Resistance to BCMA-Directed CAR T-Cell Therapy in Multiple Myeloma: Biology, Clinical Patterns, and Strategies to Overcome Treatment Failure.

B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy has revolutionized treatment for heavily pretreated multiple myeloma, achieving unprecedented response rates in patients with otherwise dismal outcomes. However, the vast majority of patients eventually relapse due to complex resistance mechanisms. These include antigen-dependent escape-such as loss of the BCMA target through genetic deletion, epitope-level mutation, or antigen downregulation via shedding and trogocytosis-as well as antigen-independent tumor adaptations like clonal evolution and lineage plasticity that allow myeloma cells to evade immune clearance despite retaining BCMA. In addition, intrinsic CAR T-cell dysfunction (poor expansion, early exhaustion, and limited persistence) and an immunosuppressive bone marrow microenvironment (enriched in regulatory T cells, myeloid-derived suppressor cells, inhibitory cytokines, and physical sanctuary sites) critically limit long-term efficacy. We propose an integrated framework linking resistance biology to clinical relapse patterns. Finally, we review emerging strategies to overcome resistance, including dual-targeted CAR T-cell designs, enhanced CAR T engineering for improved fitness and persistence, combination approaches to boost antigen density, and novel salvage therapies targeting alternative antigens. These advancements lay the groundwork for more durable remissions and personalized immunotherapeutic interventions in multiple myeloma.