Reimbursement Review

Belantamab Mafodotin (Blenrep), Pomalidomide, Dexamethasone

Sponsor: GlaxoSmithKline Inc.

Therapeutic area: Multiple myeloma

This multi-part report includes:

Clinical Review

Pharmacoeconomic Review

Clinical Review

Abbreviations

Executive Summary

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

Table 1: Background Information of Application Submitted for Review

NOC = Notice of Compliance.

Source: Draft product monograph for belantamab mafodotin.¹

Introduction

Multiple myeloma (MM) is an incurable, progressive, malignant plasma cell cancer, characterized by the abnormal proliferation of clonal B cells in the bone marrow and overproduction of the abnormal immunoglobulin M protein.² MM accounts for approximately 1% of all cancers and about 10% of all hematologic malignancies.³ MM is more common in males than females and about twice as common in Black people compared with white or Asian people.^4-7 The incidence of MM is related to older age. In 32,065 patients with MM in Canada between 1992 and 2010, approximately 80% were diagnosed at the age of 60 years or older.⁷ It is estimated that 4,100 new cases of MM were diagnosed in 2024 in Canada.⁸ The 5-year net survival for patients with MM in Canada is approximately 50%.⁹ The clinical course of MM, although variable, typically includes periods of treatment and remission separated by inevitable relapses, with the duration of response to treatment decreasing with each subsequent line of therapy.^10,11 Relapsed or refractory (r/r) MM is defined as MM that is nonresponsive to therapy or has progressed within 60 days of the last line of treatment in patients who previously achieved a minimal response or better.^12,13

Autologous stem cell transplant (ASCT) is the standard of care for newly diagnosed patients with MM if they are eligible. Patients who are ineligible for ASCT are typically treated with a combination of immunomodulatory drugs, proteasome inhibitors (PIs), and mAbs. Lenalidomide is recommended to be used as part of the front-line therapy for newly diagnosed MM (regardless of ASCT eligibility) by the International Myeloma Working Group (IMWG) and the Canadian Myeloma Research Group (CMRG) Consensus Guideline Consortium due to the overall survival (OS) benefits seen in clinical trials.¹⁴ Treatment choice in r/r MM is individualized and multifactorial, taking into consideration prior treatment history and response, timing and aggressiveness of the relapse, patient factors (e.g., performance status, age, frailty, and comorbidities), personal preferences, and jurisdictional funding and rules around reimbursement.^15,16 The general strategy for treatment beyond first line includes the use of a drug that the patient has either not been exposed to previously or demonstrated sensitivity to in the treatment regimen.¹⁷ Based on the IMWG recommendations, for patients whose disease is not refractory to lenalidomide, the preferred options for the second line are daratumumab, lenalidomide, and dexamethasone (DRd) or a combination of carfilzomib, lenalidomide, and dexamethasone, although alternatives are available.^15,17

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of belantamab mafodotin 70 mg and 100 mg vials for infusion in combination with pomalidomide and dexamethasone (Pd) in the treatment of MM in adult patients who have received at least 1 prior therapy including lenalidomide. The focus will be placed on comparing belantamab mafodotin, pomalidomide, and dexamethasone (BPd) with relevant comparators and identifying gaps in the current evidence.

Perspectives of Patients, Clinicians, and Drug Programs

The information in this section is a summary of input provided by the patient and clinician groups who responded to our call for input and from clinical expert(s) consulted by for the purpose of this review.

Patient Input

One patient group, Myeloma Canada, submitted input for this review via a survey (N = 100 completed surveys).

Patients identified infections as the most important symptom to control, followed by kidney problems, mobility, and pain. Daily activities that were most impacted were ability to travel and work, while the most impacted specific aspects of their quality of life were interruptions to life goals or accomplishments and loss of sexual desire.

Outcomes of most interest to patients were prolonged life expectancy, improved quality of life, and survival without progression of their disease. Various ocular side effects (eye pain or irritation, blurred vision, foreign body sensation, dry eyes) and infections were identified as the worst tolerability issues among 89 patients eligible to receive BPd and the 7 patients who had been treated with BPd.

The key toxicities of concern identified from the patient input are ocular harms and infections.

Clinician Input

Input From Clinical Experts Consulted for This Review

The clinical experts noted that because there are no curative therapies for MM, it is important to have new therapies with novel mechanisms of action for the patients who become resistant to current therapies. The clinical experts added the BPd will mostly be used in patients who have experienced relapse after 1 to 3 prior lines of therapy. According to the clinical experts, older patients who have already received DRd would be good candidates for BPd given the favourable toxicity profile with respect to myelosuppression. They added that any patients with pre-existing eye conditions would not be good candidates for belantamab mafodotin–containing regimens due to the ocular toxicities.

The clinical experts noted the importance of health-related quality of life (HRQoL) in assessing BPd in MM, because patients survive for a long time with this type of cancer, and due to the ocular toxicities, which may negatively impact quality of life. The clinical experts added that the main reasons to discontinue treatment would be disease progression or toxicity, namely ocular adverse events (AEs).

Clinician Group Input

Two clinician groups, Ontario Health (Cancer Care Ontario) (OH [CCO]) Hematology Cancer Drug Advisory Committee and CMRG, provided input for this Clinical Review. The OH (CCO) Hematology Cancer Drug Advisory Committee gathered information from 7 clinicians, while CMRG collected input from 20 clinicians.

There were no obvious areas of disagreement between the clinician groups and the clinical experts consulted on this review.

The OH (CCO) Hematology Cancer Drug Advisory Committee noted that BPd could fit into current second-line treatments for patients whose disease is resistant to lenalidomide or bortezomib. CMRG noted that BPd would pertain to patients who have had 1 to 3 prior lines of therapy.

Both clinician groups noted that BPd should be discontinued upon disease progression or significant toxicity, especially significant ocular toxicity. Both clinician groups noted that the outpatient setting is the appropriate setting for treatment with BPd, and ophthalmological assessment is needed.

Drug Program Input

In response to a question about how BPd compares with therapies like carfilzomib and dexamethasone (Kd); selinexor, bortezomib, and dexamethasone (SVd); isatuximab, pomalidomide, and dexamethasone (IsaPd); isatuximab, carfilzomib, and dexamethasone (IsaKd); and Pd, the clinical experts believed BPd to have very good and perhaps even superior efficacy to many of these regimens; however, 1 clinical expert also noted that it is difficult to compare to IsaPd and IsaKd, which are also quite effective. In response to a question about whether certain groups of patients should be considered for BPd, the clinical experts believed that patients with active plasma cell leukemia and patients who have experienced intolerance to (or whose disease is refractory to) bortezomib could be considered for BPd, and 1 clinical expert noted that although there are limited data, BPd will likely be used in patients with light chain amyloidosis.

In response to a question as to whether patients receiving Pd or other treatments be switched to belantamab mafodotin, the clinical experts said they believed this could be allowed. In response to a question about sequencing of belantamab mafodotin with other BCMA-targeting therapies, the clinical experts noted that belantamab mafodotin likely has some efficacy; however, 1 clinical expert noted data from an IMWG sequencing paper that suggested efficacy may be reduced. In response to a question, the clinical experts noted that if a patient experiences disease progression on a bortezomib- and lenalidomide-containing regimen in the first-line setting, there would be no reason to exclude them from BPd.

Clinical Evidence

Systematic Review

Description of Studies

The DREAMM-8 study is an ongoing phase III, open-label, multinational (140 centres in 18 countries, including 3 sites in Canada) randomized controlled trial (RCT) evaluating the efficacy and safety of BPd versus pomalidomide, bortezomib, and dexamethasone (PVd) in 302 participants with r/r MM. Patients in the BPd group received belantamab mafodotin intravenously 2.5 mg/kg on day 1 of cycle 1 and a dose of 1.9 mg/kg of cycle 2 or more in each 28-day cycle. Following screening, participants were stratified based on the number of prior lines of therapy (1 versus 2 or 3 versus ≥ 4), prior bortezomib treatment (yes or no), and prior anti CD38 treatment (yes or no). International Staging System (ISS) status (I versus II or III) was a randomization factor but was replaced with prior anti-CD38 treatment (yes or no) in Protocol Amendment 1. Treatment was continued in both groups until progressive disease per IMWG criteria, death, unacceptable toxicity, start of a new antimyeloma therapy, withdrawal of consent, or the end of the study, whichever occurred first. In the case of progressive disease, participants were followed to ascertain receipt of subsequent antimyeloma therapy, progression-free survival (PFS) on subsequent line of therapy, and survival status every 12 weeks (± 14 days) until the withdrawal of consent, loss to follow-up, death, or the end of the study. The primary outcome of the DREAMM-8 study was PFS, while key secondary outcomes included OS, duration of response (DOR) and minimal residual disease (MRD) negativity. The primary and secondary end points of the DREAMM-8 study were analyzed based on the data cut-off date of January 29, 2024.^18,19

Most patients were male (60%; about 40% were female) and had an average age of 66 years; approximately 61% were aged 65 years or older. Most patients (59%) were at ISS stage I at screening, only 10% had extramedullary disease and ███ had lytic bone lesions. The most common myeloma immunoglobulin was IgG (62% of patients), with IgA being the next most common (22%). With respect to prior lines of therapy completed before screening, 53% of patients had 1 line, 34% had 2 or 3 lines, and 14% had 4 or more lines. Most patients (91%) had a prior PI, and all patients had a previous immunomodulatory drug and had received lenalidomide. Sixty percent of patients had a prior stem cell transplant. With respect to the cytogenetic risk profile, one-third were considered high risk. Most patients (98%) had Eastern Cooperative Oncology Group (ECOG) performance status scores of 0 or 1.

Efficacy Results

Progression-Free Survival

PFS was assessed by an independent review committee (IRC). After a median follow-up of 21.8 months, progression or death occurred in 62 participants (40%) in the BPd arm versus 80 (54%) participants in the PVd arm, for a hazard ratio (HR) of 0.52 (95% confidence interval [CI]: 0.37 to 0.73; P < 0.001). The median PFS was not reached in the BPd arm (95% CI, 20.6 to not reached) and was 12.7 months (95% CI, 9.1 to 18.5) in the PVd arm. Landmark analyses of PFS at 12 months showed a higher PFS rate in the BPd arm compared with the PVd arm (71% versus 51%), as well as at 18 months (███ versus ███). █████ ███████████ or supplemental analyses were conducted, all of which yielded results consistent with the primary PFS analysis, with HRs ranging from ████ ██ ████.

The PFS benefit observed was consistent across all subgroups, with HRs ranging from 0.26 to 0.76.¹⁹ In the protocol-specified subgroups of the DREAMM-8 trial, the HR was 0.52 (95% CI, 0.31 to 0.88) for participants with 1 prior line of therapy and 0.52 (95% CI, 0.33 to 0.80) for those with more than 1 prior line. For patients exposed to bortezomib, the HR was 0.55 (95% CI, 0.38 to 0.78). Among participants whose disease is refractory to lenalidomide, the HR was 0.45 (95% CI, 0.31 to 0.65). Regarding cytogenetic risk, the HR was 0.57 (95% CI, 0.34 to 0.96) for patients at high risk and 0.51 (95% CI, 0.30 to 0.86) for those with standard risk.

Overall Survival

At the data cut-off date (January 29, 2024), median OS was not reached in either treatment arm. The OS data had reached 34.8% (105 of 302 participants) overall maturity and an information fraction equal to 48.4% (105 of 217), where 217 deaths were planned for OS analysis according to the statistical analysis plan. Follow-up for OS is ongoing and will continue until the planned interim analysis 3 (IA3) of OS at approximately 60% information fraction. The 12-month OS survival rate was higher in the BPd arm compared with the PVd arm (83% [95% CI, 76% to 86%] versus 76% [95% CI, 68% to 82%]), for a risk difference (RD) of ████ ████ ███ ██████ ██████ and this was also the case at 18 months ████ █████ ████ versus ███ █████ ████, for a RD of ████ ████ ███ ██████ ██████.

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

At least 50% of participants in both treatment arms were on treatment during the initial 12 months and had regular assessments every 4 weeks. Therefore, the patient-reported outcome dataset is more complete during this time. The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) global health status (GHS) domain, physical domain, role functioning domain, and fatigue domain remained stable across both treatment arms over time.

Conventional Assessment of DOR

DOR was defined as the time from first documented evidence of partial response (PR) or better until progressive disease or death due to any cause based on IRC assessment per IMWG criteria. The median DOR was not reached in the BPd arm (95% CI, 24.9 to not reached) and was 17.5 months (95% CI, 12.1 to 26.4) in the PVd arm. In the BPd arm, 66 (55%) participants with response had not progressed or died and had follow-up for PFS ongoing at the data cut-off date compared with 33 (31%) participants in the PVd arm.

MRD Negativity Rate

At the time of the primary analysis, the proportion of participants with a complete response or greater who achieved MRD negativity was higher in the BPd arm (37 of 155 patients, 24%) compared with the PVd arm (7 of 147 patients, 5%). Because the OS analysis was not statistically significant (because the data were immature) at the time of the PFS analysis data cut-off date, MRD negativity could not be formally tested at that time. Results of the MRD negativity analysis using investigator-confirmed response or in participants with very good partial response (VGPR) or better were consistent with the primary MRD analysis.

Complete Response Rate

There were 62 patients (40%) in the BPd group compared to 24 patients (16%) in the PVd group who had an IRC-assessed complete response (CR) or better. No formal testing of this outcome was completed.

Harms Results

When assessing harms, it should be noted that exposure to BPd was longer than PVd. For example, the median exposure to belantamab mafodotin was 13.19 months, pomalidomide 15.92 months, and dexamethasone 14.00 months in the BPd group, while exposure to bortezomib was 7.62 months, pomalidomide 8.51 months, and dexamethasone 8.08 months in the PVd group.

Adverse Events

Overall, 149 patients (more than 99%) in the BPd group and 139 patients (96%) in the PVd group had at least 1 AE, and 136 patients (91%) in the BPd group and 106 patients (73%) in the PVd group had a grade 3 or 4 AE. The 3 most frequent AEs, all more common in BPd than PVd, included vision blurred, (119 patients [79%] versus 22 patients [15%]), dry eye (91 patients [61%] versus 14 patients [10%]), and foreign body sensation in eyes (91 patients [61%] versus 9 patients [6%]). Under the category of infections and infestations, the AEs where there were differences for BPd versus PVd, were COVID-19 (56 patients [37%] versus 31 patients [21%]), upper respiratory tract infection (40 patients [27%] versus 25 patients [17%]), and pneumonia (36 patients [24%] versus 17 patients [12%]).

The most common grade 3 or greater AEs, all more common with BPd versus PVd, were neutropenia (63 patients [42%] versus 41 patients [28%]), thrombocytopenia (36 patients [24%] versus 29 patients [20%]), and pneumonia (26 patients [17%] versus 11 patients [8%]).¹⁹

Serious AEs

Overall, there were 95 patients (63%) in the BPd arm and 65 patients (45%) in the PVd arm who had a serious AE (SAE). The exposure-adjusted incidence rate for SAEs was comparable between the 2 treatment arms (45.87 per 100 person-years versus 47.87 per 100 person-years, respectively).¹⁹ The most frequently reported SAE in both treatment arms was pneumonia, which occurred in ██ patients █████ in the BPd group and ██ patients ████ in the PVd group.

Withdrawals Due to AEs

The incidence of AEs leading to discontinuation of study treatment (any component of study treatment) was 15% (22 patients) with BPd and 12% (18 patients) with PVd.¹⁹ The most common AEs leading to treatment discontinuation in the BPd arm were fatigue, keratopathy, muscular weakness, and neuralgia ███ ██████¹⁹

Mortality

The incidence of fatal SAEs (related and not related to study treatment) was the same in the 2 treatment arms (11% in both BPd and PVd arms).¹⁹ The most common fatal SAE was COVID-19 pneumonia (3% [n = 5] in the BPd arm versus 1% [n = 2] in the PVd arm) and death due to unknown cause (0 in the BPd arm versus 2% [n = 3] in the PVd arm). All other fatal SAEs were reported in 1% or less of participants.¹⁹

Notable Harms

Ocular exams were performed regularly for all participants in both treatment arms throughout the study. They were performed more frequently in the BPd arm (every 4 weeks, then decreased to every 3 months if there were no significant ocular findings after the sixth dose) than in the PVd arm (every 6 months).¹⁹ Under the original trial protocol, all ocular symptoms and examination findings were to be reported as AEs and graded by the Common Terminology Criteria for Adverse Events (CTCAE) criteria. Belantamab mafodotin dose modification was based on these assessments.

Ocular AEs (CTCAE grade) occurred in 89% of participants in the BPd arm. Vision blurred, dry eye, foreign body sensation in eyes, and eye irritation were each reported in 50% or more of the participants in this treatment arm.¹⁹ The incidence of ocular AEs (CTCAE grade) in the PVd arm was lower (30%). The most frequently reported ocular AE in this treatment arm was vision blurred (15%). Grade 3 or 4 ocular AEs (CTCAE grade) were reported in more participants in the BPd arm (43%) than in the PVd arm (2%).¹⁹ The most common grade 3 or greater ocular AEs, occurring more commonly in the patients taking BPd than those taking PVd, were blurred vision (26 patients [17%] versus none), reduced visual acuity (20 patients [13%] versus 1 patient [less than 1%]), impaired vision ███ ████████ █████ ██ █ ███████ █████ ████ ████, corneal epithelial microcysts and dry eye (12 patients each [8%] versus none), cataract (9 patients [6%] versus 6 patients [4%]), foreign body sensation (9 patients [6%] versus none), and punctate keratitis (9 patients [6%] versus 1 patient [less than 1%]).

Critical Appraisal

The open-label design of the DREAMM-8 study introduces the potential for bias, particularly with respect to patient-reported outcomes such as HRQoL. Assessment of HRQoL was also complicated by high attrition rates and missing data from patients who were unable to complete assessments due to disease progression or death, with data reported for less than half of the original intention-to-treat (ITT) population by week 53. Although study withdrawals were relatively low (less than 10%) across groups, there was a large number of patients who discontinued treatment in both groups; therefore, there was a large imbalance in patients going on to subsequent treatment in the BPd group compared with the PVd group (27% versus 52%), and this complicated the interpretation of OS.

OS data are not yet mature; therefore, this limits any conclusions that can be drawn about the data. PFS is considered a valid surrogate for OS and is frequently used as a primary outcome in pivotal trials, consistent with FDA guidance.

GRADE Summary of Findings and Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations. A final certainty rating was determined as outlined by the GRADE Working Group.^20,21

Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect. If that was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The minimal important difference (MID) for PFS and OS were obtained by asking the clinical experts for their impression of what it should be. For PFS, the clinical experts suggest that a 10% difference between groups would be considered clinically significant, while for OS they suggested it should be 5% because any gain in survival would be considered clinically meaningful to patients. For HRQoL, an MID of 10 points was identified by the sponsor as clinically significant, and the clinical experts agreed that this seemed reasonable. However, given the challenges in trying to identify 1 specific time point in which to assess response to the EORTC QLQ-C30 given the constant attrition over the course of the study, it was decided that instead of seeking 1 specific target of certainty, an overall impression of the direction of effect over time would be ascertained.

The selection of outcomes for GRADE assessment was based on the sponsor’s Summary of Clinical Evidence, consultation with clinical experts, and input received from patient and clinician groups and public drug plans. The following list of outcomes was finalized in consultation with expert committee members:

• PFS

• OS

• HRQoL (EORTC QLQ-C30 GHS)

• harms (ocular AEs, SAEs).

Table 2: Summary of Findings for BPd vs. PVd for Patients With r/r MM

AE = adverse event; CI = confidence interval; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = Global Health Status; HRQoL = health-related quality of life; ITT = intention to treat; MID = minimal important difference; NR = not reported; OS = overall survival; Pd = pomalidomide and dexamethasone; PFS = progression-free survival; PVd = pomalidomide, bortezomib, and dexamethasone; RCT = randomized controlled trial; r/r MM = relapsed or refractory multiple myeloma; SAE = serious adverse event; vs. = versus.

Note: Study limitations (which refer to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias were considered when assessing the certainty of the evidence. All serious concerns in these domains that led to the rating down of the level of certainty are documented in the table footnotes.

^aRated down 1 level for imprecision because the lower boundary of the 95% CI did not exceed the MID (10%) identified by the clinical experts.

^bRated down 1 level for study limitations. Results are from an interim analysis, and there is a risk of bias due to confounding as a result of transition of patients to subsequent treatment postprogression. Also rated down 1 level for imprecision.

^cRated down 2 levels for study limitations. Assessments of HRQoL may have been biased by a lack of blinding, and there was a significant amount of attrition and missing data. Also rated down 1 level for imprecision because of low sample size relative to the ITT.

^dRated down 1 level for study limitations. Exposure to BPd was longer than exposure to PVd. Also rated down 1 level for imprecision because the lower boundary of the 95% CI did not exceed the MID (10%) identified by the clinical experts.

Sources: Details included in the table are from the sponsor’s Summary of Clinical Evidence²² and from an additional information request.²³

Indirect Comparisons

Description of Studies

Direct evidence of comparative efficacy and safety comparing BPd with PVd has been established in the pivotal study (i.e., the DREAMM-8 study). However, due to the lack of direct evidence comparing the combination of BPd with other existing relevant comparators in the treatment of MM in adult patients who have received at least 1 prior therapy including lenalidomide, the sponsor submitted a network meta-analysis (NMA) comparing BPd with the relevant comparators in the treatment of patients with MM who were lenalidomide exposed. Analyses were also performed for a subgroup of lenalidomide-refractory population. According to the investigators, a fixed model approach was preferable over the random-effect model of analysis because the networks were sparse (with only 1 study informing most treatment comparisons) and had insufficient sample data to inform the between-study standard deviation in treatment effects.

Efficacy Results

In the treatment of MM in patients who were lenalidomide-exposed, based on the fixed-effect model analysis, a favourable effect was observed when compared BPd with some of the comparator therapies (such as BPd versus high-dose carfilzomib and dexamethasone [hKd] and BPd versus SVd for PFS and overall response rate [ORR], as well as BPd versus bortezomib and dexamethasone [Vd] for some outcomes [PFS and/or OS and/or ORR]).

In the lenalidomide-refractory population, in terms of PFS, a favourable effect was observed for BPd based on the fixed-effect model analysis when BPd was compared with hKd, Kd, and Vd.

No indirect treatment comparisons (ITCs) comparing BPd with IsaPd or BPd with Pd were conducted because the studies assessing the efficacy of IsaPd and Pd could not form a connected network with the DREAMM-8 study.

No HRQoL outcome was assessed in the NMA.

Harms Results

In the NMA, safety outcomes were not assessed.

Critical Appraisal

Overall, the sponsor’s NMA was conducted according to accepted methodological guidance. The potential key limitation of the NMA was the considerable heterogeneity across the included studies due to factors such as the prior line of therapy, ISS stages, ECOG performance status, and follow-up time at which outcomes were assessed. The heterogeneity suggests that the assumption of similarity across the included studies may not hold true for the NMA, increasing the likelihood of bias and uncertainty about the validity of the comparative efficacy results for BPd versus relevant comparator therapies used in Canada. Another important limitation is the sparsity of the networks, with most treatment comparisons informed by only 1 trial. These limitations undermine the robustness of the NMA and could bias the treatment effect estimates. Therefore, the results of NMA should be interpreted with consideration of the previously mentioned limitations. In addition, HRQoL, which patients have identified as an important outcome, and harms outcomes were not assessed in the NMA. In the lenalidomide-refractory population, only PFS was assessed. OS and ORR were not assessed due to a lack of data to form a network.

Studies Addressing Gaps in the Evidence From the Systematic Review

Description of Studies

The sponsor submitted 1 phase I/II, single-arm, open-label, multicentre study (the ALGONQUIN study) to address gaps in the evidence.

The ALGONQUIN study evaluated various doses and schedules of BPd for patients with MM whose disease was lenalidomide-refractory and who had been exposed to a proteasome inhibitor (PI). The ALGONQUIN study comprised of a dose-escalation phase (part 1) and a dose-expansion phase (part 2). A total of 87 patients with r/r MM from 9 sites in Canada were enrolled, with 61 patients in part 1 and 26 in part 2. The primary objectives of the ALGONQUIN study were to determine the recommended phase 2 dose (RP2D) and the schedule of belantamab mafodotin in part 1 as well as to establish the efficacy, as determined by ORR, for participants treated at the RP2D in part 2. The secondary objectives were to assess the safety and tolerability of the BPd in part 1 and to assess additional efficacy outcomes including PFS, DOR, and OS at the RP2D in part 2.

Efficacy Results

Maximum Tolerated Dose and RP2D

The maximum tolerated dose based on the first cycle (28 days) of treatment was determined to be 2.5 mg/kg belantamab mafodotin. The regimen of 2.5 mg/kg every 8 weeks combined with 4 mg of pomalidomide and 40 mg of dexamethasone was selected as the RP2D.

ORR, OS, and PFS in Patients Treated at RP2D

In part 2, the median duration of follow-up for patients treated at RP2D (n = 38) was 13.9 months (range, 1.1 to 28.2). Out of these 38 patients treated at RP2D, 34 had 2 consecutive assessments and were considered response evaluable. The ORR for the patients whose responses were evaluable was 85.3% (29 of 34), with 32.4% (11 of 34) reaching CR or stringent complete response (sCR), 41.2% (14 of 34) achieving VGPR, and 11.8% (4 of 34) having PR. In the 38 patients treated at RP2D, the median OS (months) was not reached (95% CI, not reached to not reached). The median PFS (months) was not reached (95% CI, 13.7 to not reached).

In the 38 patients treated at RP2D during part 2, 12 were from part 1. The median duration of follow-up for the 12 patients was 17.2 months (range, 6.0 to 28.2). The ORR was 91.7% (11 of 12), with 33.3% (4 of 12) reaching CR or sCR, 50.0% (6 of 12) achieving VGPR, and 8.3% (1 of 12) having PR. The median OS was not reached (95% CI, not reached to not reached). The median PFS was 18.3 months (95% CI, 10.8 to not reached).

ORR, OS, and PFS in All Treated Patients

The median duration of follow-up for all treated patients was 14.5 months (range, 0.9 to 42.5). Out of the 87 patients, 81 had 2 consecutive assessments and were considered response evaluable. The ORR for the patients whose responses were evaluable was 87.7% (71 of 81), with 33.3% (27 of 81) reaching CR or sCR, 39.5% (32 of 81) achieving VGPR, and 14.8% (12 of 81) having PR. The median OS was 34.0 months (95% CI, 24.4 to not reached). The median PFS was 21.8 months (95% CI, 17.8 to 32.5).

Harms Results

In patients treated at RP2D, the most common treatment-emergent AE (TEAE) of any grade was decreased visual acuity (71.1%, 27 of 38), followed by keratopathy (65.8%, 25 of 38), fatigue (57.9%, 22 of 38), infection (47.4%, 18 of 38), neutropenia (39.5%, 15 of 38), and thrombocytopenia (39.5%, 15 of 38). The most common grade 3 to 4 TEAEs included keratopathy (52.6%, 20 of 38), decreased visual acuity (39.5%, 15 of 38), neutropenia (36.8%, 14 of 38), and thrombocytopenia (34.2%, 13 of 38). Of patients treated at RP2D, 55.3% (21 of 38) had an objective decrease in best corrected visual acuity (BCVA) of grade 3 to 4, 13.2% (5 of 38) had blurred vision of grade 3 to 4, and 10.5% (4 of 38) had other ocular AEs, including dry eyes, photophobia, and eye pain.

Critical Appraisal

The ALGONQUIN study provided insights into the use of belantamab mafodotin of various doses (1.92 mg/kg, 2.5 mg/kg, and 3.4 mg/kg) and schedules (every 4 weeks, every 8 weeks, and every 12 weeks). However, it did not address major gaps or limitations existing in the pivotal DREAMM-8 study (e.g., immaturity of OS data, high uncertainty in HRQoL outcomes due to the open-label design). Overall, the certainty of the evidence generated from the ALGONQUIN study is very low due to the single-arm design. Lacking comparative data made the inferences on the efficacy and safety of BPd over currently available therapies challenging and unreliable. For instance, when there were no comparison groups, the interpretation of the OS results could be prone to bias because OS can be sensitive to natural history and progression of the disease as well as heterogeneity of patient characteristics.^24-26 The ALGONQUIN study was open label, in which investigators and patients were aware of the treatment received. The assessment for response and progression end points, such as ORR and PFS, which relies on investigators’ knowledge and experience, was prone to the impact of detection bias due to the open-label design. Additionally, the risk of reporting bias due to the open-label study design could not be ruled out for subjective harms outcomes.

Conclusions

One open-label RCT was included in this systematic review. The DREAMM-8 study was a multinational (140 centres in 18 countries with 3 sites in Canada), sponsor-funded study that randomized 302 patients with r/r MM, 1:1, to either BPd or PVd, until progressive disease, unacceptable toxicity, death, start of new antimyeloma therapy, withdrawn consent, or end of study. The findings suggest that BPd likely results in a clinically important improvement in PFS compared with treatment with PVd, after a median follow-up of 21.8 months. BPd may improve OS compared with PVd; however, the OS is still not mature at the time of this interim analysis, with an information fraction of only 48%. The evidence is less clear regarding whether BPd improves HRQoL compared with PVd after 53 weeks of treatment, and assessment of patient-reported outcomes may have been biased by the lack of blinding in this study. The main harms associated with belantamab mafodotin are ocular AEs such as blurred vision and changes in visual acuity. Belantamab mafodotin also appears to increase the risk of SAEs, including pneumonia; however, assessment of harms outcomes is complicated by the fact that patients in the BPd group were exposed to study drug longer than patients in the PVd group. Based on the fixed-effect model analysis, the sponsor-provided NMA suggested the benefit of BPd was not consistent and was influenced by both the end point assessed (PFS, OS, or ORR), as well as the choice of comparator drug, in the treatment of MM in adult patients who have received at least 1 prior therapy including lenalidomide. However, the results of the NMA should be interpreted with consideration of its associated limitations as described elsewhere in the report.

Introduction

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of belantamab mafodotin 70 mg and 100 mg vials for infusion in combination with pomalidomide and dexamethasone in the treatment of MM in adult patients who have received at least 1 prior therapy including lenalidomide.

Disease Background

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

MM is an incurable, progressive, malignant plasma cell cancer, characterized by the abnormal proliferation of clonal B-cells in the bone marrow and overproduction of the abnormal immunoglobulin M protein.² MM accounts for approximately 1% of all cancers and about 10% of all hematologic malignancies.³ MM is more common in males than females and about twice as common in Black people compared with Asian or white people.^4-7 The incidence of MM is related to older age. In 32,065 patients with MM in Canada between 1992 and 2010, approximately 80% were diagnosed at the age of 60 years or older.⁷ It is estimated that 4,100 new cases of MM were diagnosed in 2024 in Canada.⁸ The 5-year net survival for patients with MM in Canada is approximately 50%.⁹

The clinical course of MM, although variable, typically includes periods of treatment and remission separated by inevitable relapses, with the DOR to treatment decreasing with each subsequent line of therapy.^10,11 r/r MM is defined as MM that is nonresponsive to therapy or has progressed within 60 days of the last line of treatment in patients who previously achieved a minimal response or better.^12,13

Patients with MM typically present with nonspecific symptoms, including anemia, bone pain, fatigue, weight loss, and renal dysfunction.²⁷ At diagnosis, the clinical manifestations of symptomatic MM are present in approximately 70% of patients and are commonly defined using the term “CRAB” (hypercalcemia, renal insufficiency, anemia, and bone lesions).^28,29 The requirements to establish the diagnosis of MM include 10% or more clonal bone marrow plasma cells or biopsy-proven plasmacytoma plus the presence of at least 1 MM-defining event (which refers to the presence of CRAB attributable to the plasma cell disorder), clonal bone marrow plasma cell percentage (equal to or greater than 60%), free light chain ratio (equal to or greater than 100), or more than 1 focal lesion on MRI studies.³

In Canada, the International Staging System (ISS) is often used to stage MM.³⁰ The ISS disease stages are classified based on serum beta-2-microglobulin level and serum albumin level:^30,31

• Stage I: Serum beta-2-microglobulin level greater than 3.5 mg/L and serum albumin level less than 3.5 g/dL

• Stage II: Serum beta-2-microglobulin level greater than 3.5 mg/L or serum albumin level less than 3.5 g/dL

• Stage III: Serum beta-2-microglobulin level 5.5 mg/L or greater with either elevated lactate dehydrogenase or high-risk cytogenetics

It was reported that the median survival is 62 months for patients with ISS stage I MM, 44 months for those with ISS stage II disease, and 29 months for patients with ISS stage III MM.³¹

Standards of Therapy

Contents within this section have been informed by materials submitted by the sponsor and clinical expert input. The following has been summarized and validated by the review team.

ASCT is the standard of care for newly diagnosed patients with MM if they are transplant eligible. Induction therapy with lenalidomide, bortezomib, and dexamethasone or cyclophosphamide, bortezomib, and dexamethasone, followed by ASCT and then maintenance therapy, most commonly with lenalidomide, is the standard treatment course.²⁸ Patients who are ineligible for ASCT are typically treated with a combination of immunomodulatory drugs (IMiDs) (e.g., lenalidomide, pomalidomide), PIs (e.g., bortezomib, carfilzomib), and mAbs (e.g., daratumumab, isatuximab).²⁸ Lenalidomide is recommended to be used as part of the front-line therapy for newly diagnosed MM (regardless of ASCT eligibility) by the IMWG and the CMRG Consensus Guideline Consortium due to the overall survival (OS) benefits seen in clinical trials.¹⁴ The CMRG Consensus Guideline Consortium report recommends DRd as the preferred first-line therapy for fit patients who are eligible for ASCT, and note that first-line therapy should include an anti-CD38 antibody. For patients with frailty, first-line therapy with DRd is also the first-choice regimen provided there are no contraindications; however, if a triplet regimen is not tolerated by the patient, a doublet regimen consisting of lenalidomide and dexamethasone (Rd) could be a good option.³²

Treatment selection for patients with r/r MM can be challenging as there is currently no uniform standard treatment that addresses the cause of nonresponse to initial treatment. Rather, treatment choice in r/r MM is individualized and multifactorial, taking into consideration prior treatment history and response, timing and aggressiveness of the relapse, patient factors (e.g., performance status, age, frailty, and comorbidities), personal preferences, and jurisdictional funding and rules around reimbursement.^15,16 The general strategy for treatment beyond the first line includes the use of a drug that the patient has either not been exposed to previously or demonstrated sensitivity to in the treatment regimen.¹⁷ Based on the IMWG recommendations, for patients whose disease is not refractory to lenalidomide, the preferred options for the second line are DRd or a combination of carfilzomib, lenalidomide, and dexamethasone, although alternatives are available.^15,17

For patients with r/r MM in Canada, options for treatment at first relapse (second line) and beyond are based on the patient’s sensitivity or resistance to treatments and can include the following combinations: lenalidomide and dexamethasone; carfilzomib and dexamethasone (Kd); isatuximab, carfilzomib, and dexamethasone (IsaKd); pomalidomide, bortezomib, and dexamethasone (PVd); daratumumab, bortezomib, and dexamethasone (DVd); selinexor, bortezomib, and dexamethasone (SVd); isatuximab, pomalidomide, and dexamethasone (IsaPd); and pomalidomide and dexamethasone (Pd).¹⁵ Although lenalidomide is a possible option for patients in the second line and beyond, clinical experts consulted by Canada’s Drug Agency (CDA-AMC) have stated that it is most likely to be used as a first-line treatment option or maintenance and would not likely be used in later lines of therapy.¹⁵ In addition, pomalidomide-based regimens are only funded after patients have experienced treatment failure on lenalidomide and a PI, which limits their use to later lines of therapy. BCMA-directed therapies, including teclistamab and elranatamab, are approved (funding is under review) in the fourth line and beyond for patients who have received a PI, an IMiD, and an anti-CD38 drug, and whose disease has progressed or is refractory to their last line of therapy.³² CDA-AMC has recently recommended ciltacabtagene autoleucel (cilta-cel) for those who have received 1 to 3 prior lines of therapy (including a PI and IMiD) and whose disease is refractory to lenalidomide.³³

The current CDA-AMC funding algorithm for r/r MM in Canada is presented in Figure 1.

Figure 1: Current Treatment Paradigm for MM in Canada

ASCT = autologous stem cell transplant; CGP = clinical guidance panel; cilta-cel = ciltacabtagene autoleucel; DCyBord = daratumumab plus cyclophosphamide, bortezomib, and dexamethasone; DRd = daratumumab, lenalidomide, and dexamethasone; DVd = daratumumab, bortezomib, and dexamethasone; DVMp = daratumumab-bortezomib-melphalan plus prednisone; IMiD = immunomodulatory drug; IsaKd = isatuximab, carfilzomib, and dexamethasone; IsaPd = isatuximab, pomalidomide, and dexamethasone; Kd = carfilzomib and dexamethasone; KRd = carfilzomib, lenalidomide, and dexamethasone; LVEF = left ventricular ejection fraction; MM = multiple myeloma; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; Pd = pomalidomide and dexamethasone; PI = proteasome inhibitor; PVd = pomalidomide, bortezomib, and dexamethasone; R = lenalidomide; Rd = lenalidomide and dexamethasone; r/r MM = relapsed or refractory multiple myeloma; RVd = lenalidomide, bortezomib, and dexamethasone; SVd = selinexor, bortezomib, and dexamethasone; V = bortezomib; Vd = bortezomib and dexamethasone.

Notes: Patients with drug resistance cannot be retreated with the same drug(s).

Cyclophosphamide may be added to Kd, Pd, and Rd.

PVd is not represented in the algorithm as it is not commonly used or a standard of care. PVd has been recommended by pERC for r/r MM in patients who have received at least 1 prior treatment regimen including R.

^aMaintenance optional.

^bIf not resistant to an anti-CD38 biologic.

^cOnly if also sensitive to R and V.

^dMust have a PI treatment-free interval of at least 6 months before first day of SVd.

^eIf no prior treatment with any therapy that targets BCMA or any CAR T-cell therapy.

^fIf no prior treatment with any therapy that targets BCMA.

^gCyclophosphamide may be added to Kd, Pd, and Rd.

Source: CDA-AMC Funding Algorithm for Multiple Myeloma, 2024.¹⁵

Drug Under Review

The drug under review is belantamab mafodotin for injection, 70 mg vial, 100 mg vial, and 50 mg/mL IV infusion. Belantamab mafodotin is an antibody-drug conjugate that binds to the cell surface BCMA (i.e., a protein expressed on normal B lymphocytes and MM cells), internalizes into tumour cells rapidly, releases a cytotoxic agent once inside the tumour cells, and results in cell cycle arrest and apoptosis of tumour cells.¹

The current reimbursement request for the drug aligns with its Health Canada–approved indication, which is as follows: belantamab mafodotin for injection, is indicated in combination with pomalidomide and dexamethasone for the treatment of adults with r/r MM who have received at least 1 prior line of therapy, including lenalidomide.

Belantamab mafodotin has not previously been reviewed by CDA-AMC. However, CDA-AMC is currently conducting a parallel Reimbursement Review of the drug based on a different Health Canada indication, which is as follows: “Belantamab mafodotin for injection is indicated in combination with bortezomib and dexamethasone, for the treatment of adults with relapsed or refractory multiple myeloma who have received at least 1 prior line of therapy.”

The FDA and European Medicines Agency are reviewing BPd in patients with MM.

Key characteristics of belantamab mafodotin are summarized in Table 3 with other treatments available for MM.

Table 3: Key Characteristics of Belantamab Mafodotin and Main Comparators

ADC = antibody-drug conjugate; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; DRd = daratumumab, lenalidomide, and dexamethasone; DVd = daratumumab, bortezomib, and dexamethasone; iMiD = immunomodulatory drug; IsaKd = isatuximab, carfilzomib, and dexamethasone; IsaPd = isatuximab, pomalidomide, and dexamethasone; Kd = carfilzomib and dexamethasone; KDd = carfilzomib, daratumumab, and dexamethasone; KRd = carfilzomib, lenalidomide, and dexamethasone; MM = multiple myeloma; mRNA = messenger ribonucleic acid; Pd = pomalidomide and dexamethasone; PI = proteasome inhibitor; PVd = pomalidomide, bortezomib, and dexamethasone; r/r MM = relapsed or refractory multiple myeloma; SVd = selinexor, bortezomib, and dexamethasone; Vd = bortezomib and dexamethasone.

^aHealth Canada–approved indication.

^bOnly presented indication related to MM.

Sources: Draft product monograph for belantamab mafodotin,¹ product monograph for bortezomib,³⁴ product monograph for pomalidomide,³⁵ product monograph for isatuximab,³⁶ product monograph for daratumumab,³⁷ product monograph for carfilzomib,³⁸ product monograph for selinexor,³⁹ product monograph for cyclophosphamide.⁴⁰

Perspectives of Patients, Clinicians, and Drug Programs

The full patient and clinician group submissions received are available in the consolidated patient and clinician group input document for this review on the project website.

Patient Group Input

This section was prepared by the review team based on the input provided by patient groups.

One patient group, Myeloma Canada, submitted input for this review. Myeloma Canada gathered the input from a survey among patients and caregivers with respect to BPd for the treatment of r/r MM in adult patients who have previously received lenalidomide. Survey eligibility was determined by patient and caregiver self-report of their experience with myeloma, regarding treatment with lenalidomide, or BPd.

Of a total 356 responses to the survey, 100 were complete, eligible, and analyzed. Among these respondents, 90 were patients who were eligible for the treatment with BPd (n = 78) and their caregivers (n = 12). Of the 90 respondents, 7 had received 1 line of therapy, 27 had received 2 lines of therapy, 23 had received 3 lines of therapy, 21 had received 4 lines, 9 had received 5 lines or more, and 7 respondents were unsure. Of the 90 respondents, 72% had received an ASCT. Additionally, 94% of the 90 respondents had received an IMiDs, 76% had received a PI, 54% had received an anti-CD38 mAb, 9% had received a BCMA-targeted therapy (CAR T-cell therapy, bispecific, or antibody-drug conjugate), 2 had received a GPRC5D-targeted therapy, and 26 indicated “other,” most of which mentioned dexamethasone and cyclophosphamide.

Seven of the 100 survey respondents were patients who had experience with BPd (n = 4) and their caregivers (n = 3), of whom, 4 had received 4 lines of therapy, 2 had received 3 lines of therapy, and 1 had received 2 lines of therapy. Among the respondents, there were 3 patients who had experience with belantamab mafodotin as a monotherapy.

On a scale of 1 (not important or no impact) to 5 (extremely important or extreme impact), the 100 respondents rated that infections (4.58) was the most important myeloma symptom to control, followed by kidney problems (4.52), mobility (4.46), and pain (4.38). Regarding the impact of myeloma on patients’ day-to-day activities, the respondents indicated that ability to travel (3.60) and ability to work (3.49) were most significantly impacted, followed by ability to exercise (3.37) and ability to conduct volunteer activities (3.28). With respect to the psychosocial impact of myeloma, the respondents rated that interruption of life goals or accomplishments (career, retirement, and so forth) (3.51) had the most impact on quality of life, followed by loss of sexual desire (3.43), anxiety or worry (3.35), and difficulty sleeping (3.03). Regarding the financial implications of myeloma, travel costs and parking costs were identified by 35 of the 100 respondents, respectively; followed by drug costs (n = 34); lost income or pension funds due to absence from work, disability, or early retirement (n = 33); drug administration fees (n = 13); accommodation costs (n = 8); and medical supply costs (n = 6). In terms of the key factors that are important to myeloma treatment, 86 of the 100 respondents identified quality of life, manageable side effects, effectiveness of treatment (especially in achieving remission and having a long, durable, response), and accessibility or portability of treatment (including fewer or minimal visits to the hospital or cancer centre).

Regarding the outcomes that were considered extremely important, of the 89 respondents who were eligible for BPd and their caregivers, 70% selected prolongation in life expectancy, and 62% selected improvement in overall quality of life. Furthermore, 78% of respondents indicated that they were very much in favour of an estimated 2 to 3 years of extended life without myeloma getting worse. In terms of the tolerability of side effects in respondents who were eligible for the treatment with BPd and their caregivers, on a scale of 1 (not at all tolerable or bearable) to 5 (extremely tolerable or bearable), eye pain (1.99) was considered as the least tolerable side effect, followed by blurry vision (2.14), foreign body sensation in eye (2.14), infections (2.23), eye irritation (2.26), and diarrhea (2.39). Among the 7 respondents who had experience with BPd, blurry vision (3.00), dry eyes (3.29), and eye irritation (3.29) were rated the least bearable side effects, followed by infections (3.57).

Regarding the overall experience with BPd, 4 of the 7 respondents who had experience with the treatment considered that quality of life was mostly or somewhat improved, and 6 considered that the side effects were mostly or somewhat manageable.

Lastly, Myeloma Canada noted that some patients with myeloma are unable to tolerate lenalidomide and are not included in the Health Canada indication. Myeloma Canada noted that these patients may also be eligible for the treatment with BPd.

Clinician Input

Input From Clinical Experts Consulted for This Review

All CDA-AMC review teams include at least 1 clinical specialist with expertise regarding the diagnosis and management of the condition for which the drug is indicated. Clinical experts are a critical part of the review team and are involved in all phases of the review process (e.g., providing guidance on the development of the review protocol, assisting in the critical appraisal of clinical evidence, interpreting the clinical relevance of the results, and providing guidance on the potential place in therapy). The following input was provided by 3 clinical specialist(s) with expertise in the diagnosis and management of MM.

Unmet Needs

The clinical experts noted that because there are no curative therapies for MM, the focus is on having multiple classes of drugs, with distinct mechanisms, so that these alternatives can be initiated when a patient’s disease becomes resistant to their current therapy. In summary, the clinical experts noted that the more drug classes that work through different mechanisms, the better the treatment outcomes will be. One of the clinical experts added the specific example of quadruple therapies, which are coming soon (such as daratumumab in combination with lenalidomide, bortezomib, and dexamethasone) for front-line therapy, for both patients who are transplant eligible and ineligible, leaving little room for subsequent options for patients who develop resistance.

One of the clinical experts also noted that there is a need for treatments that have better toxicity profiles, are easier to administer, and require fewer clinic visits.

The clinical experts also noted options for patients whose disease becomes resistant to lenalidomide have another unmet need. One of the clinical experts added that patients whose disease is lenalidomide refractory and those with anti-CD38–refractory disease have poor outcomes, particularly if they are older adults receiving DRd, as these patients have very limited options upon relapse (Kd or SVd) and may not be eligible for more aggressive therapies like CAR T-cell therapy or bispecifics. The clinical experts added that BPd could potentially be used instead of SVd. SVd could still be an option on relapse, and Kd could be used after failure of SVd. One of the clinical experts also noted that it is important to be able to use pomalidomide-containing regimens in the second line; however, some jurisdictions limit it to after second line.

Place in Therapy

The clinical experts noted that, by their first relapse, nearly all patients have disease that is refractory to lenalidomide and have been exposed to a PI (to which their disease was not refractory). According to the clinical experts, for patients who have not been exposed to anti-CD38 therapy, the current standard of care in those who can tolerate it is IsaKd, IsaPd, or DVd for patients who are more frail. This is 1 setting where BPd could be used, although there is no evidence that BPd has superior clinical activity over IsaKd or even DVd, according to the clinical experts. Most likely, BPd could be an option after failure of IsaKd or DVd, according to the clinical experts. With respect to other BCMA therapies, although there are others on the horizon, the clinical experts noted that, at present, only cilta-cel BCMA CAR T-cell therapy would be competing in this space, and few patients will be eligible and have access to this therapy.

The clinical experts were of the opinion that most use of BPd will be in early relapse (1 to 3 prior lines of therapy). One of the clinical experts also noted that if the rule in younger patients with cilta-cel is no prior BCMA, then there may be little use of BPd in this setting as it would prevent subsequent access to cilta-cel. The other clinical expert noted that the mechanism of belantamab mafodotin is distinct from that of BCMA or CAR T-cell therapy; therefore, resistance to belantamab mafodotin may not need to equate to resistance to immunotherapies targeting BCMA. Another clinical expert added that even if CAR T-cell therapy is used in the second line, there will still be room for other BCMA-targeted therapies. One clinical expert also added that they could foresee belantamab mafodotin potentially being added to some regimens used in the first line, as BCMA is not currently being targeted in these patients. The clinical experts were of the opinion that, in older patients, BPd will likely replace Kd, SVd, and Pd, given the efficacy data, and that in later lines (fourth line or beyond), BCMA BiTEs will likely be funded this year, so most patients will likely receive those.

Patient Population

The clinical experts noted that older patients who had previously been treated with DRd would be great candidates for BPd, particularly given the favourable toxicity profile with respect to myelosuppression.

One clinical expert noted that the use of BPd in younger patients may be somewhat limited by the fact that cilta-cel is available second line and beyond, and the current requirement is for no prior BCMA exposure when using cilta-cel. This clinical expert added that, in these patients, BPd may be used in much later relapse, but that would not be common either, if BCMA BiTEs are available in fourth line or later.

One clinical expert added that patients with pre-existing eye conditions would not be good candidates for this drug, due to the ocular toxicities.

Assessing the Response to Treatment

One clinical expert highlighted the importance of improving health-related quality of life (HRQoL), while also noting that the ocular toxicity may adversely impact quality of life. The other clinical expert agreed that ocular toxicities are an important issue, adding that these toxicities will require specialized monitoring by ophthalmologists and/or optometrists. This is not currently part of the routine care of patients with MM. Otherwise the clinical experts noted that routine blood tests are used to monitor patient progress.

Discontinuing Treatment

The clinical experts noted 2 key reasons for discontinuing BPd: disease progression and harms, namely ocular toxicity. The clinical experts noted the importance of knowing how to manage dose reductions or delays to mitigate the harm associated with ocular toxicity.

Prescribing Considerations

The clinical experts emphasized the need for specialized (ophthalmologist and/or optometrist) support for managing the ocular toxicities. One of the clinical experts also noted that myeloma should be managed by hematologist oncologists.

Clinician Group Input

This section was prepared by the review team based on the input provided by clinician groups.

Two clinician groups, the OH (CCO) Hematology Cancer Drug Advisory Committee and CMRG, provided input for this Clinical Review. The OH (CCO) Hematology Cancer Drug Advisory Committee gathered information from 7 clinicians, while CMRG collected input from 20 clinicians.

The OH (CCO) Hematology Cancer Drug Advisory Committee noted that the treatment goals for adult patients with MM who have received at least 1 prior therapy including lenalidomide include disease control, improvement in symptoms, prolonged survival, and prevention of end-organ damage. CMRG noted that myeloma is incurable, as patients’ disease eventually becomes refractory to all available funded antimyeloma drugs. Both clinician groups noted that, overall, there is an unmet need for effective treatments for patients with myeloma who have progressed on prior effective drugs.

Similar to the clinical experts consulted by the CDA-AMC review team, CMRG noted that BPd would pertain to patients who have had 1 to 3 prior lines of therapy. The OH (CCO) Hematology Cancer Drug Advisory Committee noted that BPd could fit into current second-line treatments for patients whose disease is resistant to lenalidomide or bortezomib.

The OH (CCO) Hematology Cancer Drug Advisory Committee noted that BPd could be suitable for patients who are unlikely to receive CAR T-cell therapy as BPd may preclude future use of BCMA-targeted CAR T-cell therapy. CMRG noted that patients whose disease is refractory to lenalidomide or anti-CD38s may be eligible for BPd based on the subgroup results from the DREAMM-8 study. According to the input from CMRG, patients with adequate performance status and organ function, and older patients are likely to have good outcomes with BPd. Patients with other disease-related adverse prognostic factors (e.g., high-risk cytogenetics, extramedullary disease ISS II or III, and functional patients at high risk who do not perform significantly worse) could be eligible for BPd. CMRG also noted that it is uncertain whether patients who are exposed to anti-BCMA or whose disease is refractory to bortezomib are suitable for BPd, because these patients were not included in the DREAMM-8 study. According to the input from CMRG, patients who are least suitable for BPd are those whose disease is refractory to pomalidomide.

The OH (CCO) Hematology Cancer Drug Advisory Committee noted that standard myeloma response outcomes used in clinical practice should be used to determine whether a patient’s disease is responding to treatment. According to the input from CMRG, treatment responses are evaluated based on the monoclonal protein markers in the serum and/or urine, bone marrow biopsy, and, in some instances, by imaging studies. CMRG noted that clinically meaningful responses usually correlate with at least a partial remission as defined by IMWG Consensus Criteria, including improvement in symptoms (e.g., cessation of bone destruction with less pain, fractures, and need for radiotherapy), improvement in energy, and better ability to perform activities of daily living. CMRG noted treatment responses are generally assessed every 1 to 3 months, depending on clinical stability and regimen used for therapy.

Both clinician groups noted that BPd should be discontinued upon disease progression or significant toxicity, especially significant ocular toxicity. Both clinician groups noted that the outpatient setting is the appropriate setting for treatment with BPd, and ophthalmological assessment is needed.

Drug Program Input

The drug programs provide input on each drug being reviewed through the 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 for this review are summarized in Table 4.

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

4L = fourth line; ADC = antibody-drug conjugate; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; BVd = belantamab mafodotin, bortezomib, and dexamethasone; CDA-AMC = Canada’s Drug Agency; cilta-cel = ciltacabtagene autoleucel; IsaKd = isatuximab, carfilzomib, and dexamethasone; IsaPd = isatuximab, pomalidomide, and dexamethasone; Kd = carfilzomib and dexamethasone; PAG = Provincial Advisory Group; Pd = pomalidomide and dexamethasone; pERC = pan-Canadian Oncology Drug Review Expert Review Committee; PVd = pomalidomide, bortezomib, and dexamethasone; RVd = lenalidomide, bortezomib, and dexamethasone; SVd = selinexor, bortezomib, and dexamethasone; VRd = bortezomib, lenalidomide, and dexamethasone.

Clinical Evidence

The objective of this report is to review and critically appraise the evidence submitted by the sponsor on the beneficial and harmful effects of belantamab mafodotin 70 mg and 100 mg vials for infusion in combination with Pd in the treatment of MM in adult patients who have received at least 1 prior therapy including lenalidomide. The focus will be placed on comparing BPd to relevant comparators and identifying gaps in the current evidence.

A summary of the clinical evidence included by the sponsor in the review of BPd is presented in 3 sections with our critical appraisal of the evidence included at the end of each section. The first section, the systematic review, includes pivotal studies and randomized controlled trials (RCTs) that were selected according to the sponsor’s systematic review protocol. Our assessment of the certainty of the evidence in this first section using the GRADE approach follows the critical appraisal of the evidence. The second section includes indirect evidence from the sponsor. The third section includes 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 review and appraised in this document:

• 1 pivotal study identified in systematic review

• 1 indirect treatment comparison

• 1 additional study addressing gaps in evidence.

Systematic Review

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Description of Studies

Characteristics of the included studies are summarized in Table 5.

Table 5: Details of Studies Included in the Systematic Review

ADA = antidrug antibody; AE = adverse event; ASCT = allogeneic stem cell transplant; AUC = area under the concentration time curve; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; CR = complete response; CRR = complete response rate; C_max = maximum plasma concentration; DOR = duration of response; EORTC IL52 = European Organisation for Research and Treatment of Cancer Item Library 52; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; EORTC QLQ-MY20 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire 20-Item Multiple Myeloma Module; EQ-5D-3L = European Quality of Life 5 Dimensions 3 Level Scale; FACT-GP5 = Functional Assessment of Cancer Therapy – General Population; HRQoL = health-related quality of life; IMWG = International Myeloma Working Group; MM = multiple myeloma; MRD = minimal residual disease; NGS = next-generation sequencing; ORR = overall response rate; OS = overall survival; OSDI = ocular surface disease index; PFS = progression-free survival; PFS2 = progression-free survival on subsequent line of therapy; PGIC = Patient Global Impression of Change, PGIS = Patient Global Impression of Severity; PK = pharmacokinetic; PR = partial response; PRO-CTCAE = Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events; PVd = pomalidomide, bortezomib, and dexamethasone; q.3.w. = every 3 weeks; q.4.w. = every 4 weeks; RNA = ribonucleic acid; SC = subcutaneous; sCR = stringent complete response; TTBR = time to best response; TTP = time to disease progression; TTR = time to response; VGPR = very good partial response; vs. = versus.

^aEORTC IL52 applies to participants enrolled under the original protocol; EORTC QLQ-MY20 applies to participants enrolled under Protocol Amendment 1.

^bThe participating countries included Australia, Brazil, China, Czech Republic, France, Germany, Greece, Israel, Italy, Japan, Republic of Korea, New Zealand, Poland, the Russian Federation, Spain, Turkey, the UK, and the US.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

The DREAMM-8 study is a phase III, randomized, open-label, multicentre study evaluating the efficacy and safety of BPd versus PVd in patients with r/r MM.^18,19 The study included 3 sites in Canada. The DREAMM-8 study included a screening period, treatment period, and follow-up period.^18,19 During the 28-day screening period, participants were evaluated for study eligibility per protocol as defined in the inclusion and exclusion criteria. Randomization was done centrally using a randomization schedule generated by the Cenduit Interactive Response Technology, which assigned participants in a 1:1 ratio to either treatment arm A (BPd) and treatment arm B (PVd) (Figure 2). No crossover was allowed, and no more than 50% of participants with 2 or more prior lines of therapy were enrolled.^18,19

Treatment was continued in both arms until progressive disease per IMWG criteria, death, unacceptable toxicity, start of a new antimyeloma therapy, withdrawal of consent, or the end of the study, whichever occurred first.^18,19 For participants who discontinued study treatment for reasons other than progressive disease or death, disease evaluations were performed every 3 days until confirmed progressive disease (documented), death, start of a new antimyeloma treatment, withdrawal of consent, loss to follow-up, or end of the study, whichever occurred first.^18,19 In the case of progressive disease, participants were followed to ascertain receipt of subsequent antimyeloma therapy, PFS on subsequent lines of therapy, and survival status every 12 weeks (± 14 days) until the withdrawal of consent, loss to follow-up, death, or the end of the study.^18,19

Following Protocol Amendment 1, belantamab mafodotin dose modifications were required to be based on the results of the ocular examination graded by the investigator using a Keratopathy and Visual Acuity (KVA) scale.¹⁹ The KVA scale has 2 components: the corneal exam component grades the corneal exam findings from slit lamp exam (superficial punctate keratopathy, microcyst-like deposits, subepithelial haze, stromal opacity, and corneal epithelial defects), and the best corrected visual acuity (BCVA) component grades the change in BCVA. The overall KVA grade is a composite of these 2 components and is driven by the more severe finding or grade of the 2 components. Separate grades for individual components (corneal exam findings and change in BCVA) are reported in addition to the overall grade.¹⁹

The primary and secondary end points of the DREAMM-8 study were analyzed based on the data cut-off date of January 29, 2024.^18,19

Figure 2: Schematic of Study Design of DREAMM-8 Study

ECOG = Eastern Cooperative Oncology Group; G2 = grade 2; OS = overall survival; PD = progressive disease; PFS = progression-free survival; PO = orally; PS = performance score; RRMM = relapsed or refractory multiple myeloma; SC = subcutaneous.

Source: Sponsor’s Summary of Clinical Evidence.

Populations

Inclusion and Exclusion Criteria

Patients were eligible to be enrolled in the DREAMM-8 study if they were aged 18 years or older with a confirmed diagnosis of MM as defined by the IMWG criteria.¹⁶ Participants were required to have an ECOG performance status score of 0 to 2, must have received previous treatment with at least 1 prior line of MM therapy including a lenalidomide-containing regimen with documented disease progression during or after their most recent therapy, and have at least 1 aspect of measurable disease. Key exclusion criteria included prior ASCT, prior treatment or intolerance to pomalidomide, prior treatment with BCMA therapy, and intolerance or refractoriness to bortezomib.

Interventions

Belantamab Mafodotin Treatment Arm (Arm A: BPd Arm)

Belantamab mafodotin was administered intravenously at a single dose of 2.5 mg/kg on day 1 of cycle 1 and 1.9 mg/kg on day 1 of cycle 2 onwards in each 28-day cycle (Figure 3).¹⁸ Prophylaxis to mitigate ocular events was instituted for all participants. Pomalidomide 4 mg per day was administered orally on days 1 to 21 of each 28-day cycle. Dexamethasone 40 mg per day was administered orally on days 1, 8, 15, and 22 of each 28-day cycle. The starting dose of dexamethasone was reduced to 20 mg for participants older than 75 years.¹⁸

Figure 3: Summary of Dosing Schedule for BPd Treatment Arm

Belamaf = belantamab mafodotin; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; q4w = every 4 weeks.

Source: Sponsor’s Summary of Clinical Evidence.²²

Ocular prophylaxis was instituted for all participants in treatment arm A.¹⁸ While not yet clinically demonstrated, it is theoretically possible that the application of a cooling eye mask during belantamab mafodotin administration and in the first few hours after infusion may subsequently decrease ocular side effects. A cooling mask was applied at the start of belantamab mafodotin infusion during the first hour for up to 4 hours as tolerated. Corticosteroid eye drops were not required but could be used if clinically indicated at the discretion of an eye care specialist. In the event of ocular symptoms (i.e., dry eyes), the use of artificial tears could be increased up to every 2 hours, as needed.¹⁸ Dose delays and reductions were permitted throughout the study.¹⁸

The recommended dosage modifications for ocular adverse reactions are based on ophthalmic examination findings, which included corneal examination findings and changes in BCVA. During the ophthalmic examination, the eye care professional should assess the following:

• any corneal examination findings and/or any change in BCVA

• if there is a decline in BCVA, the relationship to belantamab mafodotin should be determined

• the category grading for examination findings and BCVA should be communicated to the treating physician.

The recommended dose modification of belantamab mafodotin due to ocular adverse reactions was to be determined based on the worst finding in the worse-affected eye. This finding was to be based on either a corneal examination finding or a change in BCVA. The worst category grading for ophthalmic examination findings should be communicated to the treating physician by the eye care professional. The corneal examination findings may or may not be accompanied by changes in BCVA. The recommended dose of belantamab mafodotin in the case of ocular adverse reactions was 1.9 mg/kg every 8 weeks (as opposed to every 4 weeks) but could go as low as 1.4 mg/kg every 8 weeks. The dose of belantamab mafodotin was not to be re-escalated after a dose reduction was made for ocular adverse reactions.

Pomalidomide Treatment Arm (Arm B: PVd Arm)

Pomalidomide 4 mg was administered orally daily on days 1 to 14 of each 21-day cycle, with bortezomib 1.3 mg/m² injected subcutaneously on days 1, 4, 8, and 11 of each 21-day cycle for cycles 1 through 8, and on days 1 and 8 of each 21-day cycle for cycles 9 and beyond.¹⁸ Dexamethasone was administered orally at a dose of 20 mg on the day of and day after bortezomib of each 21-day cycle or on days 1, 2, 4, 5, 8, 9, 11, and 12 of each 21-day cycle for cycles 1 through 8 and then on days 1, 2, 8, 9, and every 3 weeks for cycles 9 and beyond. For participants who were older than 75 years, had comorbidities, or were intolerant to 20 mg, dexamethasone could be administered at the lower dose of 10 mg on the day of and the day after bortezomib in treatment arm B at the discretion of the investigator. Dose delays and reductions were permitted throughout the study.¹⁸

Figure 4: Dosing Schedule for Treatment Arm B (PVd Arm) in DREAMM-8 Study

PVd = pomalidomide, bortezomib, and dexamethasone; q3w = every 3 weeks.

Source: Sponsor’s Summary of Clinical Evidence.²²

Outcomes

A list of efficacy end points assessed in this Clinical Review Report is provided in Table 6, followed by descriptions of the outcome measures. Summarized end points are based on outcomes included in the sponsor’s Summary of Clinical Evidence, outcomes identified as important to this review according to the clinical experts consulted for this review, and input from patient and clinician groups and public drug plans. Using the same considerations, we selected end points that were considered to be most relevant to inform expert committee deliberations and finalized this list of end points in consultation with members of the expert committee.

Table 6: Outcomes Summarized From the Studies Included in the Systematic Review

BCVA = best corrected visual acuity; CRR = complete response rate; EORTC QLQ C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; KVA = Keratopathy and Visual Acuity; MRD = minimal residual disease; QoL = quality of life.

The following outcomes were chosen for GRADE assessment: PFS, OS, and EORTC QLQ-C30 (GHS), as well as 2 harms outcomes (ocular AEs and total SAEs). OS was chosen because the ultimate goal of any therapy for MM is to improve survival. PFS was chosen because it was the primary outcome in the DREAMM-8 study and because it is considered by the clinical experts to be an established surrogate for OS. Both OS and PFS are of clear importance to patients. HRQoL was chosen because this is clearly important to patients. In addition, the clinical experts noted that patients with this type of cancer can survive a long time and, given their older age and the significant number of harms associated with drugs used to treat MM, it is important to assess the impact of a new intervention on HRQoL. The EORTC QLQ-C30 instrument was specifically chosen from the numerous instruments used in the DREAMM-8 study because it is a widely used instrument that is specific to oncology. The GHS domain was chosen because the clinical experts agreed that it would best capture all aspects of HRQoL for these patients. Among the harms outcomes, ocular AEs were chosen because this is a known harm associated with belantamab mafodotin. SAEs were chosen because the clinical experts believed this to be an important harm to capture.

DOR, minimal residual disease (MRD) negativity, and complete response rate (CRR) were other outcomes that data were summarized but were not assessed with GRADE.

Progression-Free Survival

The primary end point of the DREAMM-8 study was PFS, which was defined as the time from the date of randomization until the earliest date of documented disease progression or death due to any cause.¹⁸ PFS was assessed by an independent review committee (IRC) and sensitivity analyses were conducted using alternative PFS censoring rules and investigator-assessed responses.¹⁹ The analysis for PFS was conducted with a median duration of follow-up (defined as time to censoring or death) of 21.8 months.

There is no established or published MID for PFS as an end point in r/r MM. The clinical experts consulted on this review believed PFS to be an important and valid surrogate for OS in patients with r/r MM. When asked, 1 clinical expert suggested that a reasonable MID for landmark analyses at 12 and 18 months would be a 10% absolute difference between groups.

Overall Survival

OS was a key secondary end point in the DREAMM-8 study and was defined as the interval of time from randomization to the date of death due to any cause. Assessments for survival were conducted every 12 weeks (± 14 days).¹⁸

There is no established or published MID for OS as an end point in r/r MM.¹⁸ However, OS is considered the gold standard primary outcome measure in clinical studies and is a measure of direct clinical benefit to patients. It is considered the most reliable and preferred end point in oncology trials when they can be conducted to adequately assess survival.^41,42 The measurement of OS is not impacted by potential bias, and the FDA recommends that it be assessed in RCTs in oncology.^41,42 When asked, 1 clinical expert consulted on this review thought a 5% absolute difference between groups for landmark analyses at 12 and 18 months would be a reasonable MID for patients with r/r MM.

Duration of Response

DOR was a key secondary end point in the DREAMM-8 study and was defined as the time from first documented evidence of partial response (PR) or better until the earliest date of progressive disease or death due to any cause based on IRC assessment per IMWG criteria.¹⁸ Responders without disease progression were censored at the censoring time point for time to progression. There is no established or published MID for DOR as an end point in r/r MM.¹⁸

MRD Negativity

MRD was a key secondary end point in the DREAMM-8 study and was defined as the percentage of participants who achieved MRD negative status (as assessed by next-generation sequencing at 10^-5 threshold) at least once during the time of confirmed CR or better based on IRC assessment per IMWG.¹⁸ There is no established or published MID for MRD as an end point in r/r MM. The FDA considers MRD a biomarker that is a reliable quantitation of tumour burden, independent of assay.⁴³ In MM, the FDA recommends that MRD should be assessed only in patients who are in CR.

Complete Response Rate

CRR was a secondary end point in the DREAMM-8 study and was defined as the percentage of participants with a confirmed CR or better (i.e., CR or stringent complete response [sCR]) based on IRC assessment per IMWG criteria.¹⁸ While both CR and sCR require the absence of detectable M-protein in serum and urine and fewer than 5% plasma cells in the bone marrow, sCR also requires a normal free light chain ratio and no clonal cells detectable by immunohistochemistry, indicating a deeper level of response. There is no established or published MID for CRR as an end point in r/r MM.

Health-Related Quality of Life

Patients’ self-reported HRQoL was collected using the EORTC QLQ-C30. Measurement properties of the instrument are in Table 7.

Table 7: 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; HRQoL = health-related quality of life; HSCT = hematopoietic stem cell transplant; MID = minimal important difference; MM = multiple myeloma; QoL = quality of life; SD = standard deviation; SRM = standardized response mean; T1 = time 1; T2 = time 2; vs. = versus.

^aThe European Group for Blood and Marrow transplant 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 rule of thumb for interpreting the magnitude of mean differences in HRQoL scores: 0.20 represents a small change, 0.50 a moderate change, and > 0.80 a large change.

^cThe MIDs were estimated using an anchor-based approach, anchored to a structured quality-of-life interview (response options were “improved,” “deteriorated,” or “unchanged”).

Statistical Analysis

Sample Size and Power Calculation

Based on data from the OPTIMISMM study, the median PFS in treatment arm B (PVd) was expected to be approximately 12 months.⁵⁴ It was hypothesized that treatment with BPd would lead to a 40% reduction in the risk of progression or death (i.e., an expected HR of 0.6), which corresponded to an increase in median PFS from 12 months to 20 months under the exponential assumption.¹⁸ To ensure 85% power to test the null hypothesis, in which PFS HR = 1 (versus the specific alternative hypothesis, in which PFS HR = 0.6), a total of 139 PFS events were needed. The calculation assumed a comparison of PFS by log-rank test at the 1-sided alpha level of 2.5% with a 1:1 randomization ratio and an interim analysis using gamma spending function with a parameter of −3 to define a nonbinding boundary for stopping for early harm (inferior efficacy) when observing approximately25% PFS events.¹⁸

Assuming a total of 300 participants were randomized in a 1:1 ratio to receive treatment arm A (BPd) or treatment arm B (PVd) with a uniform enrolment rate of 12 participants per month, enrolment continued for approximately 25 months.¹⁸ It was estimated that the targeted 139 PFS events would be observed approximately 29 months from the time when the first participant was randomized under the alternative hypothesis, assuming an annual dropout rate of 5%. These calculations were conducted using East v6.5.¹⁸

Statistical Test or Model

PFS was analyzed across treatment arms using Kaplan-Meier (KM) analysis. The nonparametric KM method was used to estimate the survival curves for PFS, with KM curves presented by the treatment arm.¹⁸ The PFS rates at 6, 12, and 18 months with corresponding 95% CIs were also estimated from the KM analysis. The 95% CI was estimated using the Brookmeyer-Crowley method.⁵⁵ A stratified Cox proportional hazard model, with the Efron method of tie handling and the treatment arm as the sole explanatory variable, was used to assess the magnitude of the treatment difference (i.e., the HR) in PFS between the treatment arms.¹⁸ The treatment difference was compared by the stratified log-rank test at a 1-sided alpha level of 0.025. The stratified log-rank test (stratified by randomization factors) was only performed for the primary analysis of the primary estimand of PFS (i.e., based on IRC-assessed response and primary event and censoring rules).¹⁸

Multiple Testing Procedure

At the primary efficacy analysis, the family-wise error rate for testing multiple end points was strongly controlled with a step-down or hierarchical testing procedure.¹⁸ A hierarchical multiple testing strategy is illustrated in Figure 5.

The evaluation of the primary and key secondary end points was structured in terms of 2 families of hypotheses:¹⁸

• The first family focused on the primary end point, PFS. PFS was planned to be tested across 3 analyses: an analysis for harm (interim analysis 1 [IA1]), an interim analysis for efficacy (interim analysis 2 [IA2]), and the primary PFS analysis (interim analysis 3 [IA3]). IA1 was scheduled to occur after approximately 35 PFS events, representing about 25% of the PFS information fraction. IA2 was scheduled to occur after approximately 145 PFS events, representing about 84% of the PFS information fraction. If PFS did not demonstrate statistical significance at IA2, IA3 would take place after approximately 173 PFS events, corresponding to 100% of the PFS information fraction. A gamma beta-spending function with a parameter of −3 was applied to set a nonbinding boundary at IA1. The Lan-DeMets approach, which approximates the O’Brien and Fleming spending function, was used to maintain an overall 1-sided 2.5% type I error rate when testing PFS across IA2 and IA3 because these analyses provided the opportunity to claim efficacy. Efficacy boundaries were adjusted based on the actual number of PFS events observed at each analysis.

• The second family was based on the 3 key secondary end points: OS, DOR, and MRD negativity. Testing of the second family was conditional on the successful rejection of the null hypothesis for the first family. Given the testing of the first family was successful, the full alpha was propagated to the second family of hypotheses, with OS being tested first. OS was assessed across 4 planned analyses: IA2, IA3, interim analysis 4, and the final analysis. IA3 is planned after approximately 163 OS events (about 75% OS information fraction) and the final OS analysis will be conducted after approximately 217 OS events (100% OS information fraction). In cases where the null hypothesis for PFS was not rejected at IA2 but subsequently rejected at the IA3, the full alpha was propagated to allow OS testing at the 1-sided 2.5% significance level. The Lan-DeMets approach, approximating the O’Brien and Fleming spending function, was also used for OS, with efficacy boundaries adjusted according to the actual number of OS events at the time of each analysis.

• Testing of MRD negativity was conditional on the successful rejection of the null hypothesis for OS, aligned with a step-down or hierarchical testing procedure. Regardless of the timing of this rejection, MRD negativity was only tested using data from IA2, with the full alpha initially allocated to OS propagated accordingly.

A significance level of 0.025 (1-sided) was used at each step of the hierarchy testing procedure.¹⁸ The remaining secondary efficacy end points were analyzed without alpha adjustment.¹⁸ The results reported herein are based on the successful IA2 of PFS (making it the primary analysis of PFS), conducted after 249 events (data cut-off of January 29, 2024).

Data Imputation Methods

For the patient-reported outcomes, if values were missing for more than half of the scale for a given patient, then the entire score for that patient was counted as missing, while if less than half of the scores were missing, only those scores with missing values were reported as missing. There does not appear to have been any attempts made to impute missing data.

For overall response rate (ORR), patients with unknown or missing responses were counted as nonresponders.

Figure 5: Multiple Testing Strategy

IA = interim analysis; H =hypothesis; MRD = minimal residual disease negativity rate; PFS = progression-free survival; OS = overall survival.

Notes: 𝑯𝒊 denotes the 1-sided null hypothesis for the primary and key secondary end points, where 𝒊 = 𝟏, 𝟐, 𝟑 denotes the index indicating PFS, OS, and MRD negativity rate, respectively.

Source: Sponsor’s Summary of Clinical Evidence.²²

Subgroup Analyses

Subgroup analyses were performed similarly to the methods used for the primary PFS efficacy analysis but included only the participants within the relevant subgroup category.¹⁸ All subgroup analyses were based on the clinical database using an electronic case report form or vendor data (and not randomized strata). Randomization strata included number of prior lines of therapy (1 versus 2 or 3 versus 4 or more), prior bortezomib treatment (yes or no), and prior anti-CD38 treatment (yes or no). ISS status (I versus II or III) was a randomization factor but was replaced with prior anti-CD38 treatment (yes or no) in Protocol Amendment 1.

The following preplanned subgroup analyses were performed to compare the primary estimand of PFS between treatments, based on IRC-assessed response, as well as the primary estimand of OS between treatments, if data permitted. The sponsor reported HR with 95% CI for each subgroup for PFS with a sample of N = 20 or more but did not report P values and did not perform tests for interactions.

Table 8: Subgroup Analyses for DREAMM-8 Study

ISS = International Staging System; LoT = line of treatment; PI = proteasome inhibitor; vs. = versus.

Source: Sponsor’s Summary of Clinical Evidence.²²

Sensitivity Analyses

The various sensitivity analyses used are summarized in Table 9.

Secondary Outcomes of the Studies

The analyses of OS were based on the intention-to-treat (ITT) analysis set unless otherwise specified.¹⁸ OS was analyzed across treatment arms using KM analysis. The nonparametric KM method was used to estimate the survival curves for OS, with KM presented by the treatment arm.¹⁸ The OS rates at 6, 12, and 18 months with corresponding 95% CIs were also estimated from the KM analysis. The 95% CIs were estimated using the Brookmeyer-Crowley method.⁵⁵

A stratified Cox proportional hazard model with Efron's method of tie handling and treatment arm as the sole explanatory variable was used to assess the magnitude of the treatment difference (i.e., the HR) in OS between the treatment arms.¹⁸

Table 9: Statistical Analysis of Efficacy End Points for DREAMM-8 Study

CRR = complete response rate; DOR = duration of response; IRC = independent review committee; LoT = line of treatment; mITT = modified intent to treat; MRD = minimal residual disease; OS = overall survival; PFS = progression-free survival; VGPR = very good partial response.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Analysis Populations

Table 10: Analysis Populations of DREAMM-8 Study

BPd = belantamab mafodotin, pomalidomide, and dexamethasone; FLC = free light chain; ICF = informed consent form; ITT = intention to treat; mITT = modified intention to treat; PVd = pomalidomide, bortezomib, and dexamethasone.

^aMeasurable disease at baseline is defined as: participant having at least 1 of the following measurements: serum M-protein ≥ 0.5 g/dL (≥ 5 g/L), urine M-protein ≥ 200 mg/24h, or serum FLC assay: involved FLC level ≥ 10 mg/dL (≥ 100 mg/L) and an abnormal serum FLC ratio (< 0.26 or > 1.65).

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Results

Patient Disposition

There were 13 patients (8%) who withdrew from study in the BPd group and 9 patients (6%) who withdrew in the PVd group, with the most common reason being withdrawal by participant (11 patients [7%] with BPd and 8 patients [5%] with PVd (Table 11). The numbers of patients who discontinued study treatment were 99 (64%) with BPd and 116 (79%) with PVd, and the most common reason was disease progression, which was less common with BPd (44 patients [28%]) than with PVd (71 patients [48%]), and AEs, which occurred in a similar number of patients in the BPd (26 patients [16%]) and PVd (23 patients [16%]) groups.

Table 11: Summary of Patient Disposition From Studies Included in the Systematic Review

BPd = belantamab mafodotin, pomalidomide, and dexamethasone; ITT = intention to treat; mITT = modified intention to treat; PVd = pomalidomide, bortezomib, and dexamethasone.

Note: Participants could only have 1 primary reason for withdrawal.

Data cut-off date: January 29, 2024.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Baseline Characteristics

Most patients were male (60%) and had an average age of 66 years; approximately ███ were aged 65 years or older. Most patients (59%) were considered to be at ISS stage I at screening, only 10% had extramedullary disease, and 26% had lytic bone lesions. The most common myeloma immunoglobulin was IgG (62% of patients), with IgA being the next most common (22%). With respect to prior lines of therapy completed before screening, 53% of patients had 1 line, 34% had 2 or 3 lines, and 14% had 4 lines or more. Most patients (███) had a prior PI, all patients had a previous IMiD, and all patients had received lenalidomide. There were 60% of patients who had a prior stem cell transplant. With respect to cytogenetic risk profile, one-third were considered to be at high risk. Most patients (98%) had ECOG performance status scores of 0 or 1.

The baseline characteristics outlined in Table 12 are limited to those that were most relevant to this review or could affect the outcomes or interpretation of the study results.

Table 12: Summary of Baseline Characteristics From DREAMM-8 Study (ITT Population)

1L = first line; BMI = body mass index; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; ECOG = Eastern Cooperative Oncology Group; iMiD = immunomodulatory drug; ITT = intention to treat; ISS = International Staging System; PI = proteasome inhibitor; PVd = pomalidomide, bortezomib, and dexamethasone; SD = standard deviation.

^aAge was imputed when full date of birth was not provided.

^bNorth America: US; Europe: Czech Republic, France, Germany, Greece, Italy, Poland, Russian Federation, Spain, Turkey, UK; Northeast Asia: China, Japan, Republic of Korea; rest of the world: Australia, Brazil, Israel, New Zealand.

^cParticipants may have been included in more than 1 category. Only positive results were summarized.

^dResults may not have been collected or reported for all participants.

^eIf the participant had at least 1 high-risk abnormality: t(4;14), t(14;16), or 17p13del.

^fIf the participant had at least 2 high-risk abnormalities: t(4;14), t(14;16), or 17p13del.

^gIf the participant had negative results for all high-risk abnormalities: t(4;14), t(14;16), or 17p13del.

^hRelapse was defined as the time from the start date of the first prior line of the therapy to the date of randomization for participants with 1 prior line or to the start date of the second prior line of the therapy for participants with > 1 prior line.

ⁱAnalyzed in the safety population.

Data cut-off date: January 29, 2024.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Exposure to Study Treatments

Exposure to study drugs is summarized in Table 13. Exposure to each of the components of the BPd regimen was longer than exposure to components of the PVd regimen. Concomitant medications were most commonly some form of blood product (Table 15). Subsequent treatments are listed in Table 16.

Table 13: Summary of Patient Exposure From Studies Included in the Systematic Review (Safety Population)

BPd = belantamab mafodotin, pomalidomide, and dexamethasone; PVd = pomalidomide, bortezomib, and dexamethasone.

Notes: Belantamab dose measured in mg/kg; dose intensity measured in mg/kg/cycle; cumulative dose in mg/kg; average daily dose in mg/kg/day.

Bortezomib dose measured in mg/m²; dose intensity measured in mg/m²/cycle; cumulative dose in mg/m²; average daily dose in mg/m2/day.

Pomalidomide dose measured in mg; dose intensity measured in mg/cycle; cumulative dose in mg; average daily dose in mg/day.

Dexamethasone dose measured in mg; dose intensity measured in mg/cycle; cumulative dose in mg; average daily dose in mg/day.

^aTreatment duration = ([last date of the study drug] – [first dose date of the study drug]) + 1.

^bDose intensity was the cumulative actual dose ÷ (treatment duration ÷ 4 weeks).

^cDose intensity was the cumulative actual dose ÷ (treatment duration ÷ 3 weeks).

^dRelative dose intensity = (dose intensity ÷ planned dose intensity) × 100.

^ePlanned dose intensity = (cumulative planned dose in actual dosing cycles) ÷ (number of actual dosing cycles) – only actual dosing cycles up to the last dose of component were considered.

Data cut-off date: January 29, 2024.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Table 14: Dose Exposure of Belantamab Mafodotin

IQR = interquartile range.

^aIntervals for 0 to ≤ 6 months, > 6 to ≤ 12 months, and > 12 months were calculated either by using days or days converted into months.

Source: Blenrep Product Monograph, 2024.⁵⁶

Table 15: Use of Concomitant Medications in DREAMM-8 Study

BPd = belantamab mafodotin, pomalidomide, and dexamethasone; IVIG = IV immunoglobulin; PVd = pomalidomide, bortezomib, and dexamethasone.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Table 16: Summary of Subsequent Treatment From Studies Included in the Systematic Review

ADC = antibody-drug conjugate; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; IMiD = immunomodulatory drug; PI = proteasome inhibitor; PVd = pomalidomide, bortezomib, and dexamethasone.

Note: Multiple categories per participant were possible and totals may add up to more than 100%.

Data cut-off date: January 29, 2024.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Efficacy

Progression-Free Survival

After a median follow-up of 21.8 months, progression or death occurred in 62 participants (40%) in the BPd arm versus 80 (54%) participants in the PVd arm for an HR of 0.52 (95% CI, 0.37 to 0.73; P < 0.001). The median PFS was not reached in the BPd arm (95% CI, 20.6 to not reached) and was 12.7 months (95% CI, 9.1 to 18.5) in the PVd arm (Table 17 and Figure 6). Landmark analyses of PFS showed a higher PFS rate in the BPd arm compared with the PVd arm at 12 months (71% versus 51%), as well as at 18 months ████ ██████ █████

█████ sensitivity or supplemental analyses were conducted, all of which yielded results consistent with the primary PFS analysis, with HRs ranging from ████ ██ ████. To account for the effect of nonproportional hazards impact on PFS, sensitivity analysis using restricted mean survival time was conducted, yielding restricted mean survival time of 22.8 months versus 16.5 months (restricted to the common truncation time of 34.1 months) with a ratio of 1.37 favouring the BPd arm.¹⁹ In the BPd and PVd arms, new antimyeloma therapy before observing a PFS event was initiated in 8 (5%) and 19 (13%) of the participants. This indicated that more participants in the PVd arm may have deteriorated, with a documented progression expected imminently had the new antimyeloma therapy not been initiated. The prespecified supplementary analysis 2 considered the initiation of new antimyeloma therapy as an event, which yielded an HR of 0.48 (95% CI, 0.35 to 0.65) in favour of BPd, reaffirming the results of the primary analysis.¹⁹

The PFS benefit observed was consistent across all subgroups, with HRs ranging from 0.26 to 0.76.¹⁹ In the protocol-specified subgroups of the DREAMM-8 trial, the HR was 0.52 (95% CI, 0.31 to 0.88) for participants with 1 prior line of therapy and 0.52 (95% CI, 0.33 to 0.80) for those with more than 1 prior line of therapy. For patients exposed to bortezomib, the HR was 0.55 (95% CI, 0.38 to 0.78). Among participants whose disease was refractory to lenalidomide, the HR was 0.45 (95% CI, 0.31 to 0.65). Regarding cytogenetic risk, the HR was 0.57 (95% CI, 0.34 to 0.96) for patients at high risk and 0.51 (95% CI, 0.30 to 0.86) for those with standard risk.¹⁹

Figure 6: KM Curves of PFS Based on IRC-Assessed Response in DREAMM-8 Study (ITT Population)

Belamaf = belantamab mafodotin; BOR = bortezomib; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; DEX = dexamethasone; ITT = intent to treat; KM = Kaplan-Meier; POM = pomalidomide; PVd = pomalidomide, bortezomib, and dexamethasone.

Data cut-off date: January 29, 2024.

Source: Sponsor’s Summary of Clinical Evidence.²²

OS

At the data cut-off date (January 29, 2024), median OS was not reached in either treatment group (Table 17 and Figure 7). The median duration of follow-up was not specifically reported for OS; however, it was reported as 21.8 months for PFS. The OS data had reached 34.8% (105 of 302 participants) overall maturity and an information fraction equal to 48.4% (105 of 217), where 217 deaths were anticipated for OS analysis according to the statistical analysis plan. Follow-up for OS is ongoing and will continue until the next planned interim analysis of OS (IA3) at approximately 60% information fraction. The 12-month OS survival rate was higher in the BPd arm compared with the PVd arm (83% [95% CI, 76% to 86%] versus 76% [95% CI, 68% to 82%]), for an RD of ████ ████ ███ ██████ ██████ and this was also the case at 18 months (███ ████ ███ ████ ████ versus ███ ████ ███ ████ █████ for a RD of ████ ████ ███ ██████ ██████.

Figure 7: KM Curves of OS in DREAMM-8 Study (ITT Population)

Belamaf = belantamab mafodotin; BOR = bortezomib; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; DEX = dexamethasone; IRC = independent review committee; ITT = intention to treat; KM = Kaplan-Meier; OS = overall survival; POM = pomalidomide; PVd = pomalidomide, bortezomib, and dexamethasone.

Data cut-off date: January, 29, 2024.

Source: Sponsor’s Summary of Clinical Evidence.²²

European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30At least 50% of participants in both treatment arms were on treatment during the initial 12 months and, therefore, had regular assessments every 4 weeks; hence, the dataset is more complete during this period.¹⁹ At week 53, 28 of 82 patients with assessments (34%) in the BPd group had an improvement of at least 10 points on the EORTC QLQ C30 GHS, compared with 14 of 60 patients (23%) in the PVd group. Small sample sizes and more infrequent assessments (every 12 weeks in participants who had discontinued treatment) at later points limit the interpretation of the data.

The EORTC QLQ-C30 GHS quality of life domain, physical domain, role functioning domain, and fatigue domain remained stable across both treatment arms over time (Figure 8):¹⁹

Figure 8: Plot of LS Mean (95% CI) Change from Baseline of EORTC QLQ-C30 GHS Scores (ITT Population)

Belamaf = belantamab mafodotin; BOR = bortezomib; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; CI = confidence interval; DEX = dexamethasone; EORTC QLQ-C30 = European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30; GHS = global health status; ITT = intention to treat; LS =least squares; POM = pomalidomide; PVd = pomalidomide, bortezomib, and dexamethasone; WK = week.

Notes: Analysis performed using a repeated measures model with covariates of treatment group, visit, baseline value, treatment by visit interactions, baseline value by visit interactions as fixed effects, and participant as a random effect.

Time points were only included if the number of participants with analyzable data at that time point was ≥ 10 in total across both treatments.

An autoregressive with heterogeneity covariance structure was used to estimate the within participant covariance.

Conventional Assessment of DOR

DOR was defined as the time from first documented evidence of PR or better until progressive disease or death due to any cause based on IRC assessment per IMWG criteria. The median DOR was not reached in the BPd arm (95% CI, 24.9 to not reached) and was 17.5 months (95% CI, 12.1 to 26.4) in the PVd arm. In the BPd arm, 66 (55%) participants with response had not progressed or died and had follow-up for PFS ongoing at the data cut-off date compared with 33 (31%) participants in the PVd arm.

MRD Negativity Rate

At the time of the primary analysis, the proportion of participants with a complete response (CR) or greater who achieved MRD negativity was higher in the BPd arm (37 of 155 patients, 24%) compared with the PVd arm (7 of 147 patients, 5%). The length of follow-up was not specifically reported for this outcome; however, it was reported as 21.8 months for PFS. Because the OS analysis was not statistically significant at the time of the PFS analysis data cut-off date, MRD negativity could not be formally tested at that time. Results of the MRD negativity analysis using investigator-confirmed response or in participants with very good partial response (VGPR) or better were consistent with the primary MRD analysis.

Complete Response Rate

There were 62 patients (40%) in the BPd group compared to 24 patients (16%) in the PVd group who had an IRC-assessed CR or better at the time this analysis was performed. The length of follow-up was not reported; however, it was reported as 21.8 months for PFS. No formal testing of this outcome was completed.

Table 17: Summary of Key Efficacy Results From DREAMM-8 Study (ITT population)

BPd = belantamab mafodotin, pomalidomide, and dexamethasone; CI = confidence interval; CR = complete response; DOR = duration of response; HR = hazard ratio; MRD = minimal residual disease; NR = not reached; OS = overall survival; PFS = progression-free survival; PVd = pomalidomide, bortezomib, and dexamethasone; SAP = statistical analysis plan; vs. = versus.

^aCIs for time variables estimated using the Brookmeyer Crowley method.

^bHRs were estimated using a Cox proportional hazards model with stratification factors and covariates according to the corresponding footnote.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Figure 9: Subgroup Analyses — PFS Based on IRC-Assessed Response in DREAMM-8 Study (ITT Population)

Belamaf = belantamab mafodotin; BOR = bortezomib; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; CI = confidence interval; DEX = dexamethasone; ECOG = Eastern Cooperative Oncology Group; EMD = extramedullary disease; HR = hazard ratio; IRC = independent review committee; ITT = intent; PFS = progression-free survival; POM = pomalidomide; PVd = pomalidomide, bortezomib, and dexamethasone; vs. = versus.

Note: Data cut-off date: January 29, 2024.

Source: Sponsor’s Summary of Clinical Evidence.²²

Harms

Refer to Table 18 for harms data.

Adverse Events

Overall, 149 patients (more than 99%) in the BPd group and 139 patients (96%) in the PVd group had at least 1 AE, and 136 patients (91%) in the BPd group and 106 patients (73%) in the PVd group had a grade 3 or 4 AEs. The 3 most frequent AEs, all more common in BPd than PVd, included vision blurred (119 patients [79%] versus 22 patients [15%]), dry eye (91 patients [61%] versus 14 patients [10%]), and foreign body sensation in eyes (91 patients [61%] versus 9 patients [6%]). Under the category of infections and infestations, the AEs driving the differences, BPd versus PVd, were COVID-19 (56 patients [37%] versus 31 patients [21%]), upper respiratory tract infection (40 patients [27%] versus 25 patients [17%]), and pneumonia (36 patients [24%] versus 17 patients [12%]). For the system organ class of investigations, the difference was due to the contribution of both hematology and chemistry tests (Table 18).¹⁹

The most common grade 3 or higher AEs, all more common with BPd versus PVd, were neutropenia (63 patients [42%] versus 41 patients [28%]), thrombocytopenia (36 patients [24%] versus 29 patients [20%]), and pneumonia (26 patients [17%] versus 11 patients [8%]).¹⁹

Serious AEs

Overall, 95 patients (63%) in the BPd arm and 65 patients (45%) in the PVd arm had an SAE (Table 18). The exposure-adjusted incidence rate for SAEs was comparable between the 2 treatment arms (45.87 per 100 person-years versus 47.87 per 100 person-years, respectively).¹⁹ The most frequently reported SAE in both treatment arms was pneumonia, which occurred in ██ patients █████ in the BPd group and ██ patients ████ in the PVd group.

Withdrawals Due to AEs

The incidence of AEs leading to discontinuation of study treatment (any component of study treatment) was 15% (22 patients) with BPd and 12% (18 patients) with PVd (Table 18). There were no specific AEs leading to treatment discontinuation that occurred in more than 1% of patients.¹⁹ Keratopathy was a reason for treatment discontinuation in 2 patients (1%) in the BPd group and no patients in the PVd group.

Mortality

The incidence of fatal SAEs (related and not related to study treatment) was the same in the 2 treatment arms (11% in both BPd and PVd arms) (Table 18).¹⁹ The most common fatal SAE was COVID-19 pneumonia (3% [n = 5] in the BPd arm versus 1% [n = 2] in the PVd arm) and death due to unknown cause (0 in the BPd arm versus 2% [n = 3] in the PVd arm). All other fatal SAEs were reported in ≤ 1% of participants.¹⁹

Notable Harms

Ocular exams were performed regularly for all participants in both treatment arms throughout the study. They were performed more frequently in the BPd arm (every 4 weeks, then decreased to every 3 months if there were no significant ocular findings after the sixth dose) than in the PVd arm (every 6 months).¹⁹ Under the original trial protocol, all ocular symptoms and examination findings were to be reported as AEs and graded by the CTCAE criteria. Belantamab mafodotin dose modification was based on these assessments.

Ocular AEs (CTCAE grade) occurred in 89% of participants in the BPd arm. Vision blurred, dry eye, foreign body sensation in eyes, and eye irritation were each reported in50% or more of the participants in this treatment arm.¹⁹ The incidence of ocular AEs (CTCAE grade) in the PVd arm was lower (30%). The most frequently reported ocular AE in this treatment arm was vision blurred (15%). Grade 3 or 4 ocular AEs (CTCAE grade) were reported in more participants in the BPd arm (43%) than in the PVd arm (2%).¹⁹ The most common grade 3 or greater ocular AE, occurring more in the patients taking BPd than PVd, were blurred vision (26 patients [17%] versus none), reduced visual acuity (20 patients [13%] versus 1 patient [< 1%]), impaired vision ███ ████████ █████ ██ █ ███████ ██████, corneal epithelial microcysts and dry eye (12 patients each [8%] versus none), cataract (9 patients [6%] versus 6 patients [4%]), foreign body sensation (9 patients [6%] versus none) and punctate keratitis (9 patients [6%] versus 1 patient [< 1%]).

Table 18: Summary of Harms Results From DREAMM-8 Study (Safety Population)

AE = adverse event; AESI = adverse event of special interest; BCVA = best corrected visual acuity; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; KVA = Keratopathy and Visual Acuity; IRR  = infusion-related reaction; NA = not applicable; PVd = pomalidomide, bortezomib, and dexamethasone; SAE = serious adverse event.

Notes: System organ classes are presented by descending order by the number of participants in the BPd arm.

Treatment-related corneal events (corneal exam findings and changes in BCVA) were graded according to the guidelines of the KVA scale to inform dose modifications, including during and after treatment. An event is any KVA grade ≥ 1.

Investigator-reported KVA scale events are reported for assessments performed under Protocol Amendment 1 or later.

^aThe percentage of these AEs may not reflect the true incidence of these events, as the reporting guidance of ocular events was changed after Protocol Amendment 1.

^bIndividual corneal exam findings and BCVA events displayed by maximum grade may not have a temporal correlation.

Source: Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Critical Appraisal

Internal Validity

Randomization in the DREAMM-8 study appears to have been performed centrally using appropriate methodology. Stratification was performed using 3 different factors (i.e., number of prior lines of therapy, prior bortezomib use, and prior anti-CD38 use), although Protocol Amendment 1 changed the third stratification factor from ISS status to prior anti-CD38 use. Although there were some imbalances between groups in baseline characteristics (e.g., extramedullary disease, IgA, and previous stem cell transplants), the clinical expert believed that, in general, these imbalances would be more likely to bias against BPd than in favour of BPd, if they were to have any effect at all. Patients in the BPd group were offered prophylactic measures, including cooling masks, artificial tears, and corticosteroid eye drops (as needed, ordered by an eye care specialist) to reduce the risk of ocular AEs. This may have biased results, understating the risk of ocular AEs for BPd relative to PVd.

A hierarchical testing procedure was performed for multiplicity control, with PFS to be tested first, then OS, then MRD negativity. In the original protocol, DOR was to be tested after MRD negativity; however, after Protocol Amendment 3, DOR was dropped from the hierarchy. The sponsor also planned for testing of PFS at IA2, and if PFS was deemed statistically significant, no further testing of PFS was to be performed at IA3. Given the immaturity of the data, it is too early to determine whether this multiple testing procedure was adhered to; however, the plan for testing at various interim analyses does appear to have been followed.

The DREAMM-8 study was an open-label study. Although knowledge of treatment assignment could potentially bias assessment of outcomes such as PFS and ORR, the risk of this occurring was mitigated by the use of a blinded IRC to assess disease progression and response. Although a lack of blinding is less likely to have directly impacted patient response to treatment for hard clinical outcomes such as OS, PFS, and ORR, it is possible that patient-reported outcomes such as HRQoL may have been biased by patients knowing the treatment to which they were assigned. Reporting of AEs may also have been biased by patients knowing their assigned treatment. Even with blinding, the high incidence of ocular AEs and the obvious nature of these symptoms would have made it easy for patients to determine their assigned group.

HRQoL was assessed using the EORTC QLQ-C30, among other instruments. The EORTC QLQ-C30 is a validated, well-established instrument used to assess HRQoL in patients living with cancer. There are several estimates of the MID for the EORTC QLQ-C30, ranging between 6.2 and 17.3, depending on the scale used. The sponsor arrived at an MID of 10 or more for all EORTC QLQ-C30 domains. This seemed to be a reasonable estimate according to the clinical expert. In addition to the lack of blinding, which may have biased results in the DREAMM-8 study, interpretation of HRQoL scores was also impacted by the significant amount of missing data. There were missing data from the very beginning, at baseline, as only 141 of 155 patients in the BPd group and 139 of 147 patients in the PVd group reported scores on the EORTC QLQ-C30 GHS domain, for example. Missing data were not solely due to patient attrition. The loss of data continued, as at week 25 only 114 of 155 patients (74%) in the BPd group reported scores, and 90 of 147 patients (61%) in the PVd group. By week 53, this dropped further to 82 of 155 patients (53%) in the BPd group and 60 of 147 patients (41%) in the PVd group. Although study attrition is likely the major contributor to this large amount of missing data, this likely means that those patients who were healthiest are the ones being sampled for their HRQoL, potentially leading to inflated scores and response bias.

Although the number of patients who discontinued study was relatively low (less than 10%) and did not differ notably between BPd and PVd groups, there was a large proportion of patients who discontinued study treatment, with fewer patients discontinuing in the BPd group than in the PVd group (64% versus 79%). This difference between groups in patients discontinuing the study drug was accounted for by the difference in patients discontinuing due to progressive disease (28% versus 48%). This is consistent with the efficacy results of the trial, where there was a large difference in PFS between the 2 groups. The proportion of patients who discontinued the study drug due to AEs was identical between groups (16% in each), despite the large difference between groups in the number of ocular AEs. Patients who discontinued treatment were allowed to switch to a next line of therapy and remain in the study. Follow-up antimyeloma therapy was initiated in 27% of patients in the BPd group and 52% of patients in the PVd group. Although this is a common and accepted practice in oncology trials, this is a confounder when trying to assess OS data, as it is difficult to determine to what extent a patient’s extended survival is attributable to the study drug and how much is due to their subsequent therapy. It is unclear whether this difference between groups in the number of patients who went on to subsequent treatment biases results for or against the study drug or has any clear impact. The use of subsequent therapies is less likely to have impacted assessment of PFS, as most patients who went on to subsequent therapies did so because of a progression event. Therefore, they were perhaps already counted in the PFS analysis and, therefore, would not have influenced the PFS estimates. The difference in treatment discontinuations also complicates assessment of harms, as exposure to BPd was much longer than exposure to PVd. For example, total median duration of exposure to belantamab mafodotin was 13.2 months and pomalidomide was 15.9 months in the BPd group, while median exposure to bortezomib was 7.6 months and pomalidomide was 8.5 months in the PVd group. Although there were more patients who experienced an SAE in the BPd group than in PVd group (63% versus 45%, respectively), the exposure-adjusted incidence rate was 45.87 per 100 person-years in the BPd group and 47.87 per 100 person-years in the PVd group.

The DREAMM-8 study appears to have been adequately powered based on the targeted enrolment of 300 patients. The rationale for the estimates used for their power calculations were provided and seemed reasonable. The ITT population (all randomized patients, regardless of whether they received treatment) was used for the primary analysis. This is considered to be the most appropriate way to carry out analysis of efficacy outcomes. A modified ITT population was used to carry out various sensitivity analyses of efficacy outcomes, which were all supportive of the overall findings. The main differences between the modified ITT population and ITT were that the modified ITT excluded patients who were never treated as well as excluding patients who received the wrong drug (i.e., received bortezomib instead of belantamab mafodotin), representing less than 3% of the study population. Data were reported for a variety of prespecified subgroups of interest for this review, for the primary outcome of PFS. Although HR with 95% CIs were reported for each subgroup with 20 or more patients, imbalances between groups may exist, apart from those used the stratified randomization. No formal hypothesis testing and no tests for interaction were performed. Therefore, subgroup analyses should be viewed as supportive evidence for the overall primary efficacy of BPd versus PVd on PFS.

External Validity

The clinical expert believed that the patients included in the DREAMM-8 study were representative of patients who would be expected to receive this drug in Canada. The clinical expert did note that patients with plasma cell leukemia or symptomatic amyloidosis would likely be treated for MM with these types of therapies, despite being excluded from the DREAMM-8 study. There were very few patients (3%) who had an ECOG performance status score of 2 in the DREAMM-8 study, and the clinical expert indicated that they would likely treat these patients with belantamab mafodotin. Most patients in the DREAMM-8 study had only 1 prior line of therapy (53%), and only 14% had 4 or more prior lines; however, the clinical experts believe that BPd is more likely to be used in early relapse rather than in these later lines.

The clinical expert noted that the dosing of bortezomib is slightly different in the DREAMM-8 study (twice weekly) than it is in some parts of Canada (once weekly). The clinical expert did not consider this as an important generalizability issue. This is done in some jurisdictions in Canada because the 2 regimens, a higher dose weekly or a lower dose twice weekly, are seen as equivalent, and once weekly dosing is used for convenience. Patients in the BPd group were offered various measures to reduce the risk of ocular (corneal) AEs, including the use of a cooling mask, artificial tears, and potentially corticosteroid eyedrops. It is unclear whether these measures will become part of common practice when BPd is used in the community. If this is not the case, then this is a generalizability issue.

HRQoL was identified by patients and the clinical experts as an important outcome in patients with MM; however, this outcome was not formally assessed for between-group differences in the DREAMM-8 study, which should be considered a limitation of this trial. Data for OS are not yet mature; therefore, no conclusions can be drawn about the impact of BPd on OS compared with PVd, which should also be considered a limitation of this trial. PFS, which was the primary outcome of the DREAMM-8 study, is a widely used surrogate for OS, and is frequently used as a primary outcome in pivotal trials, consistent with FDA guidance.

GRADE Summary of Findings and Certainty of the Evidence

Methods for Assessing the Certainty of the Evidence

For pivotal studies and RCTs identified in the sponsor’s systematic review, GRADE was used to assess the certainty of the evidence for outcomes considered most relevant to inform expert committee deliberations. A final certainty rating was determined as outlined by the GRADE Working Group:^20,21

• High certainty: We are very confident that the true effect lies close to that of the estimate of the effect.

• Moderate certainty: We are moderately confident in the effect estimate. The true effect is likely to be close to the estimate of the effect, but there is a possibility that it is substantially different. We use the word “likely” for evidence of moderate certainty (e.g., “X intervention likely results in Y outcome”).

• Low certainty: Our confidence in the effect estimate is limited. The true effect may be substantially different from the estimate of the effect. We use the word “may” for evidence of low certainty (e.g., “X intervention may result in Y outcome”).

• Very low certainty: We have very little confidence in the effect estimate. The true effect is likely to be substantially different from the estimate of effect. We describe evidence of very low certainty as “very uncertain.”

• For RCTs: Following the GRADE approach, evidence from RCTs started as high-certainty evidence and could be rated down for concerns related to study limitations (which refers to internal validity or risk of bias), inconsistency across studies, indirectness, imprecision of effects, and publication bias.

When possible, certainty was rated in the context of the presence of an important (nontrivial) treatment effect. If that was not possible, certainty was rated in the context of the presence of any treatment effect (i.e., the clinical importance is unclear). In all cases, the target of the certainty of evidence assessment was based on the point estimate and where it was located relative to the threshold for a clinically important effect (when a threshold was available) or to the null. The MID for PFS and OS were obtained by asking the clinical experts for their impression of what it should be. For PFS, the clinical experts suggest that a 10% difference between groups would be considered clinically significant, while for OS they suggested it should be 5% because any gain in survival would be considered clinically meaningful to patients. For HRQoL, an MID of 10 points was identified by the sponsor as clinically significant, and the clinical experts agreed that this seemed reasonable. However, given the challenges in trying to identify 1 specific time point in which to assess response to the EORTC QLQ-C30 given the constant attrition over the course of the study, it was decided that instead of seeking 1 specific target of certainty, an overall impression of the direction of effect over time would be ascertained.

Results of GRADE Assessments

Table 2 presents the GRADE summary of findings for BPd versus PVd.

Indirect Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Objectives for the Summary of Indirect Evidence

In the absence of direct comparative data for BPd compared with other relevant comparators used in clinical practice (DVd, IsaKd, IsaPd, Kd, Pd, SVd, bortezomib plus dexamethasone (Vd), and cyc-doublets (i.e., cyclophosphamide in combination with another medication) in the treatment of patients with r/r MM, the sponsor conducted an ITC using a network meta-analysis (NMA) to assess the comparative efficacy of BPd in a population of patients with prior lenalidomide exposure compared with the previously mentioned relevant comparators. The objective of this section is to summarize and critically appraise the sponsor-submitted ITC evidence comparing BPd with other relevant comparators in Canadian settings.

Description of Indirect Comparisons

ITC Design

Objectives

The primary objective of the sponsor-submitted NMA was to assess the comparative efficacy of BPd in a population of patients with prior lenalidomide exposure versus relevant comparators with respect to PFS and OS. The secondary objective of the NMA was to assess the comparative efficacy of BPd in a subpopulation of patients whose disease was lenalidomide-refractory relative to comparators for the same outcomes (i.e., PFS and OS).

Study Selection Methods

A systematic literature review (SLR) was conducted in December 2021 and subsequently updated in January 2024 to identify all relevant efficacy and safety data for therapies used in the second-line or later for r/r MM. A summary of parameters applied to conduct the SLR is provided in Table 19.

Table 19: Study Selection Criteria and Methods of SLR

2L+ = second line or more; AE = adverse event; ADC = antidrug conjugate; ASCT = autologous stem cell transplant; CR = complete response; CRS = cytokine release syndrome; DOR = duration of response; HDAC = histone deacetylase; HLH/MAS = hemophagocytic lymphohistiocytosis/macrophage activation syndrome; ICANS = immune cell-associated neurotoxicity syndrome; LoT = line of treatment; MR = minimal response; MRD = minimal residual disease; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PFS2 = progression-free survival on subsequent line of treatment; PI = proteasome inhibitor; PPS = postprogression survival; PR = partial response; RCT = randomized controlled trial; r/r MM = relapsed or refractory multiple myeloma; SAE = serious adverse event; sCR = stringent complete response;; SLR = systematic literature review; TRAE = treatment-related adverse event; TTBR = time to best response; TTNT = time to next therapy; TTP = time to progression; TTR = time to systemic response; TTTF = time to treatment failure; URTI = upper respiratory tract infection; VGPR = very good partial response.

Source: GlaxoSmithKline Inc.¹⁸

Based on the SLR, the final network included a total of 12 studies investigating 12 treatments, anchored through 3 common treatments: Vd, high-dose carfilzomib and dexamethasone (hKd), and PVd. Three studies (the PANORAMA 1, NCT00813150, and NCT01478048 studies) did not report data for patients who were lenalidomide-exposed or whose disease was lenalidomide-refractory, and 1 reported data for patients whose disease was lenalidomide-refractory but not for those who were lenalidomide-exposed (the GEM-KyCyDex study). Therefore, 9 studies were included in the ITC (Table 23).

NMA Feasibility Assessment

The investigators’ feasibility assessment evaluating the level of homogeneity among included studies indicated it was feasible to conduct a network analysis.

Quality Assessment

A risk of bias assessment was conducted using the Revised Cochrane risk of bias tool for individually randomized parallel group trials (RoB 2.0).⁵⁷ The overall risk of bias was heterogeneous among included studies, but no studies were regarded as outliers, and no studies were excluded based on the risk of bias assessment.

Study and Population Characteristics

An assessment of heterogeneity in the study characteristics and the patient populations of the included studies was conducted. Table 20 presents a comparison of the characteristics of the populations included in studies comprising the network. Median age, sex (percentage female or male), race, and time since diagnosis were not available or were partially reported in the lenalidomide-exposure population. Table 21 presents the assessment of the heterogeneity in r/r MM–specific characteristics.

Table 20: Similarity of Patient Population Characteristics

ITT = intention-to-treat.

Source: GlaxoSmithKline Inc.¹⁸

Table 21: Assessment of Heterogeneity in r/r MM-Specific Characteristics

ECOG PS = Eastern Cooperative Oncology Group; ISS = International Staging System; IMiD = immunomodulatory drugs; LoT = line of treatment; NR = not reported; PS = performance status; r/r MM = relapsed or refractory multiple myeloma.

Source: GlaxoSmithKline Inc.¹⁸

ITC Analysis Methods

A summary of the analytical approaches used to conduct the NMAs is provided in Table 22.

Table 22: Indirect Comparison Analysis Methods

BPd = belantamab mafodotin, pomalidomide, and dexamethasone; CrI = credible interval; DIC = deviance information criterion; HR = hazard ratio; NMA = network meta-analysis OR = odds ratio; ORR = overall response rate; PVd = pomalidomide, bortezomib, and dexamethasone; OS = overall survival; PFS = progression-free survival; TTE = time to event; VGPR = very good partial response; vs. = versus.

Source: GlaxoSmithKline Inc.¹⁸

Results of ITC

Summary of Included Studies

A total of 9 studies were included in the ITC. The characteristics of the included studies are presented in Table 23.

Table 23: Studies and Comparators Included in the ITC Analyses

BPd = belantamab mafodotin, pomalidomide, and dexamethasone; CyKd = cyclophosphamide, carfilzomib, and dexamethasone; CyVd = cyclophosphamide, bortezomib, and dexamethasone; DVd = daratumumab, bortezomib, and dexamethasone; hKd = high-dose carfilzomib and dexamethasone; IhKd = isatuximab, high-dose carfilzomib, and dexamethasone; Kd = carfilzomib and dexamethasone; PVd = pomalidomide, bortezomib, and dexamethasone; SVd = selinexor, bortezomib, and dexamethasone; Vd = bortezomib and dexamethasone.

Source: GlaxoSmithKline Inc.¹⁸

Efficacy

The ITC was conducted in an overall lenalidomide-exposed population including patients who received prior lenalidomide but had r/r disease, with a separate analysis for a subgroup of patients whose disease was lenalidomide-refractory.

Lenalidomide-Exposed Population

The overall efficacy results of the ITC are presented in Table 24 for the lenalidomide-exposed population.

Table 24: Results of Lenalidomide-Exposed Population

BPd = belantamab mafodotin, pomalidomide, and dexamethasone; CrI = credible interval; DVd = daratumumab, bortezomib, and dexamethasone; hKd = high-dose carfilzomib and dexamethasone; hKDd = high-dose carfilzomib, daratumumab, and dexamethasone; HR = hazard ratio; IhKd = isatuximab, high-dose carfilzomib, and dexamethasone; Kd = carfilzomib and dexamethasone; OR = odds ratio; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PVd = pomalidomide, bortezomib, and dexamethasone; SVd = selinexor, bortezomib, and dexamethasone; Vd = bortezomib and dexamethasone; vs. = versus.

Notes: For PFS and OS, HR < 1 indicates in favour of BPd; HR > 1 indicates in favour of comparators. For ORR HR > 1 indicates in favour of BPd; HR < 1 indicates in favour of comparators

Source: Summarized based the sponsor’s evidence summary and ITC report.⁷²

PFS Primary Analysis: Lenalidomide-Exposed Population

The PFS analysis included 8 studies (Figure 10).^{14,19,54,58-61,63} Based on the fixed-effect model, BPd demonstrated a more favourable improvement in PFS (i.e., 95%Crl does not cross 1) compared with hKd, SVd, and Vd. However, the results did not demonstrate a more favourable PFS for BPd compared with remaining comparators (i.e., DVd; high-dose carfilzomib, daratumumab, and dexamethasone [hKDd]; isatuximab, high-dose carfilzomib, and dexamethasone; and Kd). The HRs for these comparisons varied from 0.29 to 0.86 for the various comparisons, but they all had wide 95% Crls extending across 1 (Table 24) Using the random-effect model, the results suggested that BPd ███ ███ ███████████ █ ████ █████████ ███ ██████ ███ ██ ███ █████████ ██████████ ███████████

Figure 10: PFS Network — Lenalidomide-Exposed Population [Redacted]

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OS Primary Analysis — Lenalidomide-Exposed Population

The OS analysis included || studies^{███████████} (Figure 11). Based on the fixed-effect model, BPd demonstrated a more favourable improvement in OS compared with Vd (HR, ████; 95% CrI █████ ████). However, BPd did not demonstrate a more favourable OS when compared with hKd, or hKDd, █████ ████ ████ █████████ ██████ █ ███ ████ ███████████. Using the random-effect model, the results suggested that BPd ███ ███ ███████████ █ ████ █████████ ██ ██████ ██████ ███ ██ ███ █████████ ██████████ ██████████ (Table 25).

Figure 11: OS Network — Lenalidomide-Exposed Population [Redacted]

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████ █ ██████████ █ ████████████ █ ██████████████ ██ █ ██████ ██████ ███ █ ████ ████ ███████████ █ ██████████████ ████ █ ████ ████ ███████████ █ ███████████ █ ██████████████ ███ █ ███████ ██████████████ ██ █ ███████ █████████ ███ █ ████████████ █ ██████████ █ ██████████████ ██ █ ██████████ █ ██████████████

ORR Primary Analysis — Lenalidomide-Exposed Population

The ORR analysis included || studies^{███████████} (Figure 12). Results from the fixed-effect model suggest a more favourable ORR with BPd compared with hKd (OR ████; 95% CrI ████ ██ ████), SVd (OR ████; 95% CrI ████ ██ ████), and Vd (OR ████; 95% CrI ████ ██ █████). ████████ ███████████ ███ █████████ ███████████ ██████ ████ █████ ███ ████ ███ ███ ███████████ █ ████ █████████ ███ ███████ ████ ███ ██ █████████ ██ ████ ████ ███ ████ █████████ ██████ █ ███ ████ ██████████. Using the random-effect model, the results suggested that BPd ███ ███ ███████████ █ ████ █████████ ███ ██████ ███ ██ ███ █████████ ██████████ ██████████ ███████ ███ ██ ████ (Table 25)

Figure 12: Overall Response Rate Network — Lenalidomide-Exposed Population [Redacted]

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Lenalidomide-Refractory Population

The overall efficacy results of the ITC are presented in Table 25 for the lenalidomide-refractory population.

Table 25: PFS Results in Lenalidomide-Refractory Population

BPd = belantamab mafodotin, pomalidomide, and dexamethasone; CI = confidence interval; CrI = credible interval; CyKd = cyclophosphamide, high-dose carfilzomib, and dexamethasone; CrI = credible interval; DVd = daratumumab, bortezomib, and dexamethasone; hKd = high-dose carfilzomib and dexamethasone; hKDd = high-dose carfilzomib, daratumumab, and dexamethasone; HR = hazard ratio; IhKd = isatuximab, high-dose carfilzomib, and dexamethasone; ITC = indirect treatment comparison; Kd = carfilzomib and dexamethasone; PFS = progression-free survival; PVd = pomalidomide, bortezomib, and dexamethasone; SVd = selinexor, bortezomib, and dexamethasone; Vd = bortezomib and dexamethasone; vs. = versus.

Notes: For PFS, HR < 1 indicates in favour of BPd; HR > 1 indicates in favour of comparators.

For the purpose of this analysis, inverted values have been used for the GEM_KyCyDex study’s HRs and CIs due to the publication reporting Kd vs. CyKd, rather than CyKd vs. Kd.

Source: Summarized based on the sponsor’s evidence summary and ITC report.⁷²

PFS Secondary Analysis: Lenalidomide-Refractory Population

The analysis of PFS in the lenalidomide-refractory population included studies^{████████████████████} (Figure 13). Based on the fixed-effect model, the BPd demonstrated a more favourable improvement in PFS compared with either hKd, Kd, or Vd. ████████ ███ ███████ ███ ███ ███████████ █ ████ █████████ ███ ███ ███ ████████ ████ █████████ ███████████ ██████ ████ █████ ███ ██████ ███ ███ ███ █████ ███████████ ██████ ████ ████ ██ ████ ███ █████ ███████ ███████████ ███ ████ ███ ███ ████ ███ ████ █████████ ██████ (Table 25). Using the random-effect model, the results suggested that BPd ███ ███ ███████████ █ ████ █████████ ███ ██████ ███ ██ ███ █████████ ██████████ ██████████ (Table 25).

Figure 13: PFS Network — Lenalidomide-Refractory Population [Redacted]

████ █ ██████████ █ ████████████ █ ██████████████ ████ █ ████████████████ █ ████ ████ ███████████ █ ███████████ █ ██████████████ ███ █ ███████████ █ ██████████ █ ██████████████ ███ █ ████ ████ ███████████ █ ██████████████ ████ █ ████ ████ ███████████ █ ███████████ █ ██████████████ ██ █ ██████ ██████ ████ █ ██████████ █ ████ ████ ███████████ █ ████████████ ███ █ ████████████████ █████████ ██ █ ███████████ █ ██████████████ ███ █ ████████████ █ ██████████ █ ██████████████ ██ █ ██████████ █ █████████████

Harms

The NMA did not include any harms data.

Critical Appraisal of ITC

Overall, the ITCs were conducted according to accepted methodological guidance. An SLR was used as the basis for selecting relevant studies. The SLR searched multiple databases and grey literature sources, conducted study selection and data extraction using accepted methods, and provided a Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) diagram of the study selection. The risk of bias of included studies was assessed using the Revised Cochrane risk of bias tool for individually randomized, parallel group trials (RoB 2). Feasibility assessment was performed to inform whether an NMA between the RCTs identified in the SLR would be feasible. Geometry of the evidence networks were provided for each outcome analysis. For each analysis, the goodness-of-fit to the model was assessed by using the deviance information criterion and residual deviance. The potential limitations of the NMA are discussed next.

One of the key limitations of the ITC was the significant potential heterogeneity in study-level patient demographic and disease characteristics, as well as the study characteristics across the included studies. In the sponsor’s ITC report, it was indicated that, in the studies included in the ITC, median age, gender (percentage male or female), race, and time since diagnosis were not available or rarely reported in the lenalidomide exposure population. Therefore, it was not possible to fully assess the similarities and differences of the studies. Regarding the r/r MM-specific characteristics, of the 9 included studies, 5 studies reported the prior lenalidomide exposure; 3 studies reported the number of the prior line of treatment; 2 studies reported the ISS stage; 3 studies reported ECOG performance status; 2 studies reported the prior IMiD exposure; and 6 studies reported cytogenic risk profile. Based the available information, the prior line of treatment and ECOG performance status varied across the studies, and the percentage with a high cytogenic risk profile varied from 13.7% to 35.7%. In addition, the clinical experts consulted by CDA-AMC for this review indicated that lenalidomide refractory status and anti-CD38 refractory status are 2 very important factors, as most patients starting on these regimens of BPd will not just be lenalidomide- or anti-CD38–exposed but also will have disease that is lenalidomide- /or anti-CD38–refractory. Furthermore, substantial variation was observed in the follow-up time at which outcomes were assessed across the studies, with follow-up time for reporting PFS ranging from 5.6 months to 47 months. Considering that HRs could change with duration of follow-up, these differences may significantly impact outcomes. No meta-regression analyses to adjust for factors that may bias comparisons were conducted. Therefore, the heterogeneity of treatment and prognostic modifiers discussed previously may threaten the transitivity assumption for the NMA analysis. The assumption of similarities across the included studies may not hold true for the NMA, increasing the likelihood of potential bias and uncertainty about the validity of the results estimating the comparative effectiveness of BPd compared with other existing therapies.

All evidence networks were sparsely connected and the connections between treatment nodes were informed by only 1 trial for each comparison, which was not sufficient to reliably estimate between-study variances. Therefore, the investigators chose the fixed-effect model for the primary analysis and the random-effects model for secondary analysis. However, although the model fit statistics (i.e., deviance information criterion) suggested similarity between random and fixed-effect models, the results of the analyses were sensitive to the model used and many had wide credible intervals indicating uncertainty in the results.

Furthermore, the NMA had no closed network to allow assessing the comparative effect of BPd versus IsaPd or carfilzomib and dexamethasone, which are considered relevant comparators in clinical settings in Canada.

For the lenalidomide-refractory population, the NMA assessed only PFS without OS, ORR, and HRQoL, which could not be evaluated due to lack of relevant data. Finally, the NMA did not assess harms outcomes.

Summary of ITC

Assessments based on the fixed-effect model suggest BPd may demonstrate more favourable effect than some evaluated comparators with regards to PFS, OS, and ORR in the lenalidomide-exposed population. However, the results were sensitive to model changes as using the random-effect model ███ ███ ███████████ ███████ █████████ ███ ██ ████ ██ ███ ███████████. Similarly, inconsistent results were reported from the analyses of PFS involving the lenalidomide-refractory population, with the fixed effect model suggesting a more favourable effect with BPd than comparators, whereas the random-effect model ███ ███ ████ ███ ██████████ ██ ██████ ████ ████ OS and ORR were not assessed in the lenalidomide-refractory population due to lack of data to form a network.

A potential key limitation of the NMA includes considerable heterogeneity in effect modifiers and prognostic modifiers across the included studies and sparse network. The findings reported in the NMA should be interpreted with the consideration of all its associated limitations.

The NMA did not assess HRQoL and harms outcomes. Therefore, the comparative effects of BPd versus the relevant comparators with regards to HRQoL and harms is unknown.

Studies Addressing Gaps in the Systematic Review Evidence

Contents within this section have been informed by materials submitted by the sponsor. The following has been summarized and validated by the review team.

Table 26: Summary of Gaps in the Systematic Review Evidence

AE = adverse event; BCVA = best corrected visual acuity; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; CI = confidence interval; CR = complete response; ORR = overall response rate; OS = overall survival; Pd = pomalidomide and dexamethasone; PFS = progression-free survival; PR = partial response; q.8.w. = every 8 weeks; RP2D = recommended phase 2 dose; sCR = stringent complete response; TEAE = treatment-emergent adverse event; VGPR = very good partial response.

Sources: Trudel et al. (2024).⁷³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Description of Studies

One phase I/II, single-arm, open-label, multicentre study (the ALGONQUIN study) has been summarized in this section (Table 27). The ALGONQUIN study evaluated various doses and schedules of BPd for patients with MM whose disease was lenalidomide-refractory and who had been exposed to a PI.

The ALGONQUIN study comprised a dose-escalation phase (part 1) and a dose-expansion phase (part 2). A total of 87 patients with r/r MM were enrolled, with 61 patients in part 1 and 26 in part 2. The primary objectives of the ALGONQUIN study were to determine the RP2D and the schedule of belantamab mafodotin in part 1, as well as to establish the efficacy, as determined by ORR, for participants treated at the RP2D in part 2. The secondary objectives were to assess the safety and tolerability of the BPd in part 1 and to assess additional efficacy outcomes including PFS, DOR, and OS at the RP2D in part 2.

Of note, the sponsor also submitted evidence regarding the use of bandage contact lenses for the management of ocular AEs associated with BPd. As of the time of this review, the bandage contact lenses were not an intervention relevant to the Health Canada indication; therefore, the evidence on the use of bandage contact lenses was considered out of scope by the CDA-AMC review team, and it was not appraised.

Table 27: Details of the ALGONQUIN Study

ALT = alanine transferase; ANC = absolute neutrophil count; BPd = belantamab mafodotin, pomalidomide, and dexamethasone; DOR = duration of response; ECOG = Eastern Cooperative Oncology Group; eGFR = estimated glomerular filtration rate; FLC = free light chains; MM = multiple myeloma; NA = not applicable; NR = not reported; NYHA = New York Heart Association; ORR = overall response rate; OS = overall survival; PFS = progression-free survival; PFS2 = progression-free survival on subsequent line of treatment; QTcF = corrected QT interval using Fridericia’s formula; RP2D = recommended phase 2 dose; r/r MM = relapsed or refractory multiple myeloma; ULN = upper limit of normal.

Sources: Trudel et al. (2024)⁷³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Populations

Participants were eligible for the ALGONQUIN study if they were 18 years or older with a confirmed diagnosis of MM and were previously treated with at least 1 prior line of MM therapy, including a lenalidomide-containing regimen with documented disease progression during or after their most recent therapy.

Interventions

In part 1 of the ALGONQUIN study, belantamab mafodotin was administered in 61 patients at various doses (1.92 mg/kg, 2.5 mg/kg, and 3.4 mg/kg) and schedules (every 4 weeks, every 8 weeks, and every 12 weeks). Pomalidomide and dexamethasone were used in combination with belantamab mafodotin. Pomalidomide was administered at a fixed dose of 4 mg orally every day on days 1 to 21 of each 28-day cycle. Dexamethasone was administered at a starting dose of 40 mg orally daily on days 1, 8, 15, and 22 for participants aged 75 years or younger, and at 20 mg orally every day on the same schedule for those older than 75 years. Patients continued on the treatment until disease progression, unacceptable toxicity, or consent withdrawal.

The dose (i.e., RP2D) for part 2 was determined on the basis of the totality of the safety, tolerability, and activity data during part 1. A total of 38 patients (12 patients from part 1 and 26 from part 2) were treated at the RP2D (i.e., 2.5 mg/kg every 8 weeks).

Outcomes

The primary end points part 1 of the ALGONQUIN study were to determine the maximum tolerated dose, RP2D, and schedule of BPd.

The primary efficacy end point of the ALGONQUIN study for all patients whose responses were evaluable and were treated at the RP2D (response evaluable was defined as those with 2 consecutive assessments) was to determine the objective response rate which was defined as a sCR, CR, VGPR, or PR. Main secondary end points included PFS, OS, and safety assessments in all patients who were treated.

Statistical Analysis

The statistical analysis for the ALGONQUIN study included both descriptive and inferential components. A two-sided 95% Clopper-Pearson CI was calculated for ORR in part 2 and all patients treated at the RP2D. The analysis included all patients who received at least 1 dose of the study drug. Results were summarized for all patients who were treated, by dose group, and patients treated in part 2 at RP2D. PFS and OS were analyzed using the KM method. Survival curves showed the number of participants at risk and event-free rates, along with corresponding 95% CIs, at specific time points. Descriptive statistics were used to summarize safety data.

The sample size for part 1 of the ALGONQUIN study was not driven by statistical considerations but aimed to characterize dose cohorts and determine the maximum tolerated dose and RP2D. Approximately 30 evaluable participants were planned for dose-limiting toxicity assessment, with up to 74 additional participants anticipated to determine the RP2D.

For part 2, 35 patients were required for the ORR analysis, including 12 patients carried over from part 1 at the RP2D. The remaining 23 patients were planned for r/r MM cohorts, with additional cohorts targeting dose modifications for corneal events and toxicity reduction. Up to 140 patients total, accounting for a 10% dropout rate, were projected to complete the study, with a type I error rate of 0.05, a power of 97%.

Results

Patient Disposition

Patient disposition in the ALGONQUIN study is shown in Figure 14. In part 1, participants (n = 61) had a median duration of follow-up of 17.1 months (range, 0.9 to 42.5). At the data cut-off date of February 14, 2023, 21.3% (13 of 61) of the participants were still on study treatment, while 78.7% (48 of 61) had discontinued. The primary reason for treatment discontinuation was progressive disease (50.8%, 31 of 61), followed by death (% NR, 6 patients), consent withdrawal (% NR, 6 patients), and AEs (% NR, 5 patients). In total, 12 of 61 (19.7%) deaths occurred part 1 and discontinued the study, with 6 attributable to disease progression, 3 to COVID-19, 1 to pneumocystis pneumonia, 1 to influenza, and 1 to myocardial infarction.

In part 2, participants (n = 38) had a median follow-up of 13.9 months (range, 1.1 to 28.2). At the data cut-off date of February 14, 2023, 57.9% (22 of 38) of participants remained on treatment, while 42.1% (16 of 38) had discontinued. The main reason for treatment discontinuation was progressive disease (23.7%, 9 of 38), followed by death (% NR, 4 patients), AEs (5.3%, 2 of 38), and consent withdrawal (% NR, 1 patient).

Baseline Characteristics

The summary of the baseline characteristics of the patients in the ALGONQUIN study is shown in Table 28. The study population (N = 87) had a median age of 67 years (range, 36 to 85 years) with 47.1% being female, a median time from diagnosis of 5 years (range, 1 to 21), and a median number of previous lines of therapy of 3 (range, 1 to 6). At baseline, 25%, 34.4%, and 21.8% of the study participants had ISS disease stage i, ii, and iii, respectively, while the stage information was missing in 18.4% of the study participants.

Exposure to Study Treatments

The summary of exposure to study treatments is presented in Table 29.

Figure 14: Patient Disposition in the ALGONQUIN Study

AE = adverse event; Belanmaf-Pd = belantamab mafodotin, pomalidomide, and dexamethasone; RP2D = recommended phase 2 dose.

Note: Out of the 38 patients who received belantamab mafodotin, pomalidomide, and dexamethasone, 12 participants from part 1 and 26 participants from part 2.

Source: Trudel et al. (2024).⁷³

Table 28: Baseline Characteristics of Participants in the ALGONQUIN Study

ASCT = autologous stem cell transplant; BCVA = best corrected visual acuity; ECOG = Eastern Cooperative Oncology Group; PI = proteasome inhibitor; RP2D = recommended phase 2 dose.

^aThe total of 87 participants excluded 12 patients who were enrolled in both part 1 and part 2.

^bHigh risk is defined as participants presenting with abnormality for del(17p) and/or translocations t(4;14) and/or t(14;16). Fluorescence in situ hybridization was performed locally using the individual laboratory’s cut-off values.

^cStandard risk is defined as participants with the absence of abnormality for all the following: del(17p), translocations t(4;14), and t(14;16).

Source: Trudel et al. (2024)⁷³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Table 29: Summary of Treatment Exposure in the ALGONQUIN Study

q.4.w. = every 4 weeks; q.8.w. = every 8 weeks; q.12.w. = every 12 weeks; RP2D = recommended phase 2 dose.

^a1.92 mg/kg q.4.w.: belantamab mafodotin 1.92 mg/kg, single dose, every 4 weeks; 2.5 mg/kg q.4.w., q.8.w., or q.12.w.: belantamab mafodotin 2.5 mg/kg, single dose, every 4 weeks, every 8 weeks, or every 12 weeks; 2.5 mg/kg loading: belantamab mafodotin 2.5 mg/kg loading dose followed by 1.92 mg/kg every 4 weeks; 2.5 mg/kg split: belantamab mafodotin 2.5mg/kg, split evenly with 50% of the dose administered on days 1 and 8 of every cycle; 3.4 mg/kg split: belantamab mafodotin 3.4 mg/kg, split evenly with 50% of the dose administered on days 1 and 8 of every cycle; RP2D: belantamab mafodotin 2.5 mg/kg, every 8 weeks.

Sources: Trudel et al. (2024).⁷³ Details included in the table are from the sponsor’s Summary of Clinical Evidence.²²

Efficacy

Maximum Tolerated Dose and RP2D

The maximum tolerated dose based on the first cycle (28 days) of treatment was determined to be 2.5 mg/kg belantamab mafodotin. The regimen of 2.5 mg/kg every 8 weeks combined with 4 mg of pomalidomide and 40 mg of dexamethasone was selected as the RP2D.

ORR, OS, and PFS in Patients Treated at RP2D

In part 2, the median duration of follow-up for patients treated at RP2D (n = 38) was 13.9 months (range, 1.1 to 28.2). Out of these 38 patients treated at RP2D, 34 had 2 consecutive assessments and were considered response evaluable. The ORR for the patients with evaluable responses was 85.3% (29 of 34), with 32.4% (11 of 34) reaching CR or sCR, 41.2% (14 of 34) achieving VGPR, and 11.8% (4 of 34) having PR. In the 38 patients treated at RP2D, the median OS (months) was not reached (95% CI, not reached to not reached); the median PFS (months) was not reached (95% CI, 13.7 to not reached).

In the 38 patients treated at RP2D during part 2, 12 were from part 1. The median duration of follow-up for the 12 patients was 17.2 months (range, 6.0 to 28.2). The ORR was 91.7% (11 of 12), with 33.3% (4 of 12) reaching CR or sCR, 50.0% (6 of 12) achieving VGPR, and 8.3% (1 of 12) having PR. The median OS was not reached (95% CI, not reached to not reached); the median PFS was 18.3 months (95% CI, 10.8 to not reached).

ORR, OS, and PFS in All Patients Receiving Treatment

The median duration of follow-up for all patients receiving treatment was 14.5 months (range, 0.9 to 42.5). Out of the 87 patients, 81 had 2 consecutive assessments and were considered response evaluable. The ORR for the patients whose response was evaluable was 87.7% (71 of 81), with 33.3% (27 of 81) reaching CR or sCR, 39.5% (32 of 81) achieving VGPR, and 14.8% (12 of 81) having PR. The median OS was 34.0 months (95% CI, 24.4 to not reached), and the median PFS was 21.8 months (95% CI, 17.8 to 32.5).

ORR, OS, and PFS in Patients Treated at Doses Other Than RP2D

In patients treated with belantamab mafodotin at 1.92 mg/kg, single dose, every 4 weeks (n = 12), the median duration of follow-up was 14.1 months (range, 2.3 to 30.4). Out of the 12 patients, 11 had 2 consecutive assessments and were considered response evaluable. The ORR for the patients whose responses were evaluable was 72.7% (8 of 11), with 27.3% (3 of 11) reaching CR or sCR, 36.4% (4 of 11) achieving VGPR, and 9.1% (1 of 11) having PR. The median OS for all 12 patients was 21.4 months (95% CI, 15.7 to not reached); the median PFS was 16.9 months (95% CI, 5.3 to 19.7).

In patients treated with belantamab mafodotin at 2.5 mg/kg, single dose, every 4 weeks (n = 7), the median duration of follow-up was 24.4 months (range, 12.2 to 33.1). The ORR was 100.0% (7 of 7), with 42.9% (3 of 7) reaching CR or sCR, 57.1% (4 of 7) achieving VGPR, and 0.0% (0 of 7) having PR. The median OS was 32.0 months (95% CI, 30.0 to not reached); the median PFS was 25.3 months (95% CI, 11.8 to not reached).

In patients treated with belantamab mafodotin at 2.5 mg/kg, every 12 weeks (n = 12), the median duration of follow-up was 13.7 months (range, 0.9 to 27.3). Out of the 12 patients, 11 had 2 consecutive assessments and were considered response evaluable. The ORR for the patients whose response was evaluable was 100% (11 of 11), with 27.3% (3 of 11) reaching CR or sCR, 36.4% (4 of 11) achieving VGPR, and 36.4% (4 of 11) having PR. The median OS for all 12 patients was not reached (95% CI, 22.5 to not reached); the median PFS was 22.5 months (95% CI, 10.7 to not reached).

In patients treated with belantamab mafodotin at 2.5 mg/kg loading dose followed by 1.92 mg/kg every 4 weeks (n = 5), the median duration of follow-up was 8.7 months (range, 4.8 to 35.2). The ORR was 100.0% (5 of 5), with 40.0% (2 of 5) reaching CR or sCR, 40.0% (2 of 5) achieving VGPR, and 20.0% (1 of 5) having PR. The median OS was 34.4 months (95% CI, 24.4 to not reached); the median PFS was 9.0 months (95% CI, 5.3 to not reached).

In patients treated with belantamab mafodotin at 2.5 mg/kg, single dose, split evenly with 50% of the dose administered on days 1 and 8 of every cycle (n = 8), the median duration of follow-up was 20.1 months (range, 3.0 to 42.5). The ORR was 87.5% (7 of 8), with 62.5% (5 of 8) reaching CR or sCR, 12.5% (1 of 8) achieving VGPR, and 12.5% (1 of 8) having PR. The median OS was not reached (95% CI, 21.8 to not reached); the median PFS was not reached (95% CI, 21.8 to not reached).

In patients treated with belantamab mafodotin at 3.4 mg/kg, split evenly with 50% of the dose administered on days 1 and 8 of every cycle (n = 5), the median duration of follow-up was 7.1 months (range, 1.0 to 22.8). The ORR was 80.0% (4 of 5), with 0.0% (0 of 5) reaching CR or sCR, 60.0% (3 of 5) achieving VGPR, and 20.0% (1 of 5) having PR. The median OS was 20.0 months (95% CI, 7.3 to not reached); the median PFS was 19.6 months (95% CI, 3.7 to not reached).

Harms

The summary of TEAEs by dosing cohorts in part 1 of the ALGONQUIN study is shown in Table 30. One out of 7 (14%) participants in the 2.5 mg/kg every 4 weeks cohort and 2 out of 5 (40%) participants in the 3.4 mg/kg (split) cohort and reported dose-limiting toxicities.

The summary of TEAEs occurred in patients treated at RP2D in part 2 of the ALGONQUIN study is presented in Table 31. In patients treated at RP2D, the most common TEAE of any grade was decreased visual acuity (71.1%, 27 of 38), followed by keratopathy (65.8%, 25 of 38), fatigue (57.9%, 22 of 38), infection (47.4, 18 of 38), neutropenia (39.5%, 15 of 38), and thrombocytopenia (39.5%, 15 of 38). The most common grade 3 to 4 TEAEs included keratopathy (52.6%, 20 of 38), decreased visual acuity (39.5%, 15 of 38), neutropenia (36.8%, 14 of 38), and thrombocytopenia (34.2%, 13 of 38). Of patients treated at RP2D, 55.3% (21 of 38) had an objective decrease in BCVA of grade 3 to 4, 13.2% (5 of 38) had blurred vision of grade 3 to 4, and 10.5% (4 of 38) had other ocular AEs, including dry eyes, photophobia, and eye pain.

Table 30: TEAEs by Dosing Cohorts in the Dose-Escalation Phase (Part 1) of the ALGONQUIN Study