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

"the raw data were uploaded to sra database and the accession id was prjna1023033."

"Competing interests WX is employed in Wuhan Sian Medical Technology Co., Ltd, and the other authors declare no competing interests."

"Funding This work was supported by grants from the National Natural Science Foundation of China (No.82330005 to HM, No.82070124 to HM, No. 82200145 to QW), the Natural Science Foundation of Hubei Province (No.2020CFA065 to HM) and the Fundamental Research Support Program of Huazhong University of Science and Technology (No.5003530166 to HM)."

"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."