Systematic review of BCMA-targeted therapies in relapsed/refractory (R/R) multiple myeloma (MM).

Abstract

e19528 Background: MM patients still face unmet medical needs, especially in the R/R setting. Recent breakthroughs in B cell maturation antigen (BCMA)-targeted therapies have led to a new era of treatment options, including CAR T-cell therapies and antibody-drug conjugates (ADCs). Here, we explore existing and emerging strategies that may reshape MM treatment. Methods: A comprehensive search was conducted in LARVOL CLIN – a database with 100K+ trials, 95K+ Kaplan Meier (KM) curves, and 15K+ Hazard ratios (HR)- to identify p3 trials evaluating BCMA-targeting agents in R/R MM. A meta-analysis was done using digitized KM data and HRs extracted from forest plots. Results: Five trials had mature survival data on BCMA-targeting therapies for MM (Table 1). KarMMA-3 and CARTITUDE-4 use CAR-T cell therapies idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel). CARTITUDE-4 showed significant PFS and OS benefits. DREAMM-3, DREAMM-7, and DREAMM-8 examine the ADC belantamab mafodotin (maf), as monotherapy or with dexamethasone (d) and bortezomib (V) or pomalidomide (P). DREAMM-8 is recruiting, and interim data is provided. DREAMM-7 and DREAMM-8 PFS primary endpoint was met, with DREAMM-7 also having OS benefits. ORR across all trials is higher compared to standard-of-care (SoC). Despite their effectiveness, BCMA-targeted therapies had a distinct toxicity profile: CAR-T is associated with immune-related neurotoxicity and cytokine release syndrome, while balantamab maf is linked to ocular toxicity. Conclusions: Innovative therapies such as CAR-T and ADCs outperform standard regimens, supporting the evolving landscape of R/R MM treatment. CAR-T cell therapies cilta-cel and ide-cell were approved for 2L+ and 3L+ MM, respectively, based on CARTITUDE-4 and KarMMa-3 trials. Meanwhile, the ADC belantamab maf conditional approval was withdrawn following DREAMM-3 failure to meet its primary endpoint, and it remains under evaluation. Interim results from DREAMM-7 and DREAMM-8 highlight the potential of ADC combined treatment with significant PFS benefits and favorable OS trends in R/R settings. Despite the reported adverse events, these therapies show a favorable risk-safety profile compared to current treatments. Trials outcomes summary. KarMMa-3 CARTITUDE-4 DREAMM-3 DREAMM-7 DREAMM-8 N=381 N=419 N=325 N=494 N=357 Intervention Ide-cel Cilta-cel Belantamab maf Belantamab maf + Vd Belantamab maf + Pd N=254 N=208 N=218 N=243 N=155 Control SoC SOC Pd Daratumumab + Vd PVd N=132 N=211 N=107 N=251 N=147 OS HR 0.74 0.55* 0.93 0.57* 0.77 mOS, months 41.4 vs 24.9 NR vs NR 24.1 vs 22.9 NR vs NR NR vs NR PFS HR 0.79 0.29* 0.86 0.4* 0.52* mPFS, months 23.5 vs 16.7 NR vs 11.79 11.1 vs 7.1 36.6 vs 13.4 NR vs 12.7 ORR% 71.3 vs 42.4 84.6 vs 67.3 41 vs 36 82.7 vs 71.3 77 vs 72 sCR% 35 vs 5 69 vs 18.5 14 vs 5 9 vs 3 MRD% 20 vs 1 62 vs 18 25 vs 10 24 vs 5 AE Gr3+ 93 vs 77 97 vs 94 78 vs 74 95 vs 78 91 vs 73 *Statistically significant; NR: not reached.