Concurrent administration of BCMA and GPRC5D chimeric antigen receptor (CAR) T cells in advanced multiple myeloma.

BCMA and GPRC5D-directed therapies have shown high efficacy in the treatment of relapsed or refractory myeloma with multiple new immune therapies now approved. Preclinical studies have shown that expression of BCMA and GPRC5D are heterogenous in malignant plasma cells. We conducted a phase I dose escalation trial of the BCMA CAR T cell therapy MCARH125 alone or in combination with the GPRC5D CAR T cell therapy MCARH109 in patients with heavily pre-treated relapsed or refractory multiple myeloma. Patients were treated across three dose levels and the primary objective of establishing safety of the concurrent infusion. The trial is registered in ClinTrials.gov, NCT05431608 and has now completed accrual. We treated 15 patients across 3 dose levels; this included 6 patients who received MCARH125 alone and 9 patients treated with concurrent infusion of MCARH125 and MCARH109. 1 patient each with MCARH 125 alone and the co-infusion of MCARH125 and MCARH109 developed immune effector cell associated hemophagocytic syndrome (IEC-HS). There were no instances of grade 3 or higher cytokine release syndrome (CRS) or immune effector cell associated neurologic syndrome (ICANS). The overall response for co-infusion was 78% with a median PFS of 18.2 months. Correlative analysis suggests that antigen loss maybe an important mechanism of resistance even with dual-antigen targeting and we show for the first time that expansion of one CAR population can limit expansion of the second population, as dual-CAR treated patients had significantly less BCMA-CAR expansion than BCMA-CAR alone treated patients, despite equivalent BCMA CAR T cell doses at infusion.