Challenges facing CAR T-cell immunotherapy in multiple myeloma

Chimeric antigen receptor (CAR) T-cell therapy has demonstrated considerable promise in patients with late-line refractory multiple myeloma (MM), and there has been commercial approval for its use in treating relapsed and/or refractory MM (RR MM). B-cell maturation antigen remains the most extensively studied CAR T-cell target in this disease, although several alternative antigens are also under active investigation. Despite the notable success of CAR T-cell therapy in the treatment of RR MM, challenges remain in improving response rates, extending the durability of remission, and reducing relapse after CAR T-cell therapy. Notably, the presence of high-risk disease features is strongly associated with worse outcomes after CAR T-cell therapy for RR MM. This review explores the underlying mechanisms of CAR T-cell therapy failure and outlines potential salvage strategies. In addition, based on this mechanistic understanding, we discuss emerging technologies and platforms aimed at improving CAR designs, enhancing the quality of cellular products, increasing antitumor activity, and reducing relapse and/or resistance. Moreover, several approaches are being developed to improve the safety of CAR T-cell therapy. Finally, we consider the potential for earlier application of CAR T-cell therapy in high-risk patients and propose strategies to improve clinical outcomes. Ongoing research is expected to expand the therapeutic potential of CAR T-cell therapy, particularly in patients with high-risk RR MM.