BCMA ‐Targeted Immunotherapy in Early Relapsed/Refractory Multiple Myeloma: Mechanisms, Clinical Evidence, and Practical Management

BACKGROUND: B-cell maturation antigen (BCMA), a plasma cell-restricted member of the tumor necrosis factor receptor superfamily, has emerged as the premier immunotherapeutic target in Multiple Myeloma (MM). METHODS: We performed a comprehensive, comparative review of pivotal Phase II and III clinical trials of BCMA-directed therapies, including the antibody-drug conjugate (ADC) belantamab mafodotin (belamaf), bispecific antibodies (BsAbs), and BCMA-directed chimeric antigen receptor T-cell (CAR-T) products, with explicit attention to balanced, platform-by-platform comparison of efficacy, durability, toxicity, and sequencing evidence rather than emphasis on a single agent. RESULTS: BCMA-directed therapies deliver unprecedented benefit in early relapse settings. DREAMM-7 established belamaf plus bortezomib-dexamethasone (BVd) as a new reference point, and DREAMM-8 showed benefit for belamaf plus pomalidomide-dexamethasone (BPd), although both regimens achieved comparatively modest MRD-negativity rates (24.7% and pending, respectively) relative to CAR-T and emerging BsAb combinations, and depth of response requires further maturation. MajesTEC-3 showed teclistamab plus daratumumab achieved a 36-month PFS rate of 83.4%, compared with 29.7% for daratumumab-based triplets. CARTITUDE-4 showed ciltacabtagene autoleucel produced a median PFS not reached, compared with 11.8 months with standard of care in lenalidomide-refractory patients with 1-3 prior lines, with MRD-negativity of 60.6%. Sequencing data indicate an asymmetric effect: CAR-T efficacy is substantially compromised by prior BCMA-directed BsAb exposure, whereas BsAbs largely retain meaningful activity after prior BCMA-directed CAR-T. CONCLUSIONS: BCMA-directed therapies are rapidly redefining early R/R MM treatment. Optimal sequencing, management of class-specific toxicities-including immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS), enterocolitis (IEC-EC), and hematotoxicity (ICAHT), in addition to CRS and ICANS-and inclusion in current guidelines require hematologists to develop competency across ADC, BsAb, and CAR-T platforms. Future directions include advancing BCMA therapies into frontline settings, next-generation and in vivo/allogeneic CAR-T approaches, and exploring novel combination strategies.