement Review was conducted before issuance of a Health Canada NOC/c and the scope was based on the anticipated indication.

Stakeholder Perspectives

The information in this section is a summary of input provided by the patient groups that responded to CADTH’s call for patient input and from the clinical experts consulted by CADTH for the purpose of this review.

Patient Input

One patient group, Myeloma Canada, provided input for the review of cilta-cel. Two online surveys were conducted, and a total of 200 patients and 26 caregivers provided complete responses to the patient and caregiver survey, respectively. Patient respondents indicated that their ability to work was most significantly impacted by the symptoms associated with myeloma, followed by the ability to travel and exercise, as well as their mental health. Travel cost was identified as the most significant financial implication of treatment, and the majority of patient respondents indicated they required support from a caregiver for the management of MM or treatment-related symptoms. From the perspective of the caregiver respondents, the ability to travel was most significantly impacted by caring for an individual with MM, followed by the ability to work and spend time with family and friends. Most patient respondents reported experiencing at least some side effects associated with maintenance therapy after receiving a stem cell transplant (SCT), as well as some negative impact on their overall well-being and quality of life due to the side effects associated with maintenance therapy; in turn, as reported by Myeloma Canada, these side effects had a negative impact on caregivers’ duties.

The patient respondents identified infections as the most important aspect of myeloma to control. They further indicated that mobility and kidney problems were aspects of myeloma that were important to control. The patient respondents reported that future treatment for MM should improve quality of life, have tolerable side effects, achieve remission, and extend survival without the need for continuous treatment. Patient respondents also highlighted the need for the accessibility and portability of treatments and a supportive and communicative care team. Patient respondents further noted the importance of access to alternative newer treatments and minimal trips to the hospital or community treatment centre.

Of the respondents who reported no experience with CAR T-cell therapy, the majority of patients and caregivers indicated that an estimated minimum of 1 to 2 years of extended life without requiring any drugs to control myeloma was extremely desirable; 2 patients indicated this was not desirable. Of note, this desirability is dependent on the severity of side effects and quality of the extended life. With respect to the side effects associated with cilta-cel, survey respondents who did not have experience with CAR T-cell therapy felt that cytokine release syndrome (CRS) would be the most troublesome side effect, followed by neutropenia, fever, and neuropathy.

Clinician Input

Input From the Clinical Experts Consulted by CADTH

The clinical experts consulted by CADTH highlighted that the most important goals of treatment for patients with r/rMM are prolonging survival, delaying disease progression, improving quality of life, and minimizing side effects. The clinical experts also highlighted that there is an unmet need for treatments beyond the third line that are tolerable for patients with comorbidities. The clinical experts noted that it is beneficial for any treatment to require a shorter treatment duration and lead to a longer treatment-free interval to reduce the treatment burden on this heavily pretreated patient population with a limited lifespan. In addition, the clinical experts highlighted that patients’ immune systems become weaker after multiple prior lines of therapy, thereby creating a need for treatments that are tolerated in later lines of therapy. As well, the experts noted that from the time of diagnosis, patients with high-risk disease have poor responses to treatment, which is worsened in the relapsed–refractory setting. Therefore, there is a great need for therapies that show some improved activity in people with high-risk disease. Patients who relapse quickly after prior lines of therapy (e.g., < 2 years) are also likely to have a very poor prognosis and thus are in great need of a novel intervention.

The clinical experts agreed that the majority of patients with r/rMM would eventually be eligible for cilta-cel, with the exception of patients who have died before reaching the fourth line or who are ineligible for CAR T-cell therapy due to severe disease progression or poor functional status. Eligible patients would include those who have “adequate” organ function, i.e., sufficient for them to be able to tolerate CRS and immune effector cell–associated neurotoxicity syndrome (ICANS) (definition of adequate organ function should be broad and left to the discretion of the treating centres), and who have a good Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) (i.e., score of 2 or less). In the absence of sufficient evidence to guide patient selection for cilta-cel treatment, the experts suggested that patients who have a short life expectancy (< 2 months), have progressive disease (PD) that is poorly controlled, are unable to move to a larger centre for 1 month, or who have poor functional status (ECOG PS > 2), may not be suitable for cilta-cel. The clinical experts noted that the major barrier to uptake would be capacity, as the demand for CAR T-cell therapy may be greater than the existing capacity in Canada.

The clinical experts reported that response to treatment Is typically assessed by regular monitoring that is part of the management of patients with r/rMM. The clinical experts noted that, in some cases, patients may go through pretreatment (i.e., apheresis and conditioning chemotherapy) but not receive cilta-cel. In those cases, the patients would receive supportive care until the acute crisis is resolved. If patients were to deteriorate substantially between apheresis and time of infusion, one may not proceed with cilta-cel infusion. The clinical experts reported that cilta-cel treatment can be provided by oncologists or hematologists in a specialized setting that has adequate infrastructure for cell therapy and access to excellent clinical support and multidisciplinary care, including critical and specialist care (e.g., intensive care unit, neurology, nephrology) to manage toxicities, as well as laboratory support to handle and process samples.

Clinician Group Input

The views of the clinician groups were consistent with the views of the clinical experts consulted by CADTH. Two clinician groups provided input for the review of cilta-cel: the Canadian Myeloma Research Group (CMRG) represented by 20 clinicians, and the Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee represented by 1 clinician. The clinical groups added that antibody drug conjugates, bispecific antibodies, and cellular therapies that are directed against B-cell maturation antigen (BCMA) on myeloma cells are positioned to fill the triple class–exposed or refractory space but are not currently available in Canada. Both groups indicated that patients with an ECOG PS of 0 to 2, minimal or no comorbidities, low tumour burden, and adequate organ function and blood counts would be the most likely to have the best outcomes.

Drug Program Input

The Provincial Advisory Group identified the following jurisdictional implementation issues: eligible patient population, eligibility for re-treatment, and concerns related to accessing clinical specialists and/or special settings. The clinical experts consulted by CADTH weighed evidence from the CARTITUDE-1 study and other clinical considerations to provide responses to the Provincial Advisory Group’s drug program implementation questions. Refer to Table 4 for more details.

Clinical Evidence

Pivotal Studies and Protocol-Selected Studies

Description of Studies

CARTITUDE-1 is a phase Ib/II, single-arm clinical trial of cilta-cel in patients with r/rMM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody. The main cohort described throughout this review included 113 enrolled patients and was conducted in 16 sites in the US. Of the 113 patients who underwent apheresis, 97 patients received cilta-cel infusion: 29 (30%) in phase Ib and 68 in phase II (70%). As of the final data cut-off date of January 11, 2022, there were 66 patients (58%) receiving ongoing follow-up. An additional cohort comprising 9 patients participated in 4 sites in Japan and is hereafter referred to as the Japanese cohort.

The primary objective for the phase Ib study was to characterize the safety of cilta-cel and confirm the recommended phase II dose. The primary objective for the phase II study was to evaluate the efficacy of cilta-cel through overall response rate (ORR) (at least a partial response [PR] or better) as assessed by an independent review committee (IRC). The ORR and its 2-sided 95% Clopper-Pearson exact confidence interval (CI) were assessed, and the P value from a 1-sided exact binomial test for the null hypothesis of an ORR of 30% or less was provided. Secondary end points included very good partial response (VGPR) or better rate, duration of response (DOR), minimal residual disease (MRD) negativity rate, time to response (TTR), PFS, OS, and health-related quality of life (HRQoL). An exploratory objective was to characterize the impact of the treatment process on health care resource utilization. The study was funded by Janssen Research & Development.

Four Clinical Study Reports were provided in the sponsor’s submission: the primary analysis report with a clinical data cut-off date of September 1, 2020,⁹ the safety and efficacy update reports with a clinical data cut-off date of February 11, 2021,¹⁰ and the final analysis report with a clinical data cut-off date of January 11, 2022. The final analysis report was used throughout this report unless otherwise specified.¹¹ Results from phases Ib and II were pooled together, as the study procedures and criteria were consistent between both phases.

After enrolment, patients underwent apheresis, received conditioning treatment, and then received the cilta-cel infusion. Of all patients who were enrolled and received apheresis, 97 (86%) received cilta-cel. Bridging therapy to maintain disease stability was administered to 73 patients (75.3%) between apheresis and initiation of the conditioning regimen. No patients who received bridging therapy achieved complete response (CR) while on bridging therapy; thus, all were eligible to receive cilta-cel. The median number of CAR-positive viable T cells infused was 54.3 × 10⁶ cells (range of 23.5 × 10⁶ to 93.1 × 10⁶ cells) with a median of 0.709 × 10⁶ cells/kg administered (range, 0.51 × 10⁶ to 0.95 × 10⁶ cells/kg). Patients were followed up on days 3, 7, 10, 14, 21, 28, 42, 56, 78, and 100. After day 101, they were followed up every 28 days until study completion, defined as 2 years after the last patient has received their initial dose. Three patients were re-treated with cilta-cel.

The mean age of patients was 62 years (standard deviation [SD] = 8.38), and the majority of patients were younger than 65 years (62 patients; 64%) and white (69 patients; 71%), with an ECOG PS of 1 (54 patients; 56%) and International Staging System (ISS) stage I MM at baseline (61 patients; 63%). With regard to cytogenetic risk, 23 patients (24%) were high risk at baseline. All patients received at least 3 prior lines of MM therapy, with a median of 6 prior lines (range, 3 to 18). The most common prior antineoplastic drugs used were daratumumab in 94 patients (97%) and bortezomib in 92 patients (95%), and the most common IMiDs were lenalidomide in 96 patients (99%) and pomalidomide in 89 patients (92%). Almost all patients (96 patients; 99%) had disease that was refractory to the last line of prior therapy, and 85 patients (88%) had disease that was triple-refractory, i.e., refractory to the 3 major classes of therapeutic drugs (PI, IMiD, and anti-CD38 monoclonal antibody).

Efficacy Results

The key efficacy results of the CARTITUDE-1 trial are summarized in Table 2. As of the January 11, 2022, data cut-off, after a median follow-up of 27.7 months (range, 1.5 to 40.4), the median OS was not reached (NR). Among all treated patients (i.e., patients who received cilta-cel at the targeted recommended phase II dose; N = 97), there were 30 deaths (31%), and the 24-month OS rate was ||||| |||| ||| |||| || |||||. Among all enrolled patients (N = 113), the 24-month OS rate was ||||| |||| ||| |||| || |||||. Median PFS was also NR. Among all treated patients, || patients (||%) experienced PFS events, and the estimated 24-month PFS rate was ||||| |||| ||| |||| || |||||. Among all enrolled patients (N = 113), the 24-month PFS rate was ||||| |||| ||| |||| || |||||. ORR in the all-treated analysis set was 97.9% (95% CI, 92.7 to 99.7), stringent CR (sCR) was reached by 80 patients (82.5%; 95% CI, 73.4 to 89.4), VGPR by 12 patients (12.4%; 95% CI, 6.6 to 20.6), and PR by 3 patients (3.1%; 95% CI, 0.6 to 8.8). In the all-enrolled analysis set (n = 113), the ORR was 84.1% (95% CI, 76.0 to 90.3). The ORR results from the patient subgroups of interest were consistent with the primary analysis; however, the analysis was limited by small sample sizes. Median DOR was NR. Among all treated patients, the estimated probability that patients remained in response at 12 months was ||||| |||| ||| |||| || |||||; at 24 months it was ||||| |||| ||| |||| || ||||| and at 30 months it was ||||| |||| ||| |||| || |||||. Of the 61 patients with evaluable samples, 56 patients (91.8%; 95% CI, 81.9 to 97.3) achieved MRD negativity in bone marrow at 10⁻⁵ sensitivity following treatment with cilta-cel. Median time to first response (for patients with PR or better) was 0.95 months (range, 0.9 to 10.7) and mean time to first response was 1.4 months (SD = 1.54). Median time to best response was 2.6 months (range, 0.9 to 17.8) and median time to CR or better was 2.9 months (range, 0.9 to 17.8).

The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) completion rate at baseline was 92.6% (63 patients) and declined to 83.1% (54 patients), and 65.0% (39 patients) at day 100 and day 156, respectively. The EORTC QLQ-C30 suggested improvements over time compared with baseline, with decreases observed only initially on day 7 for global health status, physical functional scale, and fatigue symptom scale. This initial worsening is consistent with the potential onset of cilta-cel adverse events (AEs) related to CRS.¹² There appeared to be consistent improvement in the pain symptom scale from baseline. The EORTC Quality of Life Questionnaire Myeloma Module (QLQ-MY20) completion rate at baseline was |||||% (|| patients) and declined to ||% (|| patients) at day 100. The EORTC QLQ-MY20 suggested improvements over time compared with baseline. The 5-level EQ-5D (EQ-5D-5L) completion rate at baseline was 92.6% (63 patients) and declined to ||% (|| patients) and ||||% (|| patients) at day 100 and day 156, respectively. The EQ-5D-5L suggested an initial decrease in both utility score and visual analogue score at day 7 followed by continuous improvement through day 100. The Patient Global Impression of Severity (PGIS) completion rate at baseline was 93% (63 patients) and declined to 78% (53 patients) and 57% (39 patients) at day 100 and day 156, respectively. Severity of pain assessed by PGIS was consistently reported as lower than baseline through day 352. Patient Global Impression of Change (PGIC) was only completed post infusion from day 28, where 67% of patients reported improvement, and the proportion increased to 87% by day 100, where the completion rate was 79% (54 patients).

In the Japanese cohort from the CARTITUDE-1 study (n = 9), the median follow-up was 8.5 months and the ORR was 100% (95% CI, 66.4 to 100). In the all-treated analysis set (n = 9), all DOR, PFS, and OS data were censored at the clinical data cut-off; therefore, median DOR, PFS, and OS were NR. The 9-month PFS rate was 100% and the estimated 12-month OS rate was 100%.

Harms Results

The key harms reported in the CARTITUDE-1 trial are summarized in Table 2. All patients in the all-treated analysis set (N = 97) experienced at least 1 AE, with || patients (||%) experiencing at least 1 grade 4 AE. The most common any-grade AEs were neutropenia (96%), CRS (95%), anemia (81%), and thrombocytopenia (80%). A total of 53 patients (55%) experienced at least 1 serious AE (SAE), with 30 patients (31%) experiencing a grade 3 or 4 SAE and 6 patients (6%) experiencing a grade 5 SAE. The most common SAEs were CRS (21%), pneumonia (6%), sepsis (5%), and ICANS (5%).

Between apheresis and the start of the conditioning treatment, 8 patients out of 113 (7%) died. Overall, 101 patients received the conditioning regimen, and 97 patients went on to receive cilta-cel. Out of the 4 patients who received the conditioning regimen but did not receive cilta-cel, 1 patient died. Out of all treated patients, 30 patients (30.9%) died: 16 due to AEs and 14 due to disease progression. No patients died within 30 days of the initial cilta-cel infusion, and 2 patients (2.1%) died within 100 days. Only 6 patients (6.2%) had a treatment-emergent adverse event (TEAE) leading to death that was considered to be related to cilta-cel; the remaining 10 deaths were not considered by the study investigators to be related to cilta-cel.

The notable harms identified in the CADTH protocol included CRS, neurologic toxicities, cytopenia, and secondary hypogammaglobulinemia. A total of 92 patients (95%) experienced CRS, with 4 patients (4%) experiencing a grade 3 or 4 CRS and 1 patient (1%) experiencing a grade 5 CRS complicated by secondary hemophagocytic lymphohistiocytosis. A total of 21 patients (22%) experienced CAR T-cell neurotoxicity, including || patients (10%) at grade 3 or 4. A total of 16 patients (17%) experienced ICANS, including 2 patients (2%) at grade 3 or 4. Other neurotoxicity was reported in 13 patients (13%), including 9 patients (9%) at grade 3 or 4. A total of 96 patients (99%) had experienced at least 1 grade 3 or 4 cytopenic AE, and the majority were transient, with recovery to grade 2 or better within the first 60 days following cilta-cel infusion. A total of 12 patients (12.4%) experienced hypogammaglobulinemia, including 2 patients (2.1%) with grade 3 or 4 events.

In the Japanese cohort, all 9 patients experienced at least 1 AE, and 8 (88.9%) experienced at least 1 grade 3 or 4 AE. Grade 3 or 4 cytopenias were reported in 8 patients (88.9%). Grade 1 or 2 CRS was reported in 8 patients (88.9%), and SAEs were reported in 1 patient (neutropenia, thrombocytopenia, fatigue, and CRS). No patient experienced CAR T-cell neurotoxicity (including ICANS or other neurotoxicity). No death was reported during the study.

Table 2: Summary of Key Results From the CARTITUDE-1 Trial (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

CI = confidence interval; CR = complete response; DOR = duration of response; ICANS = immune effector cell–associated neurotoxicity syndrome; NE = not estimable; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; SAE = serious adverse event; sCR = stringent complete response; SD = standard deviation; TEAE = treatment-emergent adverse event; TTR = time to response; VGPR = very good partial response.

^aEstimated using the Kaplan-Meier method.

^bResponse was assessed by an independent review committee, based on International Myeloma Working Group consensus criteria (2016). Percentages are calculated with the number of patients in the all-treated analysis set as denominator. Exact 95% CIs are provided.

^cResponse is defined as PR or better.

Source: CARTITUDE-1 Clinical Study Report.^9-11

Critical Appraisal

Internal Validity

CARTITUDE-1 was an open-label, single-arm phase Ib/II study in the US (16 centres) and Japan (4 centres). The primary limitation of CARTITUDE-1 was the absence of a comparator group against which the benefits and harms of cilta-cel could be compared. Single-arm trials are generally not considered as confirmatory for efficacy and are subject to several limitations that complicate their interpretation.¹³ ORR was tested against a predetermined hypothesis; however, there was no adjustment for multiplicity across the various analyses of the outcome (i.e., the various data cut-offs), so there is an increased risk of type I error. Results for the other outcomes (e.g., DOR, OS, PFS) were descriptive only. This trial does not provide any information for the effects of cilta-cel relative to the available comparator treatments used in Canada. According to the FDA assessment of the CARTITUDE-1 trial, end points such as OS and PFS are uninterpretable due to the lack of a comparator arm and were neither reviewed nor included in the FDA label.¹⁴ A limited number of patients were included in the all-treated analysis set (n = 97) and all-randomized analysis set (n = 113) of CARTITUDE-1. The magnitude of the treatment effect estimates observed in a small study sample may not be replicable in a larger study sample or generalizable to the target population in real-world clinical practice (RWCP).

It cannot be firmly concluded to what extent the improvements in ORR observed in patients would translate into OS benefits. ORR is accepted by the FDA as directly attributable to drug effect in “single-arm trials conducted in patients with refractory tumours where no available therapy exists.”¹⁵

The interpretation of efficacy in the all-treated analyses are at risk of bias in favour of cilta-cel. The population excludes patients (n = 16; 14%) who were enrolled and underwent apheresis but were subsequently unable to receive cilta-cel because they died or their disease progressed, or due to AEs or other reasons (e.g., patient choice). This population is not reflective of expected clinical practice and overrepresents the healthiest patients. Analyses based on the all-enrolled population are considered most appropriate for estimating the effect of assignment to treatment. As expected, when both were presented, the results of analyses of the all-treated population were more favourable compared with those of the all-enrolled population. Out of the 113 patients who underwent apheresis, 12 patients, including 8 patients who had died, did not receive the conditioning treatment. The clinical experts noted that, although this is common in r/rMM, the proportion of deaths is unusual, given how relatively healthy the trial population was. Only 3 patients were re-treated with cilta-cel; thus, there is not enough information to draw conclusions regarding re-treatment.

No subgroup analysis was specified in the study protocol a priori and, while the results for ORR were consistent with the primary analysis results across the patient subgroups of interest, the analysis was limited by the small sample size of some groups, such as patients who received prior allogeneic SCT.

The trial was open label, which can result in a risk of bias in the measurement of the outcomes, particularly for subjective outcomes such as ORR, PFS, HRQoL, and subjective harms. To reduce the risk of directional bias in reported outcomes, response outcomes were assessed by the investigators, an IRC, and a validated computer algorithm. The use of IRC may have mitigated this risk by following recommendations for end points based on tumour measurements.¹⁵ In addition, although the EORTC QLQ-C30 and EQ-5D-5L are comprehensive and widely used instruments designed to measure HRQoL, neither are currently validated for patients with r/rMM. Further, results for all HRQoL measures were at risk of bias due to missing data, particularly at longer follow-up (e.g., data for the EORTC QLQ-C30 were missing for ||% of all treated patients at day 100 and for ||% of patients by day 156). In addition to a diminishing sample size, the patients reporting HRQoL outcomes later in the study are expected to be the healthiest among the population. Given that the trial was nonrandomized, the impact of cilta-cel on patient-reported outcomes (PROs) in relation to other therapies is unknown.

Findings from the Japanese cohort of the CARTITUDE-1 trial were consistent with results from the main cohort; however, it only included 9 patients, which limits the interpretation of cohort findings.

External Validity

According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics of the CARTITUDE-1 study population⁹ were generally reflective of the population of patients in Canada with r/rMM. The mean age of patients in the trial was 62 years, which is younger than the mean age of 70 years at the time of diagnosis in Canada.¹⁶ If there was no access to less toxic bispecific therapies, the clinical experts would have expected a slightly larger proportion of patients to be older than 75 years of age (15% versus the trial’s 8%). However, clinicians can currently access these bispecific therapies through special access programs and would prioritize the older patient population for these therapies, making the trial’s age proportions reflective of the current population demographics. All patients met the inclusion criteria of an ECOG PS of 0 or 1 during screening, but 4 patients (4%) deteriorated to ECOG 2 on or before cilta-cel infusion. The clinical experts considered it common for patients to deteriorate after apheresis. The clinical experts also mentioned they would have expected potentially more patients with extramedullary plasmacytomas present past the third line of therapy, as this would denote worse disease, but that the 13% proportion in the trial is acceptable. They would have also expected a slightly higher proportion of patients to be of high cytogenetic risk (30% versus the trial’s 24%).

The clinical experts consulted by CADTH mentioned that the creatinine clearance required for inclusion in the trial (≥ 40 mL/min/1.73 m²) is higher than the level used to indicate poor kidney function in clinical practice (≥ 30 mL/min/1.73 m²). They also mentioned that including patients with an ECOG of 2 or less (rather than the trial’s criteria of < 2) would better align with clinical practice needs. One of the trial exclusion criteria is any prior therapy that targeted BCMA, which the clinical experts found concerning, as some clinicians would likely be giving their patients belantamab mafodotin, available through compassionate access, in their management of MM. The clinical experts noted that these patients may still respond well to CAR T-cell therapy¹⁷ and should not be excluded from cilta-cel eligibility.

With regard to prior therapy used by patients in the trial, the clinical experts noted that potentially all patients would have disease that is refractory to daratumumab within the first 3 lines of therapy (compared with 97% of patients in the trial). They also noted that selinexor is currently used as a bridging therapy in the US, but no patients had used selinexor in the trial, as selinexor (combined with dexamethasone and bortezomib) was not approved during the time of the trial.¹⁸ Finally, they noted it was surprising that 19% of patients had used anakinra for treating CRS, since it is rarely used in Canadian practice; however, they also noted this may have been due to a global shortage of tocilizumab.

The clinical experts consulted by CADTH for this review did not have any major concerns with the end points used in the CARTITUDE-1 trial. They considered OS, HRQoL, and PFS as the most important outcomes, which were secondary end points in the trial. It was noted that MRD negativity rate is not routinely used in clinical practice. All outcomes in the protocol were important to patients, clinicians, and drug plans; although they were evaluated, this trial provides no information about the efficacy and harms of cilta-cel relative to treatments that would otherwise be used in this patient population in clinical practice.

This study was a multicentre trial in the US. The clinical experts indicated there are few concerns to generalizing the findings from the pivotal study within the Canadian clinical setting.

Other Relevant Evidence

LEGEND-2 Trial

The sponsor also provided long-term (2-year and 4-year) data from LEGEND-2, a phase I, single-arm, open-label study (N = 74) conducted in 4 registered sites in China in patients with r/rMM who had received at least 3 prior lines of treatment. The cilta-cel CAR T-cell drug product studied in CARTITUDE-1 (produced in the US) and the LCAR-B38M CAR T-cell drug product studied in the LEGEND-2 study (produced in China), express an identical CAR protein targeting BCMA but were produced using different manufacturing and scale-up processes.¹⁹ Unlike cilta-cel, the LCAR-B38M CAR T-cell dose was split into 3 infusions administered over 7 days, with the number of CAR T cells administered increasing with each infusion. Patients were not required to have received an anti-CD38 antibody in prior therapy, and only 2 patients (2.7%) had received prior anti-CD38 antibody therapy. Patients with a history of allogeneic SCT were excluded from the trial.

The median age of patients was 54.5 years (range, 27 to 74), with a higher proportion of men (61%), and with a median time since initial MM diagnosis of 4 years (range, 1 to 9). LEGEND-2 provided longer-term safety and efficacy follow-up than the CARTITUDE-1 trial, with an additional median follow-up of 20.1 months. In the LEGEND-2 trial 4-year analysis, median follow-up time from dosing to cut-off was 47.8 months (range, 0.4 to 60.7). Median OS was not yet reached, but the 24-month OS rate was ||||% (95% CI, |||| || ||||), and the median PFS was 18 months (95% CI, 10.6 to 25.6). The ORR by sponsor assessment was 87.8% (95% CI, 78.2 to 94.3), with 54 patients (73%) achieving CR, 6 patients (8%) achieving PR, and 5 patients (7%) achieving VGPR. Median DOR was 23.26 months (95% CI, 13.04 to 32.69). The median time for initial response was 1.0 months (range, 0.4 to 3.5), and the median time for best response was 3.3 months (range, 0.4 to 28.5). All patients experienced at least 1 TEAE within 100 days post infusion, with AEs of grade 3 or greater in 45 patients (61%). The most common AEs were pyrexia in 68 patients (92%) and CRS in 68 patients (92%), and only 7 patients (10%) experienced a CRS of grade 3 or greater. Of the 74 patients in the analysis, 34 deaths (46%) were reported.

Critical Appraisal of LEGEND-2

LEGEND-2 was an open-label, single-arm phase I study conducted only in China (4 centres). The cilta-cel CAR T-cell drug product studied in CARTITUDE-1 (produced in the US) and the LCAR-B38M CAR T-cell drug product studied in the LEGEND-2 study (produced in China) express an identical CAR protein targeting BCMA, but were produced using different manufacturing and scale-up processes.¹⁹ The primary limitation was the absence of a comparator group against which the treatment benefits and harms of the LCAR-B38M CAR T-cell drug product could be compared. As such, there is no evidence of the effect of LCAR-B38M relative to available comparator therapies from this trial. The study protocol mentioned the use of a computerized algorithm and IRC for disease status evaluation; however, the findings are reported based on sponsor assessment (based on uniform medical reviews of source hospital medical records), leading to an increased risk of bias in the measurement of the outcome likely favouring LCAR-B38M. HRQoL was not assessed as an end point in this phase I study. The clinical experts consulted by CADTH for this review noted that the baseline characteristics of the LEGEND-2 study population would be closer to patients who are in the second line of therapy (younger and with limited use of daratumumab), rather than the fourth line of therapy and beyond. Moreover, because exposure to an anti-CD38 antibody was not required (only 2 patients had received prior anti-CD38 antibody therapy), this study population does not fully align with the reimbursement criteria for this review. The experts also mentioned that the low proportion of patients with neurotoxicity as an AE (only 1 patient) was not aligned with the results of CARTITUDE-1.

Comparative Observational Evidence for Cilta-Cel Versus Real-World Clinical Practice

The sponsor-submitted evidence consisted of 2 reports of 3 observational studies to compare cilta-cel with relevant treatment comparators in RWCP: CARTITUDE-1 versus LocoMMotion and CARTITUDE-1 versus real-world cohorts.^20,21

CARTITUDE-1 Versus LocoMMotion²⁰

The first sponsor-submitted report was an observational study comparing the effectiveness of cilta-cel (from CARTITUDE-1) versus RWCP as observed in the LocoMMotion prospective cohort study using individual patient data (IPD), with propensity score weighting and regression modelling in an attempt to adjust for known confounders. The following outcomes were planned to be assessed: clinical response (ORR, VGPR, CR or better, MRD), PFS, time to next treatment (TTNT), OS, PROs, safety, and resource utilization.²⁰

The CARITUDE-1 study consisted of 113 patients who underwent apheresis and made up the intention-to-treat (ITT) population, and 97 patients who were treated with cilta-cel (modified ITT [mITT]). The selected LocoMMotion cohort consisted of 248 patients in the ITT population and 170 patients in the mITT population. After weighting, the effective ITT and mITT population size of the LocoMMotion cohort was 118 and 108 patients, respectively.

Following adjustment, the conditional hazard ratio (HR) for OS was 0.32 (95% CI, 0.17 to 0.58) in the ITT population (median OS = not estimable (NE) [95% CI, 31.47 to NE months] versus 11.76 months [95% CI, 7.16 to NE months]), and conditional HR was 0.20 (95% CI, 0.09 to 0.41) in the mITT population (median OS = NE [95% CI, NE to NE] versus 11.33 months [95% CI, 5.45 to NE months]), both favouring cilta-cel.

For PFS, the conditional HR between treatment groups was 0.19 (95% CI, 0.11 to 0.32) in the ITT population (median PFS = 28.03 months [95% CI, 20.11 to NE months] versus 4.07 months [95% CI, 2.86 to 5.09 months]) and conditional HR was 0.15 (95% CI, 0.08 to 0.29) in the mITT population (median PFS = NE [95% CI, 24.54 to NE months] versus 2.73 months [95% CI, 2.37 to 3.68 months]), both favouring cilta-cel.

For ORR, observed proportions in the ITT and mITT populations were 84.1% and 97.9% for cilta-cel, and 29.8% and 42.9% for RWCP from LocoMMotion, respectively. The inverse probability weighting (IPW)-estimated odds ratio (OR) was 22.00 (95% CI, 11.14 to 43.35) in the ITT population and 103.87 (95% CI, 24.17 to 446.37) in the mITT population, both in favour of cilta-cel.

Overall, there was a variation in study design (phase Ib/II open-label trial versus an observational and noninterventional study), heterogeneity between cohorts before and after adjustment, as well as uncertainty of the results due to the assumptions made and residual confounding. This limits the ability to draw strong conclusions about the comparative efficacy of cilta-cel with other treatments in this clinical setting, where no effective standard of care is available. Given the adjustment of the LocoMMotion population to the CARTITUDE-1 population, the generalizability of the results is similar to that of CARTITUDE-1. Additionally, there was a total of 92 unique regimens received in RWCP in the LocoMMotion study, which may not be reflective of Canadian clinical practice, and there were no Canadian investigative sites included in either the CARTITUDE-1 or LocoMMotion studies, which may impact the generalizability of the results to patients in Canada.

CARTITUDE-1 Versus Real-World Cohorts²¹

The other sponsor-submitted report included 2 observational studies to compare cilta-cel treatment with the real-world treatments received by patients for triple class–exposed r/rMM. In both studies, propensity score weighting was used in an attempt to adjust for known confounders.²¹ One analysis compared the IPD from CARTITUDE-1 with the IPD from a cohort of patients in the long term follow-up of 3 global r/rMM clinical trials of daratumumab (POLLUX, CASTOR, and EQUULEUS; hereinafter referred to as the daratumumab trial cohort). The other analysis compared the IPD from CARTITUDE-1 with the IPD for a CARTITUDE-1-like cohort of real-world patients receiving current treatment paradigms using data from the Flatiron Health database (hereinafter referred to as the Flatiron cohort). Outcomes included in the analyses consisted of ORR, CR rate or better, PFS, and OS. The outcomes of CR and VGPR were not evaluated in the Flatiron database; therefore, an assessment of ORR and CR rate or better was not possible.

The CARTITUDE-1 trial included 113 patients in the ITT population and 97 patients in the mITT population. A total of 351 and 288 patients were included in the daratumumab trial cohort in the ITT and mITT populations, respectively. After propensity score weighting, the base-case effective sample size (ESS) of the daratumumab trial cohort ITT and mITT populations was 212 and 116, respectively. In the Flatiron cohort, 229 and 196 patients made up the ITT and mITT populations, respectively. After adjustment, the ESS for the Flatiron cohort was 192 in the ITT population and 80 in the mITT population.

The HRs for OS for the comparison of cilta-cel with RWCP in the daratumumab trial cohort were 0.25 (95% CI, 0.17 to 0.38) and 0.20 (95% CI, 0.13 to 0.31) for the ITT population (median OS = NR [95% CI, 31.47 to NE months] versus 8.05 months [95% CI, 6.34 to 11.30 months]) and mITT population (median OS = NR [95% CI, NE to NE months] versus 10.90 months [95% CI, 8.18 to 16.20 months]), respectively, in favour of cilta-cel. The HRs for OS for the comparison of cilta-cel with RWCP in the Flatiron cohort were 0.32 (95% CI, 0.19 to 0.52) and 0.25 (95% CI, 0.14 to 0.43) for the ITT population (median OS = NR [95% CI, 31.47 to NE months] versus 12.30 months [95% CI, 9.72 to 15.50 months]) and mITT population (median OS = NR [95% CI, NE to NE] versus 13.20 months [95% CI, 9.17 to 21.30 months]), respectively, in favour of cilta-cel.

The HR for PFS for cilta-cel versus RWCP in the daratumumab trial cohort was 0.26 (95% CI, 0.18 to 0.37) in the ITT population (median PFS = ||||| |||||| |||| ||| ||||| || ||| ||| |||| |||||| |||| ||| ||||| ||||||| and 0.24 (95% CI, 0.16 to 0.35) in the mITT population, with a median PFS of NR (95% CI, 24.54 to NR) versus 5.32 months (95% CI, 2.76 to 8.31), in favour of cilta-cel. Results for adjusted PFS (aPFS), and real-world PFS (rwPFS) were consistent with the overall PFS analysis for the daratumumab trial cohort. The aPFS HR for cilta-cel versus RWCP in the Flatiron cohort was 0.22 (95% CI, 0.15 to 0.33) in the ITT population (median = aPFS, ||||| |||||| |||| ||| ||||| || ||| ||| |||| |||||| |||| ||| |||| || |||||| and 0.18 (95% CI, 0.12 to 0.26) in the mITT population, with a median aPFS of NR (95% CI, 24.54 to NR), versus 4.53 months (95% CI, 2.86 to 6.77), also in favour of cilta-cel. In the Flatiron cohort, the rwPFS HR was 0.22 (95% CI, 0.15 to 0.33) in the ITT population |||||| |||||| |||| ||| ||||| || ||| ||| |||| |||||| |||| ||| |||| || ||||||| and 0.18 (95% CI, 0.10 to 0.23) in the mITT population, with an rwPFS HR of NR (95% CI, 24.54 to NR) versus 5.88 months (95% CI, 4.01 to 8.48). After inverse probability of treatment weighting (IPTW), the OR for ORR comparing cilta-cel with RWCP was 22.55 (95% CI, 10.72 to 52.03) in the ITT population and 127.35 (95% CI, 34.24 to 850.09) in the mITT population. Results for ORR were not available in the comparison with the Flatiron cohort.

Results of the base-case analyses and sensitivity analyses were consistent across end points, analysis populations, and across data sources, favouring cilta-cel over RWCP in both the daratumumab trial cohort and the Flatiron cohort for all outcomes. For all outcomes, the magnitude of effect for cilta-cel was notably large compared with RWCP; however, the results were associated with wide 95% CIs, highlighting losses to precision and reducing the ability to draw strong conclusions about the magnitude of the effect. There were important differences in the design of the included studies that limit the ability to draw strong conclusions about the efficacy of cilta-cel compared with RWCP. This includes the differences in study design (phase Ib and II single-arm trial versus published literature from 3 clinical trials comprising 2 phase III randomized controlled trials [RCTs] and 1 phase Ib open-label RCT, and a real-world cohort from electronic health records), which could not be adjusted for in the analysis using propensity scoring methods. As well, there was notable heterogeneity in populations before adjustment and the potential for residual confounding following adjustment, and small sample sizes and wide 95% CIs, highlighting losses to precision.

Other Observational Studies Identified in the Literature Search

In total, 3 published articles met the CADTH predefined inclusion criteria for this review: CARTITUDE-1 versus the Monoclonal Antibodies in Multiple Myeloma: Outcomes After Therapy Failure (MAMMOTH),²² CARTITUDE-1 versus Therapie Monitor,²³ and a meta-analysis of observational studies.²⁴

CARTITUDE-1 Versus MAMMOTH²²

This was an observational study using IPD from the CARTITUDE-1 trial and the MAMMOTH cohort to evaluate the efficacy of cilta-cel versus real-world therapies for the outcomes of ORR, PFS, and OS. Propensity score matching was used to attempt to adjust for confounding.²²

The populations for CARTITUDE-1 consisted of 113 patients in the ITT population and 97 patients in the mITT population. Corresponding populations identified from MAMMOTH included 190 and 122 patients in the ITT and mITT populations, respectively. The matched populations included 95 patients in the ITT population in each cohort, and 69 patients in the mITT cohort. In the propensity score matched analysis, results for PFS and OS favoured patients in CARTITUDE-1 compared with the matched MAMMOTH population (HR = 0.11; 95% CI, 0.05 to 0.22) and HR = 0.20 (95% CI, 0.10 to 0.39). For ORR, 80 patients (84%) achieved an ORR in CARTITUDE-1 versus 27 patients (28%) in the MAMMOTH (OR = 13.4; 95% CI, 6.6 to 27.3) ITT analysis. Results for the mITT population were also consistent with the ITT population.

In general, the results of the analyses demonstrated a clinical benefit over RWCP from MAMMOTH; however, the reduced sample sizes from propensity score matching, unexplored heterogeneity, and wide 95% CIs resulted in uncertainty in the results and the magnitude of the observed effects. Given the methodological differences across studies and the risk of bias due to residual confounding, the comparison with external, historical, real-world data is nonconfirmatory and should only be viewed as exploratory.

CARTITUDE-1 Versus Therapie Monitor²³

This observational study evaluated OS and TTNT for patients in CARTITUDE-1 versus patients receiving real-world treatments registered in the Therapie Monitor database in Germany maintained by the Oncology Information Service (OIS).²³ IPD from both cohorts was used for comparison for the outcomes of OS and TTNT (as proxy for PFS), and propensity score weighting was used to attempt to adjust known confounders.

The ITT and mITT populations for CARTITUDE-1 consisted of 113 and 97 patients, and the ITT and mITT populations of Therapie Monitor consisted of 222 and 174 patients, respectively. After weighting, the ESS for the ITT population was not reported and the ESS for the mITT population was 42 patients. In the ITT population for OS, cilta-cel was favoured over RWCP (HR = 0.14, 95% CI, 0.07 to 0.25). For TTNT, cilta-cel was also favoured over RWCP from Therapie Monitor (HR = 0.13; 95% CI, 0.07 to 0.24). Results for OS and TTNT in the mITT population were consistent with the ITT population; however, the 95% CIs were wider (OS HR = 0.26 [95% CI, 0.08 to 0.84]; TTNT HR = 0.24 [95% CI, 0.09 to 0.67]).

All analysis methods were appropriate and suggested similar results favouring cilta-cel over RWCP; however, the results of the present analysis were associated with uncertainty, given the reduced sample sizes, the lack of adjustment for potential confounding factors, the notable heterogeneity in patient populations that remained for 6 of 9 key variables after adjustment, and the wide 95% CIs, particularly for the mITT population, resulting in greater uncertainty of the results.

Meta-Analysis of Observational Studies²⁴

A frequentist, random-effects meta-analysis of observational studies evaluating cilta-cel versus physicians’ choice of treatment was identified in the published literature.²⁴ The studies included in the meta-analysis consisted of all studies summarized here and included publications for the comparison of CARTITUDE-1 with LocoMMotion, the Flatiron cohort, the daratumumab trial cohort, the MAMMOTH cohort, and the OIS database. Outcomes included OS, PFS, and ORR. No analyses of ORR were conducted in the all–index dates analyses.

In the ITT population, including all eligible index dates, the overall HR for cilta-cel compared with RWCP was 0.26 (95% CI, 0.15 to 0.47) for OS and 0.22 (95% CI, 0.1 to 0.49) for PFS. Results for the mITT population were consistent with the ITT population. The OR for ORR in the ITT population was 13.94 (95% CI, 4.88 to 39.84), while in the mITT population, the OR for ORR was 86.22 (95% CI, 17.96 to 413.88) in favour of cilta-cel.

While the comparisons of cilta-cel with external cohorts from multiple studies provided a large evidence base for comparison, there were important limitations in this evidence, including methodological differences across the data sources that could not be adjusted for in the analysis using propensity scores, and a risk of confounding (due to the inability to adjust for important prognostic factors and/or differences remaining in the distribution of prognostic factors across cohorts after adjustment). Pooling via meta-analysis could not overcome the limitations of the individual studies; rather, meta-analysis may compound the bias. Results of the included observational comparisons were consistently in favour of cilta-cel over RWCP for all outcomes assessed. Similarly, the results of the meta-analysis were in favour of cilta-cel for OS, PFS, and TTNT for both the all–index dates and first–index dates analyses in both the ITT and mITT populations and in all sensitivity analyses; however, the 95% CIs were often wide, suggesting some imprecision, unexplained heterogeneity, and uncertainty in the magnitude of the effects.

Conclusions

One sponsor-submitted phase Ib/II, single-arm, open-label trial (CARTITUDE-1) provided evidence regarding the efficacy and safety of cilta-cel for patients with r/rMM who had received at least 3 prior lines of therapy. This trial design is not intended to be confirmatory for efficacy. In general, the clinical experts consulted by CADTH considered the ORR results to be clinically meaningful, especially when compared with currently available therapies. The nonrandomized design of CARTITUDE-1 made interpreting the PFS and OS events attributable to cilta-cel challenging; according to the FDA, CARTITUDE-1 could not inform OS or PFS. The results for HRQoL remained inconclusive due to a number of important limitations. A phase I long-term LCAR-B38M trial (LEGEND-2), based only in China, showed similar findings. All patients experienced at least 1 AE, and almost half experienced an SAE. The clinical experts noted that, in their experience, cilta-cel appeared to be less toxic than other therapies available in the fourth line and beyond. They remarked that the proportion of patients who experienced grade 3 or greater CRS or ICANS and who would require specialized intensive care was relatively low.

The comparative evidence came from observational comparisons using IPD from CARTITUDE-1 and real-world cohorts using propensity scores to adjust for known confounders. Although cilta-cel was favoured for all outcomes assessed, these findings must be interpreted in the context of the methodological limitations of these studies. Propensity score methods can only adjust or match on known and measured confounders and cannot account for unknown, unmeasured, or unmeasurable confounders, nor for differences in study design across comparators. Tests for residual confounding were not conducted in any of the studies, so the results are at risk of bias due to confounding. The generalizability of the results may be limited, since patients in the comparator arms received treatments that are not currently standard of care in Canada.

Introduction

Disease Background

MM is a plasma cell cancer caused by the growth of cancer cells in the bone marrow. It was estimated that 4,000 people in Canada would be diagnosed with MM in 2022 and that 1,650 would die from MM, with slightly more cases occurring in men than women.² While new therapies have been introduced that can improve a patient’s OS and PFS, MM remains an incurable condition.³ Some estimates suggest that the median survival for patients with MM is just more than 5 years and, during this time, patients can receive 4 lines of therapy or more.^3-5 Median OS for patients with r/rMM is approximately 13 months.⁶

MM is a heterogenous condition typically affecting older adults around the age of 65 years, and patients’ outcomes can be dependent on many factors, including their disease stage, prognostic indicators, and early treatment of symptomatic disease to limit or avoid organ damage.²⁵ Typically, when MM is suspected clinically in patients they are tested for the presence of M proteins, although a small proportion of patients (approximately 2%) may present without any evidence of M protein.²⁶

Patients with MM will ultimately relapse, and progression is usually identified by a rise in M protein in the serum or urine or rise in serum free light chain ratio.⁵ The clinical experts consulted by CADTH for this review noted that these levels are usually assessed on a monthly basis following therapy to monitor for relapse. Other indications of relapse include development of CRAB symptoms (hypercalcemia, renal insufficiency, anemia, or new bone lesions) or extramedullary plasmacytomas.⁵

With respect to prognosis, the International Myeloma Working Group (IMWG) defines high-risk cytogenetic features to include at least 1 of the following:

• t(4;14), t(14;16), t(14;20), del(17p), or gain (1q) detected by fluorescence in situ hybridization (FISH)

• nonhyperdiploid karyotype, high-risk gene expression profile signature, and del(13) detected by conventional cytogenetics.

In addition, 2 clinical features are associated with aggressive disease: elevated lactate dehydrogenase (LDH) and evidence of circulating plasma cells on routine peripheral smear examination (plasma cell leukemia).²⁷ The preferred staging system for MM is the Revised ISS, which uses serum beta2-microglobulin, serum albumin, serum LDH, and bone marrow FISH results to stratify patients into 3 risk groups:

• stage I: beta2-microglobulin of less than 3.5 mg/L, serum albumin of 3.5g/dL or greater, normal LDH, and no del(17p), t(4;14), t(14;16) by FISH

• stage II: neither stage I nor III

• stage III: beta2-microglobulin of 5.5 mg/L or greater, elevated LDH, and/or del(17p), t(4;14), t(14;16) by FISH.²⁷

IMWG defines r/rMM as disease that is “nonresponsive while on salvage therapy or progresses within 60 days of last therapy in patients who have achieved minimal response or better at some point previously before then progressing in their disease course.”²⁸

Standards of Therapy

The treatment landscape for MM has changed significantly in the past number of years with the emergence of new therapies in newly diagnosed and r/rMM settings.³

According to the clinical experts, initial therapy for patients depends on whether they are eligible or ineligible for transplant at diagnosis. Initial treatment for patients who are eligible for transplant includes induction therapy for 4 months with cyclophosphamide, bortezomib, and cyclophosphamide-bortezomib-dexamethasone (CyBord), according to the clinical experts. Patients undergo induction followed by treatment with melphalan and SCT, followed by consolidation therapy with lenalidomide-bortezomib-dexamethasone in some jurisdictions (depending on local practices and funding). According to the clinical experts, patients then continue with lenalidomide maintenance therapy until disease progression, which is standard across all Canadian jurisdictions.

The clinical experts noted that for patients who are transplant-ineligible, daratumumab-lenalidomide-dexamethasone (DRd) is the most commonly used treatment; other treatment options include lenalidomide-bortezomib-dexamethasone, lenalidomide-dexamethasone, and CyBord, although CyBord is used less frequently in current practice due to approvals that include lenalidomide-based regimens. Daratumumab-based regimens, such as DRd or daratumumab-bortezomib-melphalan-prednisone, were stated to be expected to be used more frequently going forward due to recent positive recommendations from CADTH and funding approvals across jurisdictions. The clinical experts expected that daratumumab-based regimens would be the preferred front-line option, with DRd as the most likely choice.

The clinical experts noted that at relapse, treatment depends on patient factors, including age, comorbidities, and previous treatments. In the second-line treatment setting, a second transplant may be an option for transplant-eligible patients, although the clinical experts stated it is not a common approach because of available alternatives; however, patients with long responses to the first transplant will often be considered for a second transplant if their age and comorbidities are not contraindications. The clinical experts stated that most patients will receive a daratumumab-containing regimen, likely DRd or daratumumab-bortezomib-dexamethasone; patients whose disease is refractory to lenalidomide would usually receive daratumumab-bortezomib-dexamethasone, while those who previously received bortezomib would receive DRd. Current treatment practices suggest using bortezomib or another PI after treatment with lenalidomide.⁷ The clinical experts further noted that isatuximab-based regimens were another option for patients, especially for those who are not eligible for daratumumab-based regimens, but these are currently not funded in Canada. The clinical experts state that isatuximab-based regimens would likely not be effective for patients who progress on a daratumumab-based regimen.

The clinical experts stated that pomalidomide-based regimens were considered in the third or fourth line of therapy, which is in line with clinical guidelines.⁷ Regimens containing carfilzomib were acknowledged to be available to patients in the second line, although these regimens are typically reserved for relapse after daratumumab-based regimens in the third line or after. Other options in the fourth line of therapy and beyond include oral palliative chemotherapy or alkylating drugs such as cyclophosphamide. The clinical experts consulted by CADTH noted that belantamab mafodotin is another option that could be available to patients; however, this treatment is only available through special access and is not used frequently. In November 2022, the FDA requested the withdrawal of belantamab mafodotin from US markets based on the outcomes of the pivotal clinical trial (DREAMM-3), which did not meet the requirements of the US FDA Accelerated Approval regulations.⁸ Selinexor was recently reviewed by CADTH in combination with bortezomib and dexamethasone for the treatment of adult patients with MM who have received at least 1 prior therapy and received a recommendation for reimbursement with conditions; however, funding negotiations are still ongoing. The treatment practices described by the clinical experts also align with recommended regimens by National Comprehensive Cancer Network guidelines.²⁹

Despite an array of therapies, MM remains an incurable disease and patients eventually relapse and their disease becomes refractory to available treatments.⁶ The clinical experts and clinician groups consulted by CADTH agreed there is an unmet need for treatments beyond the third line that prolong survival, delay disease progression, improve quality of life, and minimize side effects. The clinical experts consulted by CADTH also noted there is a need for treatments to be tolerable, especially for patients with comorbidities and to require a shorter treatment duration and a longer treatment-free interval to reduce the treatment burden on this heavily pretreated patient population with a limited lifespan.

Drug

Cilta-cel is a BCMA-directed genetically modified autologous CAR T-cell immunotherapy. This personalized cellular therapy uses the patient’s own T cells in a process that includes T-cell collection, genetic modification of cells, cell infusion, and patient follow-up.³⁰ These T cells are activated upon binding to the targeted cells (cells expressing BCMA), resulting in their lysis.

Cilta-cel was first approved by the FDA on February 28, 2022, for the treatment of adult patients with r/rMM after 4 or more prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody. It was approved by the European Medicines Agency on March 24, 2022, for the treatment of adult patients with r/rMM who have received at least 3 prior therapies, including an IMiD, a PI, and an anti-CD38 antibody, and who have demonstrated disease progression on the last therapy. Of note, this CADTH Reimbursement Review was conducted before issuance of a Health Canada Notice of Compliance with Conditions and the scope was based on the anticipated indication. The anticipated indication and the sponsor’s initial reimbursement request was for the treatment of adult patients with r/rMM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody. Cilta-cel underwent review by Health Canada through advance consideration under its Notice of Compliance with Conditions Policy. The Notice of Compliance with Conditions was issued on February 9, 2023. The approved indication is for the treatment of adult patients with MM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody and whose disease is refractory to their last treatment.¹ The sponsor’s final reimbursement request was as per the indication. Cilta-cel has not been previously reviewed by CADTH.

Cilta-cel is a single-dose, 1-time treatment in a patient-specific infusion bag containing a suspension of CAR-positive viable T cells. The dose is 0.5 × 10⁶ to 1.0 × 10⁶ CAR-positive viable T cells per kg of body weight, with a maximum dose of 1 × 10⁸ CAR-positive viable T cells per single infusion. Cilta-cel should be administered by experienced health professionals at qualified treatment centres.¹

Key characteristics of cilta-cel and other therapies in the fourth line and beyond, as indicated in CADTH’s provisional funding algorithm,³¹ are presented in Table 3.

Table 3: Key Characteristics of Cilta-Cel and Other Therapies in Fourth Line and Beyond

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; CD38 = cluster of differentiation 38; DRESS = drug rash with eosinophilia and systemic symptoms; DVT = deep venous thrombosis; ER = endoplasmic reticulum; ICANS = immune effector cell–associated neurotoxicity syndrome; IMiD = immunomodulatory drug; Kd = carfilzomib-dexamethasone; MM = multiple myeloma; Pd = pomalidomide-dexamethasone; PE = pulmonary embolism; PI = proteasome inhibitor; PML = progressive multifocal leukoencephalopathy; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; TLS = tumour lysis syndrome; XPO1 = exportin 1.

^aSelinexor received a recommendation for reimbursement with conditions from CADTH on July 29, 2022. Funding negotiations are still ongoing, and it has not yet been publicly funded.

^bHealth Canada–approved indication.

Source: ^PrPomalyst product monograph,³² Carvykti™ product monograph,¹ Xpovio Product Monograph,³³ PrKrypolis® Product Monograph³⁴ Canadian Pharmacists Association.³⁵

Stakeholder Perspectives

Patient Group Input

This section was prepared by CADTH staff based on the input provided by patient groups. The full original patient input received by CADTH has been included in the stakeholder section at the end of this report.

One patient group, Myeloma Canada, provided input for the review of cilta-cel. Myeloma Canada supports Canadians with myeloma to access new and innovative therapies. Two online surveys were conducted by Myeloma Canada from August 28 to September 29, 2022. A total of 200 patients across Canada and outside of Canada (France and Trinidad and Tobago) provided complete responses to the patient survey (with some missing responses for each question). A total of 26 caregivers across Canada provided complete responses to the caregiver survey. All survey respondents were required to have relapsed or refractory myeloma, received at least 1 prior line of therapy, or been caring for a patient who met these criteria.

Patient respondents indicated that their ability to work was most significantly impacted by the symptoms associated with myeloma, followed by the ability to travel and exercise. Of note, patient respondents highlighted the significant impact that myeloma had on their mental health. A total of 34% of patient respondents identified travel cost as the most significant financial implication of treatment, followed by drug cost and parking cost (28% each), lost income due to absence from work or disability (27%), and lost income and pension due to early retirement (20%) (N = 198). The majority of patient respondents (58%) indicated they required support from a caregiver for the management of myeloma or treatment-related symptoms (N = 197).

From the perspective of the caregiver respondents, the ability to travel was most significantly impacted by caring for an individual with MM, followed by the ability to work and spend time with family and friends. According to caregiver respondents, drug cost was the most significant implication of caring for an individual who was receiving treatment for myeloma (46%), followed by parking cost (42%), and travel cost (39%) (N = 26).

Patient respondents (36%) reported experiencing some side effects associated with maintenance therapy after receiving SCT, while 29% of patient respondents reported significant side effects (N = 188). Furthermore, 50% of patient respondents reported some negative impact on their overall well-being and quality of life due to the side effects associated with maintenance therapy. Caregiver respondents (31%) reported some negative impact on their duties as a caregiver due to the side effects associated with maintenance therapy experienced by the individual whom they were caring for (N = 26).

One patient respondent reported experience with “ide-cel, bb2121” and 2 patient respondents reported experience with other CAR T-cell therapy, not specified. One patient indicated that the CAR T-cell therapy they received was extremely effective in helping to control their myeloma, was very effective in improving their quality of life, and the side effects were very tolerable. After receiving CAR T-cell therapy, the patient reported a treatment interruption period of 1 to 3 months, which was somewhat important to them. Overall, the patient indicated the CAR T-cell therapy met their expectations in the treatment of their myeloma. The 1 other patient respondent indicated they were awaiting to receive their CAR T-cell therapy in fall 2022.

One patient and 1 caregiver respondent reported experience with cilta-cel. The patient indicated that they received treatment with cilta-cel once in 2015 and once in 2021, and their myeloma had relapsed, and they were currently receiving a new treatment. After receiving cilta-cel, their treatment interruption period (i.e., period when they did not require any drugs to control disease) was 4 to 7 months, which was somewhat important to the patient. The patient indicated cilta-cel was effective in helping to control their myeloma, and its associated side effects were tolerable. According to the patient, the following associated side effects were bearable: thrombocytopenia, neutropenia, neuropathy, nausea, leukopenia, lymphopenia, diarrhea, constipation, and anemia. Overall, the patient felt that treatment with cilta-cel improved their quality of life and met their expectations in the treatment of their myeloma.

The caregiver respondent indicated that the patient they cared for received cilta-cel less than 3 months ago and was currently in remission. After receiving cilta-cel, the patient’s treatment interruption period was 1 to 3 months, which was extremely important to the caregiver. The caregiver indicated that cilta-cel was extremely effective in helping to control the myeloma and felt less care was required as their caregiver. According to the caregiver, the following associated side effects were difficult to care for: CRS, neurotoxicity, thrombocytopenia, neutropenia, neuropathy, lymphopenia, diarrhea, and constipation.

Of the patient respondents without experience with CAR T-cell therapy, 27% received 3 lines of therapy, 23% received 2 lines of therapy, 18% received 1 line of therapy, 20% received 4 or more lines of therapy, and 12% were uncertain (N = 197). In response to the risk associated with waiting for modified T cells to be reintroduced when preparing to receive CAR T-cell therapy, most patient respondents (40%) without experience with CAR T-cell therapy indicated they would be concerned that their myeloma would relapse but they can live with the wait, while 30% indicated they would be willing to take the risk, 27% were uncertain and would discuss with their health care provider, and 1% would be unwilling to take the risk (N = 145). With respect to the side effects associated with cilta-cel, the survey respondents who did not have experience with CAR T-cell therapy felt that CRS would be the most troublesome side effect, followed by neutropenia, fever, and neuropathy. Among the patient respondents without experience with CAR T-cell therapy, 26% would consider cilta-cel as their next treatment option; 50% were uncertain (N = 145). These patient respondents further highlighted the importance of not having to continue with ongoing treatment after receiving CAR T-cell therapy despite the associated risks.

The patient respondents identified infections as the most important aspect of myeloma to control. They further indicated that mobility and kidney problems were aspects of myeloma that were important to control. Patient respondents reported that future treatment for MM should improve quality of life, have tolerable side effects, achieve remission, and extend survival without the need for continuous treatment. Patient respondents also highlighted the need for accessibility and portability of treatments and a supportive and communicative care team. Patient respondents further noted the importance of access to alternative newer treatments and minimal trips to the hospital or community treatment centre. Of the respondents who reported no experience with CAR T-cell therapy, 74% of patients (N = 143) and 60% of caregivers (N = 15) indicated that an estimated minimum of 1 to 2 years of extended life without requiring any drugs to control myeloma was extremely desirable; 2 patients indicated this was not desirable. Of note, this desirability is dependent on the severity of side effects and quality of the extended life.

Clinician Input

Input From Clinical Experts Consulted by CADTH

All CADTH review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). In addition, as part of the cilta-cel review, a panel of 3 clinical experts from across Canada was convened to characterize unmet therapeutic needs, assist in identifying and communicating situations where there are gaps in the evidence that could be addressed through the collection of additional data, promote the early identification of potential implementation challenges, gain further insight into the clinical management of patients living with a condition, and explore the potential place in therapy of the drug (e.g., potential reimbursement conditions). A summary of this panel discussion is also presented subsequently.

Unmet Needs

The clinical experts highlighted that the most important goals of treatment for patients with r/rMM are prolonging survival, delaying disease progression, improving quality of life, and minimizing side effects. Treatments for r/rMM are changing rapidly, and the treatment regimens vary across treatment centres in Canada, depending on drug availability. After diagnosis with MM, the lines of therapy that patients will go through depend on whether or not they are transplant-eligible. Front-line therapy determines which therapies are selected for the subsequent lines of therapy, as patients’ disease becomes increasingly refractory to treatment options as patients proceed through treatment lines. Choice of therapy also depends on the patients’ functional status and comorbidities, for example, carfilzomib may not be a good choice for patients with cardiac issues. The clinical experts noted that clinicians try not to reuse the same drugs in subsequent lines of therapy. Therefore, after 3 lines of therapy, the majority of patients will be triple-refractory and will need new families of drugs such as selinexor or antibody drug conjugates (belantamab mafodotin), which are not currently funded in Canada (selinexor in combination with bortezomib and dexamethasone has recently received a recommendation for reimbursement with conditions from CADTH. The price is currently being negotiated and belantamab mafodotin is available through compassionate patient access). There is a need for treatments beyond the third line that are tolerable for patients with comorbidities. The clinical experts also noted that it is beneficial for any treatment to require a shorter treatment duration and lead to a longer treatment-free interval to reduce the treatment burden on this heavily pretreated patient population with a limited lifespan.

The clinical experts also highlighted that patients’ immune systems become weaker after multiple lines of therapy, thereby creating a need for therapies that are tolerated in later lines of therapy. As well, the experts noted that from the time of diagnosis, patients with high-risk disease have poor responses to treatment, which is worsened in the relapsed–refractory setting. Therefore, there is a great need for therapies that show some improved activity in people with high-risk disease. Patients who relapse quickly after prior lines of therapy (e.g., < 2 years) are also likely to have a very poor prognosis and thus are in great need of a novel intervention.

Place in Therapy

The clinical experts agreed that the majority of patients with r/rMM would eventually be eligible for cilta-cel, with the exception of those patients who will have died before reaching the fourth line or who will be ineligible for CAR T-cell therapy due to severe disease progression or poor functional status. The clinical experts noted that the major barrier to uptake would be capacity, as the demand for CAR T-cell therapy may be greater than the existing capacity in Canada. The clinical experts anticipated that the demand for cilta-cel for the present indication may exceed the demand for CAR T-cell therapy for patients with relapsed or refractory large B-cell lymphoma because these patients often relapse aggressively with progression that is harder to control; whereas, for patients with MM, the relapse is slower and easier to predict and control.

Patient Population

The clinical experts noted that the CARTITUDE-1 trial enrolled a broad sample of patients with r/rMM, including older patients and patients with multiple prior lines of therapy. Eligible patients would include those who have “adequate organ” function to be able to tolerate cytokine release syndrome and ICANS (definition of adequate organ function should be broad and left to the discretion of the treating centres) and who have a good ECOG PS (i.e., ≤ 2). The experts noted it would be difficult to limit cilta-cel treatment by specific patient or disease characteristics, because even patients in high-risk groups (e.g., high cytogenetic risk) appeared to benefit in the CARTITUDE-1 trial. In the absence of sufficient evidence to guide patient selection for cilta-cel treatment, the experts suggested that patients who have a short life expectancy (< 2 months), have poorly controlled PD, are unable to move to a larger centre for 1 month, or have poor functional status (ECOG > 2) may not be suitable for cilta-cel. It was also noted by the clinical experts that some patients may have a contraindication to cilta-cel, for example, patients with poor renal function may be less tolerant to CRS.

Assessing Response to Treatment

The clinical experts reported that response to treatment is typically assessed by regular monitoring that is part of the management of patients with r/rMM. This includes biochemical measurement once a month of M proteins or free light chain ratios and imaging such as PET scans that is performed less frequently. The experts noted that response is typically assessed monthly, at first. In stable patients, intervals between response assessments may be extended to every 2 to 3 months. The clinical experts defined clinically meaningful response to treatment as a durable response that is better than PR, a reduction in the severity of disease symptoms (e.g., fatigue, breathlessness), and PFS that is at least 12 months in duration. The experts agreed that, with current treatments beyond the third line, the average duration of PFS is approximately 9 to 12 months.

Discontinuing Treatment

The clinical experts noted that in some rare cases, patients may go through pre-treatment (i.e., apheresis and conditioning chemotherapy) but not receive cilta-cel. This may be due to manufacturing issues (which would be unusual), or unexpected clinical deterioration, such as severe infection. In these cases, the patients would receive supportive care until the acute crisis is resolved. If patients were to deteriorate substantially between apheresis and time of infusion, one may not proceed with cilta-cel infusion.

The clinical experts reported that for patients who relapse following CAR T-cell therapy, the subsequent therapy would depend on which therapies the patient had already received. However, the experts acknowledge that almost half of these patients may not be eligible for any subsequent therapy due to poor functional status or rapidly progressing disease and would only receive supportive care. The clinical experts noted that some patients may be eligible for enrolment in clinical trials.

Prescribing Conditions

The clinical experts reported that cilta-cel treatment can be provided by oncologists or hematologists in a specialized setting that has adequate infrastructure for cell therapy and access to excellent clinical support and multidisciplinary care, including critical and specialist care (e.g., intensive care unit, neurology, nephrology) to manage toxicities, as well as laboratory support to handle and process samples. They noted that it would be especially important to be in a setting where CRS would be quickly diagnosed and managed. The clinical experts discussed that eventually, after years of experience with CAR T-cell therapy, there may be potential for providing cilta-cel in an outpatient setting, but this is not currently a viable option.

Clinician Group Input

This section was prepared by CADTH staff based on the input provided by clinician groups. The full original clinician group inputs received by CADTH have been included in the stakeholder section at the end of this report.

Two clinician groups provided input for the review of cilta-cel: CMRG, represented by 20 clinicians, and Ontario Health (Cancer Care Ontario) Hematology Cancer Drug Advisory Committee, represented by 1 clinician. The CMRG is a Canada-wide network of researchers aiming to develop better treatments for extending life of patients with myeloma, enhancing the quality of life for those living with myeloma and related disorders, and working to find a cure for these diseases and other plasma cell disorders. The Ontario Health (Cancer Care Ontario) Drug Advisory Committees provide evidence-based clinician and health system guidance on drug-related issues in support of Cancer Care Ontario’s mandate.

Unmet Needs

Both clinician groups identified the following treatment goals:

• control the disease and its associated sequalae (i.e., bone destruction and pain, renal failure, hypercalcemia, and low blood counts) by achieving an antimyeloma response

• maintain control of myeloma and its manifestations for as long as possible (i.e., maximize PFS)

• improve OS.

Additional treatment goals identified by the CMRG included:

• minimize adverse effects of treatment

• optimize quality of life by adequately controlling the disease and minimizing toxicity with the aim to tailor the treatment approach to the individual patient.

According to the CMRG, fourth-line treatment options are limited. A pomalidomide- or carfilzomib-based regimen may be used if it was not used in third line. A regimen of bortezomib plus steroids may be used; however, it is associated with a short PFS and cannot be revisited in many jurisdictions if the patient is refractory to PIs. Cyclophosphamide can be added to many regimens or used with steroids as a doublet therapy; however, the cumulative lifetime exposure to cyclophosphamide in a patient is limited to 1 to 2 years due to its associated risks. This risk may further restrict the use of alternative alkylating drugs such as melphalan. As such, palliation, best supportive care, and local radiotherapy are often pursued within the context of the publicly funded system. Additional treatment options in Ontario identified by the Hematology Cancer Drug Advisory Committee were Special Access Program drugs (i.e., selinexor-dexamethasone, with or without bortezomib or belantamab). Of note, the CMRG indicated that antibody drug conjugates, bispecific antibodies, and cellular therapy that are directed against BCMA on myeloma cells are positioned to fill the triple class–exposed or refractory space but are not currently available in Canada.

The CMRG emphasized that myeloma remains incurable, and patients eventually become refractory to all available funded drugs. The clinician group further highlighted the most important unmet need is in patients with advanced disease who have received multiple lines of treatment and received the 3 major classes of drugs (triple-class–exposed or triple-class–refractory disease), including a PI, an IMiD, and an anti-CD38 antibody. Advanced disease progression and short DOR can lead to poor quality of life, advanced caregiver burden, and a shortened lifespan. The Hematology Cancer Drug Advisory Committee further indicated that the low response rate associated with currently available treatment options is an unmet need.

Place in Therapy

The CMRG advocated for cilta-cel to be used in patients with triple class–exposed or triple class–refractory myeloma, with cilta-cel to be used in sequence after other lines of therapy (i.e., after failure of multiple drugs). Consequently, cilta-cel is not expected to impact the sequencing of drugs earlier in the disease course or lead to a major change in the treatment algorithms before patients becoming triple-refractory. Instead, cilta-cel is expected to lead to a major shift in the current treatment paradigm for patients with advanced MM disease who previously received 3 lines of therapy. The Hematology Cancer Drug Advisory Committee suggested cilta-cel would fit into the current treatment paradigm, as per the clinical trial.

Patient Population

The CMRG suggested that the least suitable patients for treatment with cilta-cel would be frail, with rapidly proliferating disease, ongoing infection, significant organ dysfunction, and/or pre-existing pancytopenia. Patients whose disease is progressing at a rate anticipated to allow them to remain stable and relatively well during the 4- to 5-week period required for CAR T-cell processing would be the best suited for this treatment to avoid death before cell therapy product delivery. The Hematology Cancer Drug Advisory Committee suggested that patients with an ECOG PS of 0 to 2 and acceptable comorbidities would be the best suited for this treatment. The CMRG further suggested that patients with good PS, minimal or no comorbidities, low tumour burden, and adequate organ function and blood counts would be the most likely to have the best outcomes. Of note, the CMRG indicated that patients with other disease-related adverse prognostic factors, such as extramedullary disease and high-risk cytogenetics, do not fare significantly worse and should be eligible for cilta-cel.

Assessing Response to Treatment

The CMRG indicated that response to treatment is based on the M protein marker in the serum and/or urine, bone marrow biopsy and, in some instances, imaging studies; the MRD is an emerging parameter. The Hematology Cancer Drug Advisory Committee indicated that improved survival, disease control, and symptom improvement are used to determine treatment response. The CMRG indicated that a clinically meaningful response correlates with at least a partial remission per the IMWG consensus criteria (i.e., improvement in symptoms, energy, and ability to perform activities of daily living). The CMRG stated that responses are typically assessed every 1 to 3 months depending on clinical stability and treatment regimen used.

Discontinuing Treatment

Considerations regarding drug discontinuation are not applicable in the context of a single infusion of cilta-cel. Both clinician groups suggested that a major medical facility, tertiary hospital, or transplant centre with expertise in cellular therapies for hematologic malignancies is an appropriate setting for treatment with cilta-cel.

Drug Program Input

The drug programs provide input on each drug being reviewed through CADTH’s reimbursement review processes by identifying issues that may impact their ability to implement a recommendation. The implementation questions and corresponding responses from the clinical experts consulted by CADTH are summarized in Table 4.

Table 4: Summary of Drug Plan Input and Clinical Expert Response

CAR = chimeric antigen receptor; CD = cluster of differentiation; cilta-cel = ciltacabtagene autoleucel; ECOG = Eastern Cooperative Oncology Group; ICU = intensive care unit; RVd = lenalidomide-bortezomib-dexamethasone.

Clinical Evidence

The clinical evidence included in the review of cilta-cel is presented in 3 sections. The first section, the systematic review, includes pivotal studies provided in the sponsor’s submission to CADTH and Health Canada as well as those studies that were selected according to an a priori protocol. The second section includes indirect evidence from the sponsor and indirect evidence selected from the literature that met the selection criteria specified in the review. The third section includes sponsor-submitted long-term extension studies and additional relevant studies that were considered to address important gaps in the evidence included in the systematic review. Of note, no indirect evidence was submitted by the sponsor or identified in the literature that met the eligibility criteria for the review; however, estimates of the comparative efficacy of cilta-cel relative to physicians’ choice of treatment were available from the observational studies submitted by the sponsor and identified in the literature.

Systematic Review (Pivotal and Protocol-Selected Studies)

Objectives

To perform a systematic review of the beneficial and harmful effects of cilta-cel cell suspension for IV infusion, 0.5 × 10⁶ to 1.0 × 10⁶ CAR-positive viable T cells per kg body weight (maximum 1 × 10⁸ CAR-positive viable T cells) for the treatment of adult patients with r/rMM, who have received at least 3 prior lines of therapy including a PI, an IMiD, and an anti-CD38 antibody.

Methods

Studies selected for inclusion in the systematic review include pivotal studies provided in the sponsor’s submission to CADTH and Health Canada, as well as those meeting the selection criteria presented in Table 5. Outcomes included in the CADTH review protocol reflect outcomes considered to be important to patients, clinicians, and drug plans.

Of note, the systematic review protocol presented subsequently was established before the granting of a Notice of Compliance from Health Canada.

Table 5: Inclusion Criteria for the Systematic Review

AE = adverse event; CAR = chimeric antigen receptor; CD = cluster of differentiation; HRQoL = health-related quality of life; ICU = intensive care unit; SAE = serious adverse event, WDAE = withdrawal due to adverse event.

^aSelinexor received a recommendation for reimbursement with conditions from CADTH on July 29, 2022. It is currently under negotiations and has not been publicly funded yet.

The literature search was performed by an information specialist using a peer-reviewed search strategy according to the PRESS Peer Review of Electronic Search Strategies checklist.³⁶

Two CADTH clinical reviewers independently selected studies for inclusion in the review based on titles and abstracts, according to the predetermined protocol. Full-text articles of all citations considered potentially relevant by at least 1 reviewer were acquired. Reviewers independently made the final selection of studies to be included in the review, and differences were resolved through discussion.

Published literature was identified by searching the following bibliographic databases: MEDLINE All via Ovid and Embase via Ovid. All Ovid searches were run simultaneously as a multifile search. Duplicates were removed first using Ovid deduplication for multifile searches, followed by manual deduplication in Endnote. The search strategy comprised both controlled vocabulary, such as the National Library of Medicine’s MeSH (Medical Subject Headings), and keywords. The main search concept was cilta-cel. The clinical trials registries searched were the US National Institutes of Health’s clinicaltrials.gov, WHO’s International Clinical Trials Registry Platform (ICTRP) search portal, Health Canada’s Clinical Trials Database, and the European Union Clinical Trials Register.

No filters were applied to limit the retrieval by study type. Retrieval was not limited by publication date or by language. Conference abstracts were excluded from the search results. See Appendix 1 for the detailed search strategies.

The initial search was completed on October 24, 2022. Regular alerts updated the search until the meeting of the CADTH pan-Canadian Oncology Drug Review Expert Committee (pERC) on March 8, 2023.

Grey literature (literature that is not commercially published) was identified by searching relevant websites from the Grey Matters: A Practical Tool for Searching Health-Related Grey Literature checklist.³⁷ Included in this search were the websites of regulatory agencies (FDA and European Medicines Agency). Google was used to search for additional internet-based materials. See Appendix 1 for more information on the grey literature search strategy.

A focused literature search for indirect treatment comparisons (ITCs) dealing with MM was run in MEDLINE All on October 24, 2022. No limits were applied to the search.

Findings From the Literature

A total of 2 studies were identified from the literature for inclusion in the systematic review (Figure 1). A list of excluded studies is presented in Appendix 2.

Table 6: Details of Included Studies

AE = adverse event; BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; CD = cluster of differentiation; cilta-cel = ciltacabtagene autoleucel; CR = complete response; CRS = cytokine release syndrome; ECOG = Eastern Cooperative Oncology Group; EORTC = European Organisation for Research and Treatment of Cancer; EQ-5D-5L = 5-level EQ-5D; HRQoL = health-related quality of life; IMiD = immunomodulatory drug; IMWG = International Myeloma Working Group; IRC = independent review committee; LPD = last patient dosed; MM = multiple myeloma; NYHA = New York Heart Association; ORR = overall response rate; PBMC = peripheral blood mononuclear cells; PD = progressive disease; PGIC = Patient Global Impression of Change; PGIS = Patient Global Impression of Severity; PI = proteasome inhibitor; QLQ-C30 = Quality of Life Questionnaire Core 30; QLQ-MY20 = Quality of Life Questionnaire Myeloma Module; SAE = serious adverse event; sCR = stringent complete response; VGPR = very good partial response.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Figure 1: Flow Diagram for Inclusion and Exclusion of Studies

Description of Studies

CARTITUDE-1 is a phase Ib/II, single-arm clinical trial (N = 113) of cilta-cel in patients with r/rMM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 antibody. In the trial, 97 patients received the full conditioning regimen followed by cilta-cel infusion. The main cohort described throughout this review included 113 enrolled patients and was conducted in 16 sites in the US.

The primary objective for the phase Ib study was to characterize the safety of cilta-cel and confirm the recommended phase II dose. The primary objective for the phase II study was to evaluate the efficacy of cilta-cel through ORR (PR or better) as assessed by an IRC. Secondary outcomes included VGPR or better rate, DOR, MRD negativity rate, TTR, PFS, OS, and HRQoL assessments. An exploratory objective was to characterize the impact of the treatment process on health care resource utilization. The study was funded by Janssen Research & Development. Patients were enrolled from 17 sites in the US. An additional cohort of patients from 4 sites in Japan was enrolled after the global program concluded, referred to as the Japanese cohort. No Canadian sites were included.

After enrolment, patients underwent apheresis, received conditioning treatment, and then received the cilta-cel infusion. Patients were followed up on days 3, 7, 10, 14, 21, 28, 42, 56, 78, and 100. After day 101, they were followed up every 28 days until study completion, defined as 2 years after the last patient has received their initial dose. AEs were reported until 100 days after last administration of any study treatment or until the start of subsequent systemic anticancer therapy if earlier. AEs that were considered to be related to study drug after 100 days, were reported until the end of the study. Long-term follow-up would continue for up to 15 years in a follow-up study.

A summary of the design of the CARTITUDE-1 study is shown in Figure 2. There were 4 Clinical Study Reports provided in the sponsor’s submission: a primary analysis report with a clinical data cut-off date of September 1, 2020,⁹ safety and efficacy update reports with a clinical data cut-off date of February 11, 2021,¹⁰ and a final analysis report with a clinical data cut-off date of January 11, 2022.¹¹ Unless otherwise specified, the data presented are from the final Clinical Study Report with a data cut-off date of January 11, 2022, as findings were generally consistent over time.

Populations

Inclusion and Exclusion Criteria

Key inclusion and exclusion criteria for the CARTITUDE-1 study are shown in Table 66. Adult patients (aged ≥ 18 years) with a documented diagnosis of MM and documented disease progression were eligible if they had received at least 3 prior lines of therapy or were double refractory to a PI and an IMiD, and received a PI, an IMiD, and an anti-CD38 antibody. Patients were eligible if they had an ECOG PS of 0 or 1 and creatinine clearance of 40 mL/min/1.73 m² or greater. Patients who had undergone prior treatment with CAR T-cell therapy, any therapy targeted to BCMA, or prior antitumour therapy were excluded, as were most patients diagnosed or treated for invasive malignancies other than MM. Patients with cardiac conditions within 6 months of enrolment were also excluded.

Figure 2: Schematic Overview of the Study Flow Chart

Cilta cel = ciltacabtagene autoleucel.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Baseline Characteristics

The baseline demographic and disease characteristics of all patients who received cilta-cel are presented in Table 7. The mean age of patients was 62 years (SD = 8.4 years), and the majority were younger than 65 years (62; 64%), male (57 patients; 59%), and white (69 patients; 71%), with an ECOG PS of 1 (54 patients; 56%) at infusion and ISS stage I at baseline (61 patients; 63%). With regard to cytogenetic risk, 23 patients (24%) were high risk at baseline. The majority of patients had received a prior transplant (87 patients; 90%). All patients received at least 3 prior lines of MM therapy with a median of 6 prior lines (range, 3 to 18), and approximately half had received more than 5 lines of therapy (49 patients; 51%). Prior to enrolment, all patients received a PI, an IMiD, and an anti-CD38 antibody therapy. The most common antineoplastic drugs used were daratumumab in 94 patients (97%) and bortezomib in 92 patients (95%), and the most common IMiDs used were lenalidomide in 96 patients (99%) and pomalidomide in 89 patients (92%).

Table 7: Summary of Baseline Characteristics (All-Treated Analysis Set)

BCMA = B-cell maturation antigen; ECOG = Eastern Cooperative Oncology Group; FISH = fluorescence in situ hybridization; FLC = free light chain; ISS = International Staging System; MM = multiple myeloma; SD = standard deviation.

^aLast nonmissing ECOG Performance Status score on or before date of cilta-cel infusion (all patients met the inclusion criterion of ECOG Performance Status 0 or 1 during screening).

^bISS staging was derived based on serum beta2-microglobulin and albumin.

^cMaximum value from bone marrow biopsy and bone marrow aspirate was selected if both results were available. There was 1 patient with a nonevaluable bone marrow biopsy or /aspirate.

^dCytogenic risk abnormalities were based on central FISH testing or local FISH and karyotype testing if central FISH was not available.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Refractory Status

A summary of refractory status to prior MM therapies is presented in Table 8. Almost all patients (96 patients; 99%) had disease that was refractory to the last line of prior therapy, and 85 patients (88%) had disease that was triple-refractory (i.e., refractory to the 3 major classes of therapeutic drugs [PI, IMiD, and anti-CD38 monoclonal antibody]). Forty-one patients (42.3%) were refractory to 5 or more drugs.

Table 8: Summary of Refractory Status to Prior MM Therapy (All-Treated Analysis Set)

CD = cluster of differentiation; IMiD = immunomodulatory drug; MM = multiple myeloma; PI = proteasome inhibitor.

^aTwo additional patients had disease that was refractory to other anti-CD38 antibodies.

^bTAK-079 is an investigational anti-CD38 antibody.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Interventions

Randomization was not used in this study, and all patients who met the inclusion and exclusion criteria and were enrolled received apheresis. No blinding procedures were used in this open-label study.

On the day of study enrolment, eligible patients underwent apheresis to allow collection of peripheral blood mononuclear cells (target of 6 × 10⁹ peripheral blood mononuclear cells; range, 2 to 20 × 10⁹). Cilta-cel was manufactured specifically for each patient using their own T cells collected during apheresis. Batches were manufactured between August 3, 2018, and October 25, 2019. Patients who were clinically indicated to receive bridging therapy, to maintain disease stability while cilta-cel was manufactured, received it following preapproval from the sponsor. Bridging therapy was administered between the time of apheresis and the first dose of the conditioning regimen; 73 patients (75%) received bridging therapy, consisting of dexamethasone in 62 patients (64%), bortezomib in 26 patients (27%), cyclophosphamide in 22 patients (23%), and pomalidomide in 21 patients (22%). If a patient reached CR after bridging therapy, they were considered no longer eligible to receive cilta-cel.

Four weeks after apheresis, patients received a conditioning regimen of IV cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) in 3 daily doses to induce lymphodepletion and promote CAR T expansion.

Day 1 occurred 5 to 7 days later, on the day of cilta-cel infusion. Patients were first premedicated with 50 mg of diphenhydramine (or the equivalent) and 650 mg to 1,000 mg of acetaminophen (or the equivalent). Cilta-cel was then administered as a single infusion dose of 0.75 × 10⁶ CAR-positive viable T cells/kg (range of 0.5 × 10⁶ to 1.0 × 10⁶ CAR-positive viable T cells/kg, with a maximum total dose of 1.0 × 10⁸).

Apheresis, conditioning, and infusion of cilta-cel was done in the controlled environment of a qualified clinical site under the direct observation of qualified study site personnel.

Re-treatment with cilta-cel was considered for patients who met the following criteria: PD after a best response of minimal response or better; no ongoing grade 3 or higher hematologic toxicity; no ongoing grade 2 nonhematologic toxicity (with the exception of nausea, vomiting, hair loss, and constipation); and at least 6 months between the first cilta-cel infusion and detection of PD. To be eligible for re-treatment with cilta-cel, patients had to meet the eligibility criteria for the study. A maximum of 1 re-treatment was allowed per patient. Bridging therapy before re-treatment could be considered based on a patient’s clinical status and the timing of the availability of the cilta-cel infusion, following approval from the sponsor.

Outcomes

The efficacy end points identified in the CADTH review protocol that were assessed in the clinical trial included in this review are summarized subsequently. A detailed discussion and critical appraisal of the outcome measures is provided in Appendix 3.

The primary objective for the phase Ib of the CARTITUDE-1 study was to characterize the safety of cilta-cel and confirm the recommended phase II dose. The primary objective for phase II was to evaluate the efficacy of cilta-cel through ORR. ORR was defined as the proportion of patients who achieved a PR or better (calculated as sCR + CR + VGPR + PR), according to the IMWG response criteria as assessed by an IRC before the end-of-study date.²⁸ All response criteria used in this study are described in Table 37 in Appendix 4. PR is defined as a 50% or greater reduction of serum M protein and reduction in 24-hour urinary M protein by 90% or greater or reduced to less than 200 mg/24 hours; otherwise (if not measurable), it was defined as a decrease of 50% or greater in the difference between involved and uninvolved free light chain levels. If neither of these was measurable, a 50% or greater reduction in bone marrow plasma cells was sufficient as an alternative to M protein, provided the baseline percentage was 30% or greater. In addition to the previous criteria, if present at baseline, a reduction of 50% or greater in the size of soft-tissue plasmacytomas was also required.

Disease evaluations were performed by a central laboratory and ORR was assessed by IRC. The agreement between the IRC’s determination and the assessment by a validated computer algorithm developed by the sponsor was provided. This computer algorithm had been published previously as part of a pivotal study of daratumumab, bortezomib, and dexamethasone in MM.⁴³ A sensitivity analysis of ORR was also conducted, based upon investigator assessment.

Secondary outcomes were also assessed by an IRC and included a response rate of VGPR or better, DOR, TTR, PFS, OS, MRD negativity rate, and HRQoL.

VGPR or better response rate was defined as the proportion of patients with a response of VGPR or better, according to the IMWG criteria (calculated as sCR + CR + VGPR).

DOR was calculated among responders (response of PR or better) from the date of initial documentation of a response of PR or better to the date of first documented evidence of PD, as defined in the IMWG criteria. Relapse from CR by positive immunofixation or trace amount of M protein was not considered disease progression. Disease evaluation continued beyond relapse, from CR until disease progression was confirmed. The outcome was censored for patients who did not progress at the last disease evaluation before the start of subsequent antimyeloma therapy.

TTR was defined as the time between the initial cilta-cel infusion date and the first efficacy analysis where the patient met the criteria for a response of PR or better. The outcome was censored for patients with no response either at the date of disease progression or at the last evaluation of disease before the start of subsequent antimyeloma therapy.

PFS was defined as the time between the initial cilta-cel infusion date and the date of first documented disease progression (defined in the IMWG criteria) or death due to any cause, whichever occurred first. The outcome was censored for patients whose condition had not progressed and who were still alive at the last disease evaluation before the start of subsequent antimyeloma therapy.

OS was defined as the time between the initial cilta-cel infusion date and the date of the patient’s death. The outcome was censored for patients who were still alive (or with unknown vital status) at the final calendar date of follow-up.

MRD negativity was assessed by comparing baseline bone marrow aspirates to post-treatment samples by next generation flow cytometry and/or next generation sequencing. Samples were collected at day 28 and every 6 months subsequently, regardless of the status of disease determined by the results of the blood and urine measures.

HRQoL was assessed in patients enrolled in phase II of the study using the EORTC QLQ-C30, the EORTC QLQ-MY20, EQ-5D-5L utility and EQ-5D Visual Analogue Scale scores, PGIC, and PGIS. Baseline assessments were completed at screening; subsequent assessments were conducted at day 7, day 28, day 56, day 78, day 100, and then every 28 days up to study completion. Meaningful and sustained improvement in scores compared with baseline were evaluated using established meaningful change thresholds. These thresholds were calculated using the PGIS and the PGIC, which are single items to assess overall HRQoL. A detailed discussion and critical appraisal of the HRQoL measure is provided in Appendix 3.

The EORTC QLQ-C30 consists of 30 questions that are scored to create 5 multi-item functional scales (physical, role, cognitive, emotional, and social), 3 multi-item symptom scales (fatigue, pain, and nausea and vomiting) and 6 single-item symptom scales (dyspnea, loss of appetite, insomnia, constipation, diarrhea, and financial difficulties).⁴⁴ All the scales and single-item measures range in score from 0 to 100. Raw scores for each scale are computed as the average of the items that contribute to a particular scale. Scale sum scores are transformed so that a high score on the functional scales represents a high or healthy level of functioning, a high score on the symptom scales represents a high level of symptomatology, and a high score on the global health status represents a high HRQoL.⁴⁵ The recall period for the EORTC QLQ-C30 was 1 week. In terms of construct validity, the subscales for pain, fatigue, physical and global quality of life were able to discriminate between patients who improved versus patients who were stable/deteriorated.⁴⁶ In terms of internal consistency the Cronbach alpha ranged from 0.54 to 0.89 for all subscales, including in patients with r/rMM.^47-50 Mean score changes of 6 to 17 in the QLQ-C30 were considered to be important to patients with MM,⁵¹ and a change of 8 and 12 points in patients who improved and deteriorated, respectively, on the global quality of life score was considered to be important to patients.⁵²

The EORTC QLQ-MY20 was designed to be used with the EORTC QLQ-C30 to address issues of more relevance to patients with myeloma.⁵³ Four single items from the EORTC QLQ-MY20 were used to assess emotional health status (feel restless or agitated, thinking about your illness, worried about dying, worried about health in the future). The recall, response options, and interpretation of the scores for the EORTC QLQ-MY20 are similar to those for the QLQ-C30. In terms of validity, when scales were compared between patients with a higher versus a lower ECOG PS, only the disease symptoms, treatment side effects, and body image scales demonstrated differences between patient groups according to their PS.⁵³ Reliability was not assessed in patients with MM. When assessed for responsiveness to change, the scale scores for disease symptoms and body image decreased over time with treatment, while the scale scores for treatment side effects increased.⁵³ The estimated minimally important differences (MIDs) for each subscale are the following: 10 points in disease symptoms, 10 points in side effects of treatment, 13 points in body image, and 9 points in future perspective.⁵⁴

The EQ-5D-5L is a 5-item questionnaire that assesses 5 domains, including mobility, self-care, usual activities, pain/discomfort, and anxiety/depression, plus a visual analogue scale rating for “health today,” with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). The scores from these 5 domains are computed to a single utility score ranging from 0 to 1. Validity, reliability, and responsiveness were not assessed and the MID was not estimated in patients with MM.

The PGIS is a single item in which patients are asked to rate the severity of their current pain on a 5-point verbal rating scale. The PGIC is a single item in which patients are asked to rate the change in their overall health status using a 7-point verbal rating scale and was only administered post infusion.

Semistructured interviews were conducted with patients enrolled in phase II of the trial at screening, on day 100, and approximately 6 months post infusion to inform their experiences with treatment. Patients in the Japanese cohort did not participate in the interviews.

Safety and tolerability were assessed using the incidence AEs, SAEs, and deaths and laboratory abnormalities, all of which were reported from the time a signed and dated informed consent form was obtained until day 100 or the start of any subsequent systemic anticancer therapy (whichever is earlier). After day 100, only AEs considered related to cilta-cel were reported until the end of the study. All neurotoxicity and hepatitis B virus reactivation events, as well as second primary malignancy, were reported during the first year after cilta-cel infusion, regardless of the date of onset.

AEs were reported using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 guidelines with the exception of CRS and ICANS (or cell-related encephalopathy syndrome [CRES]). In phase Ib, CRS was graded according to criteria outlined by Lee et al. (2014)⁵⁵ and in phase II, CRS grading was updated to the ASTCT consensus grading system.⁵⁶ Therefore, CRS events were re-evaluated according to the new standard to allow evaluation across the entirety of the study. On the other hand, CRES (assessed in phase Ib) was replaced by ICANS in an update of the Medical Dictionary for Regulatory Activities before phase II. ICANS is derived from immune effector cell–associated encephalopathy scores that were not collected from all patients in phase Ib; therefore, the complete evaluation of ICANS across the study was not possible.

Health resource utilization was collected for all phase II patients throughout the study until day 180 (± 7 days) and included number and duration of medical care encounters, including surgeries, radiographic diagnostics, laboratory tests, and other selected inpatient and outpatient procedures; duration of hospitalization, including duration by ward (e.g., intensive care unit); number and type of diagnostic and therapeutic tests and procedures; and outpatient medical encounters and treatments.

Statistical Analysis

In phase Ib of the study, no formal statistical hypothesis testing was performed. At least 24 and up to 50 patients were planned to be enrolled in the phase Ib part of the study to confirm the recommended phase II dose and assess safety. With 24 treated patients, if the true incidence rate of certain AEs identified as potential risks was 10%, the probability of observing at least 1 patient experiencing the event would be more than 90%. The AEs identified as potential risks include CRS, cytopenias, tumour lysis syndrome, and infections. In phase II of the study, the null hypothesis tested was an ORR for cilta-cel of 50%. At the time of the protocol, the sponsor asserted that for the therapies available to treat patients with r/rMM (including daratumumab), the reported ORR is 30% or less. Enrolling 60 patients would lead to approximately 90% power to declare that the ORR was higher than 30% at the 1-sided significance level of 0.05. The ORR was estimated empirically and 2-sided 95% CIs were calculated on the basis of the exact binomial distribution. The study was to be considered successful if the lower bound of the 95% CI exceeded 30%. For the Japanese cohort, with a sample size of at least 8 patients, the probability of observing an ORR of greater than 30% is at least 80%, assuming the ORR is 50%. The median event time and survival probability curve for DOR, OS, PFS, and TTR were estimated using the Kaplan-Meier method among patients who achieved a response during the study. The durability of MRD-negative status was characterized by quantifying rates of MRD-negative status (10^–5) sustained for at least 6 or 12 months. The scores for all HRQoL assessments were summarized descriptively at relevant time points. Data from the qualitative interviews were analyzed using content analysis, and qualitative themes were presented.

A sensitivity analysis of ORR was performed based on the patients in the mITT analysis set (i.e., those who received cilta-cel) who received a product that met all of the prespecified release criteria. The agreement on ORR as assessed by an IRC compared with the validated computerized algorithm developed by the sponsor, was evaluated using the kappa statistic with a 95% CI. A sensitivity analysis was also conducted for ORR based on the investigators’ assessments.

The first analysis of the primary end point was conducted at 6 months after the last patient had received cilta-cel (data cut-off date of September 1, 2020). The analysis of VGPR or better rate, DOR, PFS, and OS were conducted for the same cut-off date. Updated analyses were undertaken 12 months after the last patient received their initial dose of cilta-cel (data cut-off date of February 11, 2021), and at the end of the study (i.e., 2 years after the last patient received their initial dose) (data cut-off date of January 11, 2022). No control for multiplicity for the statistical hypothesis testing for ORR was conducted.

Subgroup analyses of the primary outcome were conducted stratifying patients based on age, sex, race, total CAR T-positive cells infused, baseline ECOG PS, baseline ISS staging, number of prior lines of therapy, SCT history, disease type, refractory status, cytogenic risk group, baseline bone marrow plasma cells, baseline BCMA expression, and study site. The following subgroups aligned with the subgroups prespecified in the protocol for this CADTH review and are the only ones reported in the efficacy section: cytogenic risk group, SCT history (allogeneic and autologous), and number of prior lines of therapy.

Protocol Changes

The major changes to the study protocol are summarized as follows:

• In amendment 1 (August 20, 2018; n = 2), additional safety information was collected.

• In amendment 2 (March 11, 2019; n = 21), the number of patients enrolled in phase Ib was expanded, the CRS and neurotoxicity management guidelines were updated, and the CRS and neurotoxicity grading systems were updated to align with new guidelines.

• In amendment 3 (July 30, 2019; n = 64), the study was transitioned into the phase II portion, the role of the IRC was added, and an assessment of medical resource utilization was added.

• In amendment 4 (March 20, 2020; n = 113), other neurotoxicities as a safety risk were added, and additional monitoring and risk-minimization measures for cilta-cel were implemented.

• A COVID-19 appendix (April 30, 2020; n = 113) was added to provide guidance on study conduct as a result of the COVID-19 pandemic.

Analysis Populations

The efficacy population in the CARTITUDE-1 trial included all patients who received cilta-cel at the recommended phase II dose level or, equivalently, all treated patients from phase Ib and phase II of the trial (n = 97). Efficacy outcomes were also estimated in the all-enrolled analysis set (n = 113), which included all patients enrolled (i.e., who underwent apheresis), regardless of whether they received cilta-cel. HRQoL outcomes were only assessed among treated patients in phase II (n = 68). The population used for safety outcome analyses was all treated patients from phase Ib and phase II (n = 97).

Results

There were 4 Clinical Study Reports provided in the sponsor’s submission:

• primary analysis report with a clinical data cut-off date of September 1, 2020⁹

• safety and efficacy update reports with a clinical data cut-off date of February 11, 2021¹⁰

• final analysis report with a clinical data cut-off date of January 11, 2022, which was used throughout this report unless otherwise specified.¹¹

Patient Disposition

Patient disposition for the US cohort of the CARTITUDE-1 study is presented in Table 9. Of the ||| patients screened, a total of 113 patients were enrolled and underwent apheresis. Of the 113 patients who underwent apheresis, 12 patients (11%) did not receive conditioning treatment due to death (8 patients; 7%), disease progression (2 patients; 2%), and withdrawal of consent (2 patients; 2%). Of the 101 patients who received conditioning treatment, 4 did not receive cilta-cel infusion because they refused (2 patients; 2%), experienced an AE (1 patient; 1%), or died (1 patient; 1%). A total of 97 patients received cilta-cel infusion, 29 (30%) in phase Ib and 68 in phase II (70%). As of the final data cut-off date of January 11, 2022, 66 patients (58%) were receiving ongoing follow-up.

Protocol Violations

At the time of the data cut-off date of February 11, 2021, out of all enrolled patients (n = 113), a total of || patients (|||%) had protocol deviations: || patients (|||%) received a disallowed concomitant treatment and || patient (|||%) required assessment of extramedullary plasmacytoma that was not performed according to schedule, as per protocol.

Table 9: Patient Dispositions^a

Cilta-cel = ciltacabtagene autoleucel; mITT = modified intention-to-treat.

^aIncludes all patients who received cilta-cel at the targeted recommended phase II dose level.

^bAs of the data cut-off on January 11, 2022.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Exposure to Study Treatments

For all treated patients, with regard to the conditioning regimen, the median cumulative dose of cyclophosphamide infusion was 897.8 mg/m² (range, 748 mg/m² to 946 mg/m²); for fludarabine infusion, it was 89.6 mg/m² (range, 45 mg/m² to 95 mg/m²). Bridging therapy to maintain disease stability was administered to 73 patients (75.3%) between apheresis and initiation of the conditioning regimen (PIs in 44 [45%] patients; IMiDs in 26 [27%] patients; and anti-CD38 antibodies in 15 [16%] patients). No patients who received bridging therapy achieved CR while on bridging therapy, and all were eligible to receive cilta-cel, as per the study protocol. The median time from apheresis to cilta-cel infusion was 47 days (range, 41 to 167 days). The median number of CAR-positive viable T cells infused was 54.3 × 10⁶ cells (range, 23.5 × 10⁶ to 93.1 × 10⁶ cells) with a median of 0.709 × 10⁶ cells/kg administered (range, 0.51 × 10⁶ to 0.95 × 10⁶ cells/kg). The median duration of cilta-cel infusion was 19 minutes (range, 5 to 71 minutes).

In the Japanese cohort, all patients received the conditioning regimen of 300 mg/m² cyclophosphamide and 30 mg/m² fludarabine daily for 3 days. Of all 9 patients, 8 patients received a cilta-cel infusion at the target dose of 0.75 × 10⁶ CAR-positive viable T cells/kg (range of 0.5 × 10⁶ to 1.0 × 10⁶ CAR-positive viable T cells/kg) and 1 patient received a below-target dose range of cilta-cel (0.41 × 10⁶ CAR-positive viable T cells/kg).⁴²

Dose Delays and Modifications

There were || patients (||||%) who experienced a delay in administration of cyclophosphamide or fludarabine conditioning due to an AE among || patients (||||%) and for other reasons among || patients (||||%), such as personal reasons, re-apheresis, rapid disease progression, and so forth. Cilta-cel infusion was delayed for || patient (|||%) to ||| days after lymphodepletion due to a positive rhinovirus test and interrupted for || patients (|||%) to flush the line. No infusions were delayed, interrupted, or aborted due to AEs.

Concomitant Medications

Prophylactic antivirals were prescribed for || patients (||%), most commonly acyclovir for || patients (||%). Prophylactic antibiotics were prescribed for || patients (||%), most commonly levofloxacin for || patients (||%). Prophylactic antifungals were prescribed for || patients (||%), most commonly fluconazole for || patients (||%).

All patients received concomitant medications during treatment. The most common medications were nucleosides and nucleotides (|| patients; ||||%), anilides (|| patients; ||||%), and interleukin inhibitors (|| patients; ||||%). All other concomitant medications are presented in Table 10.

Medications used to manage CRS were prescribed for 88 patients (91%) and included paracetamol (70 patients; 72.2%), tocilizumab (67 patients; 69.1%), cefepime (27 patients; 27.8%), sodium chloride solution (23 patients; 23.7%), dexamethasone (20 patients; 20.6%), and anakinra (18 patients; 18.6%).

Medications used to manage ICANS were prescribed for 16 patients (17%) and included dexamethasone (9 patients; 9%), tocilizumab (4 patients; 4%), and anakinra (3 patients; 3%).

Prior to cilta-cel infusion, transfusion of blood products was required for || patients (||||%) with || patients (||||%) who required packed red blood cells and || patients (||||%) who required platelets. Following cilta-cel infusion, transfusion of blood products was required for || patients (||||%); || patients (||||%) required packed red blood cells and || patients (||||%) required platelets, including for AEs in || patients (||||%). Growth factors were required for || patients (||||%), with filgrastim being the most commonly used in || patients (||||%).

Table 10: Other Concomitant Medications^a

Note: Concomitant medications by preferred anatomical therapeutic chemical class (> 50% of patients).

^aAs of data cut-off September 1, 2022.

Source: CARTITUDE-1 Clinical Study Report.⁹

Subsequent Antimyeloma Therapy

As of the January 11, 2022, data cut-off date, among all treated patients, a total of || patients (||||%) received subsequent antimyeloma therapy. There were || patients (|||%) who received radiotherapy and || patients (|||%) who received an autologous transplant. The majority of patients received dexamethasone (|| patients; ||||%). With regard to other neoplastic drugs, || patients (||||%) received selinexor, || patients (|||%) received carfilzomib, and ||| patients (|||%) received bortezomib. With regard to monoclonal antibodies, || patients (||||%) received belantamab mafodotin and |||| patients (|||%) received daratumumab. Other treatments received included cyclophosphamide for || patients (||||%), cisplatin for || patients (|||%), etoposide for || patients (|||%), and pomalidomide for || patients (|||%). There were || patients (|||%) re-treated with cilta-cel.

Efficacy

Only those efficacy outcomes and analyses of subgroups identified in the review protocol are reported subsequently. See Appendix 3 for detailed efficacy data.

Overall Survival

As of the January 11, 2022, data cut-off, after a median follow-up of 27.7 months (range, 1.5 to 40.4 months) the median OS was still NR. Among all treated patients, there were 30 deaths (31%), and the 24-month OS rate was ||||| |||| ||| |||| || |||||. Among all enrolled patients (N = 113), the 24-month OS rate was ||||| |||| ||| |||| || |||||.

A summary of OS for all treated patients and the corresponding Kaplan-Meier plot are shown in Table 11 and Figure 3, respectively.

In the Japanese cohort (N = 9), as of the clinical cut-off date of February 11, 2021, the median follow-up was 8.5 months and median OS was NR. The estimated 12-month OS rate was 100%.

Health-Related Quality of Life

Only patients in phase II of the CARTITUDE-1 study (n = 68) completed HRQoL assessments, and these were reported only in the primary Clinical Study Report at the September 1, 2020, data cut-off.⁹

Table 11: Overall Survival (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

CI = confidence interval; NE = not estimable; OS = overall survival.

^aEstimated using the Kaplan-Meier method.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Figure 3: Kaplan-Meier Plot for Overall Survival (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

Note: Figure was redacted at the sponsor’s request.

EORTC Quality of Life Questionnaire Core 30

The EORTC QLQ-C30 completion rate at baseline was 92.6% (63 patients) and declined to 83.1% (54 patients) and 65.0% (39 patients) at day 100 and day 156, respectively. The EORTC QLQ-C30 showed improvements over time compared with baseline, with decreases observed initially on day 7 for global health status (Figure 4), physical functional scale (Figure 5), and fatigue symptom scale (Figure 7). This initial worsening is consistent with the potential onset of cilta-cel AEs related to CRS.¹² There was consistent improvement in the pain symptom scale from baseline (Figure 6).

Meaningful improvement determined by a 1-point improvement on the PGIC assessment is described in Table 12. Data were available for 56 patients (82%) at day 28 and 52 patients (76%) at day 100. At day 100, 29 patients (53.7%) reported meaningful improvements in their global health status, 29 patients (57.7%) reported meaningful improvements in physical functioning, 39 patients (72.2%) reported meaningful improvement in pain symptoms, and 28 patients (53.8%) reported meaningful improvement in fatigue.

Table 12: Meaningful Change by Day (Anchor-Based) in EORTC QLQ-C30 Scales (All-Treated Analysis Set With September 1, 2020, Data Cut-Off)

cilta-cel = ciltacabtagene autoleucel; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; MID = minimally important difference; PGIC = Patient Global Impression of Change.

^aPercentages are based on the number of patients with nonmissing data before cilta-cel infusion and post cilta-cel infusion assessment.

^bFor anchor-based MID, PGIC is used as an anchor and MID is estimated as the mean change score for the patients who improved by 1 point on the PGIC (“A little better now”) from before cilta-cel infusion to each visit during the postinfusion period.

Source: CARTITUDE-1 Clinical Study Report.⁹

Figure 4: Mean (± SE) of EORTC QLQ-C30 Global Health Status Scale Over Time (All-Treated Analysis Set With September 1, 2020, Data Cut-Off)

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; SE = standard error.

Source: CARTITUDE-1 Clinical Study Report.⁹

Figure 5: Mean (± SE) of EORTC QLQ-C30 Physical Functional Scale Over Time (All-Treated Analysis Set With September 1, 2020, Data Cut-Off)

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; SE = standard error.

Source: CARTITUDE-1 Clinical Study Report.⁹

Figure 6: Mean (± SE) of EORTC QLQ-C30 Pain Symptom Scale Over Time (All-Treated Analysis Set With September 1, 2020, Data Cut-Off)

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; SE = standard error.

Source: CARTITUDE-1 Clinical Study Report.⁹

Figure 7: Mean (± SE) of EORTC QLQ-C30 Fatigue Symptom Scale Over Time (All-Treated Analysis Set With September 1, 2020, Data Cut-Off)

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; SE = standard error.

Source: CARTITUDE-1 Clinical Study Report⁹

EORTC Quality of Life Questionnaire Myeloma Module

The EORTC QLQ-MY20 completion rate at baseline was |||||% (|| patients) and declined to ||% (|| patients) at day 100. Clinically meaningful changes defined by literature-based MIDs of 10 points⁵⁷ are presented in Table 13.

At day 100, 43 patients (81.1%) reported meaningful improvements regarding feeling restless or agitated, 27 patients (50.9%) reported improvements regarding thinking about illness, 22 patients (41.5%) reported improvements regarding being worried about dying, and 17 patients (32.1%) reported improvements regarding being worried about their health in the future.

At day 100, 35 patients (66.0%) achieved meaningful improvement in the future perspective scale, and patients showed consistent improvement over time compared with baseline through day 380, as shown in Figure 8.

Table 13: Meaningful Change (Literature-Based)^a in EORTC QLQ-MY20 and Future Perspective Subscale (All-Treated Analysis Set With September 1, 2020, Data Cut-Off)

EORTC QLQ-MY20 = 20-item European Organisation for Research and Treatment of Cancer Myeloma Module.

^aPercentages are based on the number of patients with nonmissing data before cilta-cel infusion and infusion assessment.

^bFor literature-based minimally important difference, 10 points is used.⁵⁷

Source: CARTITUDE-1 Clinical Study Report.⁹

Five-Level EQ-5D

The EQ-5D-5L completion rate for the utility score at baseline was 92.6% (63 patients) and declined to 78% (53 patients) and 57.3% (39 patients) at day 100 and day 156, respectively. The completion rates for the EQ visual analogue scale were similar. There was an initial decrease in both utility score and visual analogue score at day 7 followed by continuous improvement through day 100, as shown in Figure 9 and Figure 10.

Figure 8: Mean (± SE) of EORTC QLQ-MY20 Future Perspective Scale Over Time (All-Treated Analysis Set With September 1, 2020, Data Cut-Off)

EORTC QLQ-MY20 = European Organisation for Research and Treatment of Cancer Myeloma Module; SE = standard error.

All the scores are presented in the range of 0 to 100 after linear transformation from raw scores (in the range of 1 to 4). A higher score for restlessness or agitation indicates worse health, whereas the higher score for the future perspectives, including worry about death and health in the future and thinking about illness, indicates better outcome.

Source: CARTITUDE-1 Clinical Study Report.⁹

Figure 9: Mean (± SE) of EQ-5D-5L Utility Score Over Time (All-Treated Analysis Set With September 1, 2020, Data Cut-Off)

Note: Figure was redacted at the sponsor’s request.

Figure 10: Mean (± SE) of EQ Visual Analogue Scale Over Time (All-Treated Analysis Set With September 1, 2020, Data Cut-Off)

Note: Figure was redacted at the sponsor’s request.

Patient Global Impression of Severity and Patient Global Impression of Change

The PGIS completion rate at baseline was 93% (63 patients) and declined to 78% (53 patients) and 57% (39 patients) at day 100 and day 156, respectively. Severity of pain was consistently reported as lower than baseline through day 352. PGIC was only completed post infusion from day 28, when the completion rate was 76% (52 patients), where 67% of patients reported improvement and the proportion increased to 74% by day 56, 86% by day 78, and 87% by day 100. PGIC completion rate at day 100 was 79% (54 patients).

Qualitative Interviews

Out of 27 patients who completed interview 1 before treatment, 23 patients completed interview 2 (on day 100 ± 30 days), and 24 patients completed interview 3 (on day 184 ± 30 days). Patient experiences from interviews 2 and 3 are reported in Table 14. In interview 1, pain and fatigue were the most commonly reported symptoms (85% and 74% respectively), considered to have the greatest impact on patients’ lives and identified as the symptoms patients would most like to see improved. After cilta-cel therapy, the proportion of patients in interviews 2 and 3 who reported pain (22% and 29% respectively) and fatigue (35% and 21% respectively) decreased.

Before treatment, the most common expectations of cilta-cel treatment reported by patients were remission (41%), extended life expectancy (15%), less treatment (11%), and cure (11%). In interviews 2 and 3, respectively, 78% and 92% of patients reported their expectations of cilta-cel were met or exceeded. In interviews 2 and 3, respectively, 52% and 71% of patients perceived their experience with cilta-cel as exclusively better than their previous treatment experiences.

Table 14: Patient Experiences After Cilta-Cel Treatment From the Qualitative Interviews

CAR = chimeric antigen receptor; cilta-cel = ciltacabtagene autoleucel; HRQoL = health-related quality of life.

Source: Cohen et al. (2022)⁴¹ and CARTITUDE-1 Clinical Study Report.⁹

Progression-Free Survival

As of the January 11, 2022, data cut-off, after a median follow-up of 27.7 months (range, 1.5 to 40.4 months), the median PFS based on IRC assessment was still NR. Among all treated patients, 43 patients (44%) experienced PFS events, and the 24-month PFS rate was ||||| |||| ||| |||| || |||||. Among all enrolled patients (N = 113), the 24-month PFS rate was ||||| |||| ||| |||| || ||||). A summary of PFS for the all-treated analysis set and the corresponding Kaplan-Meier plot are shown in Table 15 and Figure 11.

Table 15: PFS (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

CI = confidence interval; NE = not estimable; PFS = progression-free survival.

^aEstimated using the Kaplan-Meier method.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Figure 11: Kaplan-Meier Plot for PFS Based on IRC Assessment (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

Note: Figure was redacted at the sponsor’s request.

In the Japanese cohort, at the clinical cut-off date of February 11, 2021, the median follow-up was 8.5 months and the ORR was 100% (95% CI, 66.4 to 100). In the all-treated analysis set (n = 9), all DOR, PFS, and OS data were censored at the clinical cut-off; therefore, median DOR, PFS, and OS were NR. The 9-month PFS rate was 100% and the estimated 12-month OS rate was 100%.⁴²

Health Resource Utilization

Health resource utilization was reported supplementary to the assessment of safety, and findings were not included in the Clinical Study Reports. The sponsor clarified that since there were a lot of missing data points, a report was not developed.⁵⁸

Overall Response Rate and Very Good Partial Response or Better Rate

ORR as assessed by the IRC was the primary end point in the CARTITUDE-1 trial. In the final data analysis with a data cut-off of January 11, 2022, ORR in the all-treated analysis set (n = 97) was 97.9% (95% CI, 92.7 to 99.7; P < 0.0001) as presented in Table 16. Stringent CR was reached by 80 patients (82.5%; 95% CI, 73.4 to 89.4), VGPR by 12 patients (12.4%; 95% CI, 6.6 to 20.6), and PR by 3 patients (3.1%; 95% CI, 0.6 to 8.8). In the all-enrolled analysis set (n = 113), the ORR was 84.1% (95% CI, 76.0 to 90.3). Stringent CR was reached by 80 patients (70.8%; 95% CI, 61.5 to 79.0), VGPR by 12 patients (10.6%; 95% CI, 5.6 to 17.8), and PR by 3 patients (2.7%; 95% CI, 0.6 to 7.6).

Subgroup analysis results were available only for the February 11, 2021, data cut-off. Results were consistent with the primary analysis results across the patient subgroups of interest, as shown in Table 17.

As part of the sensitivity analyses, the ORR was consistent across all assessment methods. ORR by computerized algorithm was 93.8% (95% CI, 87.0 to 97.7) and by investigator assessment was 96.9% (95% CI, 91.2 to 99.4). VGPR or better as assessed by the IRC for the all-treated analysis set was 94.8% (95% CI, 88.4 to 98.3), as shown in Table 16. For all patients enrolled (n = 113), the VGPR or better rate as assessed by an IRC was 81.4% (95% CI, 73.0 to 88.1).

Among the 3 patients who were re-treated with cilta-cel, best response by IRC and by investigator assessment was PD for 1 patient and stable disease for 2 patients. Best response by computer algorithm was stable disease for all 3 patients. All 3 patients had experienced PD by clinical cut-off, with PD occurring on day 32, day 41, and day 57, respectively, after re-treatment by IRC assessment, computerized algorithm, and investigator assessment. In the Japanese cohort, at the clinical cut-off date of February 11, 2021, the ORR was 100% (95% CI, 66.4 to 100).⁴²

Duration of Response

At the January 11, 2022, data cut-off, median DOR by IRC assessment was NR. For the previous data cut-off on February 11, 2021, median DOR for all patients treated was |||| |||||| |||| ||| |||| |||||| || |||. Among all treated patients, the estimated probability that patients remained in response at 12 months was ||||| |||| ||| |||| || |||||; at 24 months it was ||||| |||| ||| |||| || ||||| and at 30 months it was ||||| |||| ||| |||| || |||||. A summary of DOR for all treated patients and the corresponding Kaplan-Meier plot are shown in Table 18 and Figure 12, respectively.

As part of the sensitivity analyses, median DOR as assessed by computerized algorithm was NR in the current analysis (95% CI, |||| |||||| || ||). The probability that patients remained in response after 24 months based on assessment by computerized algorithm was ||||| |||| ||| ||||| || ||||||.

At the clinical cut-off date of February 11, 2021, median DOR was NR in the Japanese cohort.⁴²

Table 16: Overall Best Response (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

CI = confidence interval; CR = complete response; NE = not estimable; PR = partial response; sCR = stringent complete response; VGPR = very good partial response.

^aResponse was assessed by an independent review committee based on International Myeloma Working Group consensus criteria (2016). Percentages are calculated with the number of patients in the all-treated analysis set as denominator. Two-sided 95% Clopper-Pearson exact 95% CIs are provided.

^bOne-sided P value from exact binomial test for the null hypothesis of overall response rate ≤ 30% is presented. P value was not adjusted for multiplicity.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Table 17: Subgroup Analyses of ORR Based on IRC Assessment (All-Treated Analysis Set With February 11, 2021, Data Cut-Off)

CI = confidence interval; IRC = independent review committee; ORR = overall response rate.

Source: CARTITUDE-1 Clinical Study Report.¹⁰

Table 18: DOR on IRC Assessment (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

CI = confidence interval; DOR = duration of response; IRC = independent review committee; NE = not estimable.

^aEstimated using the Kaplan-Meier method.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Figure 12: Kaplan-Meier Plot for DOR on IRC Assessment (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

Note: Figure was redacted at the sponsor’s request.

Minimal Residual Disease Negativity Rate

At the January 11, 2022, data cut-off, compared with the previous data cut-off of February 11, 2021, there was no change to the proportion of patients who achieved MRD negativity in their bone marrow at 10⁻⁵ sensitivity following treatment with cilta-cel (Table 19). Of the 61 treated patients (63%) with evaluable samples, 56 (91.8%; 95% CI, 81.9 to 97.3) achieved MRD negativity in bone marrow at 10⁻⁵ sensitivity following treatment with cilta-cel.

Table 19: MRD Negativity Rate at 10⁻⁵ in Bone Marrow for Patients With Evaluable Sample (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

CI = confidence interval; CR = complete response; MRD = minimal residual disease; VGPR = very good partial response.

^aOnly MRD assessments (10⁻⁵ testing threshold) within 3 months of achieving CR or stringent CR until death, progression, or subsequent therapy (exclusive) are considered.

^bOnly MRD assessments (10⁻⁵ testing threshold) within 3 months of achieving ≥ VGPR until death, progression, or subsequent therapy (exclusive) are considered.

^cOut of 61 patients with evaluable samples, i.e., patients with an identifiable clone at baseline and who had sufficient cells to be tested at a sensitivity level of 10⁻⁵ in a post-treatment sample.

Source: CARTITUDE-1 Clinical Study Report.^10,11

Time to Response

At the January 11, 2022, data cut-off, the responders in the all-treated population (n = 95) had a median time to first response (for patients with PR or better) of 0.95 months (range, 0.9 to 10.7), and the mean time to first response was 1.4 months (SD = 1.54). Median time to best response was 2.6 months (range, 0.9 to 17.8), and median time to CR or better was 2.9 months (range, 0.9 to 17.8). These results represent an improvement in the response of 2 patients compared with the previous data cut-off of February 11, 2021. Findings are presented in Table 20.

As part of the sensitivity analyses, similar findings were observed when TTR was assessed by computer algorithm in the all-treated analysis set.

Table 20: TTR Based on IRC (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

CR = complete response; IRC = independent review committee; PR = partial response; SD = standard deviation; TTR = time to response.

^aResponse of PR or better.

Source: CARTITUDE-1 Clinical Study Report.¹¹

Harms

Only those harms identified in the review protocol are reported subsequently. Refer to Table 21 for detailed harms data from the January 11, 2022, data cut-off. Safety was analyzed in all treated patients.

Adverse Events

All patients (n = 97) experienced at least 1 TEAE, with || patients (||%) experiencing at least 1 grade 4 TEAE. The most common TEAEs were neutropenia (96%), CRS (95%), anemia (81%), and thrombocytopenia (80%).

At least 1 TEAE with a maximum severity of at least grade 3 or higher occurred in all patients. The most common grade 3 or higher TEAEs were neutropenia (95%), anemia (68%), and leukopenia (61%).

Serious Adverse Events

A total of || patients (||%) experienced at least || SAE, with || patients (||%) experiencing a grade 3 or 4 SAE and || patients (||%) experiencing a grade 5 SAE. The most common SAEs were CRS (||%), pneumonia (||%), sepsis (||%), and ICANS (||%).

Withdrawal Due to Adverse Events

There was || patient who withdrew due to an AE after receiving conditioning treatment but before receiving cilta-cel infusion.

Mortality

Between apheresis and the start of the conditioning treatment, 8 patients out of 113 (7%) died. Overall, 101 patients received the conditioning regimen, and 97 patients went on to receive cilta-cel. Out of the 4 patients who received the conditioning regimen but did not receive cilta-cel, 1 patient died. Of all treated patients, a total of 30 patients (30.9%) died during the study: 16 due to AEs and 14 due to disease progression. ||||||| || ||| || total deaths occurred after the start of subsequent therapy, including || || || deaths due to PD and 4 of the 16 deaths due to AEs. No patients died within 30 days of the initial cilta-cel infusion, and 2 patients (2.1%) died within 100 days. Only 6 patients (6.2%) had a TEAE leading to death that was considered to be related to cilta-cel; the remaining 10 deaths were not considered to be related to cilta-cel by the study investigators.

Notable Harms

The notable harms identified in the CADTH protocol included CRS, neurologic toxicities, cytopenia, and secondary hypogammaglobulinemia.

Cytokine Release Syndrome

There was no change in the findings related to CRS between the initial analysis at the September 1, 2020, data cut-off and the final analysis at the January 11, 2022, data cut-off. A total of 92 patients (95%) experienced CRS with 4 patients (4%) experiencing a grade 3 or 4 CRS and 1 patient (1%) experiencing grade 5 CRS complicated by secondary hemophagocytic lymphohistiocytosis. The median time from cilta-cel infusion to CRS onset was 7 days (range, 1 to 12), with 82 patients (90%) experiencing onset of CRS after the third day from cilta-cel infusion. The median duration of CRS was 4 days (range, 1 to 14), with 81 patients (88%) experiencing CRS for 7 days or fewer. This is excluding the patient who experienced grade 5 CRS who experienced it for 97 days.

Other Neurologic Toxicities

A total of 21 patients (22%) experienced CAR T-cell neurotoxicity, including 10 patients (10%) at grade 3 or 4. A total of 16 patients (17%) experienced ICANS, including 2 patients (2%) at grade 3 or 4. Other neurotoxicity was reported in 13 patients (13%), including 9 patients (9%) at grade 3 or 4.

Cytopenia

No analysis for cytopenia was performed for the January 11, 2022, data cut-off. As of the February 11, 2021, data cut-off, 96 patients (99%) had experienced at least 1 grade 3 or 4 cytopenic AE. The majority of these AEs were transient, with recovery to grade 2 or better within the first 60 days following cilta-cel infusion, except for 25 (out of 60) patients with thrombocytopenia, 10 (out of 95) patients with neutropenia, and 8 (out of 96) patients with lymphopenia.

Hypogammaglobulinemia

A total of 12 patients (12.4%) experienced hypogammaglobulinemia, including 2 patients (2.1%) with grade 3 or 4 events.

Table 21: Summary of Harms (All-Treated Analysis Set With January 11, 2022, Data Cut-Off)

AE = adverse event; ALT = alanine aminotransferase; AST = aspartate aminotransferase; CRS = cytokine release syndrome; HLH = hemophagocytic lymphohistiocytosis; ICANS = immune effector cell–associated neurotoxicity syndrome; SAE = serious adverse event; TEAE = treatment-emergent adverse event.

^aFrequency > 20%.

^bFrequency > 5%.

Source: CARTITUDE-1 Clinical Study Report.^9-11

In the Japanese cohort, at the clinical cut-off date of February 11, 2021, all 9 patients experienced at least 1 AE, and 8 (88.9%) experienced at least 1 grade 3 or 4 AE. Grade 3 or 4 cytopenias were reported in 8 patients (88.9%). Grade 1 or 2 CRS was reported in 8 patients (88.9%) and SAEs were reported in 1 patient (neutropenia, thrombocytopenia, fatigue, and CRS). No patient experienced CAR T-cell neurotoxicity (including ICANS or other neurotoxicity). No deaths were reported during the study.⁴²

Critical Appraisal

Internal Validity

CARTITUDE-1 was an open-label, single-arm phase Ib and II study in the US (16 centres) and Japan (4 centres).

The primary limitation of CARTITUDE-1 was the absence of a comparator group against which the benefits and harms of cilta-cel could be compared. Single-arm trials are generally not considered as confirmatory for efficacy and are subject to several limitations that complicate their interpretation; for example, it is not possible to distinguish between the effect of cilta-cel and a placebo effect or natural history of the disease in the absence of a frame of reference for comparison.¹³ ORR was tested against a predetermined hypothesis based on the sponsor’s assertion that at the time of the protocol for available therapies to treat r/rMM (including daratumumab), the reported ORR was 30%. However, for ORR, there was no adjustment for multiplicity across the various analyses of the outcome (i.e., the various data cut-offs), so there is an increased risk of type I error. Results for the other outcomes (e.g., DOR, OS, PFS) were descriptive only. This trial does not provide any information for the effects of cilta-cel relative to the available comparator treatments used in Canada. According to the FDA assessment of the CARTITUDE-1 trial, end points such as OS and PFS are uninterpretable due to the lack of a comparator arm and were neither reviewed nor included in the label. The FDA assessment noted that a single-arm study design was chosen for CARTITUDE-1, given the perceived lack of equipoise to randomize patients between cilta-cel and any of the currently available therapy options in this target population.¹⁴ There were a limited number of patients included in the all-treated analysis set (n = 97) and all-randomized analysis set (n = 113) of CARTITUDE-1. The magnitude of the treatment effect estimates observed in a small study sample may not be replicable in a larger study sample or generalizable to the target population in RWCP.

ORR was the primary end point and CARTITUDE-1 achieved the predetermined threshold for a positive outcome (lower limit of the 95% CI for ORR > 30%). It cannot be firmly concluded to what extent the improvements in ORR observed in patients would translate into OS benefits. ORR is accepted by the FDA as directly attributable to drug effect in “single-arm trials conducted in patients with refractory tumours where no available therapy exists.”¹⁵ In this trial, OS was not considered a primary or key secondary end point. However, the end point of OS is often considered important for oncology trials and was considered an important outcome by the clinical experts and patients. At the time of the final analysis, median OS was NR.

The interpretation of efficacy in the all-treated analyses is at risk of bias in favour of cilta-cel. The population excluded patients (n = 16; 14%) who were enrolled and underwent apheresis but were subsequently unable to receive cilta-cel because they died or their disease progressed, or due to AEs or other reasons (e.g., patient choice). This population is not reflective of expected clinical practice and overrepresents the healthiest patients. Analyses based on the all-enrolled population are considered most appropriate for estimating the effect of assignment to treatment. As expected, when both were presented, the results of analyses of the all-treated population were more favourable compared with those of the all-enrolled population. Out of the 113 patients who underwent apheresis, 12 patients did not receive the conditioning treatment, including 8 patients who died. The clinical experts noted that, although this is common in r/rMM, the proportion of deaths is unusual, given how relatively healthy the trial population was.

Only 3 patients were re-treated with cilta-cel; thus, there is not enough information to draw conclusions regarding re-treatment.

A subgroup analysis was not specified in the study protocol a priori, and while results for ORR were consistent with the primary analysis results across patient subgroups of interest, the analysis was limited by the small sample size of some groups, such as patients who received prior allogeneic SCT.

The trial was open label, which can result in a risk of bias in the measurement of the outcomes, particularly for subjective outcomes such as ORR, PFS, HRQoL, and subjective harms. Objective measurements of outcomes, such as OS, would not be reported with measurement bias due to the open-label design of the trial. To reduce the risk of directional bias in reported outcomes, response outcomes were assessed by the investigators, an IRC, and a validated computer algorithm. The results were consistent across the various assessment methods; any bias would likely be in favour or cilta-cel. Outcomes like HRQoL and subjective harms, which were self-reported by patients, are at risk of optimism bias, although the extent and direction of bias are uncertain.

With regard to the MRD negativity rate, there was a large amount of missing data, as only 61 patients had evaluable samples at the final data cut-off, limiting the interpretation of these findings.

In addition, although the EORTC QLQ-C30 and EQ-5D-5L are comprehensive and widely used instruments designed to measure HRQoL in the general population as well as in patient groups with diverse chronic diseases, neither are currently validated for patients with r/rMM. Further, results for all HRQoL measures were at risk of bias due to missing data, particularly at longer follow-up (e.g., data were missing for 44% of all treated patients for the EORTC QLQ-C30 at day 100 and for 60% of patients by day 156). In addition to a diminishing sample size, the patients reporting HRQoL outcomes later in the study are expected to be the healthiest among the population. Given that the trial was nonrandomized, the impact of cilta-cel on PROs in relation to other therapies is unknown.

Findings from the Japanese cohort of the CARTITUDE-1 trial were consistent with results from the main cohort; however, it only included 9 patients, which limits interpretation of cohort findings.

External Validity

According to the clinical experts CADTH consulted for this review, the CARTITUDE-1 study population is considered reflective of the requested reimbursement population. The following considerations are of importance regarding the external validity of the study.

Population: According to the clinical experts consulted by CADTH for this review, the demographic and disease characteristics of the CARTITUDE-1 study population⁹ were generally reflective of the population of patients in Canada with r/rMM. The mean age of patients in the trial was 62 years, which is younger than the mean age at the time of diagnosis of 70 years in Canada.¹⁶ If there was no access to less toxic bispecific therapies, clinical experts would have expected a slightly larger proportion of patients to be older than 75 years old (15% versus the trial’s 8%). However, clinicians can currently access these bispecific therapies through special access programs and would prioritize the older patient population for these therapies, making the trial’s age proportions reflective of the current population demographics. All patients met the inclusion criteria of ECOG 0 or 1 during screening, but 4 patients (4%) deteriorated to ECOG 2 on or before cilta-cel infusion. The clinical experts considered it common for patients to deteriorate after apheresis. The clinical experts also mentioned they would have expected potentially more patients with extramedullary plasmacytomas present past third line of therapy, as this would denote worse disease, but that the 13% proportion in the trial is acceptable. They would have also expected a slightly higher proportion of patients to be of high cytogenetic risk (30% versus the trial’s 24%).

The clinical experts consulted by CADTH mentioned that the creatinine clearance required for inclusion in the trial (≥ 40 mL/min/1.73 m²) is higher than the level used to indicate poor kidney function in clinical practice (≥ 30 mL/min/1.73 m²). They also mentioned that including patients with ECOG ≤ 2 (rather than the trial’s criteria of < 2) would better align with clinical practice needs. One of the trial exclusion criteria of CARTITUDE-1 was any prior therapy that is targeted to BCMA, which the clinical experts found concerning as some clinicians would likely be giving their patients belantamab mafodotin, available through compassionate access, in their management of MM. The clinical experts noted that these patients may still respond well to CAR T-cell therapy¹⁷ and should not be excluded from cilta-cel eligibility.

With regard to prior therapy used by patients in the trial, the clinical experts noted that potentially all patients would have disease that is refractory to daratumumab within the first 3 lines of therapy (compared with 97% of patients in the trial). They also noted that selinexor is currently used as a bridging therapy in the US, but no patients had used selinexor in the trial, as selinexor (combined with dexamethasone and bortezomib) was not approved during the time of the trial.¹⁸ Finally, they noted that it was surprising that 19% of patients had used anakinra for treating CRS since it is rarely used in Canadian practice; however, they also noted this may have been due to a global shortage of tocilizumab.

End points: The clinical experts consulted by CADTH for this review did not have any major concerns with the end points used in the CARTITUDE-1 trial. They considered OS, HRQoL, and PFS as the most important outcomes, which were secondary end points in the trial. It was noted that MRD negativity rate is not routinely used in clinical practice. All outcomes in the protocol were important to patients, clinicians, and drug plans; although they were evaluated, this trial provides no information about the efficacy and harms of cilta-cel relative to treatments that would otherwise be used in this patient population in clinical practice.

Setting: This study was a multicentre trial in the US. The clinical experts indicated that there are few concerns to generalizing the findings from the pivotal study within the Canadian clinical setting.

Indirect Evidence

A focused literature search for ITCs dealing with MM was run in MEDLINE All (1946-) on October 24, 2022. No limits were applied to the search. The literature search for ITCs identified 113 articles; however, no relevant ITCs were identified.

In total, 3 relevant articles were identified within the search for ITCs,^22-24 which are summarized in the Other Relevant Evidence Section. These studies were not included by the sponsor for consideration as they did not reflect Canadian clinical practice; however, the CADTH review team considered them relevant to the current review.

Other Relevant Evidence

Long-Term Data From the LEGEND-2 Study

The sponsor provided long-term (2 year and 4 year) data from LEGEND-2, a phase I, single-arm, open-label study conducted in 4 registered sites in China in patients with r/rMM who had received at least 3 prior lines of treatment. These data were presented in a Clinical Study Report (data cut-off, November 26, 2019)¹⁹ and a published manuscript (data cut-off, May 25, 2021).⁵⁹ LEGEND-2 provided a longer-term safety and efficacy follow-up than the CARTITUDE-1 trial with an additional 20.1-month median follow-up; median follow-up time was 47.8 months in LEGEND-2 (May 25, 2021, data cut-off date) and 27.7 months in the CARTITUDE-1 trial (January 11, 2022, data cut-off date).

The cilta-cel CAR T-cell drug product studied in CARTITUDE-1 (produced in the US) and the LCAR-B38M CAR T-cell drug product studied in the LEGEND-2 study (produced in China) express an identical CAR protein targeting BCMA but were produced using different manufacturing and scale-up processes.¹⁹

Methods

LEGEND-2 is a phase I, single-arm, open-label, multicentre study with 74 patients who were enrolled and received at least 1 injection of the LCAR-B38M CAR T-cell drug product. An overview of the LEGEND-2 trial design is presented in Figure 13 and is similar to the study design for CARTITUDE-1 with some exceptions. Unlike CARTITUDE-1, lymphodepletion was performed using cyclophosphamide 300 mg/m² or cyclophosphamide 250 mg/m² plus fludarabine 25 mg/m².

Also, unlike cilta-cel, the LCAR-B38M CAR T-cell dose was split into 3 infusions administered over 7 days, with the number of CAR T cells administered increasing with each infusion. The median total number of T cells infused was ||||||||| ||||||| || || ||||||, and the body weight–adjusted median total number of viable T cells administered was ||||||||||| ||||||| |||| || |||||||||||.

AEs were graded using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Similar to CARTITUDE-1, efficacy was assessed by the criteria of response according to IMWG consensus recommendations, including ORR, DOR for responders, OS, and PFS. With regard to statistical analysis, 2-sided 95% exact CIs based on binomial distribution were calculated for each response category. Median DOR, PFS, and OS and corresponding 95% CIs were calculated using Kaplan-Meier methods.

Populations

Baseline patient characteristics of all treated patients are presented in Table 22. The median age of patients was 54.5 years (range, 27 to 74), with a higher proportion of men (61%) and with a median time since initial MM diagnosis of 4 years (range, 1 to 9). Inclusion criteria for refractory disease were defined as being resistant to at least 3 prior regimens (which must include bortezomib or thalidomide) or as other circumstances identified by clinical doctors. Patients in the trial received a median of 3 prior lines of MM therapy (range, 1 to 9) including 54 patients (73%) who received a PI therapy, 65 patients (88%) who received an IMiD drug, and 48 patients (65%) who received both PI and IMiD drugs. Patients were not required to have received an anti-CD38 antibody in prior therapy and only 2 patients (2.7%) had received prior anti-CD38 antibody therapy.

Patients with a history of allogeneic SCT were excluded from the trial, and 18 patients (24%) had a history of prior autologous SCT.

Figure 13: Schematic Overview of the LEGEND-2 Study Flow Chart

CAR = chimeric antigen receptor; ECOG = Eastern Cooperative Oncology Group.

Note: For patients aged > 70 years and ECOG = 1, cyclophosphamide may be reduced to 250 mg/m² per investigator’s judgment with approval from the sponsor. Fludarabine dose may be reduced to 25 mg/m² if the patient’s creatinine clearance is 40 mL/min/1.73 m² to 70 mL/min/1.73 m², or per the investigator’s judgment, with approval from the sponsor.

Table 22: Baseline Patient Characteristics in LEGEND-2 (All-Treated Analysis Set)

ECOG = Eastern Cooperative Oncology Group; IMiD = immunomodulatory drug; ISS = International Staging System; MM = multiple myeloma; PI = proteasome inhibitor; SD = standard deviation.

Patient Disposition

In the LEGEND-2 trial, 86 patients were screened for eligibility, and 74 were enrolled and received at least 1 infusion of LCAR-B38M CAR T cells. By the November 26, 2019, data cut-off, 32 patients had died and 42 patients remained in follow-up. By the May 25, 2021, data cut-off (median follow-up, 47.8 months; range, 0.4 to 60.7), 2 more patients had died, 1 was lost to follow-up, and 39 patients remained in the study.⁵⁹

Exposure to Study Treatments

All 74 patients received lymphodepletion chemotherapy with cyclophosphamide, and 8 patients (10.8%) also received fludarabine in their lymphodepletion regimen. The CAR T-cell treatment was divided into a 3-dose regimen administered over 7 days. Of the 74 patients enrolled, || (||%) received all 3 infusions. |||||||| patients did not follow the 3-dose regimen, including ||| patients (||||%) who received a single infusion on day 1.

Efficacy

In the 2-year analysis of LEGEND-2 with the November 26, 2019, data cut-off, median follow-up time from dosing to cut-off was 30.4 months (range, 0.4 to 42.8). In the 4-year analysis with the May 25, 2021, data cut-off, median follow-up time from dosing to cut-off was 47.8 months (range, 0.4 to 60.7). Median OS was not yet reached in both analyses, and on the November 26, 2019, cut-off the 24-month OS rate was ||||% (95% CI, |||| || ||||) for all patients. At the May 25, 2021, data cut-off, the estimated 24-month OS rate was 63.4% (95% CI not reported). The Kaplan-Meier estimated median PFS was 18 months (95% CI, 10.6 to 25.6) for all patients treated. HRQoL, MRD negativity rate, TTR, and health care utilization were not assessed in this study.

Findings on ORR and DOR are presented in Figure 14. At the May 25, 2021, data cut-off ORR by sponsor assessment was 87.8% (95% CI, 78.2 to 94.3), with 54 patients (73%) achieving CR, 6 patients (8%) achieving PR, and 5 patients (7%) achieving VGPR. Median DOR was 23.26 months (95% CI, 13.04 to 32.69). The median time to initial response using Kaplan-Meier was 1.0 months (range, 0.4 to 3.5) and the median time to best response was 3.3 months (range, 0.4 to 28.5).

Harms

A summary of harms in the LEGEND-2 study is presented in Table 23. All patients experienced at least 1 TEAE within 100 days post infusion, with AEs of grade 3 or greater in 45 patients (61%). The most common AEs were pyrexia in 68 patients (92%) and CRS in 68 patients (92%), and only 7 patients (10%) experienced CRS of grade 3 or greater. Of the 74 patients in the analysis, 34 deaths (46%) were reported as of the May 25, 2021, data cut-off, including 28 deaths (38%) due to disease progression.

Critical Appraisal

Internal Validity

LEGEND-2 was an open-label, single-arm phase I study of LCAR-B38M, a CAR product molecularly identical to cilta-cel, that was conducted in China (4 centres). The inclusion criteria in LEGEND-2 did not require prior therapy with an anti-CD38 antibody and excluded patients with a history of allogeneic SCT.

The primary limitation of LEGEND-2 was the absence of a comparator group against which the benefits and harms of the LCAR-B38M CAR T-cell drug product could be compared. As such, the estimation of the effects of treatment relative to current standards of practice is not possible. Further, single-arm trials are generally not considered as confirmatory for efficacy and do not allow for causal conclusions. The study protocol mentioned the use of a computerized algorithm and an IRC for disease status evaluation. However, findings are reported based on sponsor assessment (based on uniform medical reviews of source hospital medical records); thus, there is a risk of bias in the measurement of the outcome due to the open-label design, likely in favour of LCAR-B38M. Due to the open-label design of the trial, the reported response outcome measures (i.e., ORR, DOR, PFS) and subjective harms are at risk of bias due to the measurement of these outcomes (since the patients and investigators who measured or reported the outcomes were aware of the treatment received). For response outcomes, the bias would likely be in favour of the LCAR-B38M CAR T-cell drug product; known, subjective harms may have been overestimated. As per CARTITUDE-1, end points such as OS and PFS are uninterpretable at the population level due to the lack of a comparator arm.

With regard to the study treatment, there were 8 patients (11%) who received fludarabine in addition to the protocol-specified lymphodepletion chemotherapy with cyclophosphamide monotherapy. The sponsors reported no major differences in findings between both groups of patients. In addition, there were 18 patients (24%) who did not receive the protocol-specified 3-dose standard regimen: 9 patients (11%) in 1 site received a single infusion and 9 patients (11%) received 2, 4, or 7 infusions. The reasons for this deviation were not specified. As such, the estimated rates of ORR and OS describe a heterogenous treatment regimen and are difficult to compare with the CARTITUDE-1 study.

External Validity

The clinical experts consulted by CADTH for this review noted that the baseline characteristics of the LEGEND-2 study population would be closer to patients who are in the second line of therapy rather than the fourth line and beyond. No patients were older than 75 years of age, which is not reflective of Canadian clinical practice. The experts noted there was limited use of daratumumab in previous lines of therapy. Moreover, because exposure to an anti-CD38 antibody was not required, this study population is less relevant to this reimbursement review. The study took place in China, with no participating Canadian sites. For these reasons, the generalizability of the results to current Canadian clinical practice may be limited. The cilta-cel CAR T-cell drug product studied in CARTITUDE-1 (produced in the US) and the LCAR-B38M CAR T-cell drug product studied in the LEGEND-2 study (produced in China) express an identical CAR protein targeting BCMA but were produced using different manufacturing and scale-up processes.

HRQoL, MRD negativity rate, TTR, and health care utilization were not assessed as end points in this phase I study.

Comparative Observational Evidence for Cilta-Cel Versus RWCP

Due to the lack of evidence from RCTs comparing cilta-cel with relevant comparator treatments, the sponsor submitted 2 reports consisting of 3 observational studies comparing cilta-cel with relevant treatment comparators using IPD from CARTITUDE-1 and the US Flatiron longitudinal database, long-term follow-up of 3 daratumumab clinical trials, and the LocoMMotion prospective cohort study. As the treatment assignments across studies were not randomized, propensity score weighting was used to adjust for potential confounding variables.^20,21

An additional 3 relevant studies were identified during screening of the search results for ITCs: 2 observational studies that used propensity score weighting to adjust for confounding, and 1 meta-analysis of observational evidence.^22-24 Although the sponsor remarked in its submission that these studies were not relevant to the review, the CADTH review team included them because they estimate the effects of cilta-cel in the requested reimbursement population relative to the comparators defined in the predetermined protocol.

The objective of this section is to summarize and critically appraise the methods and findings of the sponsor-submitted observational studies as well as the evidence identified in the published literature.

Table 23: Summary of Harms in LEGEND-2 (All-Treated Analysis Set With May 25, 2021, Data Cut-Off)

AST = aspartate transaminase; ALT = alanine aminotransferase; TEAE = treatment-emergent adverse event.

^aOne patient died 13 days post treatment due to grade 5 cytokine release syndrome.

Source: Zhao et al. (2022).⁵⁹ Reprinted in accordance with Attribution 4.0 International (CC BY 4.0) Creative Commons — Attribution 4.0 International — CC BY 4.0.

Description of the Studies

Sponsor-Submitted Observational Studies

The sponsor-submitted evidence consisted of 2 observational studies to compare cilta-cel with relevant treatment comparators in RWCP.^20,21

One sponsor-submitted report was an observational study comparing the effectiveness of cilta-cel (from CARTITUDE-1) versus RWCP as observed in the LocoMMotion prospective cohort study using propensity score weighting and regression modelling to adjust for confounding between the treatment and outcomes of clinical response (ORR, VGPR, CR or better, MRD), PFS, TTNT, OS, PROs, safety, and resource utilization.²⁰

The other sponsor-submitted report included 2 observational studies to compare cilta-cel with real-world treatments for patients with triple class–exposed r/rMM. In both studies, propensity score weighting was used to adjust for potential confounding variables²¹:

• 1 analysis comparing the IPD from CARTITUDE-1 with the IPD from a cohort of patients in the long term follow-up of 3 global r/rMM clinical trials of daratumumab (POLLUX, CASTOR, and EQUULEUS), hereinafter referred to as the daratumumab trial cohort.

• 1 analysis comparing the IPD from CARTITUDE-1 with a CARTITUDE-1–like cohort of real-world patients receiving current treatment paradigms using data from the Flatiron Health database (hereinafter referred to as the Flatiron cohort).

Outcomes included in the second report included clinical response outcomes (ORR, CR or better), PFS, TTNT, and OS.

Figure 14: LEGEND-2 4-Year Data on ORR and DOR (All-Treated Analysis Set With May 25, 2021, Data Cut-Off)

CR = complete response; CRS = cytokine release syndrome; MRD = minimal residual disease; NE = not evaluable; ORR = overall response rate; PD = progressive disease; PR = partial response; SD = stable disease; TLS = tumour lysis syndrome; VGPR = very good partial response.

Note: (A) Top portion of the figure presents best response in all patients. (B) Bottom portion of the figure presents duration of response in patients with a response.

^a ORR includes patients with ≥ PR.

^b Eight-colour flow cytometry with cell count up to 500,000 cells.

^c One patient died of pulmonary embolism or acute coronary syndrome before evaluation, 1 patient died on day 13 due to CRS and TLS, and 1 patient received chemotherapy before first assessment and was censored.

Source: Zhao et al. (2022).⁵⁹ Reprinted in accordance with Attribution 4.0 International (CC BY 4.0) Creative Commons — Attribution 4.0 International — CC BY 4.0.

Observational Evidence Identified in the Literature

In total, 3 published articles met the inclusion criteria predefined by CADTH for this review:

• An observational study using IPD from the CARTITUDE-1 trial and the MAMMOTH cohort to evaluate the efficacy of cilta-cel versus real-world therapies for the outcomes of ORR, PFS, and OS. Propensity score matching was used to balance observed confounding variables.²²

• An observational study evaluating OS and TTNT for patients in CARTITUDE-1 versus patients receiving real-world treatments registered in the Therapie Monitor database in Germany maintained by the OIS.²³ Propensity score weighting was used to adjust for potential confounding variables.

• A meta-analysis of observational studies evaluating cilta-cel versus physicians’ choice of treatment.²⁴ The studies included in the meta-analysis consisted of all studies summarized here and included publications for the comparison of CARTITUDE-1 to LocoMMotion, the Flatiron cohort, the daratumumab trial cohort, the MAMMOTH cohort, and the OIS database.

Sponsor-Submitted Observational Studies

Methods for Sponsor-Submitted Observational Study of CARTITUDE-1 Versus LocoMMotion²⁰

Objective: The objective of the study was to evaluate the comparative efficacy of cilta-cel versus RWCP, as defined by the LocoMMotion prospective cohort study, within a population similar to the cilta-cel trial.²⁰

Study selection methods: IPD from 2 sources were included in the sponsor’s study: CARTITUDE-1 and LocoMMotion. Features of the data sources included in the study are summarized in Table 24. Given that CARTITUDE-1 is a single-arm trial, an external control arm was used to assess the efficacy of cilta-cel versus available treatments for the management of patients with triple class–exposed MM who have received at least 3 prior regimens, including a PI, an IMiD, and an anti-CD38 monoclonal antibody. The LocoMMotion (NCT04035226) study was a prospective, noninterventional, multinational study that was designed as an external control arm for the CARTITUDE-1 study. Eligibility criteria for the LocoMMotion study and outcome definitions were aligned with the CARTITUDE-1 trial to recruit similar patient populations and to enable comparisons between the study populations. LocoMMotion documented RWCP patterns in patients whose disease progressed following treatment with PIs, IMiDs, and anti-CD38 monoclonal antibodies. In total, 248 patients were included across 76 sites in Europe and the US.

Comparisons of cilta-cel from the CARTITUDE-1 study (January 2022, clinical cut-off) with the RWCP of the LocoMMotion study (May 2021, clinical cut-off) were conducted using IPD from both studies within the described ITT population. In CARTITUDE-1, the ITT population included the patients who underwent apheresis (N = 113), which was the index date. For the comparator group from the LocoMMotion study, the ITT population included patients who were enrolled in the study (N = 248), with an index date defined as date of treatment initiation. Secondary analyses using the mITT populations were also conducted, with the mITT for CARTITUDE-1 consisting of patients who received cilta-cel at the targeted recommended phase II dose (N = 97), with the infusion date as the index date. The mITT for LocoMMotion consisted of a subset of patients from the ITT population who were alive and had not progressed within the number of days equal to the mean duration from apheresis to cilta-cel infusion, as observed in CARTITUDE-1, after the start of treatment (N = 170). The index date was defined as the date of treatment initiation plus the mean duration from apheresis to cilta-cel infusion as observed in CARTITUDE-1 (mean of 52 days).

The outcomes compared between CARTITUDE-1 and LocoMMotion that were included in the sponsor report consisted of the following:

• Clinical response outcomes, including:

  • ORR, defined as the proportion of patients who achieved a PR or better according to the IMWG criteria; response after the start of subsequent therapy or re-treatment with cilta-cel was not considered.

  • VGPR or better rate, defined as the proportion of patients who achieve an sCR, CR, or VGPR according to the IMWG criteria; response after the start of subsequent therapy or re-treatment with cilta-cel was not considered.

  • CR or better rate, defined as the proportion of patients who achieve a sCR or a CR according to the IMWG criteria; response after the start of subsequent therapy or re-treatment with cilta-cel was not considered.

  • MRD negativity, defined as the proportion of patients who had negative MRD by bone marrow aspirate at any time point after the initial dose of the treatment regimen initiated at baseline and before disease progression or starting subsequent therapy or re-treatment with cilta-cel. Minimal residual disease positive patients included those for whom all tested samples were found to be MRD -positive or ambiguous. Patients with missing or unevaluable MRD status were considered as MRD -positive. MRD negativity was assessed at 10⁻⁴, 10⁻⁵, and 10⁻⁶.

• PFS, defined as the time from the index date to the date of the first documented disease progression, as defined in the IMWG criteria, or death due to any cause, whichever occurred first. For patients who had not progressed and were alive, data were censored at the last disease evaluation before the start of any subsequent antimyeloma therapy or the re-treatment of cilta-cel.

• OS, defined as the time from the index date to the date of the patient’s death. If the patient was alive or the vital status was unknown, then the patient’s data were censored at the date the patient was last known to be alive. Patients who died after consent withdrawal were considered as having an OS event.

• PRO end points, including the EQ visual analogue scale and the EORTC QLQ-C30 Global Health Status, collected for CARTITUDE-1 at screening, days 7, 28, 56, 78, and 100 after infusion, and every 28 days thereafter. For LocoMMotion, PRO end points were collected at screening, days 1 and 7 of cycle 1, and at day 1 of every subsequent cycle. The index date for CARTITUDE-1 was the date of the infusion. As baseline PROs were assessed at screening only, screening values were used to impute values at infusion. For LocoMMotion, the index date was day 1. No adjusted analyses were conducted on the PRO end points; thus, the comparisons are not included in this report.

• Safety end points, including any TEAEs, TEAEs of special interest (CRS, tumour lysis syndrome, neurotoxicity, and second primary malignancy), TEAEs leading to death, TEAEs by System Organ Class and Preferred Term, serious TEAEs, and severe TEAEs (Common Terminology Criteria for Adverse Events grade ≥ 3). No adjusted analyses were conducted on the safety outcomes; thus, the comparisons are not included in this report.

Other outcomes including other PROs, medical resource use, TTNT, clinical benefit rate, DOR, and TTR were planned to be analyzed, but were not evaluated in the report submitted by the sponsor.

Analysis methods: Outcome assessments were performed by the investigator and by an IRC in both the CARTITUDE-1 and LocoMMotion studies. The results presented in the sponsor-submitted report are based on the IRC assessments.

Potential prognostic variables in patients with triple class–exposed r/rMM were identified a priori through a review of the published literature and in consultation with clinical expert input. Potentially important prognostic factors consisted of the following: age, sex, race, body weight, baseline ISS disease stage, MM type, years since initial MM diagnosis, creatinine clearance, selected hematology laboratory analytes (hemoglobin, platelets, absolute lymphocyte count, white blood cell count, absolute neutrophil count), selected chemistry laboratory analytes (aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, creatinine clearance), albumin, beta2-microglobulin, ECOG PS, number of prior lines of therapy, number of prior lines of therapy by number of years since diagnosis, prior exposure or refractoriness to commonly used MM drugs, prior treatment with radiation, cytogenetic risk, level of refractoriness, type of measurable disease, time since disease became refractory, refractory to previous lines of therapy (yes or no), LDH, history of prior SCT, number of lytic bone lesions, extramedullary disease, and percentage of plasma cells in bone marrow. The prognostic strength of a factor was assessed by univariate regression, and the population differences were assessed using standardized mean differences (SMDs), where an SMD greater than 0.2 at the covariate level was considered indicative of an imbalance between groups. This rank-ordered list was presented to and validated by external clinical experts consulted by the authors of the study. The ranking was updated as required until a consensus was reached on the final rank-ordered list of factors.

A total of 17 covariates considered to be prognostic factors were established. The covariates included in the primary propensity score and outcome regression models were refractory status, ISS stage, time to progression (prior line), extramedullary disease, number of prior lines, years since diagnosis, average duration of prior lines, age, hemoglobin (g/dL), LDH (units/L), creatinine clearance (mL/min), ECOG PS, sex, and MM type. Covariates of race, history of transplant, and cytogenetic risk were considered important, but were not included. Race and history of transplant were reported by the sponsor to have a minimal impact on results but represented a source of imbalance for other baseline variables. While cytogenetic risk is known to be an important predictive factor, the sponsor noted that coverage in LocoMMotion was low (37.9% missing), despite the fact it was a required variable to be collected in the study.

Analysis Methods

Two statistical methods were used in the analyses, based on the predefined process, adapted from the National Institute for Health and Care Excellence Decision Support Unit Technical Support Document 17,⁶⁰ a propensity score–weighted estimator and multivariable regression model.

Table 24: Key Study Design Features of Data Sources Included in the Sponsor-Submitted Observational Study — CARTITUDE-1 Versus LocoMMotion

BCMA = B-cell maturation antigen; CAR T = chimeric antigen receptor T cell; CD = cluster of differentiation; CNS = central nervous system; CR = complete response; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; HRQoL = health-related quality of life; IMiD = immunomodulatory drug; IMWG = International Myeloma Working Group; ITT = intention-to-treat; LOT = line of therapy; mITT = modified intention-to-treat; MM = multiple myeloma; MRD = minimal residual disease; NR = not reported; ORR = overall response rate; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PI = proteasome inhibitor; PK = pharmacokinetics; r/rMM = relapsed or refractory multiple myeloma; TTNT = time to next treatment; TTR = time to response; VGPR = very good partial response.

Propensity score weighting: Propensity scores were estimated using logistic regression specifying the binary treatment indicator as the dependent variable and selected baseline covariates as explanatory variables. The predicted propensity scores were then used to derive weights for each patient using the estimand-specific weighting formulas. IPW was used to reweight imbalanced baseline characteristics that were dissimilar between the CARTITUDE-1 and LocoMMotion cohorts. The primary analysis estimated the average treatment effect in the treated population (ATT) using IPW (IPW-ATT). Diagnostic metrics, including the degree of balance achieved by the different propensity score methods as measured by SMDs before and after weighting, and the achievement of overlap in estimated propensity scores in the distribution of the 2 treated cohorts, were considered when selecting an optimal propensity scoring method.

For secondary outcomes (including PFS, OS, and other measures), weighted Cox proportional hazards models were used to estimate the causal HR and corresponding 95% CIs. For some dichotomized outcomes (including ORR, VGPR or better, CR or better, and MRD negativity), weighted logistic regression models were used to estimate the OR and corresponding 95% CIs. The reported ORs were subsequently transformed to estimate response rate ratios.

Regression models: Multivariable regressions models were specified, including a treatment indicator and baseline covariates for adjustment in the model.

For time-to-event outcomes (including PFS, OS, TTNT, time to first response, DOR, and other measures), unweighted Cox proportional hazards models adjusting for covariates were used to estimate conditional HRs and their corresponding 95% CIs. For binary outcomes (including ORR, VGPR or better, CR or better, and MRD negativity), unweighted logistic regression models adjusting for covariates were used to estimate treatment effects in terms of conditional causal ORs and 95% CIs to determine the comparative efficacy of cilta-cel versus the LocoMMotion cohort.

Sensitivity analyses: In addition to the primary IPW-ATT approach, a sensitivity analysis using an alternative weighting formula for deriving the average treatment effect for the overlap population (ATO) was also conducted. Sensitivity analyses also explored the stability of the methods, wherein additional variables (race, history of prior transplant, cytogenetic risk) were included in the calculation of propensity scores.

Analysis of PRO end points: PRO end points were analyzed using a mixed-model for repeated measures, with change from baseline as the outcome and treatment, baseline value, visit, and treatment and visit interaction as fixed effects. However, given the inability to interpret unadjusted comparisons as treatment effects over time, the results were not included in the CADTH summary and appraisal.

Missing data: Complete data were available for CARTITUDE-1. For LocoMMotion, variables with a proportion of missing values of less than 25% (ISS, 12.5%; hemoglobin, 10.1%; LDH, 23.8%; creatinine clearance, 5.2%; ECOG, 1.2%; MM type, 16.5%) were imputed using the multiple imputation with chained equations approach.

Proportional hazards assumption: The proportional hazards assumption (PHA) for survival outcomes was assessed based on visual inspection of the log-cumulative hazard plot, visual inspection of the Schoenfeld residuals plot, and performance of the Grambsch-Therneau test with a P value of less than 0.05 considered to indicate a violation of the assumption. In cases where evidence was found that the PHA was violated, the sponsor considered alternative summaries of treatment effect, such as the restricted mean survival time, although results were not reported.

Results of the Sponsor-Submitted Observational Study: CARTITUDE-1 Versus LocoMMotion

Summary of Included Studies

Baseline covariates for ITT and mITT populations in the CARTITUDE-1 and LocoMMotion cohorts before and after IPW-ATT are summarized in Table 25. The CARITUDE-1 study consisted of 113 patients who underwent apheresis and made up the ITT population, and 97 patients who were treated with cilta-cel (mITT). Patients were selected from LocoMMotion based on the eligibility criteria for CARTITUDE-1. In total, 248 patients were enrolled into the LocoMMotion trial (ITT), and 170 patients were alive and progression-free after 52 days (mITT). After weighting, the effective ITT and mITT population size of the LocoMMotion cohort were 118, and 108 patients, respectively.

Prior to adjustment, there were numerous pairwise imbalances (SMD > 0.2) in baseline characteristics between CARTITUDE-1 and LocoMMotion cohorts. In the ITT population, CARTITUDE-1 enrolled more patients with pentuple refractory disease compared with the LocoMMotion population (||||% versus ||||%), and LocoMMotion included more patients with disease that was less than double (||||% versus ||||%) and triple (|||% versus ||||%) refractory. Compared with the LocoMMotion cohort, the CARTITUDE-1 group also consisted of more patients with:

• ISS stage I disease (||||% versus ||||%) and fewer with ISS stage III disease (||||% versus ||||%)

• a creatinine clearance of 90 mL/min or greater (||||% versus ||||%) and fewer with a creatinine clearance of less than 60 mL/min (||||% versus ||||%)

• an ECOG PS of 0 (||||% versus ||||%) rather than 1

• the immunoglobulin G type of MM (||||% versus ||||%) rather than non–immunoglobulin G type.

Other differences were observed for age, average duration of prior lines of therapy, time to progression on prior lines of therapy, and number of prior lines of therapy. Similar differences were observed in the mITT population, although differences were also observed for LDH and hemoglobin levels.

After adjustment, although there were no imbalances with an SMD greater than 0.2, observable differences remained in the ITT populations with regard to pentuple refractory status (||||% versus ||||%) and quadruple refractory status |||||% versus ||||||| years since diagnosis (< 6 years, ||||% versus ||||%; ≥ 6 years, ||||% versus ||||%), and hemoglobin (< 12 g/dL, ||||% versus ||||%; ≥ 12 g/dL, ||||% versus ||||%). In the mITT populations, observable differences remain in pentuple refractory status (||||% versus ||||%) and quadruple refractory status (||||% versus ||||%), extramedullary disease (||||% versus ||||||), age (≥ 65 years, ||||% versus ||||%), and ECOG PS (||, ||||% versus ||||%; ||, ||||% versus |||||).

Cytogenetic risk was considered an important risk factor; however, it was not included in the base-case analyses due to a high level of missingness in the LocoMMotion cohort (37.9% missing). When reported, there was a notable difference in the proportion of patients at a standard risk (ITT, ||||% versus ||||%; mITT, ||||% versus ||||%) and high risk (ITT, ||||% versus ||||%; mITT, |||% versus ||||%) between CARTITUDE-1 and LocoMMotion populations. Sensitivity analyses were conducted for both the ITT and mITT populations, including cytogenetic risk, race, and history of autologous SCT, for which the balance between groups was reduced based on the proportion of variables with an SMD greater than 0.2. Additional sensitivity analyses using IPW-ATO reweighting achieved the desired balance between groups in the selected prognostic variables.

Table 25: Overview of Patient Characteristics Before and After IPW-ATT

ATT = average treatment effect in the treated population; ECOG = Eastern Cooperative Oncology Group; IgG = immunoglobulin G; IPW = inverse probability of treatment weighting; ITT = intention-to-treat; ISS = International Staging System; LDH = lactate dehydrogenase; MM = multiple myeloma; RWCP = real-world clinical practice; SMD = standardized mean difference.

Note: The preweighting and postweighting distributions of demographics by intervention group are shown. SMDs > 0.2 were considered to indicate differences between groups.

Source: Sponsor-submitted indirect treatment comparison.²⁰

Table 26 outlines the real-world treatment regimens received in LocoMMotion. Patients received a total of 291 treatment regimens in their RWCP line of interest for a total of 92 unique regimens. Therefore, patients could be counted in more than 1 regimen if they received more than 1 combination in their treatment before progression or death. The 9 most frequently used regimens comprised 51.9% of all patients, and 43 patients (17.3%) received a regimen that was not received by any other patient in the sample.

Table 26: Treatment Regimens in the LocoMMotion Cohort

Source: Sponsor-submitted indirect treatment comparison.²⁰

Results

Overall survival: Results comparing OS between CARTITUDE-1 and LocoMMotion before and after adjustment are summarized in Table 27. The median OS for CARTITUDE-1 was NE (95% CI, 31.47 to NE) in the ITT population, and NE (95% CI, NE to NE) for the mITT population. The median OS for LocoMMotion RWCP estimated using IPW-ATT weighting was ||||| |||||| |||| ||| |||| || ||| in the ITT population, and 11.33 months (95% CI, 5.45 to NE) in the mITT population. Following adjustment, the conditional HR for OS was 0.32 (95% CI, 0.17 to 0.58) in the ITT population and 0.20 (95% CI, 0.09 to 0.41) in the mITT population, both favouring cilta-cel.

Results for additional analyses of OS using regression modelling, sensitivity analyses using IPW-ATO weights, and including additional variables (race, history of prior transplant, cytogenetic risk) are summarized in Figure 17. Results for these analyses were consistent with the primary analysis.

The log-cumulative hazard plot and Schoenfeld residuals plots for each outcome were visually inspected and there was no evidence of violation of the PHA before significant patient drop-off. For OS, the Grambsch-Therneau test was nonsignificant, indicating the PHA to be appropriate.

Health-related quality of life: No adjusted analyses of PRO end points were conducted; therefore, the results of PRO end points are not summarized in this report.

Table 27: Unadjusted and Adjusted Kaplan-Meier Estimated OS (ITT and mITT Populations)

ATT = average treatment effect in the treated population; CI = confidence interval; HR = hazard ratio; ISS = international staging system; ITT = intention-to-treat; LOT = line of therapy; mITT = modified intention-to-treat; MM = multiple myeloma; NE = not estimable; OS = overall survival.

Note: Adjusted results correspond to the fully adjusted scenario, which adjusted for refractory status, ISS stage, time to progress on last regimen, extramedullary disease, number of prior LOTs, years since MM diagnosis, average duration of prior LOTs, age, hemoglobin, lactate dehydrogenase, creatinine clearance, Eastern Cooperative Oncology Group Performance Status, sex, and MM type.

Source: Sponsor-submitted indirect treatment comparison.²⁰

Progression-free survival: Results comparing the PFS estimates for CARTITUDE-1 and LocoMMotion are summarized in Table 28. The median PFS for CARTITUDE-1 was 28.03 months (95% CI, 20.11 to NE) in the ITT population, and NE (95% CI, 24.54 to NE) for the mITT population. The median PFS for LocoMMotion RWCP using IPW-ATT weighting was 4.07 months (95% CI, 2.86 to 5.09) in the ITT population, and 2.73 months (95% CI, 2.37 to 3.68) in the mITT population. Following adjustment, the conditional HR for PFS between treatment groups was 0.19 (95% CI, 0.11 to 0.32) in the ITT population and 0.15 (95% CI, 0.08 to 0.29) in the mITT population, both favouring cilta-cel.

Results for additional analyses of PFS using regression modelling, sensitivity analyses using IPW-ATO weights, and including additional variables (race, history of prior transplant, cytogenetic risk) are summarized in Figure 17. Results for these analyses were consistent with the primary analysis.

The log-cumulative hazard plot and Schoenfeld residuals plots for each outcome were visually inspected and there was no evidence of violation of the PHA before significant patient drop-off. For PFS, the Grambsch-Therneau test was nonsignificant, indicating the PHA to be appropriate.

Table 28: Unadjusted and Adjusted Kaplan-Meier Estimated PFS (ITT and mITT Populations)

ATT = average treatment effect in the treated population; CI = confidence interval; ISS = international staging system; ITT = intention-to-treat; LOT = line of therapy; mITT = modified intention-to-treat; MM = multiple myeloma; NE = not estimable; PFS = progression-free survival.

Note: Adjusted results correspond to the fully adjusted scenario, which adjusted for refractory status, ISS stage, time to progress on last regimen, extramedullary disease, number of prior LOTs, years since MM diagnosis, average duration of prior LOTs, age, hemoglobin, lactate dehydrogenase, creatinine clearance, Eastern Cooperative Oncology Group Performance Status, sex, and MM type.

Source: Sponsor-submitted indirect treatment comparison.²⁰

Clinical response outcomes: Results comparing CARTITUDE-1 and LocoMMotion for clinical response outcomes, including ORR and VGPR, are summarized in Table 29. In CARTITUDE-1, the ORR for observed proportions in the ITT and mITT populations for cilta-cel were 84.1% and 97.9%, respectively. In LocoMMotion, the ORR in the ITT and mITT populations for RWCP were 29.8% and 42.9%, respectively. The IPW-estimated OR was 22.00 (95% CI, 11.14 to 43.35) in the ITT population and 103.87 (95% CI, 24.17 to 446.37) in the mITT population, both in favour of cilta-cel. For VGPR, observed proportions within the ITT and mITT populations for response rates of VGPR or better were 81.4% and 94.8% from CARTITUDE-1, and 12.5% and 17.6% for LocoMMotion. The IPW-estimated OR was 39.08 (95% CI, 18.19 to 83.98) in the ITT population and 91.55 (95% CI, 32.63 to 256.89) in the mITT population, both in favour of cilta-cel. For both the ITT and mITT populations, no analyses of a response rate of CR or better and MRD negativity were conducted due to the small number of observed values in the LocoMMotion cohort. Observed response rates of CR or better in the cilta-cel and LocoMMotion cohorts were 70.8% and 0.4% in the ITT population and 82.5% and 0.6% in the mITT population. As 2 bone marrow samples were required for evaluation of MRD negativity, the base for the calculation could not be estimated for the ITT population in CARTITUDE-1, while 0 patients were MRD-negative in the ITT population in LocoMMotion. In the mITT population of CARTITUDE-1, 91.8% patients had evaluable MRD-negative samples, while MRD negativity was not evaluable in the mITT population in LocoMMotion.

Results for additional analyses of ORR and VGPR using regression modelling, sensitivity analyses using IPW-ATO weights, and including additional variables (race, history of prior transplant, cytogenetic risk) are summarized in Figure 16. Results for these analyses were consistent with the primary analysis.

Table 29: Summary of Observed and Adjusted Comparisons for Response Outcomes

ATT = average treatment effect in the treated population; CI = confidence interval; IPW = inverse probability weighting; ITT = intention-to-treat; LOT = line of therapy; mITT = modified intention-to-treat; MM = multiple myeloma; OR = odds ratio; ORR = overall response rate; RWCP = real-world clinical practice; VGPR = very good partial response.

Note: Adjusted comparisons account for refractory status, International Staging System stage, time to progression on prior line, presence of extramedullary disease, number of prior LOTs, years since MM diagnosis, average duration of prior LOTs, patient age and sex, hemoglobin at index date, lactate dehydrogenase at index date, creatinine clearance at index date, Eastern Cooperative Oncology Group Performance Status, and MM type.

Source: Sponsor-submitted indirect treatment comparison.²⁰

Time to response: No results for TTR were included in the study comparing CARTITUDE-1 and LocoMMotion.

Safety: Only unadjusted comparisons of AEs from the CARTITUDE-1 and LocoMMotion studies were reported, and no adjusted analyses were conducted; therefore, harms results are not summarized in this report.

Critical Appraisal of Sponsor-Submitted Observational Study: CARTITUDE-1 Versus LocoMMotion

Given the lack of a comparator arm in the CARTITUDE-1 trial, the use of external real-world data to emulate a control arm was justified. The prospective, real-world LocoMMotion cohort was selected as an external control arm representing RWCP for this analysis based on its inclusion and exclusion criteria and enrolled population, which aimed to reduce the potential for selection bias and heterogeneity between populations by emulating a theoretical RCT for cilta-cel within the CARTITUDE-1 population.

In general, there was variation in the design of the CARTITUDE-1 and LocoMMotion studies, primarily that CARTITUDE-1 was a phase Ib/II, open-label trial while LocoMMotion was an observational and noninterventional study. Both studies were open label, so there is a risk of bias in the measurement of subjective outcomes, primarily for the response outcomes as well as harms and HRQoL, though harms and HRQoL results were not included in this report. In both studies, IRC was used for response outcomes; thus, the risk of bias may be reduced. Objective outcomes, including OS, should be unaffected by the open-label designs. The LocoMMotion cohort represented a broad population from Europe and the US, whereas the results from CARTITUDE-1 are drawn from US patients only. It is uncertain whether there are differences in clinical practice, or availability of treatments by region, and the direction and magnitude of potential biases remains unclear. Additionally, there were no Canadian investigative sites included in either the CARTITUDE-1 or LocoMMotion studies, which may impact the generalizability of the results to patients in Canada. Both the ITT and mITT populations were analyzed in the study. Analyses using the ITT population were considered more appropriate for comparisons, given that the mITT population excluded patients who progressed or died in the first 47 or 52 days. As such, the ITT population was more appropriate to estimate the effect of treatment assignment, while the mITT analyses were at a greater risk of bias due to the elimination of patients who were sicker, likely favouring cilta-cel. Regardless, outcomes were consistent across the ITT and mITT populations. An additional source of heterogeneity between the CARTITUDE-1 study and the LocoMMotion study affecting the generalizability of the results was the prior regimens received by patients in LocoMMotion. A total of 92 distinct regimens were used as prior treatment. Given the numerous prior treatment regimens, lack of analyses by type of prior regimen, and irrelevancy of many treatment regimens to Canadian clinical practice, the results of the study may not be generalizable to the population of patients in Canada.

As previously mentioned, the inclusion criteria for the LocoMMotion study were designed to match the inclusion criteria for the CARTITUDE-1 trial. Despite this, there was notable heterogeneity in the populations of the CARTITUDE-1 and LocoMMotion studies. The external validity of the results is generally in line with those from the CARTITUDE-1 study, given that the comparator population was adjusted for similarity to patients from CARTITUDE-1. Patients included in the CARTITUDE-1 trial were younger than those included in RWCP (i.e., patients included in LocoMMotion). Additionally, all patients had an ECOG PS of 0 or 1. Thus, the findings cannot be generalized to patients with an ECOG PS of 2 or more; however, as noted for the CARTITUDE-1 trial, the clinical experts consulted by CADTH considered generalizing to patients with an ECOG PS of 2 to be acceptable. A comprehensive list of potential prognostic covariates was identified through a review of the published literature and in discussion with clinical experts in the field consulted by the study authors. A total of 17 different potential prognostic factors were identified and 15 were considered and ranked in the analyses. Though covariates were ranked in order from most to least likely to influence the outcome of interest, the specific methods of ranking were not provided; thus, it is unclear what criteria were used to determine rank. Prior to adjustment, the baseline covariates for prognostic factors demonstrated considerable heterogeneity in refractory status, ISS stage, time to progression on prior lines of therapy, number of prior lines of therapy, duration of prior lines of therapy, age, creatinine clearance, ECOG PS, and MM type. Comparisons with externally generated cohorts are limited by the availability of information important to the analysis; indeed, the sponsor noted that due to significant missingness of data, covariates of race, history of transplant, and cytogenetic risk were not included in the adjustment. A sensitivity analysis of baseline covariate adjustment was conducted; however, results for the analyses including these covariates were not presented; thus, the impact of their exclusion remains unknown. Moreover, cytogenetic risk was considered a particularly important prognostic factor by the clinical experts consulted by CADTH; thus, its omission from the analyses must be considered. As with all nonrandomized studies, the potential for residual confounding for unobserved patient characteristics cannot be ruled out. Following adjustment, some heterogeneity remained, particularly in the mITT population, for refractory status, extramedullary disease, age, and ECOG PS.

Several assumptions were made in the analyses. The sponsor considered any patients with missing or unevaluable MRD status to be MRD-positive; in CARTITUDE-1, patients who died after consent withdrawal were considered as having an OS event. No consideration was given to the impact these assumptions had on the results, and no sensitivity or scenario analyses were conducted for these assumptions.

Multiple comparative analyses (propensity score weighting [IPW] and regression modelling) were performed for the ITT and mITT populations for CARTITUDE-1 versus the LocoMMotion study. The primary analysis method using IPW was considered appropriate, given the use of an external control arm and the need to adjust for confounding variables. Sensitivity analyses balancing baseline covariates using the ATO approach were also conducted, where perfect balance was achieved between treatment groups. The results of the adjusted treatment comparisons were consistent across end points, favouring cilta-cel over RWCP from the LocoMMotion study, with 95% CIs that did not include the null threshold. However, there was notable imprecision in all cases, as demonstrated by the wide 95% CIs, reflecting uncertainty in the magnitude of the effect. Though the reason for this imprecision was not hypothesized, it may be due to the small sample size of the CARTITUDE-1 trial, the observed heterogeneity between the populations, and potential endogeneity.

No adjusted analyses were conducted for HRQoL and safety outcomes and only naive comparisons of these outcomes from the CARTITUDE-1 and LocoMMotion trials were provided. As such, no conclusions can be drawn on the impact of cilta-cel on HRQoL or the comparative safety of cilta-cel versus current treatment options due to the risk of confounding.

Overall, given the phase Ib and phase II nature of the CARTITUDE-1 trial and the lack of a comparator arm, the ability to reach definitive conclusions on the comparative efficacy of cilta-cel was limited. Additionally, the heterogeneity between cohorts after adjustment, as well as the uncertainty of the results due to the assumptions made and the potential for residual confounding, limits the ability to draw strong conclusions about the comparative efficacy of cilta-cel versus other treatments. Given the adjustment of the LocoMMotion population to the CARTITUDE-1 population, the generalizability of the results is similar to that of CARTITUDE-1, which has previously been described in detail.

Methods of the Sponsor-Submitted Observational Study: CARTITUDE-1 Versus Real-World Cohorts²¹

Objectives

The objective of the sponsor-submitted observational study was to evaluate the comparative effectiveness of cilta-cel versus physicians’ choice as assessed in either the long-term follow-up of POLLUX, CASTOR, and EQUULEUS or Flatiron Health’s MM cohort registry.

Study Selection Methods

The data sources included in the report submitted by the sponsor included the IPD from the CARTITUDE-1 trial (data cut-off January 2022), the long-term follow-up of the global r/rMM daratumumab clinical trials (POLLUX, CASTOR, and EQUULEUS), and Flatiron Health’s longitudinal database. A flow chart depicting the selection of patients from each cohort is displayed in Figure 15.

CARTITUDE-1 was an open-label, single-arm, phase Ib and II trial; thus, observational comparisons using external control arms were conducted using CARTITUDE-1 as the index trial. All patients in the ITT and mITT population of the CARTITUDE-1 study were eligible for inclusion. The ITT population in CARTITUDE-1 included all patients who underwent apheresis, with the index date defined as the date of apheresis. The mITT population in CARTITUDE-1 consisted of all participants who received cilta-cel at the target dose, with the index date defined as the date of cilta-cel infusion. The ITT and mITT populations in CARTITUDE-1 consisted of 113 and 97 patients, respectively. The median follow-up period in CARTITUDE-1 as of the January 2022, data cut-off was 29 months for the ITT population and 27.7 months for the mITT population.

The first observational study aimed to compare patients treated with cilta-cel from the CARTITUDE-1 study and RWCP from the long-term follow-up for 3 trials of the anti-CD38 monoclonal antibody daratumumab (POLLUX, CASTOR, and EQUULEUS), hereinafter referred to as the daratumumab trial cohort. The POLLUX and CASTOR trials were both phase III, open-label RCTs, while the EQUULEUS study was an open-label, phase Ib study. To ensure similarity between CARTITUDE-1 and the daratumumab cohort, only those patients who satisfied key eligibility criteria for CARTITUDE-1 were included. These trials were selected considering various design and population characteristics, particularly the patient population, which included patients who were triple class–exposed and received at least 1 additional treatment following triple-class exposure (i.e., received ≥ 3 prior lines of therapy), with an ECOG PS less of than 2, a creatinine level of 2 mg/dL or less, and who had progressed on or within 12 months of the most recent line of therapy. These studies had also completed their primary analysis, had follow-up data available at least 6 months after primary database lock, and had provided subsequent therapy information, including line of therapy, best response, and progression status. Patients from these trials were included in the sponsor’s observational study from the point in time during their follow-up, when they fulfilled key eligibility criteria for CARTITUDE-1. Patients from both the daratumumab-based arms and the control arms (for participants who received an anti-CD38 monoclonal antibody as subsequent therapy during follow-up) were evaluated for inclusion in the study. The ITT population in the daratumumab trial cohort consisted of all participants who satisfied the eligibility criteria, with the index date defined as the start of each eligible line of therapy. The mITT population in the daratumumab trial cohort excluded eligible treatment lines, during which disease progression or death occurred within 47 days of initiating the respective line of therapy to account for the median of 47 days between apheresis and infusion in CARTITUDE-1. The index date was defined as the start of each eligible line of therapy plus 47 days. The ITT population from the daratumumab trial cohort included 351 patients (632 eligible lines of therapy), while the mITT population included 288 patients (434 eligible lines of therapy). The data cut-off for the updated analysis (2022) was June 2021, for CASTOR, September 2021, for POLLUX, and ranged from 2017 to 2019 for EQUULEUS, corresponding to an overall median follow-up of 23.9 months across all the eligible lines of therapy received after meeting the eligibility criteria.

The Flatiron Health longitudinal database represents a repository of patient-level electronic health records from community-based oncology clinics and academic centres in the US. Patients in the MM cohort registry were selected from the full Flatiron database who satisfied key eligibility criteria of CARTITUDE-1 and included the following criteria: newly diagnosed with MM (International Classification of Diseases, Ninth Revision [ICD-9] 203.0x or Tenth Revision [ICD-10] C90.0x or C90) and at least 2 documented clinical visits on or after January 1, 2011. All patients were required to be triple class–exposed with at least 1 additional treatment after triple-class exposure (i.e., received ≥ 3 prior lines of therapy). Patients were also required to have an ECOG PS of less than 2 and evidence of PD on or within 12 months of the most recent line of therapy or discontinuation of the core treatment within 60 days. The ITT and mITT populations in the Flatiron MM cohort were similar to the daratumumab trial cohort described previously. The ITT population consisted of 229 patients (482 eligible lines of therapy), and the mITT consisted of 196 patients (336 eligible lines of therapy). Patients included in the ITC initiated eligible lines of therapy between February 2016, and December 2019, and were followed until February 2021, to match the follow-up in CARTITUDE-1, corresponding to a median follow-up period of 21.9 months.

Figure 15: Flow Chart of Patient Selection in the Sponsor-Submitted Observational Study

Note: Figure was redacted at the sponsor’s request.

Outcomes evaluated in the sponsor-submitted report included ORR, CR or better rate, PFS (as well as aPFS, PFS, and rwPFS, as appropriate), and OS. The outcomes of CR and VGPR were not evaluated in the Flatiron database; therefore, an assessment of ORR and the rate of CR or better was not possible. The outcomes were defined as follows:

• OS: In all cohorts, OS was defined as the time from the index data to the date or death. If a patient was alive or their vital status was not known, they were censored at the date they were last known to be alive. Since only the month and year of death were available in the Flatiron cohort, the middle of the month was used as the date of death. Patients in CARTITUDE-1 who died after consent withdrawal were considered as having an OS event.

• aPFS: In all cohorts, an aPFS event was defined as disease progression, switch to subsequent treatment, or death due to any cause, whichever occurred first. For patients who experienced both disease progression and a subsequent treatment, the switch to subsequent treatment was considered the event. The duration was calculated as the time from index date to switch to a subsequent treatment postprogression, progression without subsequent treatment, or death, whichever occurred first. Patients who had not experienced an event were censored at their last disease evaluation. All events were ascertained by IRC in CARTITUDE-1 and by the investigator in the other cohorts.

• rwPFS: In the daratumumab and Flatiron cohorts, rwPFS was defined as disease progression, switch to subsequent treatment, or death due to any cause, whichever occurred first. Duration was calculated as the time from the index data to the date of progression, start of next treatment, or death, whichever occurred first, with the date of last follow-up used in censoring. The rwPFS was ascertained by the investigator. In the analysis of rwPFS, events in CARTITUDE-1 were defined as per aPFS, described previously.

• ORR: In both CARTITUDE-1 and the daratumumab cohort, ORR was defined as the proportion of patients who achieved a PR or better response according to IMWG criteria; ORR was assessed via IRC in CARTITUDE-1 and by the investigator in the daratumumab cohort. Patients in CARTITUDE-1 who experienced a response after the start of a subsequent therapy or re-treatment with cilta-cel were not considered.

• CR or better rate: In both CARTITUDE-1 and the daratumumab cohort, a response rate of CR or better was defined as the percentage of patients achieving CR or sCR according to IMWG criteria. CR or better rate was assessed via IRC in CARTITUDE-1 and by the investigator in the daratumumab cohort.

Analysis Methods

Using the IPD from the CARTITUDE-1 trial, comparative efficacy versus RWCP (from the daratumumab trial cohort and the Flatiron cohort) was assessed using IPTW. The main analyses consisted of IPTW with ATT weighting, allowing for reweighting of the RWCP from the daratumumab trial and Flatiron cohorts to align with CARTITUDE-1. An initial analysis was conducted in 2021, with an updated analysis conducted in April 2022. As previously mentioned, 2 analytic populations were considered: the ITT and mITT populations.

A list of potentially important prognostic factors was created by consulting studies from a literature review as well as by collecting input from clinical experts consulted by the sponsor; however, few details were provided. The sponsor noted that a total of 15 of the identified prognostic factors were available in CARTITUDE-1. In consultation with the clinical experts consulted by the sponsor, the available prognostic factors were ranked from most to least important using an evidence-informed process considering both the strength of the prognostic factor in terms of PFS and OS and the degrees of imbalance between populations. Ranked prognostic factors in order of importance included refractory status, cytogenetic profile, ISS stage, presence of total plasmacytoma, time to progression on last regimen, number of prior lines of therapy, years since diagnosis, age, hemoglobin, LDH levels, prior SCT, ECOG status, race, sex, and type of MM. All relevant prognostic factors, with the exception of LDH and plasmacytoma, were available in the daratumumab trial cohort and the Flatiron cohort. The clinical experts consulted by the sponsor also agreed on a minimum set of factors that should be adjusted for in all analyses, which included the first 8 factors in the list.

The base-case analysis versus the daratumumab trial cohort weighted patients on the following factors: refractory status, cytogenetic profile, ISS stage, total plasmacytoma, time to progression on last regimen, number of prior lines of therapy, years since MM diagnosis, and age. The fully adjusted scenario also included hemoglobin, prior SCT, ECOG score, race, sex, and type of MM, in addition to the base-case variables. The base-case scenario versus the Flatiron cohort weighted patients on the following factors: refractory status, cytogenetic profile, ISS stage, time to progression on last regimen, number of prior lines of therapy, years since MM diagnosis, and age. The fully adjusted scenario also included hemoglobin, LDH, prior SCT, ECOG score, race, sex, and type of MM, in addition to the base-case variables.

The base case adjusted for the minimum set of factors deemed important by clinicians and considered all treatment lines initiated after becoming eligible (i.e., all index dates). Patients from the daratumumab trial cohort and the Flatiron cohort were able to be included at the earliest line of therapy initiated after all key eligibility criteria were met. This differed from the CARTITUDE-1 clinical trial, in which patients may have received additional lines of therapy between the time at which they first met all eligibility criteria and the time at which they were enrolled into the clinical trial. To account for this difference, patients in the physicians’ choice of treatment cohort who received multiple subsequent therapies after meeting eligibility criteria contributed multiple observations (corresponding to all eligible lines of therapy) to the current analysis, provided they met eligibility criteria at the beginning of each line of therapy. In such cases, a patient had multiple index dates, with 1 for each eligible line of therapy.

Regression models: Multivariable regressions were conducted including a binary treatment indicator (cilta-cel or RWCP) and covariates for adjustment in the model.

For time-to-event outcomes (e.g., PFS, aPFS, PFS or rwPFS, and OS), an unweighted Cox proportional hazards model adjusting for the relevant covariates was used to derive an HR and 95% CIs. For the comparison with Flatiron, an unweighted logistic regression adjusting for the relevant covariates was used to derive an OR and 95% CIs for binary outcomes (e.g., ORR and ≥ CR rate). The variance was estimated using a robust sandwich variance estimator specifying the participant identifier to account for participants with multiple index dates.

Sensitivity analyses: A range of sensitivity and exploratory analyses was conducted to assess the impact of modifying the participant populations, statistical methods, handling of missing data, eligible lines of therapy, and variables adjusted for in the analyses for the daratumumab trial cohort and the Flatiron cohort. The sensitivity analyses for the comparisons versus the daratumumab trial cohort and Flatiron cohort included IPTW analyses with ATT weighting (not doubly robust), multivariable regression, propensity score matching (1:1 nearest neighbour or optimal matching), and IPTW analyses with average treatment effect weighting (doubly robust). An exploratory analysis including only patients’ first eligible line of therapy was also conducted. Additional sensitivity analyses conducted for the Flatiron cohort comparison included the exclusion of observations with missing values for covariates of interest and the application of additional inclusion criteria from CARTITUDE-1 to the real-world cohort (1¹ + hemoglobin ≥ 8 g/dL and platelets ≥ 50 × 10⁹/L).

Missing data: Missing values were imputed in the same way between CARTITUDE-1 and the daratumumab trial cohort and the Flatiron cohort. In CARTITUDE-1, prognostic factors were assessed at the time of apheresis for the ITT population and at the time of infusion for the mITT population, if available. If unavailable, the closest reported value before the index date was used. For the RWCP cohorts, which used different index dates, the time of assessment depended on the index date being used. For the CARTITUDE-1 population, the only variable requiring imputation was ISS stage (ITT population only). Values for the mITT were used for missing data at enrolment. If unavailable, mode value was used to impute missingness. For the RWCP cohort from the daratumumab trial cohort, the last observation was carried forward for variables (e.g., ECOG, cytogenetic profile), which was only assessed at the time of initial entry into the daratumumab clinical trials. Missing values for ISS stage were imputed using the mode value. For the RWCP cohort from Flatiron, imputation was required for ISS stage, hemoglobin, LDH, and ECOG PS. The last recorded value before the index date was used. Beta2-microglobulin values were used to impute missingness in ISS. A sensitivity analysis was conducted to assess the impact of imputation by only including complete cases for all variables except ECOG PS, which were preserved in the sensitivity analyses.

Proportional hazards assumption: The PHA for survival outcomes was assessed based on visual inspection of the log-cumulative hazard plot, visual inspection of the Schoenfeld residuals plot, and performance of the Grambsch-Therneau test with a P value of less than 0.05 considered to indicate a violation of the assumption.

Results of the Sponsor-Submitted ITC

Summary of Included Studies

As previously noted, the sponsor-submitted observational study compared the IPD from the CARTITUDE-1 trial with data from 3 daratumumab clinical trials (POLLUX, CASTOR, and EQUULEUS) and with a MM-specific population from the Flatiron cohort. Characteristics of the patients included in the observational study from each cohort are summarized in Table 30. The SMDs for covariates before and after weighting in the ITT and mITT populations between CARTITUDE-1 and the daratumumab trial cohort are summarized in Figure 18 and Figure 19, and the Flatiron cohort is summarized in Figure 20 and Figure 21 of Appendix 3.

The CARTITUDE-1 trial included 113 patients in the ITT population and 97 patients in the mITT population. A total of 351 and 288 patients were included in the daratumumab trial cohort in the ITT and mITT populations, respectively. After propensity score weighting, including covariates of refractory status, ISS stage, cytogenetic profile, time to progression on last regimen, extramedullary plasmacytomas, number of prior lines of therapy, years since MM diagnosis, and age, the base-case ESS of the daratumumab trial cohort was 212 in the ITT population and 116 in the mITT population. In the Flatiron cohort, 229 and 196 patients made up the ITT and mITT populations, respectively. After adjustment for the same covariates in the daratumumab trial cohort except for extramedullary plasmacytomas, the ESS for the Flatiron cohort was 192 in the ITT population and 80 in the mITT population.

Prior to weighting, there were notable differences (SMD > 0.2) between the CARTITUDE-1 and daratumumab trial populations in pentuple refractory status (||||% versus ||||%) versus triple or quadruple refractory status (||||% versus ||||%), time to progression on last therapy (> 4 months, ||||% versus ||||%), presence of extramedullary plasmacytosis (||||% versus |||%), number of prior lines of therapy (≤ 4, ||||% versus ||||%), years since MM diagnosis (> 6 years, ||||% versus ||||%), age (< 65 years, ||||% versus ||||%), hemoglobin level (≥ 12 g/dL, ||||% versus ||||%), and prior SCT (no, ||||% versus ||||%), with only moderate (SMD between 0.1 and 0.2) to small (SMD < 0.1) differences in remaining variables. After weighting, notable differences remained only for the variable of hemoglobin. For the mITT populations, notable differences before weighting were observed for refractory status, cytogenetic profile, time to progression on last regimen, extramedullary plasmacytomas, number of prior lines of therapy, age, hemoglobin level, prior SCT, and race. After weighting, differences remained for variables of extramedullary plasmacytomas, hemoglobin, prior SCT, and race.

Compared with the Flatiron cohort, there were notable differences in ISS stage (stage I, ||||% versus ||||%; stage II, ||||% versus ||||%; stage III, ||||% versus ||||%), cytogenetic profile (standard risk, ||||% versus ||||%; high risk, ||||% versus ||||%), time to progression on the prior line (≤ 4 months; ||||% versus ||||%), years since diagnosis (< 6 years, ||||% versus ||||%), age (< 65 years, ||||% versus ||||%), prior SCT (no, ||||% versus ||||%), and ECOG PS (ECOG 0, ||||% versus ||||%; ECOG 1, ||||% versus ||||%). After weighting, substantial differences remained for the variable of prior SCT, with moderate differences for LDH level and ECOG PS.

Table 30: Baseline Covariates Before and After Weighting; ITT and mITT Populations