Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma

Multiple myeloma (MM) bears heterogeneous cells that poses a challenge for single-target immunotherapies. Here we constructed bispecific CS1-BCMA CAR-T cells aiming to augment BCMA targeting with CS1. Sixteen patients with relapsed or refractory (RR) MM received CS1-BCMA CAR-T infusion. Six patients (38%) had cytokine release syndrome, which was of grade 1–2 in 31%. No neurological toxicities were observed. The most common severe adverse events were hematological, including leukopenia (100%), neutropenia (94%), lymphopenia (100%) and thrombocytopenia (31%). Three patients with solitary extramedullary disease (sEMD) did not respond. At a median follow-up of 246 days, 13 patients (81%) had an overall response and attained minimal residual disease-negativity, and six (38%) reached a stringent complete response (sCR). Among the 13 responders, 1-year overall survival and progression-free survival were 72.73% and 56.26%, respectively. Four patients maintained sCR with a median duration of 17 months. Four patients experienced BCMA+ and CS1+ relapse or progression. One patient responded after anti-BCMA CAR-T treatment failure. Lenalidomide maintenance after CAR-T infusion and the resistance mechanism of sEMD were preliminarily explored in three patients. CAR-T cells persisted at a median of 406 days. Soluble BCMA could serve as an ideal biomarker for efficacy monitoring. CS1-BCMA CAR-T cells were clinically active with good safety profiles in patients with RRMM. Clinical trial registration: This study was registered on ClinicalTrials.gov, number NCT04662099.