Previous HDM/ASCT Adversely Impacts PFS with BCMA-Directed CAR T-Cell Therapy in Multiple Myeloma
Authors: Gustine Joshua , Cirstea Diana , Branagan Andrew R. , Yee Andrew J. , Maus Marcela , Frigault Matthew J. , Raje Noopur 
Published: December 2024

Background: Chimeric antigen receptor (CAR) T-cell therapy targeting B-cell maturation antigen (BCMA) is highly effective in patients with multiple myeloma (MM). The clinical activity of autologous CAR-T is impacted by the functional capacity of the patient's endogenous T-cells. MM patients commonly have received high-dose melphalan and autologous stem cell transplantation (HDM/ASCT) before BCMA-directed CAR-T, but HDM/ASCT can confer an exhausted and senescent T-cell phenotype (Chung Cancer Immunol Res 2016; Lucas Biol Blood Marrow Transplant 2020; Minnie Blood 2018). Whether a previous HDM/ASCT impacts clinical outcomes to BCMA-directed CAR-T in MM is unknown.

Methods: We identified consecutive MM patients treated with a BCMA-directed CAR-T at our institution from 2017-2023. Treatment responses and progression-free survival (PFS) were assessed per the International Myeloma Working Group. Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity (ICANS) were graded according to the American Society for Transplantation and Cellular Therapy guidelines. Time-to-event outcomes were estimated using the Kaplan-Meier method, and comparisons between groups were made using the log-rank test. The Cox-proportional hazard regression method was used to fit univariate and multivariate models; the outcome measure was hazard ratio (HR) with a 95% confidence interval (CI). Calculations were made using R software (R Foundation for Statistical Computing, Vienna, Austria).

Results: A total of 104 patients were included, of whom 54 (52%) had received HDM/ASCT before CAR-T. The median time from HDM/ASCT to CAR-T infusion was 5.2 years (range, 0.7-13.2). Patients who had received a previous HDM/ASCT were significantly younger at the time of CAR-T (64 vs. 69 years; p=0.005), and had a trend for a longer time between MM diagnosis and CAR-T (6.5 vs. 5.4 years; p=0.06). There was no difference in the number of prior lines of treatment before CAR-T (p=0.80). A previous HDM/SCT was not associated with the best categorial response attainment, including complete responses (p=0.42). However, patients who had received a previous HDM/ASCT had a significantly shorter median PFS with CAR-T (9.5 vs. 21 months; p=0.01). On multivariate analysis, a previous HDM/ASCT was independently associated with a significantly shorter PFS with CAR-T (HR 2.17, 95% CI 1.25-3.74; p=0.006) after adjusting for extramedullary disease, high-risk cytogenetics, R-ISS stage, LDH, and ferritin level. In a separate multivariate analysis, a previous HDM/ASCT remained associated with shorter PFS with CAR-T (HR 1.85, 95% CI 1.08-3.19; p=0.03) after adjusting for all types of previous treatment (i.e., bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab). The time between HDM/ASCT and CAR-T did not appear to be associated with PFS. Patients who received HDM/ASCT &lt;5 and &gt;5 years before CAR-T had a similar median PFS (9.5 vs 9.2 months, respectively). A previous HDM/ASCT was also not associated with OS (p=0.13) or the incidence of CRS (p=0.20) and ICANS (p=0.99) after CAR-T.

Conclusion: Patients with MM who had received a previous HDM/ASCT had significantly shorter PFS with BCMA-directed CAR-T. These findings may have implications for treatment sequencing in MM.