Long-term follow-up of BCMA CAR-T cell therapy in patients with relapsed/refractory multiple myeloma

Abstract

Background: B-cell maturation antigen (BCMA)-targeting chimeric antigen receptor (CAR) T-cell immunotherapy has shown promising results in the treatment of relapsed or refractory multiple myeloma (R/RMM). This study presents the updated long-term outcomes from our center.

Methods: Between July 30, 2018, and September 27, 2023, 141 patients with R/RMM who received BCMA CAR-T therapy were enrolled. Patients underwent conditioning chemotherapy with cyclophosphamide and fludarabine, followed by BCMA CAR-T cell infusion at a median dose of 2.36×10⁶ cells/kg. The study evaluated overall response rates, long-term efficacy, safety profiles, and their associations with clinical and disease characteristics.

Results: At a median follow-up of 20.2 months, the safety profile of the therapy was manageable. Grade 3/4 cytokine release syndrome occurred in 36.2% of patients, with no cases of severe neurotoxicity reported. 1-month post-infusion, grade ≥3 anemia persisted in 39.6% of patients, while neutropenia (43.3%) and thrombocytopenia (52.2%) were observed. The objective response rate (ORR) among evaluable patients was 94.8%, with 50.7% achieving a complete response (CR). The 4-year progression-free survival and overall survival rates were 37.4% (95% CI, 29.1% to 48.1%) and 63.2% (95% CI, 54.8% to 72.8%), respectively, with survival curves showing gradual flattening over time. Patients with a history of autologous stem cell transplantation (ASCT) and those with extramedullary disease demonstrated significantly inferior efficacy and survival outcomes. Peak CAR-T cell expansion was positively correlated with ORR (p<0.001) and CR (p<0.001). Notably, patients with prior ASCT exhibited significantly lower CAR-T cell expansion compared with those without prior ASCT (p<0.001). Immunophenotypic analysis of infused CAR-T cells demonstrated impaired fitness in patients who received ASCT in the past year.

Conclusions: BCMA CAR-T therapy in patients with R/RMM results in significant and sustained responses, with a manageable safety profile on a large scale. Prior ASCT and extramedullary disease represent adverse prognostic factors. Patients with a history of ASCT demonstrate limited peak CAR-T cell expansion.

Keywords: Immunotherapy; Multiple Myeloma.

Figure 1. Flowchart depicting the study selection process.

Figure 2. PFS (2A), OS (2B) for all 141 patients, and response rates (2F) for 134 evaluable patients. PFS (2C) and OS (2D) compared between CR and non-CR patients, and CIR among CR patients (2E) in patients with R/RMM receiving BCMA CAR-T therapy. CIR, cumulative incidence of relapse; CR, complete remission; NR, no response; OS, overall survival; PFS, progression-free survival; R/RMM, relapsed/refractory multiple myeloma; VGPR, very good partial response.

Figure 3. Forest plot depicting the results of characteristics in patients with R/RMM receiving BCMA CAR-T therapy associated with CR rate (N=134), CIR among CR patients (N=68) (3A), PFS (N=141) and OS (N=141) (3B). ASCT, autologous stem cell transplantation; CAR-T, chimeric antigen receptor T cell therapy; CD38 Ab exposure, CD38 monoclonal antibodies exposure; chemo exposure, chemotherapy drugs exposure; CIR, cumulative incidence of relapse; CR, complete remission; DS, Durie-Salmon; ISS, International Staging System; PFS, progression-free survival; OS, overall survival; PIs+IMIDs, proteasome inhibitors combined with immunomodulatory agents; R/RMM, relapsed/refractory multiple myeloma.

Figure 4. Distribution of infused CAR-T cells at various time intervals from ASCT to BCMA CAR-T therapy: the overall ASCT group (N=55) versus the non-ASCT group (N=83) (4A, 4B); the group over 1-year post-ASCT (N=43) versus the non-ASCT group (N=83) (4C, 4D); the group within 1 year post-ASCT (N=12) versus the non-ASCT group (N=83) (4E, 4F); the group over 1-year post-ASCT (N=43) versus the group within 1-year post-ASCT (N=12) (4G, 4 F). CAR-T cell subsets were assessed by flow cytometry as follows: naive CAR-T cell (CART_N) as CD62L+CD45RA+, central memory CAR-T cell (CART_CM) as CD62L+CD45RA−, effector memory CAR-T cell (CART_EM) as CD62L−CD45RA− and effector CAR-T cell (CART_EFF) as CD62L− CD45RA+. 3 of the 141 patients lacked infused CAR-T cell phenotype data. ASCT, autologous stem cell transplantation; BCMA, B-cell maturation antigen; CAR-T, chimeric antigen receptor T cells.