ClonoSEQ MRD negativity at day 90 is a strong predictor for progression-free and overall survival after BCMA-directed CAR T-cell therapy for relapsed multiple myeloma.

Abstract Introduction: Next-generation sequencing (NGS)-based minimal residual disease (MRD) assessments are increasingly utilized in multiple myeloma (MM) for their value in predicting progression-free (PFS) and overall survival (OS). The clonoSEQ® Assay (Adaptive Biotechnologies; Seattle, WA) is an FDA-cleared NGS-based MRD (NGS-MRD) assessment. This study evaluates the prognostic impact of NGS-MRD status at day 90 (D90) following standard-of-care (SOC) BCMA CAR T-cell therapy (CAR-T) in patients with MM. Methods: We retrospectively analyzed 171 MM patients treated with SOC BCMA CAR-T, idecabtagene vicleucel (110/171) and ciltacabtagene autoleucel (cilta-cel), at Moffitt Cancer Center from May 2021 to September 2024 who had trackable clonotype and D90 NGS-MRD testing. Differences between groups were analyzed by Chi-square test for nominal variables and t-test for continuous variables. PFS and OS were measured by Kaplan-Meier method following the landmark approach at D90, and significance was assessed using log-rank test. Univariable Cox proportional hazard regression analyses were performed to determine the association of pre-specified variables with PFS and OS. The independent effect on PFS and OS of MRD status against intervening variables was evaluated by multivariable Cox proportional hazard regression analyses. Results: Of 171 patients, 114 (67%) were NGS-MRD negative (<1 in 105 nucleated cells) at D90. Median age was 67 (range 43-88), and 47% were female. Patients were heavily pretreated with median 5 prior lines of therapy (range 3-13). Patients were grouped by MRD status, MRD positive(+) or negative(-).MRD(-) patients were more likely to have received cilta-cel (41% vs 25%, p=0.03), and prior autologous stem cell transplant (74% vs 58%, p=0.04). No other differences were observed in baseline characteristics. Rates of cytokine release syndrome, immune effector cell-associated neurotoxicity (ICANS), non-ICANS neurotoxicity, steroid, tocilizumab or anakinra use, intensive care unit admission, and hospital stay were comparable between groups. At 3 months, MRD(-) had higher overall response rate (98% vs 68%, p<0.0001) and very good partial response or better rate (≥VGPR, 58% vs 40%, p=0.03) with sustained superiority at 1 year (≥VGPR 68% vs 41% p=0.003). Free light chain normalization at D90 was more frequent in MRD(-) (97% vs 74%, p<0.0001). Median PFS was significantly longer in MRD(-) (20 vs 11 months, p=0.0007) as was OS (38 vs 26 months, p=0.005) compared to MRD(+). When stratified by MRD status and response, MRD(-) regardless of response had superior PFS (20 vs 12 vs 6 months, p=0.001) compared to MRD(+) with ≥VGPR or <VGPR respectively. The rate of sustained MRD(-) at 1 year was 57% (16/28). Median PFS favored sustained MRD(-) (33 vs 14 months, p=<0.0001) compared to loss of MRD negativity. Median follow up was 16 months (range, 1-42 months). Univariable analyses showed improved PFS for MRD(-) (Hazard ratio [HR] 0.4, 95% confidence interval [CI] 0.3-0.7, p=0.0003) and cilta-cel (HR 0.5, CI 0.3-0.8, p=0.009). Conversely, high-risk cytogenetics (HR 1.8 CI 1.2-2.9, p=0.009), penta-class refractoriness (HR 1.9, CI 1.2-3.1, p=0.01), and baseline ferritin above upper limit of normal (>ULN) (HR 2.0, CI 1.2-3.1, p=0.006) were associated with inferior PFS. MRD(-) also conferred improved OS (HR 0.4, CI 0.2-0.8, p=0.008), while high-risk cytogenetics (HR 2.1, CI 1.1-4.5, p=0.03) and ferritin >ULN (HR 2.4, CI 1.2-4.7, p=0.02) were associated with worse OS. Multivariable analyses including MRD(-), high-risk cytogenetics, penta-class refractoriness, ferritin >ULN, and cilta-cel showed MRD(-) remained independently associated with superior PFS (HR 0.4, CI 0.2-0.6, p<0.0001) along with ciltacel (HR 0.6, CI 0.3-1.0, p=0.04), while high-risk cytogenetics (HR 2.1, CI 1.3-3.5, p=0.001), penta-class refractoriness (HR 2.1, CI 1.3-3.3, p=0.005), and ferritin >ULN (HR 1.8, 1.1-2.9, p=0.02) were associated with worse PFS. MRD(-) remained associated with improved OS (HR 0.4, CI 0.2-0.8, p=0.009), while high-risk cytogenetics (HR 2.2, CI 1.0-4.6, p=0.04) and ferritin >ULN (HR 2.5, CI 1.2-5.0, p=0.009) were associated with inferior OS. Conclusion: In this large SOC cohort of MM patients, NGS-MRD negativity at D90 post BCMA CAR-T was independently associated with improved PFS and OS. Our data support the use of D90 NGS-based MRD testing as a prognostic tool for survival outcomes and the development of MRD-driven interventions post CAR-T.