Concurrent administration of BCMA and GPRC5D CAR T cells for advanced multiple myeloma

B-cell maturation antigen (BCMA)- and G protein-coupled receptor class C group 5 member D (GPRC5D)-directed therapies have shown high efficacy in the treatment of relapsed or refractory multiple myeloma, with multiple new immune therapies now approved. Preclinical studies have shown that the expression of BCMA and GPRC5D is heterogeneous in malignant plasma cells. We conducted a phase 1 dose-escalation trial of the BCMA chimeric antigen receptor (CAR) T-cell therapy MCARH125 alone or in combination with the GPRC5D CAR T-cell therapy MCARH109 in patients with relapsed or refractory multiple myeloma. Patients were treated across 3 dose levels, with the primary objective of establishing the safety of concurrent infusion. We treated 15 patients across 3 dose levels, including 6 patients who received MCARH125 alone and 9 patients treated with the concurrent infusion of MCARH125 and MCARH109. One patient each with MCARH 125 alone and the coinfusion of MCARH125 and MCARH109 developed immune effector cell-associated hemophagocytic syndrome. There were no instances of grade ≥3 cytokine release syndrome or immune effector cell-associated neurologic syndrome. The overall response for coinfusion was 78%, with a median progression-free survival of 18.2 months. Correlative analysis suggests that antigen loss may be an important mechanism of resistance even with dual-antigen targeting, and we show, to our knowledge for the first time that expansion of 1 CAR population may limit expansion of the second population because patients treated with dual CARs had significantly less BCMA CAR expansion compared with patients treated with BCMA CAR alone, despite equivalent BCMA CAR T-cell doses at infusion. This trial was registered at www.clinicaltrials.gov as NCT05431608.