Determinants of Efficacy and Optimization of Chimeric Antigen Receptor T-Cell Therapy for Treating Multiple Myeloma:...

Chimeric antigen receptor (CAR) T-cell therapy has transformed the treatment of relapsed and refractory multiple myeloma (MM), with BCMA-directed products demonstrating unprecedented response rates in heavily pretreated patients. Despite these advances, variabilities in response durability, treatment-related toxicities, and the emergence of resistance underscore the need for strategies that extend beyond CAR construct design alone. Accumulating evidence has indicated that the therapeutic outcomes of this approach are determined by a complex interplay between tumor burden, antigen dynamics, CAR T-cell functional fitness, and host immune context at the time of infusion. Effector-to-target balance and antigen load, in particular, have emerged as modifiable biological determinants of efficacy and safety, with pre-infusion disease control and response to bridging therapy exerting a profound influence on post-infusion CAR T-cell expansion, persistence, and clinical outcomes. Soluble BCMA (sBCMA) has also gained increasing attention as a practical biomarker that integrates tumor burden and antigen dynamics to facilitate the biologically informed optimization of treatment timing and patient selection. In addition to tumor- and antigen-related factors, the intrinsic properties of CAR T-cell products-including the spatial organization and clustering of CAR molecules on the T-cell surface-represent an additional layer of biological determinants that correlate with treatment responses. The quantitative functional assessment of CAR T-cell products may complement conventional clinical and tumor-based biomarkers and improve the prediction of therapeutic potency prior to infusion. This review summarizes recent advances in CAR T-cell therapy for treating MM, focusing on key mechanisms of resistance, the optimization of pre-infusion disease control, the integration of biological markers into clinical decision-making, and emerging combinations and sequential strategies. We also propose a design-oriented and patient-centered framework that integrates CAR engineering with disease biology and host immune factors to enhance the consistency, durability, and safety of CAR T-cell therapy. Such biologically guided optimization strategies will likely prove critical for fully realizing the transformative potential of CAR T-cell therapy across the evolving treatment continuum of MM.