Safety and Efficacy of Belantamab Mafadotin in Patients with Relapsed/Refractory Multiple Myeloma: A Real-World Experience

Introduction: Belantamab Mafadotin (Belamaf) is a BCMA directed antibody drug conjugate previously approved for relapsed-refractory multiple myeloma (RRMM) based on the results of DREAMM-1 study. While initial trial led to the accelerated approval of belamaf, confirmatory trials failed to demonstrate statistically significant benefit from this therapy, eventually leading to its withdrawal from commercial use in U.S. However, two recent randomized controlled trials (DREAMM-7 and DREAMM-8) have shown significant superiority of belamaf combinations over standard of care therapy in RRMM. Herein, we report clinical outcomes with belamaf, both as single agent and combination therapy for RRMM patient (pt) population, in a real-world setting.

Methods: Five U.S. academic institutions contributed data to this multicenter retrospective study, which included pts who had received belamaf under a commercial FDA label or an expanded access program (EAP) between 10/10/2019 and 09/28/2023. Only pts who received ≥1 therapeutic doses were included. All pts had at least three months of follow up available at data cut off for safety and efficacy analysis. Responses were determined per IMWG response criteria. Adverse events (AEs) were graded based on CTCAE v5.0 criteria. Kaplan-Meier analysis was used for PFS and OS assessments. A multivariable cox proportional hazards model was utilized to determine predictors of PFS and OS.

Results: A total of 81 pts were included; 20 (24.7%) pts received therapy under EAP after removal of belamaf from the commercial market. All except 6 (7.4%) pts received belamaf as monotherapy. Nearly two-third (67.0%) of the entire cohort would have been considered ineligible for the DREAMM-1 trial; main reasons for ineligibility were: prior BCMA-directed therapy (BDT) (14.8%), ECOG performance status (PS) ≥2 (37.0%), any severe baseline cytopenia (23.5%), and renal insufficiency (43.2%). Median pt age was 67 (range 37-85) years with 42.0% of pts above 70 years of age. The median number of prior lines of therapy (LOT) was 5 (range 2-15). All except one pt were triple class exposed, 92.5% were triple class refractory, 45.7% were penta-class refractory, and 14.8% were refractory to prior BDT. More than half (56.8%) of pts had high risk cytogenetics (as defined by IMWG criteria), 37.0% had extramedullary disease (EMD), and all of those exposed to prior BCMA were refractory to BDT.

All grade ocular toxicity was seen in 69.1% of pts with grade 3 or greater events in 42.9%. Grade 3-4 hematological toxicities included neutropenia (19.8%), anemia (28.4%), and thrombocytopenia (30.9%). More than one-quarter (27.2%) of the pts experienced an infection, with 63.0% of these infections being severe (grade ≥3). A total of 46.9%, 35.8%, and 53.1% of the pts had dose delay/interruption, dose reduction, and treatment discontinuation, respectively, due to treatment-related toxicities.

Best ORR and complete response or better were 40.0% and 15.0%, respectively. Best ORR was 30.0%, 16.7% and 32.4% for patients with EMD, BCMA-refractory, and penta-refractory disease, respectively. Median time to first response was 25.5 days (95% CI 7.0-139.0) while the median time to best response was 64.0 days (95% CI 20.0-378.0). Median duration of response was 13.1 months (95% CI 10.1-26.9). With a median follow-up of 11.3 (range 0.3-44.6) months for the entire pt population, median PFS was 5.1 months (95% CI, 2.7-9.97) and median OS was 12.3 months (95% CI, 6.17-17.0). Median PFS in pts with high-risk cytogenetics, BCMA refractory disease, and EMD was 5.1 (95% CI 2.7-10.1), 1.1 (95% CI 0.7-5.1), and 2.2 (95% CI 1.1-3.8) months, respectively. After adjusting for pt and disease related characteristics on a multivariable analysis, presence of EMD was the only predictor of inferior PFS (HR 1.3, CI 8.8-10.6, p=0.003) and OS (HR 1.6, CI 11.3-13.4, p=0.00).

Conclusion: In this large real-world experience, belamaf demonstrated similar efficacy to the DREAMM-1 population despite pts with heavily pre-treated disease, worse performance status, and cytopenias. The efficacy was suboptimal in pts with BCMA refractory and EMD. Overall, our study indicated a reasonable safety and efficacy of belamaf in patients with triple class RRMM treated in the real-world setting.