Impact of low disease burden on the safety and efficacy of BCMA CAR-T in patients with Relapsed/Refractory multiple myeloma

Abstract Background: Chimeric antigen receptor T-cell (CAR-T) therapies targeting B-cell maturation antigen (BCMA) have demonstrated robust responses in relapsed/refractory multiple myeloma (RRMM). Five-year follow-up data from CARTITUDE-1 revealed a 33% long-term remission rate in patients with RRMM. Lower baseline disease burden (LDB) trended toward association with long-term progression-free survival. However, the efficacy and safety profile of BCMA CAR-T in patients (pts) with LDB in a real-world setting remains uncharacterized. Methods: We retrospectively analyzed all pts with RRMM who received standard of care (SOC) autologous BCMA CAR-T therapy at our institution. Demographic and disease characteristics prior to CAR-T infusion were collected. Key endpoints included minimal residual disease (MRD) negativity, progression-free survival (PFS), and overall survival (OS). Safety outcomes included cytokine release syndrome (CRS), immune effector-cell associated neurotoxicity syndrome (ICANS), transaminitis, late neurotoxicity, immune effector cell associated enterocolitis (IEC-EC), secondary primary malignancy (SPM), neutropenia, and infections (early: <30 days; late: 30–100 days post-CART infusion). Pts were stratified by baseline disease burden at the time of lymphodepletion. LDB was defined as: serum free light chains <100 mg/L, M-protein ≤ 0.5 g/dL, bone marrow plasma cells <10%, and < 2 active extramedullary disease (EMD) sites. Baseline characteristics and outcomes were compared between LDB and non-LDB groups. Categorical variables were analyzed using Fisher's exact or chi-squared tests, and continuous variables were assessed with Wilcoxon rank-sum test. PFS and OS were measured from CART infusion and compared between groups using Kaplan Meier and Cox proportional hazards (cph). Multivariate cph model adjusted for R-ISS stage, prior lines of therapy (LOT), EMD, prior T-cell redirection refractoriness, and triple-class refractoriness based on clinical relevance. Results: We identified 120 pts with MM who received SOC BCMA CAR-T therapy with ciltacabtagene autoleucel (n=99) and idecabtagene vicleucel (n=21). The median age was 66 years, 68 (57%) were male, 65 (54%) had ISS stage ≥ 2, 82 (64%) had high risk cytogenetics, 75 (63%) pts had RISS stage ≥ 2, 21 (20%) had EMD, and 45 (38%) had LDB. Pts had received a median of 4 LOT (range: 1-14), 90 (75%) had prior autologous stem cell transplant, 96 (80%) were triple class refractory, and 13 (11%) were refractory to prior T-cell redirection therapy. With a median follow-up of 17 months, the 18-month PFS and OS were 74% (95% CI: 65%–84%) and 94% (95% CI: 89%–99%), respectively. MRD negativity was achieved in 89% of evaluable pts. When stratified by disease burden, pts with LDB had fewer median LOT compared to those without LDB (4 vs 5, p=0.003) and were less refractory to alkylators (11% vs 29%, p=0.013) and proteasome inhibitors (69% vs 83%, p=0.003). No significant differences were observed in baseline characteristics, including age, gender, ISS staging, R-ISS staging, high-risk cytogenetics, EMD, prior transplant, or refractoriness to other drug classes. With regards to efficacy, the LDB group had a lower risk of progression or death compared to the non-LDB group (HR: 0.39; 95% CI: 0.15–1.00; p=0.05), but no differences in OS were observed. On multivariate analysis, LDB remained independently associated with improved PFS (HR 0.32 (95% CI: 0.12 – 0.88, p=0.03). In terms of safety, the LDB group had significantly lower rates of CRS (71% vs 92%, p=0.005) and transaminitis (24% vs 52%, p=0.006), with no differences in ICANS incidence. While neutropenia rates were similar, the LDB group were less likely to experience a neutropenia reoccurrence following initial neutrophil recovery (51% vs 72%, p=0.03). Infection rates were found to be higher in the non-LDB group (p=0.01), with more early infections (16% vs 11%), late infections (11% vs 5%) and both early and late infections (17% vs 11%). No significant differences were observed in late neurotoxicity, IEC-EC, and SPM. Conclusion: In this retrospective, real-world study, low disease burden was associated with improved PFS and a more favorable safety profile, including lower rates of CRS, transaminitis, neutropenia reoccurrence after initial recovery, and infections. These findings suggest that LDB may serve as an important clinical marker for predicting both enhanced efficacy and reduced toxicity of BCMA CAR-T therapy in patients with RRMM.