BCMA Biology, Mechanisms of Action, and Unmet Needs in Relapsed/Refractory Multiple Myeloma

Al-Ola Abdallah outlined the biological rationale for targeting BCMA, explaining that the antigen is present on approximately 95% of myeloma cells and plays a central role in promoting myeloma cell survival and proliferation through the NF-kappa B pathway, making it a highly specific and compelling therapeutic target with limited off-target toxicity. He reviewed the currently approved BCMA-targeted agents, including two chimeric antigen receptor T-cell (CAR-T) therapies (idecabtagene vicleucel and ciltacabtagene autoleucel), three T-cell engaging bispecific antibodies (teclistamab, elranatamab, and linvoseltamab), and one antibody-drug conjugate (ADC), belantamab mafodotin. Zahra Mahmoudjafari then differentiated the mechanisms of action across the three drug classes, noting that CAR-T therapies work through genetic engineering and carry risks of cytokine release syndrome (CRS) and neurotoxicity, bispecific antibodies engage both BCMA and CD3 to redirect T cells against myeloma cells, and belantamab mafodotin delivers a cytotoxic payload directly to BCMA-expressing cells, which accounts for its distinct ocular toxicity profile and associated Risk Evaluation and Mitigation Strategy (REMS) program. Dr. Abdallah underscored the significant unmet need that existed prior to the availability of BCMA-directed therapies, noting that triple-refractory patients had a median overall survival of only 9 months and penta-refractory patients as few as 5 months, compared with 17 months observed in penta-refractory patients who received BCMA-directed therapy at his institution.

Throughout the conversation, the experts provided a comprehensive reflection on the field and the factors that may shape how clinicians approach care moving forward.

Our next episode, 'Shifting the Paradigm: Evidence, Earlier Use, and Sequencing of BCMA-Targeted Therapies in Relapsed/Refractory Multiple Myeloma,' further explores relapsed/refractory multiple myeloma, highlighting how BCMA-targeted therapies have transformed the treatment paradigm, the evidence supporting their use in earlier lines of therapy, and how earlier introduction of these agents may impact long-term disease control and sequencing strategies.