Phase I Study of a BCMA-Directed CAR-T Cell Therapy for Relapsed/Refractory Multiple Myeloma Manufactured in <3 Days Using the High-Performance Platform

Background: Although Chimeric antigen receptor (CAR)-T cell therapy has achieved effective efficacy in patients with multiple myeloma (MM), the lack of durable response and high cost are still main directions of improvement of CAR-T cell therapy. The traditional process of autologous CAR-T cells needs to be expanded and cultured in vitro for a long time (9-14 days). Here, we developed an efficient BCMA-targeting CAR-T cell production process called High-Performance platform, which can be produced within 3 days. And the clinical safety and efficacy of the product in the treatment of relapsed/refractory MM (RRMM) were evaluated in a Phase I clinical trials.

Methods: A phase 1 clinical trial (NCT04537442) has been launched to evaluate the safety and efficacy of this BCMA CAR-T cell product for the treatment of relapsed/refractory MM. The CAR-T cell products were produced with traditional or High-Performance processes. The enrolled RRMM patients had received at least 2 prior treatment regimens, and one of the patients had CNS invasion and presented rapid extramedullary disease (EMD) progression into multiple organs. Patients were subjected to a lymphodepleting regimen with Cy (250 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). The efficacy was assessed by the International Uniform Response Criteria for Multiple Myeloma, and the toxicity is graded by CTCAE 5.0.

Results: As of July 22, 2022, 16 patients had been infused with the autologous BCMA CAR-T cells, and 16 patients had reached at least 1 month of follow-up. 9 patients had enrolled in the traditional group at a dose of 1×10⁶ CAR+ cells/kg. Among the 9 infused patients, treatment-related grade ≥3 AEs included thrombocytopenia (n=4, 44%), neutropenia (n=6, 67%), leukopenia (n=9, 100%), lymphopenia (n=5, 56%), neutropenia (n=6, 67%), anemia (n=2, 22%), and creatinine increased (n=1, 11%). 2 patients (22%) did not occur Cytokine release syndrome (CRS) and 7 patients (78%) had grade 1-2 CRS. No grade 3-4 CRS reactions developed and no ICANS occurred. Meanwhile, all toxicities were fully reversible. As of this data cut-off, the overall response rate (ORR) for the 9 evaluable patients was 100%, including 1sCRs, 3CRs, 4VGPRs and 1PR. 7 patients had enrolled in the High-Performance processes group (HP group) at a dose of 2×10⁷ CAR+ cells. Treatment-related grade ≥3 AEs included thrombocytopenia (n=5, 71%), neutropenia (n=5, 71%), leukopenia (n=7, 100%), lymphopenia (n=6, 86%), neutropenia (n=5, 71%), anemia (n=3, 43%), ALT increased (n=1, 14%) and AST increased (n=2, 29%). All patients (n=7, 100%) had grade 1-2 CRS. No ICANS developed. All toxicities were fully reversible. Among the 7 patients who had reached at least 1 month of follow-up, the overall response rate (ORR) was 100%, including 3sCRs, 1VGPRs and 3PR.

Expansion of CD3+/CAR+ T-cells in blood was analyzed at Day4, Day7, Day10, Day14, Day21, Day28 postinfusion by flow cytometry. The CAR-T expansion was much higher in HP group. Cmax was ≈5.8-times higher for HP group (C_max=2970.0×10⁶/L) compared with traditional group (C_max=509.2×10⁶/L). AUC_0-28d was ≈5.2-times higher for HP group (AUC_0-28d=28540×10⁶/L) compared with traditional group (AUC_0-28d=5482×10⁶/L). The robust CAR-T cell expansion induced to a better efficacy in HP group, which had 3 patients achieved sCR. The data showed that patients in the HP group had a higher probability of converting to sCR 3 months after CAR-T infusion.

Conclusions: Initial data from this Phase I study demonstrate that low doses of BCMA CAR-T cells manufactured by High-Performance production processes have encouraging clinical activity and a manageable safety profile in patients with RRMM. HP CAR-T cells expand rapidly in vivo, persist at relatively high levels for prolonged periods, and demonstrate better efficacy.

No relevant conflicts of interest to declare.