Effective Treatment of Relapsed/Refractory Multiple Myeloma by Bi-Epitope BCMA-Specific Chimeric Antigen Receptor-Modified T Cells

Abstract

Background: Relapsed and refractory (R/R) multiple myeloma (MM) patients have very poor prognosis. Chimeric antigen receptor-modified T cells (CAR-T) is an emerging approach in treating hematopoietic malignancies. Methods: We conducted the clinical trial of bi-epitope targeting CAR-T against BCMA (LCAR-B38M) in 20 R/R myeloma cases. CAR-T cells were intravenously infused after lymphodepleting chemotherapy. The trial was registered with ClinicalTrials.gov (NCT03090659). Finding: After CAR-T cells infusion, 9 cases experienced a mild cytokine release syndrome (CRS), 10 had severe but manageable toxic reactions and 1 died due to very severe CRS and tumor lysis syndrome. Among the 19 evaluable cases, the objective response rate was 94.7%, with 12 achieving stringent complete response (sCR) and 6 reaching very good partial response (VGPR), while one was non-responder (NR). With a median follow-up of 315 days, 12 patients remained in sCR or VGPR, whereas 4 relapsed after sCR and 2 had progressive disease (PD) after VGPR. CAR-T cells were consistently detectable in 12 cases with stable response but at very low level in half of relapsed and PD patients. Extramedullary lesions constituted a high risk factor for relapse/PD (p=0.004). Two PD cases received CAR-T re-induction. One achieved VGPR while the other was NR. Interpretation: Our study demonstrates a strong anti-MM effect of LCAR-B38M owing to its design of bi-epitopic structure of CAR, while most adverse effects are clinically manageable. CAR-T represents a promising therapy for R/R MM. Funding: This study was funded by the Chinese National Key Basic Research Project 973 (2013CB966800); the National Key Research and Development Program (2016YFC0902800); and the Shanghai Rising-Star Program (17QA1402200). Declaration of Interest: The authors declare no conflict of interest. Ethical Approval: The trial was a Phase 1, open-labeled, multicenter study to evaluate the safety and efficacy of LCAR-B38M CAR-T cells in R/R MM, which was approved by the Institutional Review Boards of three participating hospitals.