Risk score and survival outcomes for multiple myeloma patients with disease refractory to BCMA CAR-T.

Abstract

Abstract Introduction: Chimeric antigen receptor T-cell (CAR-T) therapy targeting B-cell maturation antigen (BCMA) has revolutionized the treatment of relapsed and refractory multiple myeloma (MM). Although BCMA CAR-T is associated with high response rates (70-90%), a subset of patients do not respond and/or have short remissions (<6 months). The survival outcomes for MM patients with disease refractory to BCMA CAR-T is unknown, but previous studies have shown primary refractory disease to frontline triplet or quadruplet therapy is associated with inferior survival (Majithia Leukemia 2016; Charalampous Blood Advances 2023). This prompted us to identify the baseline risk factors and survival outcomes for MM patients with disease refractory to BCMA CAR-T. Methods: We identified consecutive MM patients treated with BCMA CAR-T at our institution from 2017-2024. Patients were considered to have refractory disease if progressive disease occurred within 6 months of BCMA CAR-T. All of the non-refractory patients had at least 6 months of follow-up. High-risk MM (HRMM) was defined according to the recently revised criteria (Avet-Loiseau JCO 2025). Treatment outcomes to BCMA CAR-T were analyzed according to the International Myeloma Working Group. Logistic regression models were fit to identify at baseline the predictors associated with primary refractory disease to BCMA CAR-T. Overall survival (OS) was calculated from both the time of BCMA CAR-T infusion and time of relapse after BCMA CAR-T among refractory patients. The Kaplan-Meier method was used to calculate time-to-event outcomes, and comparisons were made using the log-rank test. Results: A total of 158 patients were treated with BCMA CAR-T (ide-cel: n=77, cilta-cel: n=46, investigational: n=35). After a median follow-up of 25 months (95% CI 23-30), the median PFS and OS for all patients were 15 months (95% CI 11-18) and 42 months (95% CI 32-NR), respectively. Forty-two patients (27%) had refractory disease to BCMA CAR-T. On multivariate analysis, baseline revised HRMM (OR 2.98, 95% CI 1.37-6.73; p=0.007) and LDH >210 U/L (OR 3.72, 95% CI 1.72-8.31; p=0.001) were independently associated with higher odds of having refractory disease. We then constructed a risk score to estimate the likelihood of refractory disease prior to BCMA CAR-T infusion. Patients with 0, 1, and 2 adverse risk factors (i.e., HRMM, high LDH) had a risk of refractory disease of 5%, 33%, and 48%, respectively (p<0.0001). By univariate analysis, refractory disease was associated with significantly shorter OS following BCMA CAR-T (HR 7.82, 95% CI 4.72-12.9; p<0.0001). Patients with refractory disease had significantly shorter median OS (8.5 months vs not reached [NR]) and estimated 12-month OS (35% vs 94%). After adjusting for baseline characteristics (i.e., LDH, EMD, BCMA CAR-T drug product), refractory disease remained independently associated with shorter OS on multivariate analysis (HR 5.87, 95% CI 3.43-10.03; p<0.0001). Among patients with refractory disease (n=42), 29 patients (69%) received salvage therapy after BCMA CAR-T relapse. The overall response rate and median PFS to the first salvage therapy was 52% and 2.3 months (95% CI 1.7-4.7), respectively. Thirty-four patients (81%) with refractory disease have died after BCMA CAR-T relapse. The median OS from BCMA CAR-T relapse was 5 months (95% CI 2-10 months), and the estimated 12-month OS was 25%. Patients with revised HRMM had significantly shorter median PFS (1.7 vs 5.9 months; p=0.02) and OS (4 vs 13 months; p=0.03) after BCMA CAR-T relapse. Conclusion: Approximately one-quarter of MM patients have disease refractory to BCMA CAR-T. We developed a risk score to predict at baseline the MM patients who will have early relapse (<6 months) following BCMA CAR-T. Patients with refractory disease to BCMA CAR-T have a poor prognosis, and clinical trials targeting this new unmet need in MM are needed.