Efficacy and Safety of CAR-T Therapy with Safety Switch Targeting Bcma for Patients with Relapsed/Refractory Multiple Myeloma in a Phase 1 Clinical Study

Background: Encouraging results are seen from several early phase clinical trials on the cellular immunotherapy based on chimeric antigen receptor (CAR)-engineered T (CAR-T) targeting B cell maturation antigen (BCMA) for the treatment of relapsed/refractory (RR) multiple myeloma (MM). We developed an anti-BCMA CAR-T cell product manufactured via gamma-retrovirus-mediated transduction of activated T cells to express a second-generation CAR with the 4-1BB costimulatory domain along with a truncated epidermal growth factor receptor (tEGFR) as a safety switch. The preclinical study confirmed its high reactivity against MM cells.

Methods: A phase 1 clinical trial (NCT03093168) has been launched to evaluate the safety and feasibility of this BCMA CAR-T cell product for treating RRMM. The enrolled RRMM patients had received at least 2 prior treatment regimens, including a proteasome inhibitor and an immunomodulatory agent, or are double-refractory, and have over 5% BCMA expression on plasma cells (Nine patient with extramedullary plasmacytoma does not express BCMA). Patients were subjected to a lymphodepleting regimen with Cy (300 mg/m², d-5 to d-3) and Flu daily for 3 days (25 mg/m², d-5 to d-3) prior to the CAR-T infusion (d0) at a dose of 9×10⁶CAR⁺ cells/kg. The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma, and the toxicity is graded by CTCAE 4.03.

Results: As of March 1th, 2019, 46 patients had been infused with this intended dose of the autologous BCMA CAR-T cells, and 44 patients had reached at least 1 month of follow-up. As of this data cut-off, the overall response rate (ORR) for the 44 evaluable patients was 79.6%, including 2sCRs, 16CRs, 8VGPRs and 8PRs, and 16 patients reached MRD-negative response. The CAR-T cell expansion and persistence were consistently observed throughout these patients. The medianPFS is 15mon, and the median OS result has not been reached (49.16% progression-free survival, and 53.95% overall survival at 24 months). Among the 44 infused patients, 22.7% had grade 1-2 Cytokine release syndrome (CRS ) and 6.8% (3 patients) had grade 3 CRS. No grade 4 CRS reactions developed and all toxicities were fully reversible.

Conclusions: Our result demonstrates the high potential of this single CAR-T infusion therapy for RRMM, including 2sCRs, 16CRs and ongoing clinical responses for more than 26 months, with manageable CRS to date. These initial data provide strong evidence to support the further development of this anti-myeloma cellular immunotherapy.