Belantamab mafodotin is an antibody-drug conjugate (ADC) targeting B-cell maturation antigen (BCMA), initially approved by the U.S. Food and Drug Administration (FDA) in 2020 as monotherapy for triple-class refractory multiple myeloma based on the DREAMM-2 trial.1 However, the subsequent DREAMM-3 trial, which compared single-agent belantamab to pomalidomide and dexamethasone, did not meet its primary endpoint of progression-free survival (PFS) (11.2 months vs. 7.0 months, respectively; p=0.56), leading to the FDA withdrawing approval in 2022.2 Recently, the DREAMM-7 and DREAMM-8 trials compared belantamab-based triplets to triplet controls (unlike the doublet control arms used in many myeloma trials) and demonstrated impressive PFS benefit, sparking renewed interested in belantamab.3,4
The phase III DREAMM-7 trial compared belantamab, bortezomib, and dexamethasone (BVd) to daratumumab, bortezomib, and dexamethasone (DVd) in 494 patients who had relapsed after at least one prior line of therapy.3 Both BVd and DVd were given in 21-day cycles, with belantamab intravenously administered on day one of every cycle and dosed at 2.5 mg/kg, with the option to reduce to 1.9 mg/kg to manage toxicity. The rate of complete response (CR) or better was 35% in the BVd arm versus 17% in the DVd arm, while the rate of achieving CR and minimal residual disease (MRD) negativity (at 10-5 using next-generation sequencing) was 25% in the BVd arm versus 10% in the DVd arm. After a median follow-up of 28.2 months, median PFS was 36.6 months in the BVd arm and 13.4 months in the DVd arm (hazard ratio [HR] = 0.41; 95% CI 0.31-0.53; p<0.001). Subgroup analysis of PFS demonstrated that the HR still favored BVd in those with Revised International Staging System stage II or III multiple myeloma, high-risk cytogenetics, and extramedullary disease (although the CI crossed 1 for extramedullary disease). Overall survival (OS) at 18 months was 84% versus 73%, respectively, which did not meet statistical significance.
The phase III DREAMM-8 trial enrolled 307 participants who had relapsed after at least one prior line of therapy and randomized them at a ratio of one to one to either belantamab, pomalidomide, and dexamethasone (BPd) or pomalidomide, bortezomib, and dexamethasone (PVd).4 BPd was given on 28-day cycles, with belantamab administered on day one. Unlike in the DREAMM-7 trial, the dose was reduced to 1.9 mg/kg preemptively starting with cycle two. CR was achieved in 40% of patients in the BPd group versus 16% in the PVd group, while CR plus MRD negativity occurred in 24% with BPd and 5% with PVd. After a median follow-up of 21.8 months, 12-month PFS was 71% in the BPd group compared to 51% in the PVd group (HR=0.52; 95% CI 0.37-0.73; p<0.001). In subgroup analysis, the HR favored BPd in all subgroups, although the HR notably crossed 1 in the anti-CD38 refractory, triple-class exposed, and extramedullary disease groups. OS data was immature and not statistically significant, but 12-month OS was 83% with BPd compared to 76% with PVd.
Ocular toxicity (including keratopathy, blurred vision, and decreased visual acuity) was notable in both trials. DREAMM-7 reported that 79% of patients treated with belantamab experienced grade 3-plus ocular toxicity (34%), leading to dose reductions in 44%, delays in 78%, and discontinuation in 9%. Similarly, DREAMM-8 reported 89% of patients treated with belantamab experienced grade 3-plus ocular toxicity (43%); notably, although 2% discontinued belantamab due to ocular toxicity, 91% experienced resolution of ocular toxicities at the time of data cutoff. Despite the higher rates of ocular toxicity associated with belantamab, there was no significant difference over time in health-related quality of life (QOL) as measured by the European Organization for Research and Treatment of Cancer’s QLC-C30 QOL questionnaire between the treatment and control arm in either study.
In Brief
In summary, both the DREAMM-7 and DREAMM-8 studies demonstrated PFS benefit surpassing that seen in many trials of triplet therapies for relapsed/refractory multiple myeloma (RRMM), even those with doublet comparators. For example, the HR for disease progression or death was 0.41 (95% CI 0.31-0.53) in DREAMM-7 and 0.52 (95% CI 0.37-0.73) in DREAMM-8, compared to 0.59 (95% CI 0.45-0.78) in the CANDOR trial (carfilzomib, daratumumab, and dexamethasone vs. carfilzomib and dexamethasone [Kd]) and 0.58 (95% CI 0.42-0.79) in the IKEMA trial (isatuximab plus carfilzomib and dexamethasone vs Kd). Despite advances in novel immunotherapies such as chimeric antigen receptor T-cell (CAR-T) therapy and bispecific antibodies, lack of access to an academic hospital or caregiver support may make these treatments unattainable for many patients, particularly in rural areas of the United States. With belantamab-based triplets, more patients can have access to a BCMA ADC that can be intravenously administered at local infusion centers without need for inpatient admission. It should be noted that in these global studies, Black patients were underrepresented, comprising 4% of participants in DREAMM-7 and 0% in DREAMM-8.
Patients unable to tolerate high-grade cytokine release syndrome (CRS) or neurotoxicity from CAR-T therapy may also be candidates for belantamab. However, belantamab-based therapy should ideally be avoided in patients in whom BCMA CAR-T therapy is being considered in the future. (Based on existing data, the PFS of 35 months of ciltacabtagene autoleucel dropped to nine months in those previously exposed to a BCMA ADC.)5 Another unmet need is salvage therapy in transplant-ineligible patients who progress after anti-CD38 monoclonal antibody and lenalidomide therapy (as per the MAIA trial).6 Further data is needed to understand the PFS benefit with belantamab-based regimens in this population, as the HR notably crossed 1 in anti-CD38 refractory patients in the DREAMM-8 trial.
As we advance care of those with RRMM, belantamab-based triplet regimens are a promising new option for many patients. Appropriate dosing/pausing of therapy, close monitoring with a risk evaluation and mitigation strategy program for ocular toxicity, and prompt ophthalmological intervention may mitigate toxicities.
Disclosure Statement
Dr. Kumar has received research funding from Bristol Myers Squibb and Janssen and will be receiving an honorarium from Sanofi for a speaking engagement. Dr. Chung has received research funding from Abbvie, Bristol Myers Squibb, Caelum, CarsGen, Cellectis, Janssen, K36 Therapeutics, and Merck Consulting, and he reported consulting activity for Janssen. Dr. Pan has received honoraria from Sanofi. Dr. Chari has received research funding from Janssen, and he reported consulting activity for Abbvie, Adaptive, Amgen, Antengene, Bristol Myers Squibb, Forus, Genentech/Roche, GlaxoSmithKline, Janssen, Karyopharm, Millenium/Takeda, and Sanofi/Genzyme.
