Sustained MRD negativity via multimodal NGS/NGF overcomes high-risk cytogenetics and predicts long-term survival in transplant-eligible multiple myeloma: A real-world cohort study

Abstract Background: Dozens of clinical trials demonstrated that achievement of MRD negativity represents a paradigm shift in MM therapeutics. However, it remains unclear what the guiding significance of MRD detection is in clinical practice, especially sustained MRD negativity (10-6 sensitivity), detected via multimodal highly sensitive methods (NGS and NGF), and there are few studies on the dynamic changes of MRD under standard treatment regimens in clinical practice.Elucidating the real-world prognostic significance of sustained MRD negativity is essential to validate its utility in guiding clinical decisions.This study provides the real-world evidence that sustained dual-platform MRD negativity abrogates the poor prognosis of HRCA MM. Methods: 242 transplant-eligible NDMM patients (2019–2023) received serial MRD assessments via next-generation sequencing (NGS) and next-generation flow cytometry (NGF). MRD was assessed at the following timepoints: post-induction, post-ASCT, post-consolidation, and 6-monthly during maintenance therapy. Sustained MRD negativity required dual NGS/NGF negativity (10-6 sensitivity) across ≥2 consecutive tests ≥1 year apart. Validation in 1,334 samples demonstrated inter-method correlation (Pearson r = 0.86) and 76.2% concordance (κ = 0.64 at 10-5,κ = 0.54 at 10-6). Dual-platform assessment minimized false negativity. Extramedullary disease was assessed by PET-CT, low-dose WBCT, and DWI at timepoints. Results: All patients received PI-based induction followed by ASCT. The median follow-up time from diagnosis was 38 months (range: 7–64 months). During this period, 78 patients (32.2%) experienced PD and 27 patients (11.1%) died. HRCA were present in 153 (65.1%), including 1q21+ (51.9%), del(17p) (10.6%), t(4;14) (23.8%), and t(14;16) (1.7%); 60 (39.2%) had double-hit MM, predominantly characterized by 1q21+ and t(4;14). The median time to MRD negativity was 8.6 months post-diagnosis, with an MRD negativity rate of 59.6%. MRD negativity at any assessment point correlated with better prognosis. Regarding the timing of MRD negativity, 14.8% occurred after induction, 21.5% post-ASCT, 5.1% after consolidation, and 18.2% during maintenance, with 81.2% (33/41) achieving negativity within 1 year of maintenance. For patients achieving MRD negativity post-induction, post-ASCT, and during maintenance, 5-year PFS was 91.7%, 70.2%, and 80.5% respectively (p = 0.023). Correspondingly, sustained MRD negativity rates were 93.3%, 64.7%, and 80.0% in these cohorts. Sustained MRD negativity (45.9% of patients) correlated with superior 3-year PFS: 96.5% vs. 69.8% (transient negativity) vs. 57.0% (persistent positivity; p < 0.001) and 5-year PFS: 93.4% vs. 51.2% vs. 32.2%. Multivariate analysis confirmed sustained MRD negativity as the strongest PFS predictor (HR = 0.16, 95% CI 0.07–0.48; p = 0.001). In HRCA subgroups, sustained MRD negativity conferred superior 3-year PFS: 94.3% vs. 43.2% in persistently positive cases (HR = 0.27, 95% CI 0.18–0.40; p < 0.001). Strikingly, sustained negativity achieved comparable 3-year PFS across genetic risk strata: 100% in standard-risk, 95% in single HRCA, and 93.4% in ≥2 HRCA (p = 0.14 for heterogeneity). For double-hit MM, sustained negativity was associated with 83% 5-year OS vs. 24% in persistently positive cases (p = 0.023). Of patients progressing, 32.7% had preceding MRD conversion. Notably, 92% of conversions occurred within 2 years of first negativity, and conversion after sustained negativity led to faster progression (median 13 vs. 22 months from conversion, p = 0.034). Conclusions: Dual-platform (NGS/NGF) monitoring is mandatory to detect MRD at 10-6 –10-5 levels, where NGF has limited sensitivity. MRD negativity after induction therapy is associated with long-term maintenance of MRD negativity. Notably, in patients with HRCA, sustained MRD negativity correlates with significantly improved prognosis. Critically, loss of sustained MRD negativity predicts accelerated disease progression, mandating close monitoring post-conversion. Sustained MRD negativity confirmed by multimodal NGS/NGF can serve as a surrogate endpoint for functional cure, regardless of baseline risk, supporting its adoption as a primary endpoint in clinical trials and practice.