新型 BCMA 靶向疗法克服多发性骨髓瘤耐药的潜力

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, -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.