Introduction: B-cell maturation antigen is an important therapeutic target in multiple myeloma. Several chimeric antigen receptor T-cell (CAR-T) products, bispecific T-cell engagers, and antibody – drug conjugates targeting BCMA are approved for relapsed/refractory disease.Areas Covered: This review summarizes the current landscape of BCMA-directed therapies, outlines mechanisms of resistance, and discusses strategies to overcome resistance.Expert Opinion: Resistance to BCMA-directed therapies is multifactorial and varies by modality. Antigen-related escape, including TNFRSF17 biallelic loss, non-truncating mutations in the BCMA extracellular domain, γ-secretase – mediated shedding, and transcriptional downregulation, is the dominant mechanism after prolonged exposure to bispecifics. T-cell – intrinsic dysfunction, characterized by exhaustion, trogocytosis, and impaired fitness, is a key driver of relapse after CAR-T therapy. Tumor-intrinsic genomic complexity and plasma cell identity escape, a recently described state of highly proliferative, lineage-divergent plasma cells with downregulation of BCMA, predict primary refractoriness across modalities. Development of multi-antigen targeting approaches and combination therapies is a promising strategy to improve outcomes.
Singh et al. (Sat,) studied this question.