[Predictive value of next-generation sequencing-based measurable residual disease quantitative stratification for...

Objective: To evaluate the predictive value of next-generation sequencing (NGS) -based quantitative minimal residual disease (MRD) stratification for early disease progression in patients newly diagnosed with multiple myeloma (NDMM) after induction therapy. Methods: This retrospective cohort study analyzed the clinical data of 408 patients with NDMM admitted to the Department of Hematology, the First Affiliated Hospital of Soochow University between 2019 and 2024, who received the bortezomib + lenalidomide + dexamethasone (VRD) regimen induction therapy combined with autologous hematopoietic stem cell transplantation (auto-HSCT). Bone marrow samples were collected after 4 cycles of induction therapy and before auto-HSCT, and MRD was detected by NGS technology with a sensitivity of 10-6. Patients were divided into the ultra-deep negative group (<10(-6)), low-load positive group (≥10(-6) and ≤10(-3)), and high-load residual group (>10(-3)) according to MRD burden, and the clinical characteristics and prognosis of each group were compared. Results: After cycles of VRD induction therapy, the overall response rate was 96.8% (395/408), and 197 patients (48.3%) achieved complete remission or better. The positive rates of del (17p) were 4.4%, 15.5%, and 10.8%, respectively (P=0.030) and the positive rates of t (4;14) were 13.3%, 19.0%, and 28.4% (P=0.021) in the ultra-deep negative group (90 patients), low-load positive group (142 patients), and high-load residual group (176 patients), respectively, with the highest rate observed in the high-load residual group. The risk of disease progression in the ultra-deep negative group was reduced by 86% compared with the high-load residual group (HR=0.14, 95%CI: 0.08 - 0.26, P<0.001). The 24-month cumulative incidence of progression (CIF) in the ultra-deep negative group, low-load positive group, and high-load residual group was 1.2% (95% CI: 0.1% - 5.9%), 8.3% (95% CI: 4.4% - 13.9%), and 23.2% (95% CI: 17.2% - 29.7%), respectively. Using the high-load residual group as reference, the risk of disease progression was significantly reduced in both the ultra-deep negative group (sHR = 0.15, 95% CI: 0.08 - 0.31) and the low-load positive group (sHR=0.33, 95% CI: 0.22 - 0.50) (both P<0.001). The risk of disease progression in the ultra-deep negative group was also significantly lower than that in the low-load positive group (sHR=0.48, 95% CI: 0.24 - 0.94, P=0.032). Multivariate analysis revealed that the MRD level was an independent prognostic factor, and the risk of disease progression in the high-load residual group was significantly higher than that in the ultra-deep negative group (sHR=6.65, 95% CI: 3.58 - 12.33, P<0.001) . Conclusion: NGS-based quantitative MRD stratification has independent predictive value for early disease progression in patients with NDMM after induction therapy.