Bispecific BAFF-R/BCMA CAR T cells control growth of heterogeneous plasma cells in multiple myeloma

Multiple myeloma treatment has experienced tremendous advances through chimeric antigen receptor (CAR) therapies directed to the B cell maturation antigen (BCMA), but remissions are usually transient. To mitigate the risk of BCMA immune escape, we aimed for a simultaneous targeting of BCMA together with the B cell-activating factor receptor (BAFF-R). Single-cell RNA sequencing discovered increased BAFF-R gene (TNFRSF13C) expression in relapsed and refractory multiple myeloma cases, and it emerged as prognostic marker for long-term complete responses. BAFF-R was expressed in plasma cells at earlier maturation stages compared with BCMA-positive plasma cell phenotypes. Bispecific BAFF-R/BCMA CARs endowed T cells with cytolytic efficacy against multiple myeloma cell lines and primary multiple myeloma cells. In vivo, the dual CAR compensated for BCMA downregulation when BAFF-R was expressed, preventing the evolution of antigen escape mutants that drive resistance to CAR T cell therapy. Our study proposes BAFF-R as a complementary target antigen suitable to eliminate malignant plasma cells with less advanced differentiation, lack of BCMA, and occurrence in dismal prognosis patients.