Research progress of targeted BCMA CAR-T therapy for relapsed/refractory multiple myeloma antigen-negative relapse

Chimeric antigen receptor T cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has emerged as a novel and effective modality for the treatment of relapsed or refractory multiple myeloma (RRMM), achieving remarkable therapeutic outcomes. However, relapse remains a major problem impeding the long-term efficacy of this therapy, with antigen-negative relapse being a particularly challenging issue. The mechanisms underlying BCMA antigen-negative relapse encompass a spectrum of phenomena, including diminished or lost tumor antigen expression, BCMA shedding, impaired antigen presentation, trogocytosis, antigen mutations, and alternative splicing. To overcome the problem of antigen-negative relapse in BCMA CAR-T therapy, a variety of strategies are being explored. These include dual/multi-specific CAR-T cell therapy, combination therapies with antibody-drug conjugates (ADCs) or bispecific T-cell engagers (BiTEs), integration with hematopoietic stem cell transplantation (HSCT), identification of novel targets, and the development of innovative cell therapies such as CAR-NK and CAR-M (CAR-Macrophage). Additionally, the optimization of CAR-T cells through gene editing technologies to enhance their durability and anti-tumor activity is a burgeoning area of research. In future, targeted BCMA CAR-T therapy is poised to place greater emphasis on individualization and precision medicine, combining multiple therapeutic approaches to reduce the incidence of relapse, thereby improving treatment efficacy and longevity.