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

ABSTRACT 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.