Impact of the kinetics of circulating anti-BCMA CAR-T cells and normal lymphocytes on the outcome of MM patients.

Chimeric antigen receptor (CAR)-T-cell therapy has improved response rates in relapsed/refractory multiple myeloma (RRMM), yet long-term disease control remains limited, with only 20% of patients remaining progression-free at 5 years. Therefore, identifying early predictors of treatment success is critical. Here, we used next-generation flow cytometry to analyze T-cell populations in blood at leukapheresis, before infusion, and post-anti-BCMA CAR-T infusion, together with CAR-T-cell kinetics and phenotypes before, during, and after the expansion peak, in 53 RRMM patients. Anti-BCMA CAR-T cells peaked at Day +14 (72%), comprising >65 distinct populations, predominantly central memory (CM) T-helper (Th) 1 and Th1/2 CAR-TCD4+ and CM CAR-TCD8+ cells. Multivariate analyses revealed that higher frequencies of TCD4+ naive and Th22 transitional memory (TM) cells at leukapheresis, together with circulating tumor plasma cells (CTPCs) before infusion, but none of the specific CAR-T-cell populations, were predictors of progression-free survival (PFS). Based on these variables, we built a risk score that together with disease stage (International Staging System-Revised [ISS-R]) independently predicted, before CAR-T-cell infusion, which RRMM patients were most likely to benefit from anti-BCMA CAR-T therapy. These findings suggest that long-term PFS is primarily influenced by the patient's immune landscape and the tumor burden rather than anti-BCMA CAR-T-cell properties.