CADTH Reimbursement Review

Teclistamab (Tecvayli)

Sponsor: Janssen Inc.

Therapeutic area: Relapsed or refractory multiple myeloma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Executive Summary

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

Table 1: Background Information on Application Submitted for Review

NOC/c = Notice of Compliance with Conditions.

^aProject Orbis provides a framework for the collaborative review of new cancer treatments among international regulatory partners aiming to give patients access to promising cancer treatments across the globe. Health Canada is one of the Project Orbis partners.

Introduction

Multiple myeloma (MM) is a plasma cell cancer characterized by the clonal proliferation of malignant plasma cells (B-cells) and the overproduction of the abnormal immunoglobulin M protein.¹ Older individuals and men of all ages (as opposed to women) are more likely to develop MM and it is twice as common in individuals who are Black compared to white or Asian individuals.^2,3 In 2022, it was estimated that 4,000 people in Canada were diagnosed with MM and 1,650 people in Canada died from MM.⁴ The 5-year survival probability for patients with MM is estimated to be approximately 50%,⁵ and although survival rates have improved in recent years due to advances in therapeutic options, MM remains incurable.^6,7 The majority of patients with MM will relapse and many patients will become refractory to commonly used therapies.⁸ The most common symptoms of MM are fatigue and bone pain,³ with other symptoms including kidney problems, recurrent infections, fever, and nervous system problems.⁹

Diagnosis of MM typically occurs during a visit to a primary care physician, occurring either incidentally when laboratory tests for other conditions are ordered, or if MM is suspected based on signs and symptoms.¹⁰ According to the International Myeloma Working Group (IMWG) criteria, a patient is considered to have relapsed and/or refractory MM if they have attained a minimal response or better at some point during previous treatments but the disease is currently nonresponsive on salvage therapy, or they experience disease progression within 60 days of their last therapy.^11,12 Patients with relapsed or refractory multiple myeloma (RRMM) often undergo multiple rounds of treatment, with the duration of remission, the depth of response, progression-free survival (PFS), and overall survival (OS) decreasing with each subsequent line of therapy.³ According to the clinical experts consulted by CADTH for this review, the current approach to the treatment of MM at relapse depends on several factors, including patient factors (i.e., age, comorbidity, and beforexicity), line of therapy, and prior therapies received. There is no preferred standard of care for the treatment of RRMM in the fourth-line setting and beyond, and at this stage of the disease, patients may be exposed to a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody,^7,13 and in some cases receive more than 1 PI or iMiD, further limiting treatment options in later lines of therapy. The clinical experts consulted by CADTH noted that treatment options at relapse include a PI (bortezomib, carfilzomib) containing combinations such as cyclophosphamide in combination with bortezomib and dexamethasone, carfilzomib in combination with dexamethasone with or without cyclophosphamide, or selinexor in combination with bortezomib and dexamethasone. The clinical experts mentioned that later relapses can be treated through clinical trials or with regimens such as belantamab mafodotin, which is currently available through a special access program. The clinical experts and clinician groups consulted by CADTH for this review agreed that there is an unmet need for treatments beyond the third line that prolong survival, delay disease progression, prevent disease complications, improve quality of life, and minimize side effects.

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of teclistamab (1.5 mg/kg of body weight administered by subcutaneous [SC] injection) in the treatment of adult patients with RRMM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody.

Stakeholder Perspectives

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

Patient Input

CADTH received 1 patient group submission from Myeloma Canada, which has existed for more than 15 years to support the growing number of Canadians diagnosed with myeloma and those living longer than ever with the disease to access new and innovative therapies. Myeloma Canada gathered information for this review through a patient and caregiver survey (33 patients and 3 caregivers) that was conducted from August 28 to September 6, 2023.

Patient respondents indicated that their ability to travel was the factor most significantly impacted by symptoms associated with myeloma, followed by the ability to work and to exercise. Patient and caregiver respondents identified the following factors as those most important to myeloma treatment: improved quality of life, manageable side effects along with the effectiveness of treatment, especially in achieving remission and having a long and durable response, and treatment accessibility or portability (including fewer or minimal visits to the hospital or cancer centre). In terms of treatment outcomes, 13 of the 22 respondents rated improved quality of life as extremely important, 6 respondents rated it as very important, and 3 respondents rated it as somewhat important. A total of 17 of the 22 patients rated the estimated minimum of 1 year to 21 months of life extension as extremely desirable, and 5 patients rated it as very desirable. All caregiver respondents felt that caring for someone with myeloma had the most impact on “anxiety/worry,” followed by “interruption of life goals/accomplishments (e.g., career, retirement)”.

From August 28 to September 30, 2022, Myeloma Canada also conducted a different survey about a chimeric antigen receptor (CAR) T-cell therapy, which received more than 200 responses, only 2 of which had experience with the CAR T-cell therapy. While the teclistamab survey received far fewer total responses (33), there were 11 patients with teclistamab experience. Myeloma Canada emphasized that this is indicative of the comparative ease with which teclistamab can and has been made accessible to Canadians with triple-class exposed RRMM.

Clinician Input

Input From Clinical Experts Consulted by CADTH

The clinical experts consulted by CADTH for this review highlighted that the most important goals of treatment for patients with MM are to prolong survival, delay disease progression, prevent disease complications, improve quality of life, and minimize side effects. The clinical experts noted that clinicians try not to reuse the same drugs in subsequent lines of therapy, and after receiving 3 lines of therapy, the majority of patients will be triple-refractory and will need new families of drugs. The clinical experts also mentioned that beyond the third line of therapy, the treatment options get more restricted, and some patients do not respond to the current standard therapies. Thus, there is a need for treatments for fourth-line therapy and beyond that are tolerable for patients. The clinical experts consulted by CADTH indicated that, given that the prognosis of MM worsens as patients move on to subsequent lines of therapy, any patient with RRMM will require this intervention. The clinical experts noted that teclistamab is not the first approved treatment that targets underlying disease processes; however, this drug has a novel mechanism of action that is very different from any currently available therapies. The clinical experts agreed that there is no evidence that some patients are more likely to respond to treatment, and there are no disease-specific characteristics that would make a patient ineligible for treatment with teclistamab. The clinical experts noted that classic methodological assessments of interventions concern A versus B, comparing 1 versus the other without the consideration of sequencing beyond the initial drug failure; in this light, according to the clinical experts, the use of teclistamab represents a new class of drugs that can help sustain quality of life and extend the duration of life in the patient with RRMM.

The clinical experts identified OS, PFS, and clinical response outcomes as the most important outcomes for assessing the response to treatment. The clinical experts agreed that the best possible response to treatment would be complete remission that is minimal residual disease (MRD)–negative, and less deep responses that include complete response (CR), very good partial response (VGPR), partial response (PR), and stable disease. The clinical experts further noted that CR and VGPR are the most desirable outcomes in most situations; even achieving stable disease is acceptable. The clinical experts consulted by CADTH indicated that the main reason for discontinuing treatment with teclistamab would be the relapse of MM. The clinical experts further noted that as with any treatment, it can be expected that some patients will be forced to discontinue treatment due to intolerable side effects. The clinical experts consulted mentioned that currently, all patients receiving teclistamab are treated at tertiary care centres and are admitted to the hospital for the first few doses. The clinical experts also noted that depending on the situation, patients starting treatment with teclistamab will require treatment at a larger hospital capable of providing management and monitoring; however, after patients receive the first few doses of this treatment, they can receive ongoing therapy at community centres and smaller cancer centres.

Clinician Group Input

The clinician group input was obtained from 2 clinician groups: the Canadian Myeloma Research Group (CMRG) and the Ontario Health (Cancer Care Ontario) (OH-CCO) Hematology Cancer Drug Advisory Committee (OH-CCO’s Drug Advisory Committees). CMRG gathered information through teleconferences with physicians and OH-CCO’s Drug Advisory Committees gathered information through videoconferencing and email communications.

Both CMRG and OH-CCO’s Drug Advisory Committees mentioned that myeloma remains incurable, and patients eventually become refractory to all available funded drugs. One major unmet need mentioned by clinician groups is that patients with advanced disease who have received multiple lines of treatment and have already received the 3 major drugs (triple-class exposed or refractory) — including an IMiD, PI, and anti-CD38 monoclonal antibody — have no other substantial treatment options other than CAR T-cell therapy. CMRG also emphasized that the clinical features associated with advanced disease and short duration of responses lead to a poor quality of life, significant caregiver burden, and a shortened patient lifespan. Thus, this situation also represents 1 of the most pressing unmet needs in Canada for patients with MM. Another unmet need noted by OH-CCO’s Drug Advisory Committees is to achieve ease of administration (i.e., SC injection and no need for apheresis).

Both clinician groups agreed that teclistamab is another option for triple-class exposed patients. They believe that currently, it would be used in sequence after other lines of therapy for myeloma (i.e., after failure of multiple drugs); it is not expected to impact the sequencing of drugs earlier in the disease course or lead to a major change in treatment algorithms before patients becoming triple-class exposed or refractory.

Drug Program Input

The Provincial Advisory Group identified the following jurisdictional implementation issues: relevant comparators, considerations for the initiation of therapy, considerations for the discontinuation of therapy, considerations for the prescribing of therapy, generalizability, funding algorithm, care provision issues, and system and economic issues. The clinical experts consulted by CADTH weighed evidence from the MajesTEC-1 study and other clinical considerations to provide responses to the Provincial Advisory Group’s drug program implementation questions. Refer to Table 5 for more details.

Clinical Evidence

Systematic Review

Description of Studies

The MajesTEC-1 trial (n = 165) is a phase I and phase II, open-label, multicentre study assessing the efficacy and safety of teclistamab administered to adult patients with RRMM. The study is still ongoing and being conducted in 39 sites across 10 countries, including in Canada with patients who were enrolled at 4 Canadian sites. The MajesTEC-1 study was conducted in 3 parts: part 1 or dose escalation (phase I), part 2 or dose expansion (phase I) at a proposed recommended phase II dose (1.5 mg/kg subcutaneously weekly), and part 3 or dose expansion (phase II) in cohorts of patients with RRMM with unmet medical needs. The primary objectives reported in phase I of the MajesTEC-1 study were to identify the proposed recommended phase II dose and dose schedule assessed to be safe in part 1, and to characterize the safety and tolerability of teclistamab at the proposed recommended phase II dose in part 2. The primary objective of phase II of the MajesTEC-1 trial was to evaluate the efficacy and safety of teclistamab at the proposed recommended phase II dose. In phase II of the MajesTEC-1 study, cohort A enrolled patients with RRMM who had received at least 3 prior lines of therapy that included a PI, an IMiD, and an anti-CD38 monoclonal antibody, while cohort C enrolled patients who had received at least 3 prior lines of therapy that included a PI, an IMiD, an anti-CD38 monoclonal antibody, and an anti–B-cell maturation antigen treatment (CAR T-cells or an antibody-drug conjugate [ADC]). The primary efficacy outcome for the MajesTEC-1 trial was overall response rate (ORR), and the secondary efficacy outcomes included VGPR or better, CR or better, stringent complete response (sCR), time to response (TTR), duration of response, OS, PFS, MRD-negativity rate, and patient-reported outcomes. Time to next treatment (TTNT) was an exploratory outcome in phase II of the MajesTEC-1 study. Disease responses were evaluated by an independent review committee (IRC) using IMWG 2016 criteria in both phase I and phase II, cohort A.

In the MajesTEC-1 study, the median age of the patients was 64.0 years (range = 33.0 years to 84.0 years) |||| ||||| || ||| ||||| |||||||||| ||||| |||| |||| || ||||| || |||. Ninety-six (58.2%) patients were male and 69 (41.8%) patients were female. Most patients were white (81.2%), and 12.7% of patients identified as Black or African American. Most patients had an Eastern Cooperative Oncology Group Performance Status (ECOG PS) score of 1 (66.1%), while 33.3% of patients had an ECOG PS score of 0. The most common immunoglobulin isotypes were immunoglobulin G (55.2%) and immunoglobulin A (17.6%). The median time from diagnosis of MM to enrolment in the study was 6.0 years (range = 0.8 years to 22.7 years). Twenty-eight (17.0%) patients had 1 or more extramedullary plasmacytomas at baseline. Of the 147 patients with baseline cytogenetic data reported, 38 (25.9%) patients had at least 1 high-risk abnormality, including del(17p) (15.6%) and t(4;14) (10.9%) abnormality. Of the 162 patients with baseline International Staging System (ISS) data reported, 85 (52.5%) patients were ISS stage I while 20 (12.3%) patients were ISS stage III.

Efficacy Results

The primary analysis at the clinical cut-off date of September 2021 and the final analysis at the clinical cut-off date of August 2023 were prespecified analyses, and the Clinical Study Reports submitted by the sponsor with clinical cut-off dates of March 2022 and January 2023 were interim analyses. As the final report for the pivotal study is not yet available, information for the following sections was extracted from the more recent Clinical Study Report with a clinical cut-off date of January 4, 2023, submitted by the sponsor for this review. However, data from the clinical cut-off date of September 7, 2021, was also used to supplement the included data when necessary.

Overall Survival

At the time of analysis, using the January 4, 2023, data cut-off, the median duration of follow-up was 22.8 months (range = 0.3 months to 33.6 months). The estimated median OS was 21.9 months (95% confidence interval [CI], 15.1 months to not evaluable [NE] months). In the full analysis set (FAS), deaths were reported in || |||||||| ||||||| in phase I and || |||||||| ||||||| in phase II, cohort A, of the MajesTEC-1 trial. The 9-month OS probability was ||||| |||| ||| ||||| || ||||||, the 12-month OS probability was ||||| |||| ||| ||||| || ||||||, and the 24-month OS probability was ||||| |||| ||| ||||| || ||||||.

Progression-Free Survival

At the time of analysis, using the January 4, 2023, data cut-off, the estimated median PFS was 11.3 months (95% CI, 8.8 months to 16.4 months) in the MajesTEC-1 trial. In the FAS, the 9-month PFS probability was ||||| |||| ||| ||||| || ||||||, the 12-month PFS probability was ||||| |||| ||| ||||| || ||||||, and the 24-month PFS probability was ||||| |||| ||| ||||| || ||||||.

CR or Better

At the time of analysis, using the January 4, 2023, data cut-off, || |||||||| ||||||| |||| ||| ||||| || ||||||| in phase I and || |||||||| ||||||| |||| ||| ||||| || ||||||| attained CR or better (CR or sCR).

Stringent Complete Response

At the time of analysis, using the January 4, 2023, data cut-off, || |||||||| ||||||| |||| ||| ||||| || ||||||| in phase I and || |||||||| ||||||| |||| ||| ||||| || ||||||| in phase II, cohort A, attained sCR.

MRD-Negativity Status

Updated data regarding the MRD-negativity rate based on the January 4, 2023, clinical cut-off date are not available.

At the time of the data cut-off date of September 7, 2021, 37 (24.7%) patients (95% CI, 18.0% to 32.4%) attained MRD negativity at 10^–5 bone marrow cells. Among 43 patients who attained CR or better, 18 (41.9%) patients (95% CI, 27.0% to 57.9%) attained MRD negativity at 10^–5 bone marrow cells.

VGPR or Better

At the time of analysis, using the January 4, 2023, data cut-off, || |||||||| ||||||| |||| ||| ||||| || ||||||| in phase I and || |||||||| || ||||||||||||||||||||| ||| ||||| || ||||||| attained VGPR or better (VGPR, CR, or sCR).

Overall Response Rate

At the time of analysis, using the January 4, 2023, data cut-off, 104 (63.0%) patients (95% CI, 55.2% to 70.4%) had attained an overall response (PR or better), and ORR was similar across patients treated in phase I and phase II, cohort A, ||||||| |||| ||||||| || |||||| ||| |||||| |||| ||| ||||| || ||||||| |||||||||||||. Of the 104 responders (who attained PR or better), 51 (49.0%) patients maintained their response until the clinical cut-off date |||||| || |||||||| ||||| || ||||||||||| ||, including 46 (44.2%) patients who were still on treatment. Of the 104 responders, || |||||||| ||||||| had disease progression after initial response, of whom || ||||||| ||||||| died after disease progression, || |||||||| ||||||| discontinued the study treatment, and ||||||| |||||| remained on study treatment. A total of 19 (18.3%) patients died after achieving response and without experiencing disease progression, and |||||| |||||| had subsequent therapy after response and without progressive disease. Of the 63 respondents who changed their dosing schedule from weekly to biweekly (every 2 weeks) or monthly, 42 (66.7%) patients maintained their response until the clinical cut-off date of January 4, 2023, including 41 (65.1%) patients who remained on treatment.

Subgroup Analysis

Only results of the ORR subgroup analyses that were deemed clinically meaningful by the clinical experts consulted by CADTH for this review are reported. At the time of analysis, using the January 4, 2023, data cut-off, 32 of 43 (74.4%) patients who received 3 or fewer prior lines of therapy attained an overall response. Of the 122 patients who received more than 3 prior lines of therapy, 72 (59.0%) patients attained overall response, and 32 of 60 (53.3%) patients with high cytogenetic risk and/or extramedullary disease attained overall response.

Time to Response

At the time of analysis, using the January 4, 2023, data cut-off, in 104 responders, the median time to first response was 1.18 months (range = 0.2 months to 5.5 months) while the median time to best response was 3.96 months (range = 1.1 months to 18.7 months). Most patients demonstrated their first response rapidly, by the start of the second treatment cycle in the MajesTEC-1 study (depending on the dosing schedule, teclistamab was administered to patients in 21-day or 28-day cycles).

Duration of Response

At the time of analysis, using the January 4, 2023, data cut-off, the median duration of response was 21.6 months (95% CI, 16.2 months to NE months) in the MajesTEC-1 trial. Among 104 responders, || |||||||| ||||||| in phase I and || |||||||| ||||||| in phase II, cohort A, had disease progression or died due to any cause. The probability of patients remaining in response at 9 months was ||||| |||| ||| ||||| || ||||||. The probability of patients remaining in response at 18 months was ||||| |||| ||| ||||| || ||||||. The probability of patients remaining in response at 24 months was ||||| |||| ||| ||||| || ||||||.

Patient-Reported Outcomes

Patient-reported outcomes were assessed using the 30-item European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) assessment, the EQ-5D-5L questionnaire, and the Patient Global Impression–Severity (PGI-S) scale. The health-related quality of life (HRQoL) results were reported only for phase II, cohort A, of the MajesTEC-1 study. Analyses were conducted in the HRQoL-evaluable population of patients who had evaluable assessment at baseline and follow-up time points for each domain of EORTC QLQ-C30 (i.e., cycle 2, day 1; cycle 3, day 1; and so forth).

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30

At the time of analysis, using the January 4, 2023, data cut-off, the results of a post hoc analysis of the EORTC QLQ-C30 showed |||||||||||| |||| |||| |||| |||||||| || |||| ||| ||||||| |||||| |||||| |||||||||||| |||| |||||||||||| || |||||| |||||| ||||||| ||| |||||||||||| |||| ||| |||||||| ||||||||| |||||||| || |||||| |||||||||||||||||||.

At the time of analysis, using the September 7, 2021, data cut-off, meaningful improvement from baseline (10 points using the literature-based meaningful change threshold [MCT]¹⁴) to cycle 2, cycle 4, and cycle 6 was reported by up to 35.8% of patients for global health status, up to 23.9% of patients for physical functioning, up to 68.7% of patients for fatigue system scale, and up to 78.8% of patients for pain.

EQ-5D-5L

At the time of analysis, using the January 4, 2023, data cut-off, the results of a post hoc analysis of the EQ-5D-5L showed |||||||||||| |||| |||| |||| |||||||| || ||||||| |||||| ||| ||| |||| |||||||||||.

At the time of analysis, using the September 7, 2021, data cut-off, meaningful improvement from baseline (7 points using the literature-based MCT^15,16) in EQ VAS scores at cycle 2, cycle 4, and cycle 6 was reported by 23.8%, 28.6%, and 30.2% of patients, respectively. By cycle 8, 50% of patients had reported meaningful improvement in the EQ VAS score.

Time to Next Treatment

TTNT was an exploratory end point in phase II, cohort A, of the MajesTEC-1 study, and it was not reported in the Clinical Study Report at the clinical data cut-off date of January 4, 2023.

At the time of analysis, using the September 7, 2021, data cut-off, subsequent antimyeloma therapy and/or death due to progressive disease was reported for || |||||||| |||||||, with a median TTNT of |||| |||||| |||| ||| |||| || || |||||||.

Harms Results

At the time of analysis, using the January 4, 2023, data cut-off, patients in the MajesTEC-1 study had experienced at least 1 treatment-emergent adverse event (TEAE). The most common TEAEs occurring in at least 25% of patients in either phase of the study were cytokine release syndrome (CRS) (72.1%), neutropenia (71.5%), anemia (54.5%), thrombocytopenia (42.4%), lymphopenia (36.4%), diarrhea (33.9%), and pyrexia (31.5%). In the MajesTEC-1 study, || |||||||| ||||||| experienced TEAEs of Common Terminology Criteria for Adverse Events (CTCAE) grade 3, || |||||||| ||||||| experienced TEAEs of grade 4, and || |||||||| ||||||| experienced TEAEs of grade 5. The most common TEAEs of grade 3 or grade 4 were neutropenia (65.5%), anemia (37.6%), lymphopenia (34.5%), and thrombocytopenia (22.4%). The most common TEAEs of grade 5 were COVID-19 (10.8%) and general physical health deterioration (2.4%). At the time of analysis, using the January 4, 2023, data cut-off, 113 patients (68.5%) had experienced at least 1 serious TEAE in the MajesTEC-1 trial. The most common serious TEAEs occurring in at least 5% of patients in either phase of the study were COVID-19 (68.5%), pneumonia (20.6%), CRS (10.9%), pyrexia (8.5%), acute kidney injury (5.5%), and general physical health deterioration (5.5%). At the time of analysis, using the January 4, 2023, data cut-off, |||||||| |||||| stopped study treatment due to TEAEs in the MajesTEC-1 trial. The most common reasons for stopping study treatment included |||||||| ||||||||| ||||||| |||||||||||| ||||||||| ||||||||| ||||||| ||| |||||||||| ||||||||| ||||||. A total of || |||||||| ||||||| died during the study, including || |||||||| ||||||| who died due to TEAEs.

In the MajesTEC-1 study, several adverse events of clinical interest were identified, including CRS, neurologic adverse events and neurotoxicity, immune effector cell-associated neurotoxicity syndrome (ICANS), systemic administration-related reactions, injection-site reactions, hypogammaglobulinemia, cytopenia, and infections. At the time of analysis, using the January 4, 2023, data cut-off, 119 (72.1%) patients had experienced CRS events, of whom 83 (50.3%) patients experienced grade 1 events, and 35 (21.2%) patients experienced grade 2 events. One (0.6%) patient experienced CRS events of grade 3, and no patients experienced CRS events of grade 4 or grade 5. ||||| || || |||||||| ||||||| ||||||||||| || |||||||||||||||| ||||||| |||||| ||| || |||||||| ||||||| ||||||||||| ||||||||||||||||||||||| ||| |||| |||||| ||||||||||||| ||||| |||||||| |||||||| ||||||| |||||| |||||||| ||||||||||||||| ||||||||||||| |||||||| ||||||| ||||||||| ||||||| ||||||||||||| ||||||| ||| |||||||||| ||||||| |||||||||| ||||||| In the MajesTEC-1 study, a total of 132 (80.0%) patients had infections of any grade. The most common infections and infestations included |||||||| |||||||| ||||||||| |||||||| |||||||||| |||||||| ||||| ||||||||||| ||||||||| |||||||| ||||||||||||||| |||||||| ||||||||| |||||||| ||| ||||||| ||||| ||||||||| ||||||. In the MajesTEC-1 trial, 71 (43.0%) patients experienced at least 1 infection and infestation of grade 3 or grade 4, while 21 (12.7%) patients experienced at least 1 infection and infestation of grade 5. At the time of analysis, using the January 4, 2023, data cut-off, || |||||||| ||||||| had experienced at least 1 hypogammaglobulinemia TEAE, including || |||||||| ||||||| with a case of hypogammaglobulinemia, and ||||||| |||||| with a case of hypoglobulinemia. A total of 152 (92.1%) patients experienced at least 1 treatment-emergent cytopenic event, including neutropenia (71.5%), anemia (55.8%), thrombocytopenia (42.4%), and lymphopenia (36.4%). A total of 108 (65.5%) patients experienced treatment-emergent neutropenia of grade 3 or higher, 62 (37.6%) patients experienced anemia of grade 3 or higher, 37 (22.4%) patients experienced thrombocytopenia of grade 3 or higher, and 57 (34.5%) patients experienced lymphopenia of grade 3 or higher. A total of 61 (37.0%) patients experienced at least 1 case of injection-site reaction events, including 32.1% of cases of grade 1 and 4.8% of cases of grade 2.

Critical Appraisal

The MajesTEC-1 trial was a multicentre, single-arm, open-label, phase I and phase II study. Due to the lack of a comparator arm, the benefit of teclistamab compared to placebo or reference treatment was not documented. A single-arm study design is usually used when the purpose of the study is to provide preliminary evidence of the efficacy of a treatment and to collect additional safety data, and is not intended to be confirmatory for efficacy.¹⁷ Thus, a single-arm study design is a subject of several limitations that complicate the interpretation of the study results. The open-label design of the MajesTEC-1 study may increase uncertainty in subjective outcomes, including clinical response outcomes, PFS, HRQoL, and safety outcomes, introducing bias due to the inherent subjectivity of the outcome in an unblinded assessor. This bias would be less likely in more objective outcomes, such as OS, if assessed against a predetermined hypothesis. According to the FDA, the ORR can be evaluated in a single-arm study as a direct measure of a drug antitumour activity if it is defined as the sum of PRs plus CRs.¹⁸ In the MajesTEC-1 trial, the estimated ORR was tested against a predetermined hypothesis of an ORR greater than 45% (with a lower bound of the ORR 2-sided 95% CI above 30%). ORR achieved the predetermined threshold for a positive outcome in the MajesTEC-1 trial. However, for ORR, there was no adjustment for multiplicity across the various analyses of the outcome (i.e., the various data cut-offs), which may have increased the risk of false-positive conclusions. Additionally, this report presents interim analysis results because a prespecified final analysis was not available; therefore, there is the potential that the benefit of teclistamab is overestimated, but the presence and extent of any overestimation is uncertain.^19-21

Disease responses were evaluated by the IRC using IMWG 2016 criteria in both phase I and phase II, cohort A. The time-to-event end points, including OS and PFS, were identified as important outcomes by clinical experts and patient and clinician groups consulted by CADTH for this review. However, OS and PFS were not adjusted for multiplicity in the MajesTEC-1 study, and the lack of a comparator group limited the estimation of relative effects of treatment with teclistamab. In addition, the longer-term efficacy of teclistamab for OS and PFS is unknown as the MajesTEC-1 study is ongoing. The clinical experts and patient and clinician groups consulted by CADTH for this review highlighted improvement in HRQoL as an important outcome and treatment goal for patients with RRMM. The analyses of HRQoL outcomes were undertaken post hoc, which introduced a risk of bias in the selection of the reported results. In addition, analyses for HRQoL were performed in HRQoL-evaluable patients and only for phase II, cohort A, rather than in the intention-to-treat (ITT) population of the MajesTEC-1 study, which may have biased the results; however, the extent of the bias with respect to the direction and magnitude of effect is uncertain. The size of the HRQoL-evaluable population in the MajesTEC-1 study gradually decreased over time and the rate of missing data was high among those who remained in the study at longer follow-up visits. Therefore, data from later time points should be interpreted with caution due to the possibility that HRQoL scores could have been overestimated if patients with better HRQoL were more likely to complete the questionnaires.²²

According to the clinical experts, the patient population in the MajesTEC-1 study generally reflects patients in clinical practice in this setting. To be enrolled in the MajesTEC-1 study, patients with RRMM were required to have an ECOG PS score of 0 or 1 and have a measurable disease. The clinical experts consulted noted that this would not be reflective of clinical practice and that clinicians would prescribe teclistamab to patients with an ECOG PS score of 2 or 3 and to patients without biochemically measurable disease. Patients who had previously received antitumour therapy, such as a monoclonal antibody, or cytotoxic therapy within 21 days before the first dose of teclistamab, were excluded from the study; the clinical experts found this concerning as a washout period of 21 days is less relevant in this population. One of the exclusion criteria of the pivotal MajesTEC-1 study was any prior BCMA-targeted therapy. Additional supporting data were presented for phase II, cohort C, at the time of the clinical cut-off date of March 16, 2022, to address the use of teclistamab in patients previously treated with BCMA-targeted therapy in accordance with the Health Canada indication for teclistamab. Findings from phase II, cohort C, of the MajesTEC-1 study were consistent with the results from the pivotal cohort (phase I and phase II, cohort A); however, only 40 patients were included, which limits interpretation of the cohort findings. According to the clinical experts consulted by CADTH, the demographic and disease characteristics of the MajesTEC-1 study population were reflective of patients living in Canada with RRMM. The mean age of patients in the MajesTEC-1 trial was 64 years, with clinical experts noting that in the real-world setting, the mean age of patients with relapsed disease receiving fourth-line therapy and beyond would be around 70 years.²³ About 26% of patients in the MajesTEC-1 trial had at least 1 high-risk abnormality, including del(17p) and t(4;14), although clinical experts noted that the proportion of patients with cytogenetic risk is slightly higher in clinical practice. In the MajesTEC-1 study, 63 (38.2%) patients switched from weekly to biweekly dosing of teclistamab, including 54 patients who met the response criteria and 9 patients who had switched from biweekly to monthly dosing. Clinical experts consulted by CADTH believed that there would be more patients in clinical practice switching to less frequent dosing of teclistamab. According to the clinical experts consulted by CADTH and patient and clinician group input, OS, PFS, clinical response outcomes, and HRQoL are the most important outcomes for assessing the response to treatment. However, due to its study design, the MajesTEC-1 trial provided no information about the efficacy and harms of teclistamab relative to treatments that would otherwise be used in this patient population in clinical practice. In the MajesTEC-1 trial, the study population was drawn from a number of sites around the globe, including in Canada. The clinical experts indicated no major concerns with generalizing the findings from the pivotal study to the Canadian clinical setting.

GRADE Summary of Findings and Certainty of the Evidence

The selection of outcomes for the Grading of Recommendations Assessment, Development and Evaluation (GRADE) assessment was based on the sponsor’s Summary of Clinical Evidence,⁸³ consultation with clinical experts, and input received from patient and clinician groups and public drug plans. Table 2 presents the GRADE summary of findings for teclistamab in patients with RRMM in the MajesTEC-1 study.

Table 2: Summary of Findings for Teclistamab for Patients With Relapsed or Refractory Multiple Myeloma

CI = confidence interval; CR = complete response; NE = not evaluable; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; sCR = stringent complete response; VGPR = very good partial response.

Note: Details included in Table 2 are from the sponsor’s Summary of Clinical Evidence.⁸³

^aIn the absence of a comparator arm, conclusions about efficacy relative to any comparator could not be drawn and certainty of evidence started at the level of very low.

^b–1 level for serious study limitations. The reported result is from an interim analysis, and the effect may be overestimated.^19-21 There was a risk of selection bias; it was not clear whether patients were enrolled consecutively.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

Additional Supporting Data

In the MajesTEC-1 study, efficacy and safety results for phase II, cohort C, were presented to support the results of the pivotal study in accordance with the Health Canada indication for teclistamab, and to address the question from the Provincial Advisory Group regarding the use of teclistamab in patients previously treated with BCMA-targeted therapy. Phase II, cohort C, enrolled patients with RRMM who had received 3 or more prior lines of therapy, including a PI, an IMiD, an anti-38 monoclonal antibody, and a BCMA-targeted treatment (e.g., CAR T-cell therapy, ADC). At the time of analysis, using the March 16, 2022, data cut-off, 40 patients had received at least 1 dose of teclistamab in phase II, cohort C, and were included in the FAS.

At the time of analysis, using the September 7, 2021, data cut-off, 38 patients were enrolled in phase II, cohort C, including 22 (57.9%) patients who were still on treatment. Baseline characteristics for these 38 patients are summarized as follows. More patients were enrolled in MajesTEC-1 study phase II, cohort C by the data cut-off date of March 16, 2022 (N = 40); however, the baseline data for the 40 patients were not reported in the Clinical Study Report.²⁵ The median age of the patients was 63.5 years (range = 32 years to 82 years). A total of 24 (63.2%) patients were male and 14 (41.8%) were female. Most patients (89.5%) were white and 7.9% of patients identified as Black or African American. All patients were triple-class exposed, and a majority of patients were penta-exposed (78.9%). The most common immunoglobulin isotypes were immunoglobulin G, presenting in 18 (47.4%) patients. The median time from diagnosis of MM to enrolment in phase II, cohort C, was 6.5 years (range = 1.1 years to 24.1 years). Eleven (28.9%) patients had at least 1 extramedullary plasmacytoma at baseline. Of the 34 patients with baseline cytogenetic data reported, 11 (32.4%) patients had at least 1 high-risk abnormality, most commonly del(17p). A total of 20 (52.6%) patients were ISS stage I while 9 (23.7%) patients were ISS stage III. Prior anti-BCMA therapy included an ADC in 71.1% of patients and CAR T-cell therapy in 39.5% of patients.

Efficacy

At the time of analysis, using the March 16, 2022, data cut-off, the estimated median OS was 13.2 months (95% CI, 8.3 months to NE months). The median duration of follow-up was 12.5 months (range = 0.7 month to 14.4 months). In phase II, cohort C, deaths were reported in 17 (42.5%) patients in the FAS, and the proportion of patients who were censored (alive at the time of the data cut-off date) was 57.5% (23) of patients. The estimated 6-month OS probability among patients was ||||||||| ||| ||||| || ||||||, the 9-month OS probability was ||||| |||| ||| ||||| || ||||||, and the 24-month OS probability was ||||| |||| ||| ||||| || ||||||.

In phase II, cohort C, the estimated median PFS was ||| |||||| |||| ||| ||| || || |||||||. By the data cut-off date, a total of 24 (60.0%) patients had had a PFS event, and || |||||||| ||||||| were censored. The estimated 6-month PFS probability among patients in phase II, cohort C, was ||||| |||| ||| ||||| || ||||||. The 9-month PFS probability was ||||| |||| ||| ||||| || ||||||, and the 24-month PFS probability was ||||| |||| ||| ||||| || ||||||.

At the time of analysis, using the March 16, 2022, data cut-off, 11 (27.5%) patients (95% CI, 14.6% to 43.9%) in phase II, cohort C, attained CR or better (CR or sCR), 11 (27.5) patients (95% CI, 14.6% to 43.9%) attained sCR, 19 (47.5%) patients (95% CI, 31.5% to 63.9%) attained VGPR or better (VGPR, CR, or sCR), and 21 (52.5%) patients (95% CI, 36.1% to 68.5%) attained an overall response (PR or better). At the time of analysis, using the March 16, 2022, data cut-off, of the 21 patients who had attained PR or better, the median time to first response was 1.2 months (range = 0.2 month to 4.9 months), while the median time to best response was 2.9 months (range = 1.1 months to 9.5 months). At the time of analysis, using the March 16, 2022, data cut-off, the estimated median duration of response was not reached in phase II, cohort C. Among 21 responders (with a PR or better response), 15 (23.8%) patients had disease progression or died due to any cause. The estimated probability of patients remaining in response at 9 months was ||||| |||| ||| ||||| || ||||||, while the probability of patients remaining in response at 12 months was ||||| |||| ||| ||||| || ||||||.

Harms

At the time of analysis, using the March 16, 2022, data cut-off, all patients in phase II, cohort C, of the MajesTEC-1 study had experienced at least 1 TEAE. The most common TEAEs of any grade occurring in at least 20% of patients in phase II, cohort C, were CRS (67.5%), neutropenia (65.0%), anemia (50.0%), thrombocytopenia (45.0%), lymphopenia (45.0%), constipation (35.0), diarrhea (35.0%), pyrexia (32.5%), injection-site erythema (32.5%), and arthralgia (25.0%). In phase II, cohort C, 9 (22.5%) patients experienced TEAEs of grade 3, 20 (50.0%) patients experienced TEAEs of grade 4, and 8 (20.0%) patients experienced TEAEs of CTCAE grade 5. The most common TEAEs of grade 3 or grade 4 were neutropenia (62.5%), lymphopenia (42.5%), anemia (35.0%), and thrombocytopenia (30.0%). At the time of analysis, using the March 16, 2022, data cut-off, 24 (60.0%) patients had experienced at least 1 serious TEAE. The most common TEAEs were COVID-19 (10.0%), CRS and febrile neutropenia (7.5%), and anemia (5.0%). At the time of analysis, using the March 16, 2022, data cut-off, no patients had experienced a TEAE leading to treatment discontinuation. A total of 17 (42.5%) patients had died, of whom 8 (20.0%) patients had died within 30 days of the last dose of teclistamab. In phase II, cohort C, of the MajesTEC-1 study, several adverse events of clinical interest were identified, including CRS, neurologic adverse events and neurotoxicity, ICANS, injection-site reactions, hypogammaglobulinemia, cytopenia, infections, and tumour lysis syndrome (TLS). At the time of analysis, using the March 16, 2022, data cut-off, 26 (65.0%) patients in phase II, cohort C, had experienced 44 CRS events of any grade. A total of 21 (52.5%) patients in phase II, cohort C, had experienced at least 1 neurologic TEAE. The most common neurologic TEAEs included headache (22.5%), ICANS and insomnia (10.0%), encephalopathy (5.0%), peripheral sensory neuropathy (7.5%), dizziness (5.0%), and motor dysfunction (5.0%). At the time of analysis, using the March 16, 2022, data cut-off, a total of 10 (25.0%) patients had experienced at least 1 neurotoxicity event, including headache (12.5%) and ICANS (10.0%). A total of 26 (65.0%) patients in phase II, cohort C, had at least 1 treatment-emergent infection of any grade. The most common infections and infestations included COVID-19 (12.5%), bronchitis (10.0%), pneumonia (7.5%), cytomegalovirus infection reactivation (5.0%), implant site infection (5.0%), and laryngitis (5.0%). A total of 10 (25.0%) patients had experienced infections of grade 3 or grade 4, and 10 (25.0%) patients had experienced serious infections. At the time of analysis, using the March 16, 2022, data cut-off, proportions of patients with hypogammaglobulinemia were not reported. A total of 4 (10%) patients had experienced ICANS. All cases of ICANS were concurrent with CRS events, and no patients discontinued treatment due to ICANS. A total of 35 (87.5%) patients in phase II, cohort C, experienced at least 1 treatment-emergent cytopenic event, including neutropenia (67.5%), anemia (50.0%), thrombocytopenia (45.0%), and lymphopenia (45.0%). Hemorrhagic events were reported for 5 (12.5%) patients, 1 of which was of grade 2.

Findings from phase II, cohort C, of the MajesTEC-1 study were consistent with the results from the pivotal cohort (phase I and phase II, cohort A); however, only 40 patients were included, which limits interpretation of the cohort findings. Since the patients who took part in phase II, cohort C, were from the MajesTEC-1 study, it is reasonable to expect that the same limitations of the pivotal MajesTEC-1 study (phase I and phase II, cohort A) with respect to internal and external validity are relevant to phase II, cohort C, of the MajesTEC-1 study.

Long-Term Extension Studies

No long-term extension studies were submitted by the sponsor.

Indirect Comparisons

The efficacy and safety of teclistamab among adult patients with RRMM who had received at least 3 prior lines of therapy have been previously assessed in the MajesTEC-1 study. However, no head-to-head evidence of teclistamab compared against other treatments for RRMM was available for this review. Due to this gap in evidence, the sponsor submitted 6 indirect treatment comparisons (ITCs), of which 3 ITCs were used to inform the pharmacoeconomic model, including 2 ITCs comparing the relative efficacy of teclistamab with real-world physician’s choice (RWPC) therapy (from the LocoMMotion and daratumumab trials)^26-29 and another ITC comparing the relative efficacy of teclistamab with ciltacabtagene autoleucel (from the CARTITUDE-1 trial).³⁰ Of the 3 ITCs submitted by the sponsor that were not included in the pharmacoeconomic model, 1 published ITC compared the relative efficacy of teclistamab with RWPC therapy (from the Flatiron Health database),^29,31 and 2 conference abstracts compared the relative efficacy of teclistamab with belantamab mafodotin (from the DREAMM-2 study),³² and selinexor in combination with dexamethasone (from the STORM study, part 2).³³ No systematic review was reported by the sponsor.

Sponsor-Submitted ITCs Used to Inform Pharmacoeconomic Model

Three ITCs that were used to inform the pharmacoeconomic model were selected because they met the selection criteria. The sponsor stated that they included the most relevant comparators for the submission, including treatments that are reimbursed in Canada or have received a recommendation for reimbursement from CADTH for the indication under review. Given the absence of a comparator group in the MajesTEC-1 study, an external control group was used to establish the comparative efficacy of teclistamab versus treatments used in current clinical practice. To estimate the comparative efficacy, an inverse probability of treatment weighting (IPTW) estimator of the average treatment effect in the treated (ATT) was chosen for the main ITC analyses. This propensity score–based method allowed the RWPC cohorts from the LocoMMotion study and the daratumumab trials cohort, as well as the population in the CARTITUDE-1 study, to be reweighted to match the MajesTEC-1 trial’s population. There was sufficient overlap between patient characteristics between the MajesTEC-1 study and the LocoMMotion, CARTITUDE-1, and 4 daratumumab trials (the APOLLO, POLLUX, CASTOR, and EQUULEUS studies) to justify weighting techniques that do not depend on matching or excluding incompatible subpopulations. Propensity scores were estimated under an assumed logistic regression model using each cohort (the MajesTEC-1 study, the LocoMMotion study, the CARTITUDE-1 study, and the daratumumab trials cohort) as the dependent variable and selected baseline covariates as independent variables. The estimated propensity scores were then used to derive weights for each participant using the appropriate weighting formulas for the desired target population.

To ensure that the most important clinical factors were balanced between populations, an evidence-informed process (through a literature review of studies conducted to identify clinical outcomes in triple-class exposed patients with RRMM, and input from clinical experts) was used to select the prognostic factors for adjustment. In 2 ITCs comparing the relative efficacy of teclistamab with RWPC therapy from the LocoMMotion study and ciltacabtagene autoleucel from the CARTITUDE-1 study, treatment weights were rescaled to sum up to the original number of participants in the comparator studies. For the binary outcomes (e.g., ORR, CR or better, VGPR or better), a weighted logistic regression was used to derive an estimate of a conditional odds ratio (OR) and the corresponding 95% CI, transformed to response-rate ratio.³⁴ For the time-to-event outcomes (i.e., PFS, duration of response, TTNT, and OS), a weighted Cox proportional hazards model was used to derive an estimate of the hazard ratio (HR) and the corresponding 95% CI. The appropriateness of the proportional hazards assumption used in the estimation of the HR of the survival outcomes was assessed based on visual inspection of the log-cumulative hazard plot, visual inspection of the Schoenfeld residuals plot, and the performance of the Grambsch-Therneau test (with a P value less than 0.05 considered to indicate a violation of the assumption).³⁵

Teclistamab (MajesTEC-1 Study) Versus RWPC (LocoMMotion Study)

The MajesTEC-1 trial (n = 165) is an ongoing, phase I and phase II, multicentre, open-label, single-arm study. Eligible patients must have received a diagnosis of MM under IMWG diagnostic criteria, and have had prior exposure to at least 1 PI, 1 IMiD, and 1 anti-CD38 monoclonal antibody. In terms of efficacy outcomes, the primary outcome in the MajesTEC-1 trial is ORR; secondary outcomes include PR or better response, VGPR or better response, CR or better response, OS, PFS, MRD-negativity rate, duration of response, and TTR; and the exploratory outcome is TTNT. The LocoMMotion trial (n = 248) was a prospective, noninterventional study of real-life standard of care in patients with a documented diagnosis of MM according to IMWG diagnostic criteria who had received at least 3 prior lines of therapy including, at a minimum, PIs, IMiDs, and anti-CD38 monoclonal antibodies. The primary outcome in the LocoMMotion study was ORR; secondary outcomes included VGPR rate, CR rate, sCR rate, MRD-negativity rate, clinical benefit rate, duration of response, TTR, TTNT, PFS, and OS. Approximately 90 unique treatment regimens were used in the LocoMMotion study, including corticosteroids, PIs, IMiDs, alkylating drugs, and anti-CD38 monoclonal antibodies, and various combinations, reflecting the existing variety of real-life antimyeloma treatments in this population.²⁸ A total of 17 prognostic factors that were identified a priori as important for population alignment were available from both studies. Before weighting, moderate (standardized mean difference [SMD] greater than 0.1 and less than or equal to 0.2) to substantial (SMD greater than 0.2) differences were observed for many of the variables included in the main IPTW analysis. After reweighting, observable differences remained in the ITT populations with regard to refractory status, and time to progression on last regimen. Cytogenetic risk was considered an important risk factor; however, it was not included in the main analyses due to a high level of missingness in the LocoMMotion study cohort (37.1%). As the LocoMMotion study population only included a low number of non-white patients, adding the race variable to the adjustment led to high weights for these patients and decreased balance for all the other variables.

Following adjustment, the estimated HRs of OS and PFS for teclistamab versus RWPC therapy were |||| |||| ||| |||| || ||||| ||| |||| |||||| |||| || |||||| ||||||||||||| || |||||| || |||||||||||. For duration of disease and TTNT, following adjustment, the estimated HR for teclistamab versus RWPC therapy was |||| |||| ||| |||| || ||||| ||| |||| |||| ||| |||| || |||||| ||||||||||||| || |||||| || |||||||||||. For ORR, following adjustment, the OR for teclistamab versus RWPC therapy was 4.89 (95% CI, 3.19 to 7.47), in favour of teclistamab. For CR or better, following adjustment, the OR for teclistamab versus RWPC therapy was |||||| |||| ||| ||||| || |||||||||| || |||||| || |||||||||||. For VGPR or better, following adjustment, the OR for teclistamab versus RWPC therapy was ||||| |||| ||| |||| || ||||||| || |||||| || |||||||||||. The results of the sensitivity analyses, including the analysis adjusted for all variables, were consistent with the main analysis results. No results for HRQoL and safety outcomes were reported in the ITC comparing the MajesTEC-1 and LocoMMotion trials.

Critical Appraisal

The sponsor-submitted ITC comparing the relative efficacy of teclistamab with RWPC therapy from the LocoMMotion trial had a number of limitations that challenged the internal and external validity of the findings. No systematic search was conducted to identify relevant studies; therefore, there is a risk of selection bias. There was variation in the design of the MajesTEC-1 and LocoMMotion studies, as the MajesTEC-1 study was a phase I and phase II trial while the LocoMMotion study was an observational, noninterventional study. Both studies were open label, so there is a risk of bias in the measurement of subjective outcomes, particularly PFS, and clinical response outcomes. Objective outcomes including OS should be unaffected by the open-label designs. The definitions of end points were similar across the studies; however, the median duration of follow-up was 14.1 months in the MajesTEC-1 study²⁸ and 16.1 months in the LocoMMotion study.²⁸ PFS and the clinical response outcomes were assessed based on IMWG criteria by an IRC in the MajesTEC-1 study and by an independent response review committee in the LocoMMotion study to reduce bias. In the MajesTEC-1 trial, there was a high degree of concordance between ORR assessments by the IRC and by the computerized algorithm used. The sensitivity analysis of ORR based upon investigator assessment was consistent with the primary analysis using IRC assessment based on IMWG response criteria, and similar comparisons were done with PFS in the MajesTEC-1 trial. The LocoMMotion study used a total of 90 different treatment regimens and given that not all treatment regimens are relevant to Canadian clinical practice in fourth-line settings and beyond (e.g., daratumumab, ixazomib, melphalan), the study results may not be generalizable to Canadian clinical practice. There was notable heterogeneity in the populations of the MajesTEC-1 and LocoMMotion studies. Of the 17 prognostic factors that were identified a priori, 15 variables were considered in the IPTW analyses for adjustment. Cytogenetic risk was considered an important risk factor by clinical experts; however, it was not included in the main analyses due to a high level of missingness in the LocoMMotion trial cohort (37.1%). The clinical experts consulted by CADTH noted that cytogenetic risk is an important prognostic factor, and omitting this factor could result in potential bias. After reweighting, populations from the MajesTEC-1 and LocoMMotion trials were more balanced, except for observed differences persisting in refractory status and time to progression on the final regimen. While the weighted populations were balanced with respect to known, measured prognostic factors, it remains unclear whether other unmeasured clinically relevant variables were unaccounted for. The variables not included in the planned adjustment set (unknown or unmeasured prognostic factors) can result in residual confounding and bias the estimates.³⁶ Assessment of residual bias was not performed or reported. Therefore, the results of the IPTW analysis may be considered to have a high risk of residual bias;³⁷ however, the magnitude and direction of any bias is unknown. In addition, the interpretation of the outcomes is challenging due to systematic differences in study design. The sponsor stated that due to a small sample size in the MajesTEC-1 and LocoMMotion trials, a scaled ATT weighting approach was used to scale treatment weightings so that they were summed to the original number of participants in the comparator studies. No information was reported in this IPTW analysis regarding the distribution of weights generated by the weighting process and the number of patients with extremely high and extremely low weights (including patients assigned 0 weight). Therefore, it remains unclear if patients with 0 weights (when there is no overlap with the target study) were excluded from the adjusted sample of the LocoMMotion study in accordance with the National Institute for Health and Care Excellence (NICE) Decision Support Unit (DSU) Technical Support Document,³⁷ and what the effective sample size in the LocoMMotion study was after reweighting to estimate the number of nonweighted patients. Thus, due to the lack of clarity, the evidence obtained from this IPTW analysis remains uncertain, limiting the interpretation and generalizability of the results. Several sensitivity analyses were conducted, and results of the sensitivity analyses were consistent with the main analyses. For the OS, PFS, TTNT, and clinical response outcomes, the results of the adjusted treatment comparisons were consistent across end points, favouring teclistamab over RWPC therapy; this is consistent with the opinion of the clinical experts consulted for this review. However, these findings must be interpreted in the context of the methodological limitations of these studies. Safety outcomes were not analyzed in the ITC report and no justification was provided, which precludes a balanced judgment of comparative benefit relative to comparative harms. Outcomes that are important to patients, such as HRQoL, were also not analyzed in this ITC.

Teclistamab (MajesTEC-1 Study) Versus Ciltacabtagene Autoleucel (CARTITUDE-1 Study)

The MajesTEC-1 trial (n = 165) is an ongoing, phase I and phase II, multicentre, open-label, single-arm study. Patients in the MajesTEC-1 trial received teclistamab at a recommended dose of 1.5 mg/kg subcutaneously once a week, followed by step-up doses of 0.06 mg/kg and 0.3 mg/kg. The index date in the MajesTEC-1 study was defined as the date of the first dose for the MajesTEC-1 study. The CARTITUDE-1 study (n = 113) is an open-label, single-arm, phase Ib and phase II clinical trial evaluating the safety and efficacy of ciltacabtagene autoleucel in adult patients with RRMM. Eligible patients were diagnosed with MM according to IMWG diagnostic criteria and must have received at least 3 prior lines of therapy or must be double-refractory to an IMiD and a PI. In the CARTITUDE-1 study, following apheresis and premedication, ciltacabtagene autoleucel was administered as a single infusion dose of 0.75 × 10⁶ CAR-positive viable T-cells per kg. The primary outcome in the CARTITUDE-1 study is ORR; secondary outcomes include VGPR rate, CR rate, sCR rate, MRD-negativity rate, clinical benefit rate, duration response, TTR, TTNT, PFS, and OS. The ITT population in the CARTITUDE-1 trial includes all patients who underwent apheresis with the index date defined as the date of apheresis.

Before weighting, moderate to substantial differences were observed for many of the main analysis variables. After weighting, populations in the MajesTEC-1 and CARTITUDE-1 studies were more balanced. After adjustment, differences remained in the ITT populations with regard to refractory status, age, hemoglobin level, and creatinine clearance. Following adjustment, the estimated HRs of OS and PFS for teclistamab versus ciltacabtagene autoleucel were |||| |||| ||| |||| || ||||| ||| |||| |||| ||| |||| || ||||||||||||||||||| || |||||| || |||||||||||||| ||||||||||. Following adjustment, the estimated HR of duration of response for teclistamab versus ciltacabtagene autoleucel was |||| |||| ||| |||| || |||||. Following adjustment, the estimated HR of TTNT for teclistamab versus ciltacabtagene autoleucel was |||| |||| ||| |||| || |||||| || |||||| || |||||||||||||| ||||||||||. No sensitivity analysis was performed in this ITC. No results for clinical response outcomes, including ORR, CR or better, and VGPR or better, were included in the ITC comparing the MajesTEC-1 and CARTITUDE-1 trials. No results for HRQoL and safety outcomes were included in the ITC comparing the MajesTEC-1 and CARTITUDE-1 studies.

Critical Appraisal

No systematic search was conducted to identify relevant studies; therefore, there is a risk of selection bias. Both the MajesTEC-1 and CARTITUDE-1 studies included in the ITC were presented with an unclear risk of bias for statistical analysis and a high risk for the measurement of subjective outcomes, such as PFS or clinical response outcomes, due to the open-label study design. Objective outcomes including OS should be unaffected by the open-label designs. The MajesTEC-1 trial cohort represented a broad population from Europe, Canada, and the US, whereas the results from the CARTITUDE-1 trial are drawn from US patients only. Therefore, it is unclear whether differences in clinical practice or treatment availability exist across regions, and the direction and magnitude of potential biases remain unclear. After weighting, populations in the MajesTEC-1 and CARTITUDE-1 trials were more balanced, although observable differences remained between the trials in refractory status, age, hemoglobin level, and creatinine clearance. While the weighted populations were balanced with respect to known, measured prognostic factors, it remains unclear whether other unmeasured clinically relevant variables were unaccounted for. The variables not included in the planned adjustment set (unknown or unmeasured prognostic factors) can result in residual confounding and bias the estimates.³⁶ Assessment of residual bias was not performed or reported. Therefore, the results of the IPTW analysis may be considered to have a high risk of residual bias;³⁷ however, the magnitude and direction of any bias is unknown. In addition, the interpretation of the outcomes is challenging due to systematic differences in study design and duration of follow-up. The sponsor stated that due to a small sample size in the MajesTEC-1 and CARTITUDE-1 studies, a scaled ATT weighting approach was used to scale treatment weightings so that they were summed to the original number of participants in the comparator studies. No information was reported in this IPTW analysis regarding the distribution of weights generated by the weighting process and the number of patients with extremely high and extremely low weights (including patients assigned 0 weight). Therefore, it remains unclear if patients with 0 weights were excluded from the adjusted sample of the CARTITUDE-1 study in accordance with the NICE DSU Technical Support Document,³⁷ and what the effective sample size in the CARTITUDE-1 study was after reweighting to estimate the number of nonweighted patients. Thus, due to the lack of clarity, the evidence obtained from this IPTW analysis remains uncertain, limiting the interpretation and generalizability of the results. No methods for handling missing data were performed or reported in the ITC comparing teclistamab with ciltacabtagene autoleucel. For OS, PFS, and TTNT, the results of the adjusted treatment comparisons were consistent across end points, favouring ciltacabtagene autoleucel over teclistamab; however, these findings must be interpreted in the context of the methodological limitations of these studies. According to the clinical experts consulted by CADTH for this review, the population of the CARTITUDE-1 study was relatively healthy compared to the MajesTEC-1 trial’s population. Although all clinical response outcomes (ORR, CR or better, VGPR or better) were available in both studies, they were not assessed in this analysis. Safety outcomes were not analyzed in the ITC report, and no justification was provided, which precludes a balanced judgment of comparative benefit relative to comparative harms. Outcomes that are important to patients, such as HRQoL, were also not analyzed in this ITC.

Teclistamab (MajesTEC-1 Study) Versus Physician’s Choice Therapy (APOLLO, POLLUX, CASTOR, and EQUULEUS Studies)

The MajesTEC-1 trial (n = 165) is an ongoing, phase I and phase II, multicentre, open-label, single-arm study. Patients in the daratumumab trials were triple-class exposed and were treated with a physician’s choice (PC) of therapy after discontinuing the trial treatments. The daratumumab trials cohort consisted of patients from the long-term follow-up data from the POLLUX, CASTOR, EQUULEUS, and APOLLO studies. Because this ITC analysis retrospectively included patients participating in long-term follow-up clinical trials of daratumumab, it was possible to include patients in the earliest line of therapy initiated after all key selection criteria were met. However, this differed from the MajesTEC-1 study, 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 in the clinical trial. To account for this difference, patients in the daratumumab trials became eligible for this analysis after having at least 3 prior lines of therapy, and patients who received multiple subsequent therapies after meeting eligibility criteria contributed multiple observations. Overall, 1,577 patients were initially included in the daratumumab trials cohort, of whom 642 patients were triple-class exposed and had received at least 1 treatment regimen. Of the 642 patients, 427 patients with 806 observations met the MajesTEC-1 trial’s key inclusion criteria.²⁷ A total of 248 unique regimens were used in the RWPC from the daratumumab trials cohort. The primary outcome in the POLLUX study was PFS; secondary outcomes included time to progression, VGPR or better, MRD-negativity rate, ORR, OS, TTR, and duration of response. The primary outcome in the CASTOR study was PFS; secondary outcomes included time to progression, VGPR or better, MRD-negativity rate, ORR, OS, and TTR. The primary outcome in the EQUULEUS study was the proportion of adverse events and dose-limiting toxicities; secondary outcomes included ORR, OS, CR or better, and duration of response; and exploratory outcomes included PFS, MRD-negativity rate, and pharmacokinetics. The primary outcome in the APOLLO study was PFS; secondary outcomes included VGPR or better, MRD-negativity rate, ORR, OS, duration of response, TTNT, and TTR. In the daratumumab trials cohort, the index date was defined as the start of each eligible line of therapy.

Before weighting, moderate to substantial differences were observed for many variables. After weighting, substantial differences were observed with regard to prior stem cell transplant, ECOG PS, race, and type of MM. After adjustment, the resulting effective sample size in the daratumumab trials cohort was 264 patients compared to the original 806 patients. Following adjustment, the estimated HR for OS and PFS for teclistamab versus PC therapy was |||| |||| ||| |||| || ||||| ||| |||| |||| ||| |||||| |||||| ||||||||||||| || |||||| || |||||||||||. Following adjustment, the estimated HR of TTNT for teclistamab versus PC therapy was |||| ||||||| |||| || |||||| || |||||| || |||||||||||. For ORR, following adjustment, the OR for teclistamab versus PC therapy was |||| |||| ||| |||| || |||||| For CR or better, the OR for teclistamab versus PC therapy was ||||| |||| ||| |||| || ||||||. For VGPR or better, following adjustment, the OR for teclistamab versus PC therapy was ||||| |||| ||| |||| || ||||||. Results from the fully adjusted scenario analysis were consistent with the main analysis results. No results for HRQoL and safety outcomes were included in the ITC comparing the MajesTEC-1 study and the daratumumab trials cohort.

Critical Appraisal

There was variation in the design of the MajesTEC-1 study and the 4 daratumumab trials included in the IPTW analysis. The MajesTEC-1 study was a phase I and phase II trial while the POLLUX, CASTOR, and APOLLO studies were open-label, phase III, randomized controlled trials (RCTs), and the EQUULEUS trial was an open-label, nonrandomized, phase Ib study. Both the MajesTEC-1 study and the daratumumab trials were open label, so there was a risk of bias in the measurement of subjective outcomes, particularly PFS, and clinical response outcomes. Objective outcomes, including OS, should have been unaffected by the open-label designs. In addition, although 3 of the daratumumab trials included in the ITC were RCTs (the POLLUX, CASTOR, and APOLLO trials), and the EQUULEUS trial was an open-label, nonrandomized phase Ib study, patients selected from the daratumumab trials cohort were included in the analysis retrospectively. A total of 248 unique treatment regimens were used in the daratumumab trials cohort, many of which were not relevant to Canadian clinical practice; thus, the study results may not be generalizable to the Canadian setting. There was notable heterogeneity in the populations of the MajesTEC-1 study and the daratumumab trials cohort. Nine of the 17 prognostic factors identified a priori were used for ATT weighting in the main analysis. After weighting, populations from the studies were balanced with respect to known, measured prognostic factors. While the weighted populations were balanced with respect to known, measured prognostic factors, it remains unclear whether other unmeasured clinically relevant variables were unaccounted for. The variables not included in the planned adjustment set (unknown or unmeasured prognostic factors) can result in residual confounding and bias the estimates.³⁶ Assessment of residual bias was not performed or reported. Therefore, the results of the IPTW analysis may be considered to have a high risk of residual bias;³⁷ however, the magnitude and direction of any bias is unknown. In addition, IPTW cannot adjust for differences related to other sources of heterogeneity, such as differences in study design, or median duration of follow-up. After adjustment, the effective sample size was reduced to approximately 32.8% (264 of 804) of patients in the original sample size in the daratumumab trials cohort. A small effective sample size implies that the estimates are being influenced by a subset of the patients from the daratumumab trials and are caused by a violation of the transportability of the effects across cohorts.²⁰ The proportional hazards assumption was tested for the time-to-event outcomes, and the Grambsch-Therneau test was significant for PFS and TTNT analyses, indicating potential violation of this assumption. The Cox proportional hazards model assumes that the HR across treatment groups does not change over time; therefore, violation of the proportional hazards assumption may lead to misleading and erroneous scientific conclusions.^38,39 For the OS, PFS, TTNT, and clinical response outcomes, the results of the adjusted treatment comparisons were consistent across end points, favouring teclistamab over PC therapy; this is consistent with the opinion of the clinical experts consulted for this review. However, these findings must be interpreted in the context of the methodological limitations of these studies. Safety outcomes were not analyzed in the ITC report, and no justification was provided, which precluded a balanced judgment of comparative benefit relative to comparative harms. Outcomes that are important to patients, such as HRQoL, were also not analyzed in this ITC.

Other ITCs Not Included in the Pharmacoeconomic Model

The ITCs submitted by the sponsor had a number of limitations that challenged the internal and external validity of the findings. No systematic search was conducted to identify the comparator studies included in the 3 ITCs that were not used to inform the pharmacoeconomic model; therefore, there is a risk of selection bias. The selection criteria used to identify the comparator were consistent with the objective, and studies were included if they assessed treatment for RRMM, included patients with triple-class exposed RRMM who had received at least 3 prior lines of therapy, and had reported sufficient efficacy outcome data. However, no details were provided regarding the timing of the literature review, or the databases used. It is not possible to know whether the results may have differed if data from different RRMM studies or databases had been used. The list of excluded studies is not available and the risk of bias of the included studies was not assessed. Given the absence of a comparator group in the MajesTEC-1 study, an external control group was used to establish the relative efficacy of teclistamab versus treatments used in current clinical practice.

Teclistamab (MajesTEC-1 Study) Versus RWPC Therapy (Flatiron Health Database)

An ITC using the IPTW approach was conducted to assess the relative efficacy of teclistamab compared with RWPC therapy, using individual patient-level data from the MajesTEC-1 trial (for teclistamab) and the nationwide deidentified electronic health record–derived Flatiron Health database (for the RWPC cohort). Key eligibility criteria of the MajesTEC-1 study were applied to the RWPC therapy cohort, including a diagnosis of MM using IMWG criteria of prior exposure to 3 or more lines of therapy. Patients in the Flatiron Health database cohort who received multiple subsequent therapies after meeting eligibility criteria contributed multiple observations to the ITC analysis. The MajesTEC-1 trial cohort included data from 165 patients, while the unadjusted population of the RWPC Flatiron Health cohort included 420 unique patients, corresponding to 766 eligible lines of therapy. The propensity score–based method of IPTW with an ATT weighting was used to reweight the RWPC Flatiron Health cohort to align with the MajesTEC-1 trial’s population and adjust for imbalances between patient populations. For the MajesTEC-1 trial, a clinical cut-off of March 16, 2022, was used, with a median duration of follow-up of 14.1 months. For the RWPC Flatiron Health cohort, patients who had 2 or more documented clinical visits on or after January 2011 were included, with a median duration of follow-up of 18.2 months. After weighting, the effective sample size of the RWPC Flatiron Health cohort reduced to 42.6% of the original population.

Following adjustment, the estimated HR of OS for teclistamab versus RWPC therapy from the Flatiron Health cohort was 0.82 (95% CI, 0.59 to 1.14). For PFS, following adjustment, the estimated HR for teclistamab versus RWPC from the Flatiron Health cohort was 0.43 (95% CI, 0.33 to 0.56). For TTNT, following adjustment, the estimated HR for teclistamab versus RWPC from the Flatiron Health cohort was 0.36 (95% CI, 0.27 to 0.49). No results for safety or HRQoL were included in the ITC comparing the MajesTEC-1 study and the Flatiron Health cohort.

Critical Appraisal

As the Flatiron Health database was not selected using a systematic approach, there is a risk of selection bias. It is not possible to know whether the results may have differed if data from different RRMM studies or databases had been used. Numerous therapies were used in the RWPC groups from the Flatiron Health cohort, many of which were not relevant to Canadian clinical practice; thus, the ITC results may not be generalizable to the Canadian setting. Additionally, patients included in the present analysis initiated eligible lines of therapy between 2016 and 2021; however, clinical practice has changed since the enrolment of patients from these sources and may not be reflective of current treatment standards in Canada. Patients selected from the Flatiron Health cohort were included in the analysis retrospectively. Data analyzed retrospectively from databases are prone to unique biases (e.g., selection bias, confounding) compared with those collected from prospective interventional studies, which cannot be controlled using IPTW methods. Outcomes in the MajesTEC-1 study were assessed by the IRC while outcomes in the Flatiron Health cohort were assessed by the investigators; thus, the risk of bias in the outcome measurements is increased relative to the same outcomes as measured in the MajesTEC-1 study. The duration of follow-up in the MajesTEC-1 trial was 14.1 months versus 18.2 months in the Flatiron Health cohort. There were important differences in the design of the studies including in this ITC, as the MajesTEC-1 study was a phase I and phase II study while the Flatiron Health cohort was a real-world cohort from electronic health records in the US, which limits the ability to draw strong conclusions about the efficacy of teclistamab relative to RWPC therapy due to differences in clinician and patient behaviours, the heterogeneity of treatments for intercurrent events, and differences in data collection and intake. Such methodological differences could not be adjusted for in the IPTW analysis, and the magnitude and direction of any resulting bias is uncertain. There was evidence of heterogeneity between the MajesTEC-1 trial’s population and the Flatiron Health cohort. It remains unclear how balanced populations were for other variables that may be clinically relevant but could not be adjusted due to lack of data, or those variables that were not part of the planned adjustment (unknown or unmeasured prognostic factors), which leaves the potential for residual confounding.³⁶ After weighting, the effective sample size of the Flatiron Health cohort was reduced by 57.4% from the included population. The reduction in the effective sample size reflects the heterogeneity between the trials among the variables included in the weighting process. A small effective sample size implies that the weighted estimates are being influenced by a subset of patients from the Flatiron Health cohort who may not be representative of the entire study population; this may limit the generalizability of the results. For OS and PFS, the results of the adjusted treatment comparisons were consistent across end points, favouring teclistamab over RWPC therapy from the Flatiron Health cohort. However, these findings must be interpreted in the context of the methodological limitations of these studies.

Teclistamab (MajesTEC-1 Study) Versus Belantamab Mafodotin (DREAMM-2 Study)

An unanchored matching-adjusted indirect comparison (MAIC) was conducted to compare the efficacy of teclistamab with belantamab mafodotin using individual patient data from the MajesTEC-1 trial (n = 150) and summary-level data from the DREAMM-2 trial (n = 97). The MajesTEC-1 trial was an open-label, single-arm, phase I and phase II study while the DREAMM-2 trial was an open-label, 2-arm, phase II study. The DREAMM-2 study’s eligibility criteria were applied to patients from the ITT population of the MajesTEC-1 study. Compared to patients in the DREAMM-2 study’s population, the MajesTEC-1 study’s population had a higher proportion of patients who had ISS stage I disease. All patients had triple-class exposed RRMM who had received at least 3 prior lines of therapy. Individual patient data from the MajesTEC-1 trial were weighted to match the aggregated DREAMM-2 trial baseline patient characteristics. The following factors were used to adjust for imbalances between patient populations: refractory status, cytogenetic profile, ISS staging, the presence of extramedullary disease, and the number of prior lines of therapy. The effective sample size of the MajesTEC-1 trial after propensity score matching was 33 patients. The comparative efficacy of teclistamab relative to belantamab mafodotin was estimated for ORR, CR or better, OS, PFS, and duration of response. For binary outcomes, the relative effects were quantified using an OR and 95% CI derived from a weighted logistic regression analysis, while time-to-event outcomes were estimated using a weighted Cox proportional hazards model.

Following adjustment, the estimated HR of OS for teclistamab versus belantamab mafodotin was 0.95 (95% CI, 0.47 to 1.92). For PFS, following adjustment, the estimated HR for teclistamab versus belantamab mafodotin was 0.63 (95% CI, 0.34 to 1.15), and the estimated HR of duration of response was 0.19 (95% CI, 0.05 to 0.73). Following adjustment, the OR of ORR for teclistamab versus belantamab mafodotin was 2.05 (95% CI, 0.92 to 4.57), while the OR of CR or better was 2.13 (95% CI, 0.80 to 5.65). No results for safety or HRQoL were included in the ITC comparing the MajesTEC-1 and DREAMM-2 trials.

Critical Appraisal

The open-label design of the studies can result in a risk of bias in the study conduct, including the measurement of the outcomes, and increase uncertainty in subjective outcomes such as PFS and ORR. The bias will likely favour the experimental intervention, although the extent of bias is uncertain. The effective sample size was reduced after adjustment in the MAIC analysis to approximately 22.0% (33 of 150) of the patients in the original population in the MajesTEC-1 study. The reduction in the effective sample size reflects the heterogeneity between the trials among the variables, including in the weighting process. Small effective sample size implies that the weighted estimates are being influenced by a subset of patients from the MajesTEC-1 study who may not be representative of the entire study population; this may limit the generalizability of the results. Populations from the studies were balanced with respect to known, measured prognostic factors. It remains unclear how balanced populations were for other variables that may have been clinically relevant but could not be adjusted due to lack of data, or those variables that were not part of the planned adjustment (unknown or unmeasured prognostic factors), which leaves the potential for residual confounding.³⁶ In the MAIC analysis, the results in efficacy estimates were imprecise (i.e., wide CIs) in the end points assessed (including HR = 1), and the upper and lower boundaries of the CIs suggest the potential for different conclusions regarding the efficacy of teclistamab relative to the comparator drugs. Therefore, no superiority conclusions could be drawn from the MAIC submitted by the sponsor due to methodological limitations and imprecision in the effect estimates.

Teclistamab (MajesTEC-1 Study) Versus Selinexor in Combination With Dexamethasone (STORM Study, Part 2)

An unanchored MAIC was conducted to compare the efficacy of teclistamab with selinexor in combination with dexamethasone using individual patient data from the MajesTEC-1 trial (n = 150) and summary-level data from the STORM trial, part 2 (n = 122). The eligibility criteria of the STORM trial, part 2, were applied to patients from the ITT population of the MajesTEC-1 study. Compared to patients in the STORM trial, part 2, the MajesTEC-1 trial’s population had a higher proportion of patients with Revised International Staging System (R-ISS) stage II. The 2 populations were similar in age, ECOG PS, and cytogenetic status. All patients had triple-class exposed RRMM. After applying the eligibility criteria of the STORM trial, part 2, individual patient data from patients in the MajesTEC-1 study were weighted to match the aggregated baseline patient characteristics from the STORM trial, part 2. For binary outcomes, the relative effects were quantified using an OR and 95% CI derived from a weighted logistic regression analysis, while time-to-event outcomes were estimated using a weighted Cox proportional hazards model. The following factors were used to adjust for imbalances between patient populations: refractory status, cytogenetic profile, ISS staging, presence of extramedullary disease, and the number of prior lines of therapy. The effective sample size of the MajesTEC-1 study after matching was 37 patients.

Following adjustment, the estimated HR of OS for teclistamab versus selinexor in combination with dexamethasone was 0.52 (95% CI, 0.28 to 0.95). Following adjustment, the estimated HR of PFS for teclistamab versus selinexor in combination with dexamethasone was 0.58 (95% CI, 0.30 to 1.11), and the estimated HR of duration of response was 0.04 (95% CI, 0.01 to 0.10). Following adjustment, the OR of ORR for teclistamab versus selinexor in combination with dexamethasone was 3.14 (95% CI, 1.48 to 6.69), while the OR of CR or better was 16.3 (95% CI, 3.5 to 77.1). No results for safety or HRQoL were included in the ITC comparing the MajesTEC-1 trial and the STORM trial, part 2.

Critical Appraisal

The open-label design of the studies can result in a risk of bias in the study conduct, including the measurement of the outcomes, and increase uncertainty in subjective outcomes such as PFS and ORR. The bias will likely favour the experimental intervention, although the extent of bias is uncertain. The effective sample size was reduced after adjustment in the MAIC analysis to approximately 24.7% (37 of 150) of the patients in the original population in the MajesTEC-1 study. The reduction in the effective sample size reflects the heterogeneity between the trials among the variables, including in the weighting process. Small effective sample size implies that the weighted estimates are being influenced by a subset of patients from the MajesTEC-1 study who may not be representative of the entire study population; this may limit the generalizability of the results. It remains unclear how balanced populations were for other variables that may have been clinically relevant but could not be adjusted due to lack of data, or those variables that were not part of the planned adjustment (unknown or unmeasured prognostic factors), which leaves the potential for residual confounding.³⁶ In the MAIC analysis, the results in efficacy estimates were imprecise (i.e., wide CIs) in the end points assessed, and the upper and lower boundaries of the CIs suggest the potential for different conclusions regarding the efficacy of teclistamab relative to the comparator drugs. Therefore, no superiority conclusions could be drawn from the MAIC submitted by the sponsor due to methodological limitations and imprecision in the effect estimates.

Studies Addressing Gaps in the Evidence From the Systematic Review

The sponsor submitted 2 ongoing head-to-head clinical studies comparing teclistamab to currently available fourth-line and beyond lines of therapy in patients with RRMM. The MajesTEC-3 trial is a multicentre, open-label, randomized, phase III study comparing the efficacy of teclistamab in combination with daratumumab versus investigator’s choice of daratumumab in combination with pomalidomide and dexamethasone, or daratumumab in combination with bortezomib plus dexamethasone in patients with RRMM. In the MajesTEC-3 trial, the primary outcome is PFS and the secondary outcomes include ORR, CR or better, MRD-negativity status, OS, and safety outcomes. The estimated completion date of the MajesTEC-3 study is October 2026. The MajesTEC-9 trial is a phase III, randomized, open-label, multicentre study comparing teclistamab with investigator’s choice of pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone in patients with RRMM who have received 1 prior line to 3 prior lines of therapy, including an anti-CD38 monoclonal antibody, and lenalidomide. In the MajesTEC-9 trial, the primary outcome is PFS and the secondary outcomes include ORR, duration of response, and OS. The estimated completion date of the MajesTEC-9 study is May 2031.

Conclusions

One sponsor-submitted phase I and phase II, single-arm, open-label study (the MajesTEC-1 trial) provided evidence regarding the efficacy and safety of teclistamab for patients with RRMM who had received at least 3 prior lines of therapy. In general, the clinical experts consulted by CADTH for this review considered the OS, PFS, ORR, and CR results to be clinically meaningful, especially when indirectly compared to currently available therapies in this population. However, the evidence for the treatment effect of teclistamab is very uncertain due to the single-arm design of the study, which is not intended to be confirmatory for efficacy, and the lack of a comparator group, which limits the estimation of relative effects of treatment with teclistamab compared with other treatment options. Additionally, the estimates of the benefit of teclistamab may be overestimated because this report presents results of the interim analysis; however, the presence and extent of any overestimation is uncertain. The results for the HRQoL remained inconclusive due to a number of important limitations, including post hoc analysis, attrition bias, and increased risk of type I error. Notable harms that occurred more frequently in the MajesTEC-1 study included infections, CRS, and cytopenia. In general, TEAEs were stated by the clinical experts consulted by CADTH for this review to be manageable.

The evidence about the comparative efficacy of teclistamab relied on 1 single-arm study, and no direct evidence of teclistamab compared to other comparators was available for this review. Six ITCs were submitted by the sponsor comparing the efficacy of teclistamab with RWPC therapy, ciltacabtagene autoleucel, selinexor, and belantamab mafodotin in patients with RRMM. Although teclistamab was favoured over RWPC therapy for OS, PFS, and TTNT, the comparative efficacy estimates remain uncertain due to the methodological limitations, heterogeneity in the populations and studies, and potential for residual confounding. Although teclistamab was favoured over RWPC therapy for key response outcomes, no superiority conclusions could be drawn about the relative efficacy of teclistamab compared to RWPC for ORR, CR or better, or VGPR or better, due to methodological limitations and imprecision in the effect estimates (i.e., wide 95% CIs). Although the results suggest that ||||||||||| || |||||||| || |||||||||||||| |||||||||| ||| ||| |||| ||| ||||, these findings must be interpreted in the context of the methodological limitations of these studies. For OS and PFS, no superiority conclusions could be drawn about the relative efficacy of teclistamab compared to belantamab mafodotin and selinexor due to methodological limitations and imprecision in the effect estimates. No conclusions could be drawn from the 6 sponsor-submitted ITCs about the relative efficacy of teclistamab to the comparator drugs for the clinical response outcomes, including ORR, CR or better, or VGPR or better, due to methodological limitations and imprecision in the effect estimates (wide 95% CIs). No conclusions could be drawn on the relative safety of teclistamab to the comparative drugs because no safety analysis was performed. No HRQoL outcomes were evaluated in the sponsor-submitted ITCs.

There is an unmet need for fourth-line and beyond treatment options for RRMM, as patients with drug resistance after second-line or third-line therapy cannot be treated again with the same drug. In general, the indirect evidence was aligned with some outcomes identified as important to patients with RRMM who are seeking additional fourth-line and beyond treatment options that prolong survival and delay disease progression.

Introduction

Disease Background

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

MM is a plasma cell cancer characterized by the clonal proliferation of malignant plasma cells (B-cells) and the overproduction of the abnormal M protein.¹ Older individuals and men of all ages (as opposed to women) are more likely to develop MM and it is twice as common in individuals who are Black compared to white or Asian individuals.^2,3 In 2022, it was estimated that 4,000 people in Canada were diagnosed with MM and 1,650 individuals living in Canada died from MM.⁴ The 5-year survival probability of patients with MM is estimated to be approximately 50%,⁵ and although survival rates have improved in recent years due to advances in therapeutic options, MM remains incurable.^6,7 The majority of patients with MM will relapse and many patients will become refractory to commonly used therapies.⁸ Patients with RRMM often undergo multiple rounds of treatment, with the duration of remission, depth of response, PFS, and OS decreasing with each subsequent line of therapy.³

The majority of MM cases develop from an asymptomatic premalignant plasma cell condition called monoclonal gammopathy of undetermined significance (MGUS), which is characterized by the presence of abnormal M protein in the blood.³ MGUS can evolve into smouldering (asymptomatic) MM, which is a more advanced asymptomatic, premalignant stage that progresses into MM at a much faster rate compared to MGUS.³ The most common symptoms of MM are fatigue and bone pain,³ with other symptoms including kidney problems, recurrent infections, fever, and nervous system problems.⁹ Disease stage, along with other factors, can impact MM prognosis. Commonly recognized factors that impact the prognosis of MM include beta₂-microglobulin (B2M) (high levels are associated with poor prognosis), serum albumin (low levels are associated with poor prognosis), lactate dehydrogenase (LDH) (high activity is predictive of poor prognosis), and chromosomal changes (shorter remission duration is associated with chromosome deletions or translocations).⁴⁰ In addition to these factors, prognosis may be influenced by age, creatinine levels, and performance status. In general, older patients, those with high creatinine levels, and those with poor overall function tend to have worse outcomes compared to younger individuals, those with lower creatinine levels, and those with better overall function.⁴¹

The diagnosis of MM typically occurs during a visit to a primary care physician, occurring either incidentally when laboratory tests for other conditions are ordered, or if MM is suspected based on signs and symptoms.¹⁰ In 2016, the IMWG updated the diagnostic criteria for MM due to the emergence of novel treatment options, advances in laboratory and imaging techniques, and data indicating that early treatment in high-risk asymptomatic patients can improve survival.^3,42 The updated criteria allows for earlier diagnosis and for treatment to be initiated before organ damage. The diagnosis of MM is based on the presence of 1 or more myeloma-defining events, along with either 10% or more clonal bone marrow plasma cells or biopsy-proven plasmacytoma.³ Myeloma-defining events include the presence of end-organ damage known as the CRAB criteria (hypercalcemia, renal insufficiency, anemia, and bone lesions) along with 3 specific biomarkers: a clonal bone marrow plasma cell percentage greater than or equal to 60%, a free light chain ratio greater than or equal to 100, and more than 1 focal lesion on MRI studies.³ It is recommended that the initial laboratory investigation for MM include a complete blood count to test, a peripheral blood smear, and a serum analysis, as well as baseline metabolic tests.⁴³ To quantify the percentage of plasma cells relative to total nucleated cells, bone marrow aspiration and core biopsy are required. Finally, chromosomal aberrations should be assessed.⁴³ The use of whole-body low-dose CT to detect osteolytic lesions in MM is becoming increasingly popular; however, if unavailable, a conventional radiography skeletal survey is a reasonable alternative.⁴³

Several systems are used for staging MM, including ISS, the R-ISS, and the Durie-Salmon staging system.^1,44,45 The Durie-Salmon staging system uses blood tests along with urine tests and X-rays to stage MM; however, unlike the ISS, the blood tests assess hemoglobin, calcium, and M-protein levels.⁴⁴ The ISS is commonly used in Canada and uses blood tests that assess albumin levels and B2M levels to stage MM (advanced stage MM is associated with lower albumin and higher B2M levels):⁴⁴

• stage I — B2M is less than 3.5 mg/L; serum albumin is 3.5 g/dL or greater

• stage II — B2M is less than 3.5 mg/L; serum albumin is less than 3.5 g/dL; or B2M is 3.5 mg/L to 5.5 mg/L, irrespective of serum albumin

• stage III — B2M is greater than 5.5 mg/L.

The preferred staging system for MM is the R-ISS,⁴⁵ which combines elements of tumour burden (ISS) and disease biology (the presence of high-risk cytogenetic abnormalities or an elevated LDH level) to create a unified prognostic index that helps in clinical care as well as in the comparison of clinical trial data. R-ISS uses serum B2M, serum albumin, serum LDH, and bone marrow fluorescence in situ hybridization (FISH) results to stratify patients into 3 risk groups:^44,45

• stage I — B2M is less than 3.5 mg/L, serum albumin is 3.5 g/dL or greater, normal LDH, and with no del(17p), t(4;14), t(14;16) by FISH

• stage II — neither stage I nor stage III

• stage III — B2M is 5.5 mg/L or greater, elevated LDH, and/or del(17p), t(4;14), t(14;16) by FISH.

According to the IMWG criteria, a patient is considered to have refractory MM when they are nonresponsive to therapy or experience disease progression within 60 days of their last line of therapy.^11,12 A patient is considered to have relapsed MM if they experience disease progression after being previously treated and require a salvage therapy but do not meet the criteria for primary refractory MM or RRMM.^11,12 Finally, a patient is considered to have relapsed and refractory MM if they have attained a minimal response or better at some point during previous treatments but the disease is currently nonresponsive on salvage therapy, or they experience disease progression within 60 days of their last therapy.^11,12

Standards of Therapy

Content in this section has been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the CADTH review team.

According to the clinical experts and clinician groups consulted by CADTH for this review, initial therapy for patients with MM depends on whether patients are transplant eligible or ineligible at diagnosis, which is aligned with CADTH's Provisional Funding Algorithm for MM.¹³ According to the clinical experts and clinician groups, the majority of patients who are ineligible for transplant can be given daratumumab, lenalidomide, and dexamethasone as frontline therapy. A small number of patients will receive lenalidomide in combination with dexamethasone, and some other combinations of drugs that do not contain daratumumab, such as lenalidomide in combination with bortezomib and dexamethasone. The clinical experts consulted by CADTH mentioned that the current approach to the treatment of RRMM depends on several factors, including patient factors (i.e., age, comorbidity, and beforexicity), line of therapy, and prior therapies received. The clinical experts further noted that treatment options at relapse include a PI (bortezomib, carfilzomib) containing combinations such as cyclophosphamide in combination with bortezomib and dexamethasone, selinexor in combination with bortezomib and dexamethasone, or carfilzomib in combination with dexamethasone with or without cyclophosphamide. According to the clinical experts and clinician groups, patients who are eligible for transplant can receive induction therapy with either cyclophosphamide in combination with bortezomib and dexamethasone, or lenalidomide in combination with bortezomib and dexamethasone, and then lenalidomide maintenance until disease progression. The clinical experts consulted noted that the majority of patients who relapsed after a prior stem cell transplant will not have received daratumumab, and second-line therapy for these patients will likely include an anti-CD38 antibody. These combinations include isatuximab in combination with carfilzomib and dexamethasone, daratumumab in combination with lenalidomide and dexamethasone, isatuximab in combination with pomalidomide and dexamethasone, and selinexor in combination with bortezomib and dexamethasone. The clinical experts mentioned that later relapses can be treated through clinical trials or with regimens such as belantamab mafodotin, which is presently available through a special access program. Currently, access to bispecific antibodies for the treatment of relapsed myeloma is limited. Other treatments aim to control symptoms, such as those used to control pain, or bisphosphonates for bone diseases.

There is no preferred standard of care for the treatment of RRMM in the fourth-line setting and beyond, and at this stage of the disease, patients may be exposed to PIs, IMiDs, and anti-CD38s,^7,13 and in some cases receiving more than 1 PI or iMiD, further limiting treatment options in later lines of therapy. Generally, the second-line treatment options available to a patient with RRMM depend on the patient’s response to the therapy received in first-line, and the choice of a third-line treatment option depends on their response to the therapy received in the second-line treatment. According to the Provisional Funding Algorithm for MM developed by CADTH,¹³ patients with drug resistance cannot be treated again with the same drug; however, in later lines, previously used treatments are often recycled when accessible due to a lack of novel options.^46-48

The pan-Canadian Oncology Drug Review Expert Review Committee (pERC) recommends the reimbursement of carfilzomib in combination with dexamethasone for patients with RRMM with good performance status who have received 1 prior line to 3 prior lines of treatment, with reimbursement being conditional on cost-effectiveness being improved to an acceptable level.^13,49 pERC recommends the reimbursement of pomalidomide combined with dexamethasone in patients with RRMM who displayed disease progression on their previous treatment regimen and who did not experience improvement with at least 2 prior lines of therapy, including both bortezomib and lenalidomide. Funding is conditional on cost-effectiveness being improved to an acceptable level.^13,50,51 pERC recommends the reimbursement of selinexor in combination with bortezomib and dexamethasone for the treatment of adult patients with MM who have received at least 1 prior therapy.^13,52 pERC recommends the reimbursement of ciltacabtagene autoleucel (Carvykti) 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 who are refractory to their last treatment.^13,53 According to the Provisional Funding Algorithm for MM, selinexor in combination with bortezomib and dexamethasone is recommended for third-line therapy and beyond in patients who are sensitive to bortezomib but not to anti-CD38 monoclonal antibodies and lenalidomide.¹³

In Canada, coverage for pomalidomide in combination with dexamethasone with or without cyclophosphamide, and carfilzomib in combination with dexamethasone with or without cyclophosphamide, is determined on a case-by-case basis while ciltacabtagene autoleucel is under consideration for negotiation at the pan-Canadian Pharmaceutical Alliance.⁵³ Coverage for selinexor varies across provinces in Canada. For example, selinexor is publicly funded in British Columbia⁵⁴ but is only available through the Exceptional Access Program In Ontario.⁵⁵

Drug Under Review

Teclistamab injection is indicated for treating adult patients with RRMM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody, and who have demonstrated disease progression on their last therapy. The reimbursement request aligns with the Health Canada indication for teclistamab.

Teclistamab is a bispecific antibody that targets the CD3 receptor expressed on the surface of T-cells and BCMA expressed on the surface of malignant MM and healthy B-lineage cells and plasma cells.⁵⁶ Teclistamab redirects CD3-positive T-cells to BCMA-expressing myeloma cells to induce the killing of tumour cells.⁵⁷

The recommended dosage for teclistamab is 1.5 mg/kg of body weight after receiving step-up doses of 0.06 mg/kg and 0.3 mg/kg of body weight. One hour to 3 hours before each teclistamab step-up dose and the first full-strength treatment dose, all patients must receive a corticosteroid (16 mg oral or IV dexamethasone), an antihistamine (50 mg oral or IV diphenhydramine or equivalent), and an antipyretic (650 mg to 1,000 mg oral or IV acetaminophen or equivalent).⁵⁸ Patients should be treated with teclistamab until disease progression or unacceptable toxicity. Dose delays may be required to manage toxicities related to teclistamab.⁵⁸ The recommendations for restarting teclistamab after a dose is delayed is outlined in Table 3.

Table 3: Recommendations for Restarting Teclistamab After Dose Delay

^aAdminister pretreatment medications before teclistamab dose and monitor patients accordingly.

Source: Product monograph for Tecvayli.⁵⁸

Teclistamab is administered as an SC injection by a health care provider with appropriate medical equipment and medical personnel to manage administration-related reactions.⁵⁸ Dose reductions are not recommended for teclistamab.⁵⁸ Patients should remain in the proximity of a health care facility and be monitored daily for 48 hours for signs and symptoms of CRS after the administration of all step-up doses of teclistamab; alternatively, hospitalization for patients may be considered.⁵⁸

The key characteristics of teclistamab and other therapies for the treatment of adult patients with RRMM in fourth-line therapy and beyond, as indicated in CADTH's Provisional Funding Algorithm for MM,¹³ are presented in Table 4.

Table 4: Key Characteristics of Pharmacotherapies for Multiple Myeloma

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; DRESS = Drug Rash with Eosinophilia and Systemic Symptoms; DVT = deep vein thrombosis; ICANS = immune effector cell-associated neurotoxicity syndrome; IMiD = immunomodulatory drug; MM = multiple myeloma; PI = proteasome inhibitor; PML = progressive multifocal leukoencephalopathy; RRMM = relapsed or refractory multiple myeloma; SC = subcutaneous; SJS = Stevens-Johnson syndrome; TEN = toxic epidermal necrolysis; TLS = tumour lysis syndrome.

^aHealth Canada–approved indication.

Sources: Product monographs for Tecvayli,⁵⁸ Carvykti,^53,59 Xpovio,⁶⁰ Pomalyst,⁶¹ and Kyprolis.⁶²

Stakeholder Perspectives

Patient Group Input

This section was prepared by the CADTH review team based on the input provided by patient groups. The full original patient input received by CADTH has been included in the Stakeholder section of this report.

CADTH received 1 patient group submission from Myeloma Canada. Myeloma Canada has existed for more than 15 years to support the growing number of Canadians diagnosed with myeloma and those living longer than ever with the disease to access new and innovative therapies. Over the years, as a part of this mission, Myeloma Canada has collected data on the impact of myeloma and its treatments on patients and caregivers by conducting surveys. The results of a patient and caregiver survey conducted by Myeloma Canada from August 28 to September 6, 2023, were provided to the CADTH review. The results of the survey were shared across Canada and internationally via email and social media. A total of 33 patients and 3 caregivers were initially asked similar questions regarding disease experience. Upon verifying their eligibility for or experience with teclistamab, survey respondents were divided into 3 subsets as follows:

• Subset 1: This subset consisted of 22 patient respondents (1 was from outside of Canada) who would currently be eligible for treatment with teclistamab from Alberta (n = 1), British Columbia (n = 5), New Brunswick (n = 1), Ontario (n = 8), Quebec (n = 5), Saskatchewan (n = 1), and France (n = 1). Twelve respondents identified themselves as male and 9 as female. One respondent was between 50 years and 59 years, 10 respondents were between 60 years and 69 years, 10 respondents were between 70 years and 79 years, and 1 respondent was between 80 years and 89 years. Eleven respondents lived in an urban area, 7 lived in a suburban area, and 4 lived in a rural area.

• Subset 2: This subset consisted of 11 patient respondents who had received or were currently receiving treatment with teclistamab. Six respondents identified themselves as female, 5 respondents identified as male, 8 respondents lived in urban areas, 2 in a suburban area, and 1 in a rural area. One respondent was aged between 40 years and 49 years, 1 respondent was between 50 years and 59 years, 2 respondents were between 60 years and 69 years, and 7 respondents were between 70 years and 79 years.

• Subset 3: This subset consisted of 3 caregivers of patients who would currently be eligible for treatment with teclistamab. All caregivers lived in an urban area and were female. One caregiver was between 40 years and 49 years, 1 caregiver was between 60 years and 69 years, and 1 caregiver was between 70 years and 79 years.

Patient respondents indicated that their ability to travel was the factor most significantly impacted by symptoms associated with myeloma, followed by the ability to work and exercise. Regarding the most significant financial implication of myeloma treatment on a household, 12 of 36 respondents identified the loss of income or pension funds due to absence from work, disability, or early retirement, and 12 of 36 respondents chose travel costs. Moreover, they felt that “loss of sexual desire” had the greatest impact on quality of life, and it was the option most frequently rated as severe impact. All caregivers felt that caring for someone with myeloma had the most impact on “anxiety/worry,” followed by “interruption of life goals/accomplishments (e.g., career, retirement)”. Eighteen of 33 patient respondents indicated that they needed a caregiver, 13 respondents answered that they did not need a caregiver, and 2 respondents indicated that they did not need a caregiver but would benefit from a caregiver’s help.

Patient and caregiver respondents identified the following factors as those most important to myeloma treatment: improved quality of life, manageable side effects along with the effectiveness of treatment, especially in achieving remission and having a long and durable response, and treatment accessibility or portability (including fewer or minimal visits to the hospital or cancer centre). Regarding the time it takes to make a round trip (to and from) the hospital or cancer centre to receive treatment, 20 of 36 respondents indicated “less than 1 hour 1 way,” 10 respondents selected “30 minutes to 1 hour 1 way,” 3 respondents selected “2.5 hours or more 1 way,” and 2 respondents selected “1 to 2 hours 1 way.” When all 33 patients and 3 caregivers were asked how often they visit the hospital or cancer centre for treatment, 19 respondents mentioned once a month, 7 respondents mentioned once a week, and 4 respondents mentioned every 2 weeks. In terms of the importance of controlling various aspects of myeloma, infections were the most important aspect to control, followed by kidney problems, mobility, gastrointestinal issues, relapse, and secondary cancers. Regarding receiving prior lines of therapy, 12 patient respondents indicated that they received 3 prior lines of therapy, 10 respondents indicated that they or the person they care for received 4 prior lines of therapy, and 3 respondents indicated that they or the person they care for had received 5 prior lines of therapy or more. Regarding receiving autologous stem cell transplant for myeloma treatment, 25 respondents indicated that they had received it, while 3 respondents indicated they or the person they care for were not eligible for an autologous stem cell transplant.

In terms of improving quality of life, 13 of the 22 respondents rated it as extremely important, 6 respondents as very important, and 3 respondents as somewhat important. A total of 17 of the 22 respondents rated the estimated minimum of 1 year to 21 months of life extension as extremely desirable, and 5 respondents as very desirable. A total of 11 respondents indicated having experience with teclistamab: 5 respondents received teclistamab as monotherapy, 1 patient indicated they were unsure, and 5 respondents received teclistamab in combination with another drug and provided the drug name(s). Of these 5 patient respondents, 2 patients are receiving daratumumab in combination with teclistamab, 1 respondent is receiving talquetamab in combination with teclistamab and the remaining 2 respondents described supportive care drugs, not a combination therapy (IV immunoglobulin, steroids, Benadryl). In terms of the impact of teclistamab on their quality of life compared to previous treatments, 5 respondents indicated no impact, 3 respondents mentioned some impact, 2 respondents stated significant impact, and 1 respondent indicated a little impact. In terms of side effects, 10 respondents rated respiratory infections as the least bearable side effect, followed by COVID-19, fungal infections, and ICANS.

Myeloma Canada also conducted another survey on CAR T-cell therapy from August 28 to September 30, 2022. It received more than 200 responses, only 2 of which had experience with the CAR T-cell therapy. While the teclistamab survey received far fewer total responses (33), there were 11 patients with teclistamab experience. Myeloma Canada emphasized that comments from patients currently receiving teclistamab were largely very positive, with multiple patients at different points in the survey indicating that it was the best treatment they had received for myeloma.

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, providing guidance on the potential place in therapy). The following input was provided by 2 clinical specialists with expertise in the diagnosis and management of MM.

Unmet Needs

The clinical experts consulted by CADTH for this review highlighted that the most important goals of treatment for patients with MM are prolonging survival, delaying disease progression, preventing disease complications, improving quality of life, and minimizing side effects. Clinical experts noted that although MM is traditionally considered an incurable malignancy, it is known that a small percentage of patients who undergo a stem cell transplant do not relapse. The clinical experts mentioned that the current treatment approach and choice of therapy for MM depends on several factors, including patient factors (i.e., age, comorbidity, and beforexicity), line of therapy, and prior treatments received. After diagnosis with MM, the lines of therapy that patients will undergo depend on whether or not they are transplant eligible. The clinical experts noted that clinicians try not to reuse the same drugs in subsequent lines of therapy. The common treatment options for MM relapse include a PI-containing combination, such as cyclophosphamide in combination with bortezomib and dexamethasone, selinexor in combination with bortezomib and dexamethasone, or carfilzomib in combination with dexamethasone with or without cyclophosphamide. The clinical experts also highlighted that after receiving 3 lines of therapy, the majority of patients will be triple-refractory and will need new families of drugs. The clinical experts also noted that beyond the third line of therapy, treatment options get more restricted, and some patients do not respond to the current standard therapies. The clinical experts indicated that, most importantly, very poor responses and very short remissions are observed in patients with high-risk cytogenetics. Thus, there is a need for treatments beyond the third line of therapy that are tolerable for patients.

Place in Therapy

The clinical experts consulted indicated that, given the level of evidence for the drug under review, it would be an appropriate treatment to use in the setting of RRMM. However, it is unknown whether teclistamab would be used as a complementary therapy, as the study assessing the efficacy of teclistamab when used in combination with other treatments (the MajesTEC-3 study) is ongoing. The clinical experts noted that teclistamab is not the first approved treatment that targets underlying disease processes; however, this drug has a novel mechanism of action that is very different from any currently available therapies. The clinical experts agreed that teclistamab would not be reserved for patients who are intolerant to other treatments or for whom other treatments are contraindicated, but instead would be available to any patient who meets eligibility requirements. The clinical experts agreed that teclistamab will not necessarily change the current treatment paradigm; however, this drug will be included in the treatment sequence, with the timing of treatment depending on the evidence for its use in different lines. The clinical experts also noted that as teclistamab is being introduced as a treatment for RRMM, it is expected that patients will have been treated with some other treatments before being eligible for this drug. The clinical experts noted that classic methodological assessments of interventions concern A versus B and implication of 1 or the other without the consideration of sequencing beyond the initial drug failure. In this light, the use of teclistamab represents a new class of drugs that can help sustain quality of life and extend the duration of life in the patient with RRMM.

Patient Population

The clinical experts consulted indicated that the MajesTEC-1 study enrolled a broad sample of patients with RRMM, including older patients who had received multiple prior lines of therapy and had measurable disease. Clinical experts agreed that there is no evidence that some patients are more likely to respond to treatment, and there are no disease-specific characteristics that would make a patient ineligible for treatment with teclistamab. Given that the prognosis of MM worsens as patients move on to subsequent lines of therapy, any patient with relapsed MM will require this intervention. This is especially true in cases where patients have exhausted other treatment options; however, it may also be appropriate to use teclistamab earlier in the relapse even if all other options have not been exhausted. The clinical experts highlighted that patients eligible for treatment will be identified at the time of MM relapse, usually based on biochemical evidence of relapse, and in some cases also based on other signs or symptoms of relapse. The clinical experts also noted that diagnostic tests for relapsed MM are well established and include serum protein electrophoresis, immunoglobulin free light chains, and other tests, and that a companion diagnostic test is not specifically required.

Assessing the Response Treatment

Clinical experts consulted by CADTH noted that response to treatment is usually assessed through regular monthly monitoring as part of the management of patients with RRMM. However, in many situations where the patient is stable on treatment that has predictable side effects, follow-up may be reduced to every 2 months, or sometimes less frequently. The clinical experts highlighted that if patients are followed relatively closely, difficulties or delays in diagnosing RRMM are unlikely. The clinical experts mentioned that the response to treatment for almost all patients is assessed by monitoring serum protein, electrophoresis, serum free light chains, or other tests. They further noted that these tests are objective and their interpretation does not really vary among physicians.

The clinical experts identified PFS, OS, and clinical response outcomes as the most important outcomes for assessing the response to treatment. The clinical experts agreed that the best possible response to treatment would be complete remission that is MRD-negative, and less deep responses include CR, VGPR, PR, and stable disease. Clinical experts further noted that CR and VGPR are the most desirable outcomes in most situations; even achieving stable disease is acceptable.

Discontinuing Treatment

The clinical experts consulted indicated that the main reason for discontinuing treatment with teclistamab would be relapse of MM. The clinical experts further noted that as with any treatment, it can be expected that some patients will be forced to discontinue treatment due to intolerable side effects.

Prescribing Considerations

The clinical experts consulted mentioned that currently, all patients receiving teclistamab are treated at tertiary care centres and are admitted to the hospital for the first few doses. The clinical experts indicated that depending on the situation, patients starting treatment with teclistamab will require treatment at a larger hospital capable of providing management and monitoring; however, after patients receive the first few doses of this treatment, they can receive ongoing therapy at community centres and smaller cancer centres. The clinical experts noted that the issue of intensive monitoring and hospitalization only affects the first 2 doses to 3 doses, after which treatment becomes more routine.

Clinician Group Input

This section was prepared by the CADTH review team based on the input provided by clinician groups. The full original clinician group input received by CADTH has been included in the Stakeholder section of this report.

CADTH received 2 clinician group submissions from the CMRG and OH-CCO’s Drug Advisory Committees. CMRG is a Canada-wide network of researchers aiming to develop better treatments for extending the life of patients with myeloma, enhancing quality of life for those living with myeloma and related diseases, and working to find a cure for these diseases and other plasma cell disorders. OH-CCO’s Drug Advisory Committees provide timely evidence-based clinical and health system guidance on drug-related issues in support of OH-CCO’s mandate, including the Provincial Drug Reimbursement Programs and the Systemic Treatment Program.

CMRG gathered information through teleconferences with physicians, and OH-CCO’s Drug Advisory Committees gathered information through videoconferencing and email communications. CMRG stated that newly diagnosed patients with myeloma living in Canada are classified into those who are transplant eligible or transplant ineligible, based on age and fitness. Transplant-eligible patients receive bortezomib-based induction with lenalidomide in combination with bortezomib and dexamethasone, or cyclophosphamide in combination with bortezomib and dexamethasone followed by high-dose melphalan and an autologous stem cell transplant, and then lenalidomide maintenance until disease progression. Transplant-ineligible patients were previously most often treated with lenalidomide in combination with dexamethasone or lenalidomide in combination with bortezomib and dexamethasone followed by single-drug lenalidomide (also given until disease progression). More recently, daratumumab-based combinations such as daratumumab in combination with lenalidomide and dexamethasone, or the combination of daratumumab, cyclophosphamide, bortezomib, and dexamethasone, and the combination of bortezomib, melphalan, and prednisone are preferred and include provisions for the long-term continuous administration of selected drugs. CMRG noted that second-line therapy depends on whether patients have progressed on lenalidomide (currently, this includes most patients who have undergone an autologous stem cell transplant or who are transplant-ineligible). Key in second-line therapy is the inclusion of an anti-CD38 antibody, such as daratumumab or isatuximab, which represents a high priority for virtually all patients. Other relevant anti-CD38 monoclonal antibody–containing regimens have been approved by Health Canada and could be used in second-line treatment and beyond. Treatment options for myeloma are extremely limited after the second line or third line of therapy. Both CMRG and OH-CCO’s Drug Advisory Committees emphasized that the overall treatment goals are to delay progression, improve OS, minimize adverse effects, control symptoms such as bone destruction and pain, renal failure, hypercalcemia, and low blood counts, and improve quality of life.

Both CMRG and OH-CCO’s Drug Advisory Committees mentioned that myeloma remains incurable, and patients eventually become refractory to all available funded drugs. One major unmet need is that patients with advanced disease who have received multiple lines of treatment and have already received the 3 lines of drugs (triple-class exposed and refractory), including an IMiD, PI, and anti-CD38 monoclonal antibody, have no other substantial treatment options other than CAR T-cell therapy. CMRG also emphasized that the clinical features associated with advanced disease and the short duration of responses lead to a poor quality of life, significant caregiver burden, and a shortened patient lifespan. Thus, this situation also represents 1 of the most pressing unmet needs in Canada for patients with MM. Another unmet need noted by OH-CCO’s Drug Advisory Committees is to achieve ease of administration (i.e., SC injection and no need for apheresis). Both clinician groups agreed that teclistamab is another option for triple-class exposed patients. They believe that it will currently be used sequentially after other lines of therapy for myeloma (i.e., after the failure of multiple drugs). Both clinician groups noted that teclistamab is not expected to impact the sequencing of drugs earlier in the disease course or lead to a major change in treatment algorithms before patients become triple-class exposed and refractory.

CMRG indicated that patients with a good performance status, minimal or no comorbidities, relatively low tumour burden, adequate organ function, and satisfactory blood counts are those most likely to have the best outcomes with teclistamab. CMRG further highlighted that the rates of immune-related complications are lower with bispecific antibodies such as teclistamab, in general, making them more broadly applicable to patients and more amenable to patients with more comorbidities (disease-related or otherwise). CMRG also mentioned that teclistamab represents an off-the-shelf treatment, which can be administered quickly even for rapidly proliferative myeloma. Chronological older age does not seem to be an exclusion factor for treatment with teclistamab. CMRG noted that overall, patients with poor disease-related prognostic factors, such as extramedullary myeloma and high-risk cytogenetics, should be eligible for the treatment under review. Both clinician groups expressed that treatment responses with teclistamab are based on standard myeloma response measures, CRS, and ICANS toxicity grading scales. CMRG further elaborated that responses to treatment are also based on the M protein markers in the serum and/or urine, bone marrow biopsy and, in some instances, on imaging studies (standardized IMWG criteria). These parameters are aligned with those used in the clinical trials, which also included the emerging parameter of marrow MRD. Clinically meaningful responses usually correlate with at least a partial remission by IMWG consensus criteria. These include improvement in symptoms (cessation of bone destruction with less pain, fractures, and need for radiotherapy), improvement in energy, and a greater ability to perform activities of daily living. In myeloma, responses are generally assessed every 1 month to 3 months, depending on clinical stability and the regimen used for therapy.

Both CMRG and OH-CCO’s Drug Advisory Committees agreed that treatment discontinuation is based on ongoing efficacy, disease progression, and long-term tolerability. Both clinician groups highlighted that teclistamab must be administered and monitored by hematologists or oncologists who have the knowledge and expertise to manage the potential short-term and long-term adverse events that can be associated with its use. Both clinician groups also recommended administration of the initial dosing in centres that have or are willing to develop the necessary infrastructure, experience, and support to safely administer T-cell redirecting therapies — for example, clinical assessment tools for CRS or ICANS grading or treatment, ICU support, and ready tocilizumab availability. CMRG recommended that, given that prior anti-BCMA exposure does not preclude responsiveness to subsequent anti-BCMA CAR T-cell therapy, patients previously treated with anti-BCMA therapy who did not progress during it (i.e., nonrefractory to anti-BCMA therapy other than anti-BCMA CAR T-cell therapy) should be given access to teclistamab.

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 5.

Table 5: Summary of Drug Plan Input and Clinical Expert Response

BCMA = B-cell maturation antigen; CAR = chimeric antigen receptor; cilta-cel = ciltacabtagene autoleucel; CNS = central nervous system; CRS = cytokine release syndrome; ECOG PS = Eastern Cooperative Oncology Group Performance Status; ICANS = immune effector cell-associated neurotoxicity syndrome, IMiD = immunomodulatory drug; MM = multiple myeloma; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; PI = proteasome inhibitor; RRMM = relapsed or refractory multiple myeloma; SC = subcutaneous.

Clinical Evidence

The objective of CADTH’s Clinical Review Report is to review and critically appraise the clinical evidence submitted by the sponsor on the beneficial and harmful effects of teclistamab (1.5 mg/kg body weight administered by SC injection) in the treatment of adult patients with RRMM who have received at least 3 prior lines of therapy, including a PI, an IMiD, and an anti-CD38 monoclonal antibody. The focus will be placed on comparing teclistamab to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of teclistamab is presented in 3 sections, with CADTH’s critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies that were selected according to the sponsor’s systematic review protocol. CADTH’s assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. Another section includes indirect evidence from the sponsor. The last section includes a description of ongoing additional studies that were considered by the sponsor to address important gaps in the systematic review evidence.

Included Studies

Clinical evidence from the following is included in the CADTH review and appraised in this document:

• One pivotal study identified in the systematic review

• Six sponsor-submitted ITCs.

Systematic Review

Content in this section has been informed by materials submitted by the sponsor. The following has been summarized and validated by the CADTH review team.

Description of Studies

Characteristics of the included study are summarized in Table 6.

Table 6: Details of MajesTEC-1 Study

ADC = antibody-drug conjugate; AE = adverse event; BCMA = B-cell maturation antigen; CABG = coronary artery bypass graft; CAR = chimeric antigen receptor; CNS = central nervous system; CR = complete response; ECOG PS = Eastern Cooperative Oncology Group Performance Status; FLC = free light chain; HRQoL = health-related quality of life; IMiD = immunomodulatory drug; IMWG = International Myeloma Working Group; mAb = monoclonal antibody; MM = multiple myeloma; MRD = minimal residual disease; MRU = medical resource utilization; NK = natural killer; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PI = proteasome inhibitor; POEMS = polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes; PR = partial response; q.2.w. = every 2 weeks; RO = receptor occupancy; RP2D = recommended phase II dose; RRMM = relapsed or refractory multiple myeloma; SAE = serious adverse event; SC = subcutaneous; TTNT = time to next treatment; TTR = time to response; VGPR = very good partial response.

Note: Details included in Table 6 are from the sponsor’s Summary of Clinical Evidence.⁸³

^aAccording to IMWG diagnostic criteria, MM is defined as clonal bone marrow plasma cells of 10% or greater or biopsy-proven bony or extramedullary plasmacytoma and at least 1 of the following: i) evidence of end-organ damage, specifically: hypercalcemia: serum calcium is greater than 0.25 mmol/L (> 1 mg/dL) higher than the upper limit of normal or greater than 2.75 mmol/L (> 11 mg/dL); renal insufficiency: creatinine clearance is less than 40 mL per minute or serum creatinine is greater than 177 μmol/L (> 2 mg/dL); anemia: a hemoglobin value of more than 20 g/L below the lower limit of normal, or a hemoglobin value of less than 100 g/L; bone lesions: there are 1 or more osteolytic lesions on skeletal radiography, CT, or PET-CT; ii) any 1 or more of the following biomarkers of malignancy: clonal bone marrow plasma cell percentage of 60% or greater; involved to uninvolved serum free light chain ratio of 100 or more; more than 1 focal lesion on MRI studies.

^bRelapsed or refractory myeloma is defined as disease that is nonresponsive while on salvage therapy, or progresses on or within 60 days of the last therapy in patients who have attained minimal response or better at some point previously before then progressing in their disease course.

^cIf central laboratory assessment is not available, relevant local laboratory measurement must exceed the minimum required level by at least 25%.

^dBased on the investigator’s determination of response by the IMWG 2016 criteria on or within 12 months of the last line of therapy.

Sources: Clinical Study Report for the MajesTEC-1 study⁶⁵ and Clinical Study Protocol for the MajesTEC-1 study.⁶⁶

Description of the MajesTEC-1 Study

The MajesTEC-1 trial is a phase I and phase II, open-label, multicentre study of teclistamab administered to adult patients with RRMM. The study is still ongoing and being conducted in 39 sites across 10 countries, including in Canada with patients who were enrolled at 4 Canadian sites; however, Canada, Germany, Italy, and the UK only participated in part 3 of the study. All patients received study treatment if all inclusion and exclusion criteria were met.

Description of Phases and Cohorts of the MajesTEC-1 Study

The MajesTEC-1 study was conducted in 3 parts, including part 1 or dose escalation (phase I), part 2 or dose expansion (phase I) at a proposed recommended phase II dose (1.5 mg/kg subcutaneously weekly), and part 3 or dose expansion (phase II) in cohorts of patients with RRMM with unmet medical needs (phase II). The main focus of the review is to assess the efficacy of receiving teclistamab at a dose of 1.5 mg/kg subcutaneously weekly within a population of patients with RRMM (40 patients in phase I and 125 patients in phase II, cohort A) who have received at least 3 prior lines of therapy, excluding anti-BCMA therapy. Additional supporting information was provided by the sponsor regarding the use of teclistamab in patients with RRMM previously treated with BCMA-targeted therapy in phase II, cohort C (n = 40).

Phase I of the MajesTEC-1 Study

The primary objectives reported in phase I of the MajesTEC-1 study were:

• to identify the proposed recommended phase II dose and dose schedule assessed to be safe in part 1

• to characterize the safety and tolerability of teclistamab at the proposed recommended phase II dose in part 2.

Treatment with teclistamab started with biweekly IV dosing and was then changed to weekly IV dosing after analysis of emerging safety and pharmacokinetic data. After a review of safety and efficacy data and considering the greater convenience of SC drug administration for patients and health care providers, the sponsor amended the protocol to evaluate SC administration. Dose escalation in phase I continued in parallel for both routes of administration. A wide range of escalating dose levels of teclistamab were evaluated. In part 1 of phase I, both accelerated and standard titration were used for dose escalation for IV administration of teclistamab, while for SC administration of teclistamab, the study drug was administered using standard titration only. Proposed recommended phase II doses for IV and SC administration of teclistamab were evaluated in part 2 of phase I, where up to 40 patients could receive teclistamab at the proposed recommended phase II doses identified in part 1 of phase I to further characterize antitumour activity and safety in additional patients at the relevant doses.

Phase II of the MajesTEC-1 Study

The primary objective of phase II was to evaluate the efficacy and safety of teclistamab at the proposed recommended phase II dose. The dose level and schedule selected as recommended phase II doses in phase I (1.5 mg/kg subcutaneously weekly) was evaluated in cohorts of patients with RRMM, including phase II, cohort A and cohort C. In the MajesTEC-1 study in phase II, cohort A and cohort C, enrolment began after at least 20 patients had received teclistamab 1.5 mg/kg subcutaneously weekly for at least 1 treatment cycle. Phase II, cohort A, enrolled patients with RRMM who had received at least 3 prior lines of therapy that included a PI, an IMiD, and an anti-CD38 monoclonal antibody. Phase II, cohort C, enrolled patients who had received at least 3 prior lines of therapy that included a PI, an IMiD, an anti-CD38 monoclonal antibody, and a BCMA-targeted treatment (CAR T-cells or an ADC). Enrolment in phase II, cohort B, was not planned because the intended patient population was enrolled in phase II, cohort A, including patients who were more heavily pretreated with at least 4 prior lines of therapy and considered penta-drug refractory.

In the MajesTEC-1 study, 340 patients were treated with teclistamab, with 165 patients in the pivotal study (patients in phase I and phase II, cohort A, who received SC teclistamab at a dose of 1.5 mg/kg weekly), 177 patients in the phase I group (dose escalation and dose expansion), and 38 patients in phase II, cohort C (patients with prior BCMA-targeted therapy who received 1.5 mg/kg SC teclistamab weekly) (Figure 1). At the time of the data cut-off date of March 16, 2022, 40 patients in phase II, cohort C, had received teclistamab at a dose of 1.5 mg/kg subcutaneously weekly.

Figure 1: Analysis Populations — MajesTEC-1 Study, Data Cut-Off Date of September 7, 2021

CCO = clinical cut-off; RP2D = recommended phase II dose; SC = subcutaneous.

Note: Details included in Figure 1 are from the sponsor’s Summary of Clinical Evidence.⁸³

^a Patients treated at RP2D (1.5 mg/kg teclistamab subcutaneously weekly) in phase I are presented in both pivotal RP2D data and phase I (dose escalation and dose expansion) data.

^b A patient must have received the first dose of teclistamab on or before this date to be included in the indicated population. At the data cut-off date of January 4, 2023, both efficacy and safety analyses were performed in the all-treated analysis set (N = 165).

^c One patient in the 6 mg/kg SC cohort who received their first step-up dose on March 17, 2021, was excluded from the efficacy analyses for phase I (dose escalation and dose expansion) because the cohort was incomplete at the time of the data cut-off for inclusion in the efficacy analysis and the only patient enrolled in it had not yet received a treatment dose.

^d All patients treated with teclistamab intravenously received their first dose before March 18, 2021.

^e Patients evaluated in stage I of the analysis for cohort C were included in the efficacy analysis, and all had received at least 1 dose of teclistamab on or before March 23, 2021. At the data cut-off date of March 16, 2022, both efficacy and safety analyses for cohort C were performed in the full analysis set (n = 40).

Source: Clinical Study Report for the MajesTEC-1 study (2021).⁶⁵

Screening Phase

The screening phase of the MajesTEC-1 study began when the first screening assessment was performed. Screening procedures were performed 28 days before the first dose of the study drug. Eligibility criteria were reviewed and a full clinical evaluation was performed at screening, and before the first dose. Measurements collected at the time point closest to, but before, the first administration of the study drug were defined as baseline values for safety assessment and treatment decisions.

Treatment Phase

The treatment phase began with the first administration of the study drug and continued until the completion of the end of treatment visit. Patients received the study drug until disease progression, unacceptable toxicity, withdrawal of consent, death, or end of study defined as 2 years after the last patient’s first dose. An end of treatment visit was to be completed within 30 days with an additional week’s grace period after the last dose of the study drug or before the start of a new anticancer therapy, whichever comes first. An end of treatment visit was required for all patients, including those who discontinued treatment for any reason, except for lost to follow-up, death, or withdrawal of consent to participate in the study.

Follow-Up Phase

The follow-up phase started after the end of treatment visit or treatment discontinuation, if the end of treatment visit was not performed.

Populations

Inclusion and Exclusion Criteria

Eligible patients should have been aged at least 18 years and had a documented diagnosis of RRMM according to the IMWG criteria. Patients must have received at least 3 prior lines of antimyeloma therapy that included an IMiD, a PI, and an anti-CD38 monoclonal antibody, and have had progressive, measurable disease at screening informed by IMWG (except for in part 1, phase I). Patients must have had an ECOG PS score of 0 or 1, and laboratory values within the study specified the criteria for enrolment.

For patients in phase I and phase II, cohort A, previous treatment with a BCMA-targeted therapy was not allowed, while in phase II, cohort C, prior therapy must have included a BCMA-targeted therapy (ADC or CAR T-cell therapy) in addition to the requirement to have received at least 3 prior lines of therapy including a PI, an IMiD, and an anti-CD38 monoclonal antibody. Patients were excluded if they had prior antitumour therapy, such as targeted therapy within 21 days or at least 5 half-lives, or monoclonal antibody, cytotoxic, PI, or IMiD therapy within 21 days before the first dose of teclistamab. Patients were also excluded if they had received gene-modifying adoptive cell therapy (e.g., CAR T-cells, natural killer cells) within 3 months, or radiotherapy within 14 days or focal radiation within 7 days. Also, patients were excluded if they had received a cumulative dose of corticosteroids equivalent to 140 mg or more of prednisone within 14 days before receiving the first dose of the study drug, had an allogeneic stem cell transplant within 6 months, or had received an autologous stem cell transplant within at least 12 weeks before receiving the first dose of study drug.

Interventions

Phase I (Part 1 and Part 2) of the MajesTEC-1 Study

During dose escalation (part 1 of phase I), the following biweekly and weekly treatment dosages of teclistamab were examined up to the recommended phase II dosage:

• teclistamab IV from 0.0003 mg/kg to 0.0192 mg/kg every 2 weeks

• teclistamab IV from 0.0192 mg/kg to 0.72 mg/kg weekly

• teclistamab SC from 0.08 mg/kg to 1.5 mg/kg weekly.

Patients treated with teclistamab intravenously were hospitalized for at least 36 hours from the start of any priming doses and the start of the first full dose of the study drug, and at least 24 hours from the start of the second full dose of the study drug. IV administration of teclistamab was administered over at least 4 hours in the controlled environment of a clinical research centre under the supervision of site staff. Patients treated in the initial cohort for SC administration were hospitalized for at least 48 hours from the start of any priming injection of the study drug and from the start of the first full injection of the study drug, and at least 24 hours from the start of the second full injection of the study drug. SC administration of teclistamab was administered by health professionals at treatment centres with adequate medical equipment and personnel to manage severe reactions. Additional cohorts received weekly weight-based treatment doses higher than the recommended phase II dose and other dosing schedules for the SC route of administration (with treatment doses up to 6 mg/kg and with flat dosing). Approximately half of the IV treatment doses and all SC treatment doses were preceded by step-up dosing.

Patients had the option to switch from weekly to biweekly dosing (day 1 and day 15) if they attained a PR or better and received at least 4 cycles of treatment (phase I) or attained a CR or better for at least 6 months (phase II). Patients could switch to monthly dosing with approval (phase I) or if they attained CR or better at cycle 12, day 1, or later, and had been receiving biweekly dosing for at least 6 months. Per investigator discretion, patients were permitted to switch to less frequent dosing to help manage toxicity.

During dose expansion (phase I, part 2), patients received treatment with teclistamab at dosages of 0.72 mg/kg IV weekly and 1.5 mg/kg teclistamab subcutaneously weekly (Figure 2). Depending on the dosing schedule, teclistamab was administered to patients participating in phase I in 21-day or 28-day cycles (Figure 3). Dosing schedules were either monthly, biweekly, or weekly. For monthly dosing, teclistamab was administered on day 1 in each 28-day cycle. For biweekly dosing, teclistamab was administered on day 1 and day 15 in each 28-day cycle and dose escalation was initiated at the minimum anticipated biological effect level–based starting dose of 0.0003 mg/kg. For weekly dosing, teclistamab was administered on day 1, day 8, and day 15 in each 21-day cycle. Dose escalation for IV dosing of teclistamab began at a dose level that was determined to be safe during the accelerated phase of dose escalation for biweekly dosing. Dose escalation for weekly SC dosing began at a cleared dose level approved by the safety evaluation team.

Phase II (Part 3) of the MajesTEC-1 Study

The step-up and treatment doses were selected for phase II (part 3) of the MajesTEC-1 study after review of safety, efficacy, pharmacokinetic, and pharmacodynamic data from patients treated during the dose escalation phase (part 1, phase I). During phase II, all patients received initial step-up doses of 0.06 mg/kg and 0.3 mg/kg administered on day 1 and day 3 (range = 2 to 7 days after step-up doses), respectively, after which teclistamab maintenance doses were administered weekly at a dose of 1.5 mg/kg via SC injection until disease progression, unacceptable toxicity, withdrawal of consent, death, or end of study.

Figure 2: Dose Escalation or Dose Expansion Cohorts Evaluated in Phase I of MajesTEC-1 Study

Q.2.w. = every 2 weeks; RP2D = recommended phase II dose; SC = subcutaneous.

Note: Details included in Figure 2 are from the sponsor’s Summary of Clinical Evidence.⁸³

^a Includes 8 cohorts (7 cohorts with q.2.w. dosing [N = 12] and 1 cohort with weekly dosing [N = 1]).

^b Includes 1 cohort without step-up dosing (N = 1) and 1 cohort with a step-up dose (N = 4).

^c Includes 1 cohort with 1 step-up dose (N = 12) and 1 cohort with 2 step-up doses (N = 5).

^d Dose levels were expanded in part 2 (proposed RP2Ds).

Source: Clinical Study Report for the MajesTEC-1 study (2021).⁶⁵

Dose Modifications

In phase I, patients were permitted to undergo dose reduction to the next lower dose level for the applicable route of administration. In phase II, dose reductions of teclistamab by 50% subcutaneously weekly could be considered in exceptional circumstances and after consultation with the sponsor.

In the MajesTEC-1 study, dose delay was the primary method for managing toxicities related to teclistamab. In the event of prolonged treatment interruption, disease evaluations were to continue every 4 weeks if possible. If a dose interruption was more than 28 days, treatment with teclistamab was to be permanently discontinued.

In phase I of the MajesTEC-1 study, patients who were enrolled in weekly cohorts could change from weekly dosing to biweekly or monthly dosing of teclistamab, if the patient attained a response of confirmed PR or better and received a minimum of 4 cycles of therapy. Patients in phase II could be treated biweekly if the patient attained a CR or better for a minimum of 6 months. The biweekly treatment dose was the same as the patient’s corresponding weekly dose.

Figure 3: Dosing Schedule for Cohorts Evaluated in Phase I — 21-Day and 28-Day Cycle Schedules

TEC = teclistamab.

Notes: Details included in Figure 3 are from the sponsor’s Summary of Clinical Evidence.⁸³

One cohort exploring a treatment dose of 6 mg/kg administered monthly and preceded by 4 step-up doses (0.03 mg/kg, 0.09 mg/kg, 0.3 mg/kg, and 1.5 mg/kg) was evaluated in phase I.

Source: Clinical Study Report for the MajesTEC-1 study (2021).⁶⁵

Disease Evaluations

Disease evaluations were performed at screening and within 3 days before day 1 of each cycle, before the study drug was administered. Disease evaluations were tested at a central laboratory until disease progression. In the event of prolonged treatment interruption, disease evaluations were to continue every 3 weeks to 4 weeks (phase I) or every 4 weeks (phase II), if possible. For patients who discontinued study treatment before disease progression, disease evaluations were to continue until confirmed disease progression, death, the start of a new treatment for MM, withdrawal of consent for study participation, lost to follow-up, or the end of the study, whichever occurred first. Responses for all patients treated with the recommended phase II dosage of teclistamab (phase I and phase II, cohort A) were assessed by an IRC, using the 2016 IMWG response criteria⁶³ (Table 7).

In the MajesTEC-1 study, evaluations of quantitative immunoglobulins, serum M-protein quantitation by electrophoresis, serum immunofixation, urine immunofixation, and urine M-protein quantitation by electrophoresis were performed on day 1 of each cycle until disease progression. Serum free light chain evaluations were performed on day 1 of each cycle before dosing, until disease progression for patients with free light chain–only measurable disease, when CR was suspected and until sCR was confirmed, or before CR, if necessary. Bone marrow aspirate or biopsy was performed on day 1 of cycle 3, at the time of suspected CR or sCR, and at disease progression. For confirmed CR or sCR, an additional aspirate was collected 12 months after day 1 of cycle 1, and yearly thereafter. Skeletal surveys, including additional imaging (X-ray, CT scan, or MRI) were performed locally whenever clinically indicated based on symptoms. Evaluations of extramedullary plasmacytomas were assessed by clinical examination or radiologic imaging for all patients with a history of plasmacytomas, or if clinically indicated, at screening and then until the development of confirmed CR or confirmed disease progression — every 4 weeks for physical examination (if applicable) or every 12 weeks for radiologic assessment (for patients with a history of plasmacytomas or as clinically indicated for others).

Table 7: Criteria for Response to Multiple Myeloma Treatment

CR = complete response; IgA = immunoglobulin A; IgG = immunoglobulin G; IgM = immunoglobulin M; IMWG = International Myeloma Working Group; MR = minimal response; PR = partial response; sCR = stringent complete response; VGPR = very good partial response.

^aAll response categories (CR, sCR, VGPR, PR, MR, and progressive disease) required 2 consecutive assessments made at any time before the institution of any new therapy; CR, sCR, VGPR, PR, MR, and stable disease categories also required no known evidence of progressive or new bone lesions if radiographic studies were performed. VGPR and CR categories required serum and urine studies regardless of whether disease at baseline was measurable on serum, urine, both, or neither.

^bClarifications were made to the criteria for coding CR and VGPR in patients in whom the only measurable disease was by serum free light chain levels. CR in such patients indicated a normal free light chain ratio of 0.26 to 1.65 (or reference range in testing laboratory) in addition to CR criteria listed earlier. VGPR in such patients required a 90% or greater decrease in the difference between involved and uninvolved free light chain levels.

^cIn some cases, it was possible that the original M-protein light chain isotype was still detected on immunofixation but the accompanying heavy-chain component had disappeared; this would not be considered as a CR even though the heavy-chain component was not detectable, since it was possible that the clone evolved to one that secreted only light chains. Thus, if a patient had IgA lambda myeloma, then to qualify as CR, there should have been no IgA detectable on serum or urine immunofixation; if free lambda was detected without IgA, then it must have been accompanied by a different heavy-chain isotype (e.g., IgG, IgM).

^dThese clarifications were made to the criteria for coding progressive disease: bone marrow criteria for progressive disease was to be used only in patients without measurable disease by M protein and by free light chain levels; “25% increase” referred to M protein and free light chains, and did not refer to bone lesions or soft tissue plasmacytomas; and the “lowest response value” did not need to be a confirmed value.

Source: Clinical Study Protocol for the MajesTEC-1 study.⁶⁶

Safety Monitoring for Teclistamab Dosing

For phase II (part 3), all patients were hospitalized for safety monitoring for at least 48 hours after each step-up dose and the first treatment dose. Patients who experienced neurotoxicity of grade 2 or higher were to be hospitalized for at least 48 hours after the subsequent dose of teclistamab. Patients who experienced a systemic administration-related reaction or CRS of grade 2 or grade 3 were to be hospitalized for at least 48 hours after the subsequent dose of teclistamab.

Safety in the MajesTEC-1 trial was measured by the monitoring of adverse events, laboratory tests, vital sign measurements, physical triplicate electrocardiograms (phase I only), physical examination findings (including neurologic assessment and mini-mental state exam), the assessment of immune effector cell-associated encephalopathy tool score (phase II only), the assessment of ECOG PS grade, and concomitant medication usage. Adverse events were coded using the Medical Dictionary for Regulatory Activities Terminology (version 24.0). The severity of adverse events was assessed using the National Cancer Institute’s CTCAE (version 4.03), except for CRS, which was graded according to a CRS-revised grading system. Clinically significant abnormalities that persisted at the end of the study or at the time of early withdrawal were followed by the investigator until resolution or clinical stability. Safety monitoring may have been performed more frequently if clinically indicated, and adverse events were evaluated by the investigator according to standard practice.⁶⁶

Pretreatment Medication

All patients in the MajesTEC-1 study were required to receive the following pretreatment medications before each step-up dose and the first treatment dose of teclistamab: steroids (dexamethasone at a dose of 16 mg), antihistamines (diphenhydramine at a dose of 50 mg or equivalent), and antipyretics (acetaminophen at a dose of 650 mg to 1,000 mg or equivalent). Additionally, patients who experienced events of CRS of grade 2 or higher or systemic administration-related reactions were required to receive dexamethasone before the next dose of teclistamab and patients who experienced CRS of any grade or systemic administration-related reactions were required to receive the antihistamine and antipyretic before at least the next dose of teclistamab. Histamine₂ receptor antagonists (ranitidine at a dose of 50 mg or equivalent) and antiemetics (ondansetron at a dose of 16 mg or equivalent) could be administered as an optional pretreatment medication, per investigator discretion.

Concomitant Medications

During the MajesTEC-1 study, patients may be prescribed any concomitant medications or treatments deemed necessary for supportive care (treatments for adverse events or serious adverse events), including standard supportive care therapies (antiemetics, antidiarrheals, anticholinergics, antispasmodics, antipyretics, antihistamines, analgesics, antibiotics and other antimicrobials, histamine₂ receptor antagonists or proton pump inhibitors, and other medications intended to treat symptoms or signs of disease), bisphosphonates, growth factor support, erythropoietin-stimulating drugs, transfusions, antibiotics or other anti-infective drugs, and corticosteroids used as pretreatment medications.

The following medications were prohibited during the study: any chemotherapy, anticancer immunotherapy (other than teclistamab), experimental therapy, radiotherapy, plasmapheresis (unless in exceptional circumstances unrelated to disease progression), corticosteroids in excess of 10 mg daily of prednisone or equivalent, other immunosuppressant drugs (unless used as protocol-specified pretreatment or post-treatment medications to treat an adverse event), vaccination with live, attenuated vaccine within 4 weeks before the first dose of teclistamab during treatment, IV contrast infusions, routine transfusions on study drug administration days, transdermal patches, and cytochrome P450 substrates with narrow therapeutic index. For patients receiving warfarin, investigators were to consider switching from warfarin to a different anticoagulant.

Subsequent Anticancer Therapy

Unless the patient was intolerant to the study drug, subsequent antimyeloma therapy could not be initiated until disease progression was established according to the IMWG criteria (in part 3 only). Once disease progression was confirmed, the choice of subsequent therapy was at the discretion of the investigator.

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 8, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence as well as any outcomes identified as important to this review according to the clinical experts consulted by CADTH, and stakeholder input from patient and clinician groups and public drug plans. Using the same considerations, the CADTH review team selected end points that were considered to be most relevant to informing CADTH’s expert committee deliberations and finalized this list of end points in consultation with members of the expert committee. Select efficacy and notable harms outcomes that were considered important for informing CADTH’s expert committee were assessed using GRADE.

The secondary outcomes for phase I used for the supportive efficacy analyses included ORR, VGPR or better, CR or better, sCR, OS, PFS, duration of response, and TTR.

For phase II of the MajesTEC-1 trial, the primary end point was ORR (PR or better), and secondary outcomes included VGPR or better, CR or better, sCR, TTR, duration of response, OS, PFS, MRD-negativity rate, and HRQoL outcomes. TTNT was an exploratory outcome in phase II of the MajesTEC-1 study.

Table 8: Outcomes Summarized From the MajesTEC-1 Study

AE = adverse event; CR = complete response; CRS = cytokine release syndrome; HRQoL = health-related quality of life; ICANS = immune effector cell-associated neurotoxicity syndrome; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PR = partial response; sCR = stringent complete response; TEAE = treatment-emergent adverse event; TTNT = time to next treatment; TTR = time to response; VGPR = very good partial response.

Note: Details included in Table 8 are from the sponsor’s Summary of Clinical Evidence.⁸³

Sources: Clinical Study Report for the MajesTEC-1 study (2021),²⁴ Clinical Study Report for the MajesTEC-1 study (2021),⁶⁵ and Clinical Study Protocol for the MajesTEC-1 study (2020).⁶⁶

OS was defined as the time from the date of the first dose of the study intervention to the date of the patient’s death, due to any cause.

PFS was defined as the time from the date of the first dose of the study intervention to the date of the first documented disease progression, as defined in the IMWG criteria,^12,63 or death due to any cause, whichever occurred first. Relapse from CR was not considered as disease progression.

CR or better was defined as the proportion of participants achieving CR or sCR according to the IMWG response criteria^12,63 during or after the study intervention but before the start of subsequent antimyeloma therapy.

MRD-negativity status was defined as the proportion of patients who attained MRD-negative status (at 10^–5) at any time point after the initial dose and before progressive disease or subsequent antimyeloma therapy. Participants with missing or unevaluable MRD status were grouped separately.

VGPR or better was defined as the proportion of patients achieving VGPR, CR, or sCR according to the IMWG response criteria^12,63 during or after the study intervention but before the start of subsequent antimyeloma therapy.

sCR was defined as the proportion of patients achieving an sCR according to the IMWG criteria.^12,63

ORR was defined as the proportion of participants who attained PR or better (i.e., PR, VGPR, CR, or sCR) according to the IMWG response criteria^12,63 (Table 9) during or after study intervention but before the start of subsequent antimyeloma therapy, as assessed by the IRC.

TTR was defined as the time between the date of the first dose of study intervention and the first efficacy evaluation at which the patient had met all criteria for PR or better.

Duration of response was defined as the date of the initial documentation of a response (PR or better) to the date of the first documented evidence of progressive disease, as defined in the IMWG criteria,^12,63 or death due to disease progression, whichever occurred first. Relapse from CR was not considered as disease progression.

TTNT was an exploratory outcome for phase II and was defined as the time from the date of the first dose of the study drug to the start of the next line of treatment.

Adverse events or serious adverse events were encoded using the Medical Dictionary for Regulatory Activities and graded according to the National Cancer Institute’s CTCAE version 4.03⁶⁷ with the exception of CRS, which was evaluated according to the American Society for Transplantation and Cellular Therapy grading system.⁶⁸ TEAEs are defined as adverse events with onset during the treatment phase or that are a consequence of a pre-existing condition that has worsened since baseline.⁶⁶

Considerations that informed the selection of efficacy outcomes to be summarized and assessed using GRADE included the following:

• survival outcomes were identified by the patient and clinician group input, and specified by the clinical experts consulted by CADTH to include OS and PFS (OS and PFS were also key inputs in the sponsor’s pharmacoeconomic model)

• CR, sCR, VGPR, and ORR were identified as important by the clinical experts and by the patient and clinician group input (as response to treatment)

• duration of response was identified as important by the clinical experts consulted by CADTH and patient and clinician group input

• hypogammaglobulinemia and infections were identified as important safety outcomes by clinical experts consulted by CADTH for this review.

Table 9: Summary of Outcome Measures and Their Measurement Properties

EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ VAS = EQ visual analogue scale; HRQoL = health-related quality of life; HSCT = hematopoietic stem cell transplant; MID = minimal important difference; MM = multiple myeloma; QoL = quality of life; SRM = standardized response mean; vs. = versus.

^aThe European Group for Blood and Marrow Transplantation criteria for response were used to determine the patients’ disease phase.

^bTo assess the magnitude of the difference in scores between patients who improved, deteriorated, and remained stable, SRMs were calculated and compared against Cohen’s rule of thumb for interpreting the magnitude of mean differences in HRQoL scores: 0.20 represents a small change, 0.50 represents a moderate change, and more than 0.80 represents a large change.

^cThe MIDs were estimated using 2 approaches. The anchor-based approach was anchored to a structured QoL interview (response options were improved, deteriorated, or unchanged) while the distribution-based approach was based on the standard deviations of baseline scores as well as the receiver-operating characteristic curve method.

^dThe MIDs were estimated using 2 approaches. The anchor-based approach was anchored to a structured QoL interview (response options were improved, deteriorated, or unchanged) while the distribution-based approach was based on the standard deviations of baseline scores.

Statistical Analysis

In the MajesTEC-1 trial, analysis of efficacy outcomes was based on the FAS for patients who received teclistamab at the recommended phase II dose (phase I and phase II, cohort A). The rates of ORR, VGPR or better, CR or better, and sCR with 2-sided 95% CIs were presented for each cohort (phase I and phase II, cohort A). VGPR, CR, or sCR after the start of subsequent anticancer therapy was not considered.

For the ORR calculation, patients who were NE for response were listed as such and were considered nonresponders. Patients with no postbaseline data were considered as nonresponders. Response after the start of subsequent therapy with teclistamab was not considered.

Time to first response was analyzed for patients in the FAS who attained a response (PR or better), using disease response as assessed by the IRC. Descriptive statistics (mean, standard deviation [SD], median, and range) were provided for each cohort. Time to first response, time to best response, time to CR or better response, and time to VGPR or better response were summarized similarly. Analysis was performed based on the IRC assessment.

The distribution of duration of response was estimated using the Kaplan-Meier method, and the corresponding median duration of response and its 95% CI were reported.

For OS, the Kaplan-Meier method was used to estimate the distribution of OS for each cohort, and the median OS with 95% CI was derived. Patients who were lost to follow-up were censored at the time of being lost to follow-up. Patients who died after consent withdrawal but with death data collected were considered as having an OS event. If the patient was alive or the vital status was unknown, then the patient’s survival time was censored at the date the participant was last known to be alive. The date of the patient being last known alive was determined by the maximum collection or assessment date from among selected data domains within the clinical database.

For PFS, the Kaplan-Meier method was used to estimate the distribution of PFS for each cohort and the median PFS with 95% CI was derived. For patients who had not progressed and were alive, their event times were censored at the date of the last disease evaluation before the start of any subsequent antimyeloma therapy. Patients without any postbaseline disease assessment were censored at the date of the first dose of the study intervention. The number and proportion of patients who had a PFS event or were censored were reported. The reasons for censoring were summarized accordingly. The Kaplan-Meier PFS curve was also plotted by cohort. Analysis was performed based on IRC assessment.

The MRD-negativity rate and its 2-sided 95% CI were estimated for each cohort (phase I and phase II, cohort A).

Safety Outcomes

Unless otherwise specified, all safety outcomes were based on the FAS. Descriptive statistics or frequency counts and percentages by cohort were derived for continuous and categorical safety variables, respectively.

Patient-Reported Outcomes

Three patient-reported outcome measures were evaluated using the EORTC QLQ-C30 and EQ-5D-5L questionnaires, and PGI-S. At the time of analysis, using the January 4, 2023, data cut-off, a post hoc analysis was performed in EORTC QLQ-C30 and EQ-5D-5L only in phase II, cohort A, in HRQoL-evaluable patients requiring a baseline and at least 1 postbaseline assessment. Within-group mean change in EORTC QLQ-C30 scales and the EQ-5D-5L tool was analyzed at the group level using mean change from baseline and at the individual level with the proportion of patients with a meaningful change from baseline. Change from baseline in the EORTC QLQ-C30 scales and the EQ visual analogue scale (EQ VAS) and utility were fitted to a mixed model of repeated measures including patients as a random effect, and baseline value and time as fixed effects. Compliance rates for completion of the 3 patient-reported outcome measures were assessed at each time point based on the number of participants in each cycle. Descriptive statistics by cohort were provided for EORTC QLQ-C30 scales and the EQ VAS and utility value. The frequency of responses for the PGI-S single item was summarized as number and percentage responding to each response category. Within-group changes were analyzed at the group level using mean change from baseline and at the individual level with the proportion of participants with a meaningful change from baseline.

At the time of analysis, using the September 7, 2021, data cut-off date, meaningful change at the individual level was assessed for the EORTC QLQ-C30 scales and EQ VAS using 2 methods. The first approach defined meaningful change based on a literature review and another relied on an MCT, defined as at least half of SD from baseline values. The achievement of a meaningful (10-point) improvement¹⁴ from baseline through cycle 6 using the literature-based MCT was summarized for global health status, physical functioning, fatigue, and pain of the EORTC QLQ-C30 tool. The achievement of a meaningful (7-point) improvement^15,81 from baseline through cycle 6 using the literature-based MCT was summarized for the EQ VAS tool.

Sample Size and Power Calculation

For part 1 of phase I of the MajesTEC-1 study, at least 6 patients were enrolled at the safe and tolerable proposed recommended phase II dose(s). The total number of patients in part 1 depended on the frequency of the dose-limiting toxicities and when the recommended phase II dose(s) was determined. For part 2 of phase I of the MajesTEC-1 study, a sample size of up to 40 patients receiving the proposed recommended phase II dose was determined to provide a sufficient probability of observing at least 1 toxicity.

For part 3 (phase II) of the MajesTEC-1 study, the reported sample size requirements for hypothesis testing were as follows.

• Cohort A: Approximately 100 patients treated with teclistamab would be sufficient to achieve at least 85% power such that the lower bound of the ORR 2-sided 95% CI would be above 30%, under an assumed ORR among those treated with teclistamab of 45%. Patients treated with teclistamab who had had a nonevaluable response were counted as nonresponders in the ORR assessment.

• Cohort C: Simon’s 2-stage design was used to test the null hypothesis that the ORR was at most 15% against the alternative that the ORR was at least 35%. Cohort C required 34 response-evaluable patients; assuming a nonevaluable rate of 10%, a total of 38 patients were to be enrolled. After the first 21 patients were enrolled and had been followed for at least 2 cycles to be evaluable for response, the stage I analysis was to be performed. This design yields a type I error rate of 0.025 and a power of 80% under an assumed ORR of 35%.

Statistical Testing

General Statistical Testing Methods

No formal statistical hypothesis testing was conducted in part 1 or part 2 of the study. For each of the 3 parts of the study, data were summarized using descriptive statistics by dose level and by part. The number of observations, mean, SD, coefficient of variation, median, and range were used to summarize continuous variables, where appropriate. The number of observations and their percentages were used to summarize categorical variables.

Interim Analyses

In phase II, futility interim analyses occurred in cohort A. The ORR was analyzed after 30 patients in cohort A became the futility evaluable analysis set. The Lan-DeMets alpha spending function (O’Brien-Fleming type)⁸² was used as a beta-spending function to determine the futility boundary. With this beta-spending function, the stopping boundary in the cohort A interim analysis was identified as up to 6 responders of 30 patients.

In cohort C, the stage I analysis of futility was performed when the first 21 patients were enrolled and had been followed for at least 2 cycles to be evaluable for response. Further enrolment could be terminated if 3 or fewer responses were observed in the first stage. Otherwise, an additional 17 patients were to be enrolled to ensure there were a total of 34 response-evaluable patients with 2 stages combined. The null hypothesis was to be rejected if 10 or more responses were observed in 34 response-evaluable patients.

Subgroup Analyses

Subgroup analyses were performed during the primary efficacy analyses on the cut-off date of September 7, 2021, in the efficacy analysis set. ORR was estimated within the prespecified subgroups: sex, age, renal function, hepatic function, race, ECOG PS, number of lines of prior therapy, refractory status, prior autologous stem cell transplant, prior allogeneic stem cell transplant, type of myeloma, ISS, R-ISS, cytogenetic risk, bone marrow plasma cells, extramedullary plasmacytomas, prior anti-BCMA exposure, and BCMA tumour expression. Details pertaining to the subgroup analyses on the data cut-off date of January 4, 2023, were available only on select subgroups that were deemed clinically meaningful by the clinical experts consulted by CADTH for this review, including the number of lines of prior therapy, and cytogenetic risk.

Sensitivity Analyses

Sensitivity analyses were performed during the primary efficacy analyses on the cut-off date of September 7, 2021, using disease response based on computerized algorithm and investigator assessment according to IMWG in the efficacy analysis set.

There were no sensitivity analyses performed or reported at the time of the data cut-off date of January 4, 2023. No adjustment for multiple testing or type I error control was used.

Analysis Populations

Analysis sets for the MajesTEC-1 trial included in the systematic review are summarized in Table 11.

Table 10: Statistical Analysis of Efficacy End Points in MajesTEC-1 Study: Clinical Data Cut-Off of January 4, 2023

CR = complete response; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EQ VAS = EQ visual analogue scale; MCT = meaningful change threshold; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PGI-S = Patient Global Impression–Severity; sCR = stringent complete response; SD = standard deviation; TTR = time to response; VGPR = very good partial response.

Note: Details included in Table 10 are from the sponsor’s Summary of Clinical Evidence.⁸³

Sources: Clinical Study Protocol for the MajesTEC-1 study⁶⁶ and Clinical Study Reports for the MajesTEC-1 study.^24,65

Table 11: Analysis Populations of MajesTEC-1 Study: Clinical Cut-Off Date of January 4, 2023

RP2D = recommended phase II dose.

Sources: Clinical Study Reports for the MajesTEC-1 study.^24,65

Protocol Amendments

Overall, there were 11 amendments (final amendment dated July 5, 2021) in the MajesTEC-1 trial. The amendment dated March 20, 2017, included the provision of additional clarity to safety measures, the revision of the definition of dose-limiting toxicity, the inclusion of patients with a disease that is relapsed or refractory to established therapies with known clinical benefit in RRMM or patients who are intolerant of those established MM therapies, and a candidate for treatment with teclistamab in the opinion of the treating physician; the amendment excluded allogeneic stem cell transplant up to 6 months before the first dose of the study drug, the modification of dose escalation rules, and the correction of a dose modification guideline. The amendment dated September 2, 2017, included revisions to the inclusion and exclusion criteria that were made for compliance with health agency regulations, the implementation of additional safety measures, and the addition of an explanation to the risks section to clarify that the risks with the study drug are unknown because the toxicological profiles in monkeys may not be relevant to humans. The amendment dated December 12, 2017, included the specification of the grade for TLS that is considered to be a dose-limiting toxicity, and the removal of the recommendation for anti–interleukin-6 therapy for the treatment of grade 2 or higher neurotoxicity. The amendment dated March 26, 2018, included increasing the dosing of teclistamab frequency from biweekly to weekly in new patients enrolled in the study. The dosing change decision was based on preliminary pharmacokinetic data from the first 7 patients who showed insufficient drug exposure beyond day 8 following the first dose of teclistamab. In addition, the patients remaining in the study who were originally dosed on a biweekly schedule would continue on the biweekly schedule.

The amendment dated October 3, 2018, included permission to modify the dosing schedule to align with pharmacokinetic data (weekly versus biweekly dosing schedule), the revision of dose escalation rules for part 1, and clarification of the administration of required preinfusion medication, the exclusion of specific postinfusion medication instructions, and the clarification of disease evaluation schedules and procedures. The amendment dated March 12, 2019, included the investigation of an alternative SC administration method of teclistamab, as it was hypothesized that SC administration should reduce the risk of CRS. The overall reason for this amendment was to add details to evaluate teclistamab administered subcutaneously in part 1 and part 2 of the MajesTEC-1 trial, and to update the required duration of hospitalization for dosing of the study drug at specific cycles and days based on recent pharmacokinetic and safety data. The amendment dated May 23, 2019, included adding time and events schedules to support twice-weekly dosing of the study drug, and updating the rules for dose escalation in the standard titration phase based on the safety and pharmacodynamic profile to date. The amendment dated May 23, 2019, included the addition of the option of a commercially available saline IV bag plus sponsor-provided diluent additive liquid for the dilution of the study drug before administration, an increase in the sample size to allow for continued enrolment in IV dose escalation, the allowance of a 2-hour infusion time for newly enrolled patients, and the updating of the intrasubject dose escalation criteria and discontinuation criteria. The amendment dated July 2, 2020, included the addition of phase II (or part 3) details to the MajesTEC-1 study, the addition of rules to stop enrolment during part 2 if the dose-limiting toxicity rate reaches a specified range, and the inclusion of the definition of women of childbearing potential. The amendment dated October 26, 2020, included providing updated data for the recommended phase II dose, providing a futility analysis for cohort A and cohort B in part 3, and clarifying the inclusion criteria for part 3 cohorts and the plan for enrolment of the cohorts.

Protocol Deviations

At the cut-off date of September 7, 2021, major protocol deviations were reported for 13 (7.9%) patients — none of which affected patient safety or data integrity. The most frequent major protocol deviations included not meeting eligibility criteria (4.3%) and receiving the wrong treatment or incorrect dose (3.0%). No major protocol deviations were related to COVID-19.

Protocol deviations based on the January 4, 2023; clinical cut-off date were not available at the time of review.

Results

Patient Disposition

Patient disposition in the MajesTEC-1 study is summarized in Table 12. At the time of analysis, using the January 4, 2023, data cut-off, patients were treated with teclistamab at the recommended phase II dose. In the MajesTEC-1 trial, 90 of 165 (54.5%) patients discontinued from the study. The reasons for study discontinuation included death (50.3%) and withdrawal by patient (4.2%).

At the time of analysis, using the January 4, 2023, data cut-off, similar proportions of patients discontinued the study treatment in phase I and phase II, cohort A (||||| ||| |||||| ||||||||||||). The reasons for study drug discontinuation included |||||||||||||||||| |||||||| ||||| |||||||| ||||||||| |||||||| ||||||| ||||||| ||||| ||||||| ||||||| || ||||||| ||||||||| ||||||| ||| ||||| |||||||||||| || || || ||| |||||||| ||||||| |||||||| || ||||||||| ||| ||| |||||||| || |||| ||||||| |||| ||||||||| |||| |||||||| |||||| |||||| |||||||| ||| |||||||||| ||||||| ||||||| || |||||||||||.

Table 12: Summary of Patient Disposition From MajesTEC-1 Study

FAS = full analysis set; RP2D = recommended phase II dose.

Note: Details included in Table 12 are from the sponsor’s Summary of Clinical Evidence.⁸³

^aPatients who refused further treatment included “(w)ithdrawal by patient” from phase I RP2D.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

Baseline Characteristics

The baseline characteristics outlined in Table 13 are limited to those that are most relevant to this review or were considered to affect the outcomes or interpretation of the study results. In the MajesTEC-1 trial, the median age of the patients was 64.0 years (range = 62.5 years to 64.0 years), with ||||| || ||| ||||| |||||||||| ||||| |||| |||| || ||||| || |||. Ninety-six (58.2%) patients were male and 69 (41.8%) patients were female. Most patients were white (81.2%), and 12.7% of patients identified as Black or African American. Most patients had an ECOG PS score of 1 (66.1%), and 33.3% of patients had an ECOG PS score of 0.

Table 13: Summary of Baseline Characteristics of MajesTEC-1 Study, Full Analysis Set

ECOG PS = Eastern Cooperative Oncology Group Performance Status; FLC = free light chain; IgA = immunoglobulin A; IgD = immunoglobulin D; IgE = immunoglobulin E; IgG = immunoglobulin G; IgM = immunoglobulin M; IMWG = International Myeloma Working Group; ISS = International Staging System; MM = multiple myeloma; NE = not evaluable; R-ISS = Revised International Staging System; RP2D = recommended phase II dose; SD = standard deviation.

Notes: Details included in Table 13 are from the sponsor’s Summary of Clinical Evidence.⁸³

Percentages were calculated with the number of participants in the full analysis set with available data as the denominator.

^aIncludes patients without a positive immunofixation but with evidence of FLC kappa by FLC testing.

^bIncludes patients without a positive immunofixation but with evidence of FLC lambda by FLC testing.

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

^dR-ISS staging was derived based on the combination of serum beta₂-microglobulin and albumin, genetic risk, and the level of lactate dehydrogenase.

^eThe maximum value from either a bone marrow biopsy or bone marrow aspirate was selected if both results were available.

Source: Clinical Study Report for the MajesTEC-1 study (2021).⁶⁵

The most common immunoglobulin isotypes were immunoglobulin G (55.2%) and immunoglobulin A (17.6%). The median time from diagnosis of MM to enrolment in the study was 6.0 years (range = 0.8 years to 22.7 years). Twenty-eight (17.0%) patients had 1 or more extramedullary plasmacytomas at baseline. Of the 147 patients with baseline cytogenetic data reported, 38 (25.9%) patients had at least 1 high-risk abnormality, including del(17p) (15.6%) and t(4;14) (10.9%) abnormality. Of the 162 patients with baseline ISS data reported, 85 (52.5%) patients were ISS stage I while 20 (12.3%) patients were ISS stage III.

In the MajesTEC-1 trial, 164 (99.4%) patients were refractory at any point to prior therapy and 148 (89.7%) patients were refractory to their last line of therapy. Of the 165 patients in the trial, 128 (77.6%) patients were triple-class refractory and 50 (30.3%) patients were penta-refractory (with at least 2 PIs, at least 2 IMiDs, and at least 1 anti-CD38 monoclonal antibody). The refractory status of patients in the MajesTEC-1 trial is summarized in Table 14.

Table 14: Summary of Refractory Status to Prior Multiple Myeloma Therapy for Patients in MajesTEC-1 Study, Full Analysis Set

IMiD = immunomodulatory drug; PI = proteasome inhibitor.

Note: Details included in Table 14 are from the sponsor’s Summary of Clinical Evidence.⁸³

Source: Clinical Study Report for the MajesTEC-1 study (2021).⁶⁵

Exposure to Study Treatments

Patient exposure to study treatments in the MajesTEC-1 study is presented in Table 15. At the time of analysis, using the January 4, 2023, data cut-off, patients received a median of 9.3 months (range = 0.2 month to 33.6 months) of study treatment. The median duration of study treatment was |||| |||||| ||||||| ||| || |||| ||||||| in phase I, and ||| |||||| ||||||| ||| || |||| ||||||| in phase II, cohort A. Of the 165 patients, || |||||||| ||||||| |||||||| ||||||||||| ||| || |||||||||||| || |||||||| ||||||| |||||||| ||||||||||| ||| || ||||| || ||||||| ||| || |||||||| ||||||||||||||||||||||||| ||| || ||||| || ||||||. At the time of analysis, using the January 4, 2023, data cut-off, || |||||||| ||||||| |||| ||||| || ||||||||| |||| |||||||||||| ||| ||| |||||||| ||||||| |||||||||||| ||||| |||||||||| ||| |||||| |||| ||||||||| |||||| ||| ||||||||| |||||| ||| ||||||| |||||||||| ||||||| ||||| || ||||||| |||||||||||| ||| ||| |||||| |||||| || ||||| |||||||| ||| ||||||||||||| ||||| ||| |||||| |||||||| |||| ||||||||| ||| ||| |||||||||| |||||||||| || ||||||| || |||||| |||||| ||||||| |||||| ||| ||||| ||||||| ||||| || ||||||| (Table 15).

At the time of analysis, using the January 4, 2023, data cut-off, 63 (38.2%) patients had switched from weekly to biweekly dosing, including 54 patients who attained CR or better, and 9 patients who attained PR or VGPR or better. Of the 63 patients, 41 (65.1%) patients had maintained their response and were still receiving treatment at the time of analysis, using the January 4, 2023, data cut-off, with a range of 1 month to 25 months of follow-up after the initial dose schedule change. The median time to biweekly dosing was 11.3 months (range = 3.2 months to 29.5 months). The median duration of follow-up after a schedule change to biweekly dosing was 12.6 months (range = 1.0 month to 24.7 months). The reasons for the first schedule change (i.e., to biweekly dosing) among patients who did not meet protocol-defined criteria based on response included adverse events (4.8%), including neutropenia in 2 patients and injection-site rash in 1 patient and other (5%). Nine patients switched from biweekly to monthly dosing.

At the time of analysis, using the January 4, 2023, data cut-off, the cycle duration differed between phase I and phase II, cohort A, of the MajesTEC-1 trial. Among patients treated in phase I (21-day cycles), || |||||||| ||||||| |||| ||||||| ||| || ||||||||||| || |||||||||||||| |||| ||||||| ||| || |||||||||||| ||| || |||||||| ||||||| |||| ||||||| ||| || ||||| || ||||||| ||||| |||||||| ||||||| || ||||||||||||||||| |||||||| || |||||||| ||||||| |||| ||||||| ||| || |||||||||||| || ||||||||||||||| |||| ||||||| ||| || |||||||||||| ||| || |||||||| |||||| |||| ||||||| ||| || ||||| || ||||||.

Table 15: Summary of Treatment Exposure From MajesTEC-1 Study, Full Analysis Set

SD = standard deviation.

Note: A summary of treatment exposure was presented at the time of analysis, using the January 4, 2023, data cut-off date.

^aDose intensity (mcg/kg per week) was calculated as the sum of total treatment doses (mcg/kg) received (excluding step-up doses before cycle 1; any step-up doses that were received after cycle 1 were considered) divided by the protocol-specified cycle length in weeks on teclistamab after the step-up dosing period.

^bFor all patients with a schedule change, the first schedule change was to biweekly dosing. A patient could later change to a monthly (or back to weekly) dosing schedule.

^cOne patient may have had multiple schedule changes. (Consequently, numbers do not add up to the number of patients with a schedule change).

^dThe protocol-defined criteria for a schedule change to biweekly dosing in phase I was if a patient had attained an investigator response of confirmed PR or better and received a minimum of 4 cycles of therapy. The protocol-defined criteria for a schedule change to biweekly dosing in phase II was if a patient had had an investigator response of CR or better for a minimum of 6 months. (Be advised that a phase II patient with an investigator response of CR or better for a minimum of 173 days was considered to have met the criteria to switch; this reflects the protocol-specified visit window of ± 7 days).

^ePercentages were based on the number of patients who were still on treatment.

^fFor all patients with a schedule change, the first schedule change was to biweekly dosing. A patient could later change to a monthly (or back to weekly) dosing schedule.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

Pretreatment Medications

All pretreatment medications (required and optional) administered at any time during the study are summarized in Table 16. In the MajesTEC-1 trial, all 165 patients (100.0%) received steroids, antipyretics (anilides), and antihistamines (histamine₁ receptor antagonists) as a pretreatment medication. The median total dose of steroids received as a pretreatment medication was 64.0 mg (range = 48.0 mg to 340.0 mg).

Concomitant Medications

All 165 patients received concomitant medication during treatment with teclistamab (Table 17). The most frequently used medications were nucleosides and nucleotides excluding reverse transcriptase inhibitors (93.9%), followed by anilides (81.2%), natural opium alkaloids (80.6%), and combinations of sulfonamides and trimethoprim (52.7%).

Table 16: Pretreatment Medications, Full Analysis Set [Redacted]

H₁ = histamine₁; H₂ = histamine₂.

Note: Details included in Table 16 are from the sponsor’s Summary of Clinical Evidence.⁸³

Source: Clinical Study Report for the MajesTEC-1 study (2021).⁶⁵

Table 17: Concomitant Medication Use, Full Analysis Set

Note: Details included in Table 17 are from the sponsor’s Summary of Clinical Evidence.⁸³

Source: Clinical Study Report for the MajesTEC-1 study (2021).⁶⁵

Subsequent Antimyeloma Treatment

At the time of analysis, using the September 7, 2021, data cut-off, of the 104 responders (with PR or more) in the MajesTEC-1 study, || |||||||| ||||||| received 1 or more subsequent antimyeloma therapies, with a median TTNT of 12.7 months. The most common antimyeloma treatments included glucocorticoids (17.0%), nitrogen mustard analogues (13.9%), PIs (12.1%), monoclonal antibodies (5.5%), and subsequent radiotherapy (5.5%).

At the time of analysis, using the January 4, 2023, data cut-off, subsequent antimyeloma therapy was reported for || |||||||| |||||||, including || |||||||| ||||||| in phase I and || |||||||| ||||||| in phase II, cohort A. The median time to subsequent antimyeloma treatment was 20.1 months (95% CI, 12.7 months to NE months); however, details pertaining to the specific subsequent therapies received by patients in this data cut-off are not reported.

Efficacy

The primary analysis at the data clinical cut-off of September 2021 and the final analysis at the data clinical cut-off of August 2023 were prespecified analyses, and the sponsor-submitted Clinical Study Reports with March 2022 and January 2023 clinical cut-offs present interim analyses. As the final clinical report for the pivotal study is not yet available, information for the following sections was extracted from the more recent Clinical Study Report with a clinical cut-off date of January 4, 2023, submitted by the sponsor for this review. However, data from the clinical cut-off date of September 7, 2021, was also used to supplement the included data when necessary.

Findings for key efficacy outcomes in the MajesTEC-1 trial are summarized in Table 20.

Overall Survival

At the time of analysis, using the January 4, 2023, data cut-off, the median duration of follow-up was |||| |||||| |||| ||| ||| || |||| ||||||||||| |||||| |||| ||| ||| || |||| ||||||||||| |||||| |||| ||| ||| || |||| ||||||| in phase I, and 22.3 months (range = 0.3 month to 26.5 months) in phase II, cohort A. The estimated median OS was |||| |||||| |||| ||| ||| || |||| ||||||||||| |||||| |||| ||| ||| || |||| ||||||| in phase I, and |||| |||||| |||| ||| ||| || |||| ||||||||||| |||||| |||| ||| ||| || |||| ||||||| in phase II, cohort A. In the FAS, deaths were reported in |||| |||||| |||| ||| ||| || |||| ||||||| in phase I and |||| |||||| |||| ||| ||| || |||| ||||||||||| |||||| |||| ||| ||| || |||| ||||||| in phase II, cohort A. The number of patients who were censored (alive at the time of data cut-off) was |||| |||||| |||| ||| ||| || |||| ||||||| and |||| |||||| |||| ||| ||| || |||| ||||||| in phase I and phase II, cohort A, respectively. In the FAS, the estimated 9-month OS probability |||| |||||| |||| ||| ||| || |||| ||||||||||| |||||| |, the 12-month OS probability was |||| |||||| |||| ||| ||| || |||| ||||||||||| |||||| |||| ||| ||| || |||| |||||||, and the 24-month OS probability was |||| |||||| |||| ||| ||| || |||| ||||||||||| |||||| |||| ||| ||| || |||| |||||||. The Kaplan-Meier curve of OS for patients in the FAS is presented in Figure 4.

Progression-Free Survival

At the time of analysis, using the January 4, 2023, data cut-off, the estimated median PFS was |||| |||||| |||| ||| ||| || |||| ||||||| in phase I, and |||| |||||| |||| ||| ||| || |||| ||||||| in phase II, cohort A. In the FAS, the estimated 9-month PFS probability was ||||| |||| ||| ||||||| ||||||, the 12-month PFS probability was ||||| |||| ||| ||||| || ||||||, and the 24-month PFS probability was ||||| |||| ||| ||||| || ||||||. The Kaplan-Meier curve for PFS for patients in the FAS is provided in Figure 5.

Figure 4: Kaplan-Meier Plot for Overall Survival, Full Analysis Set

RP2D = recommended phase II dose.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

Figure 5: Kaplan-Meier Plot for Progression-Free Survival, Full Analysis Set

RP2D = recommended phase II dose.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

CR or Better

At the time of analysis, using the January 4, 2023, data cut-off, || |||||||| ||||||| |||| ||| ||||| || ||||||| in phase I and || |||||||| ||||||| |||| ||| ||||||| ||||||| in phase II, cohort A, attained CR or better (CR or sCR) (Figure 6).

sCR

At the time of analysis, using the January 4, 2023, data cut-off, || |||||||| ||||||| |||| ||| ||||| || ||||||| in phase I and || |||||||| ||||||| |||| ||| ||||||||||||| in phase II, cohort A, attained sCR (Figure 6).

Figure 6: Response Rate and Depth of Response, Full Analysis Set

CR = complete response; IMWG = International Myeloma Working Group; IRC = independent review committee; PR = partial response; ORR = overall response rate; sCR = stringent complete response; VGPR = very good partial response.

^a ORR is defined as the proportion of patients who attain PR or better (i.e., PR, VGPR, CR, or sCR) according to the IMWG response criteria,^12,63 during or after study intervention but before the start of subsequent antimyeloma therapy, as assessed by the IRC.

^b CR or better is defined as the proportion of patients achieving CR or sCR according to the IMWG response criteria,^12,63 during or after the study intervention but before the start of subsequent antimyeloma therapy, as assessed by the IRC.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

MRD-Negativity Status

Updated data regarding the MRD-negativity status based on the January 4, 2023, clinical cut-off date are not available.

At the time of the data cut-off date of September 7, 2021, 37 (24.7%) patients (95% CI, 18.0% to 32.4%) had attained MRD negativity at 10^–5 bone marrow cells. Among 43 patients who attained CR or better, 18 (41.9%) patients (95% CI, 27.0% to 57.9%) attained MRD negativity at 10^–5 bone marrow cells.

VGPR or Better

At the time of analysis, using the January 4, 2023, data cut-off, || |||||||| ||||||| |||| ||| ||||| || ||||||| in phase I and || |||||||| ||||||| |||| ||| ||||||| ||||||| in phase II, cohort A, attained VGPR or better (VGPR, CR, or sCR) (Figure 6).

Overall Response Rate

In the MajesTEC-1 trial, ORR was the primary outcome for phase II, cohort A, and the secondary outcome for phase I.

At the time of analysis, using the January 4, 2023, data cut-off, 104 (63.0%) patients (95% CI, 55.2% to 70.4%) attained an overall response (PR or better), and ORR was similar across patients treated in phase I and phase II, cohort A ||||||| |||| ||| ||||| |||||||| ||| |||||| |||| ||| ||||| || ||||||, respectively) (Figure 6).

Of the 104 responders (who attained PR or better), 51 (49.0%) patients maintained their response until the clinical cut-off date |||||| || |||||||| ||||| || ||||||||||| ||, including 46 (44.2%) patients who were still on treatment (Table 18). Of 104 responders, || |||||||| ||||||| had disease progression after initial response, of whom || ||||||| ||||||| died after disease progression, || |||||||| ||||||| discontinued the study treatment, and ||||||| |||||| remained on study treatment. A total of 19 (18.3%) patients died after achieving response and without experiencing disease progression, and ||||||| |||||| had subsequent therapy after response and without progressive disease.

Table 18: Summary of Responders in MajesTEC-1 Study, Full Analysis Set [Redacted]

CCO = clinical cut-off; PD = progressive disease.

^aIncludes patients who had not progressed, died, started subsequent therapy, or ended study until the CCO date of January 4, 2023.

^bIncludes patients who died without PD being assessed (including deaths after subsequent therapy).

^cIncludes patients who did not have PD assessed.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

Of the 63 responders who changed dosage schedule, || |||||||| ||||||| |||||||||| ||||| |||||||| ||||| ||| |||||||| ||||||| ||||| ||||||||| || |||||||| ||||||| ||| |||||| ||||||||||| (Table 19). |||| || || |||||||| ||||||| ||| ||||||| ||||||||||| ||||| ||||||| ||||||||| || ||||||||||| |||||| |||| ||||| ||||||| |||||||||||||||||||| ||||||| |||||||||||| ||| ||||| |||||||||| |||||||||| |||||| |||||| || ||||| ||||||||||||||| ||||||||| |||||| |||| ||||| ||||||||| |||||||| ||| ||||||| |||||||||||| ||||||| |||||||||||| ||||||||| |||||| ||| |||||||||| ||||||| ||||| |||||||| ||| ||||||||||||||||| ||||||||

Table 19: Summary of Responders With Schedule Change in MajesTEC-1 Study, Full Analysis Set [Redacted]

CCO = clinical cut-off; IRC = independent review committee; PD = progressive disease.

^aBased on time from first dosage schedule to last dose date, or disease progression as assessed by the IRC.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

Subgroup Analysis

Only results of the ORR subgroup analyses that were deemed clinically meaningful by the clinical experts consulted by CADTH for this review are reported.

At the time of analysis, using the January 4, 2023, data cut-off, 32 patients of 43 (74.4%) patients who received 3 or less prior lines of therapy attained an overall response. Of the 122 patients who received more than 3 prior lines of therapy, 72 (59.0%) patients attained overall response, and 32 of 60 (53.3%) patients with high cytogenetic risk and/or extramedullary disease attained overall response.

At the time of analysis, using the September 7, 2021, data cut-off, ORR was 60.8% (73 of 120) of patients, 62.1% (72 of 116) of patients, 61.4% (27 of 44) of patients, and 59.7% (80 of 134) of patients in those who were refractory to PI and IMiD, triple-refractory, penta-refractory, and refractory to last line of therapy, respectively.

Time to Response

At the time of analysis, using the January 4, 2023, data cut-off, of 104 patients who attained PR or better, the median time to first response was 0.9 months (range = 0.2 month to 2.3 months) while the median time to best response was 3.6 months (range = 1.7 months to 18.7 months). Most patients demonstrated their first response rapidly, by the start of cycle 2 (Figure 7).

Figure 7: Response and Follow-up in MajesTEC-1 Study per IRC Assessment, Full Analysis Set

AE = adverse event; CR = complete response; D/C = discontinued; IRC = independent review committee; PD = progressive disease; PR = partial response; RP2D = recommended phase II dose; sCR = stringent complete response; VGPR = very good partial response.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

Duration of Response

At the time of analysis, using the January 4, 2023, data cut-off, with a median duration of follow-up of 22.8 months, the median duration of response was |||| |||||| |||| ||| |||| || || ||||||| in phase I and |||| |||||| |||| ||| |||| || || ||||||| in phase II, cohort A. Among 104 responders (with a PR or better response), || |||||||| ||||||| in phase I and || |||||||| ||||||| in phase II, cohort A, had disease progression or died due to any cause. The probability of patients remaining in response at 9 months was ||||| |||| ||| ||||| || ||||||| The probability of patients remaining in response at 18 months was ||||| |||| ||| ||||| || ||||||| The probability of patients remaining in response at 24 months was ||||| |||| ||| ||||| || |||||||

Table 20: Summary of Key Efficacy Results From MajesTEC-1 Study, Full Analysis Set

CI = confidence interval; CR = complete response; DoR = duration of response; IRC = independent review committee; MRD = minimal residual disease; NE = not evaluable; OS = overall survival; PFS = progression-free survival; PR = partial response; sCR = stringent complete response; SD = standard deviation; VGPR = very good partial response.

Note: Details included in Table 20 are from the sponsor’s Summary of Clinical Evidence.⁸³

^aKaplan-Meier estimate.

^bThe MRD-negativity rate was reported as of the clinical data cut-off date of September 7, 2021.

^cPR or better.

^dThe number of events refers to the number of responders (PR or better) who developed disease progression or died due to any cause. DoR was calculated as the number of months from the first documented response to progression, death due to any cause, or the date of censoring.

Source: Clinical Study Report for the MajesTEC-1 study (2021).²⁴

Patient-Reported Outcomes

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30: The results of a post hoc analysis for mean change from baseline in EORTC QLQ-C30 scales, including global health status, fatigue, pain score, and physical functioning, are presented in Table 21. Analyses were conducted in the HRQoL-evaluable population of patients who had evaluable assessment at baseline and follow-up time points for each domain of EORTC QLQ-C30 (i.e., cycle 2, day 1; cycle 3, day 1; and so forth). At the time of analysis, using the January 4, 2023, data cut-off, the EORTC QLQ-C30 compliance rate (defined as the proportion of evaluable forms of all expected forms) at baseline was ||||| |||||||| |||||||||| ||||| |||||||||||||| || ||||| || ||||| |||||| ||||||||| || ||||| ||| ||| ||||| |||||| ||||||||| || ||||| ||. The EORTC QLQ-C30 showed improvements over time from baseline on pain and fatigue system scale, improvements from cycle 4 onward on global health status, and improvements with the decrease initially observed in cycle 2 on physical functioning.

At the time of analysis, using the January 4, 2023, data cut-off, the least squares mean (LSM) of change from baseline in global health status was ||| |||| ||| ||| || ||||| || ||||| || ||| |||| ||| ||| || ||||| || ||||| ||| ||| |||| |||| ||| ||| || ||||| || ||||| ||. The LSM of change from baseline in fatigue symptom scale was ||| |||| ||| |||| || |||| || ||||| || |||| |||| ||| ||||| || ||||| || ||||| ||| ||| |||| |||||| || ||| || ||||| ||. The LSM of change from baseline in pain was ||||| |||| ||| ||| || ||||| || ||||| || ||| |||| ||| ||||| || |||||| || ||||| ||, and ||||| |||| ||| ||| || |||||| || ||||| ||. The LSM of change from baseline in physical functioning was |||| |||| ||| |||| || |||| || ||||| || ||| |||| ||| |||| || |||| || ||||| ||| ||| ||| |||| ||| |||| || ||||| || ||||| ||.

Table 21: Summary of Selected Scales for EORTC QLQ-C30 Assessment and Change From Baseline (Phase II, Cohort A) [Redacted]

CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; LSM = least squares mean; SD = standard deviation.

Note: 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 indicates better health on the global health and functional scales (physical, role, emotional, cognitive, and social) and greater symptom severity on the symptom scales (fatigue, nausea and vomiting, pain, dyspnea, sleep disturbance, appetite loss, constipation, and diarrhea).

Source: Sponsor-submitted additional information.⁸³

At the time of analysis, using the September 7, 2021, data cut-off, meaningful improvement from baseline (10 points using the literature-based MCT¹⁴) to cycle 2, cycle 4, and cycle 6 (i.e., the first 6 months) was reported by up to 35.8% of patients for global health status, up to 23.9% of patients for physical functioning, up to 68.7% of patients for fatigue system scale, and up to 78.8% of patients for pain.

EQ-5D-5L: The results of post hoc analysis for mean change from baseline in EQ-5D-5L scores, including utility score and EQ VAS, are presented in Table 22. At the time of analysis, using the January 4, 2023, data cut-off, the EQ-5D-5L compliance rate (defined as the proportion of evaluable forms of all expected forms) at baseline was ||||||||||| ||||||||| || ||||| || ||||| |||||| ||||||||| || |||||| ||||| |||||| ||||||||| || ||||| ||| ||| ||||| |||||| ||||||||| || ||||| ||. EQ-5D-5L showed improvements over time from baseline on utility scores and EQ VAS from cycle 4 onward.

Table 22: Summary of EQ-5D-5L Assessment and Change From Baseline (Phase II, Cohort A), Full Analysis Set [Redacted]