Daratumumab, bortezomib, lenalidomide and dexamethasone, upfront autologous transplant and lenalidomide maintenance for newly diagnosed multiple myeloma

Abstract Background: The quadruplet induction regimen of daratumumab, bortezomib, lenalidomide (Len), and dexamethasone (DVRD) has shown deeper responses and improved survival compared to triplet induction (VRD) in prospective clinical trials for transplant-eligible newly-diagnosed multiple myeloma (MM). DVRD induction followed by autologous hematopoietic cell transplantation (autoHCT) and Len maintenance has become the standard of care for transplant-eligible, newly diagnosed MM patients. Real world data for this approach is still scarce. Methods: We performed a retrospective, single-center analysis on newly-diagnosed MM patients, who received DVRD induction, autoHCT, and Len maintenance between January 2021 and August 2024. High-risk cytogenetic abnormalities (HRCA) were defined as del17p, t(4;14), t(14;16), 1q21 gain or amplification by fluorescence in situ hybridization. We also identified high-risk patients using the 2025 International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) risk classification (Avet-Loiseau et al. JCO 2025). Primary outcome was progression-free survival (PFS). Minimal residual disease (MRD) status was determined in bone marrow samples using an 8-color next generation flow (NGF) assay with a sensitivity of 1/10⁵ cells (0.001%) on 2 million events. Results: Seventy-one patients were included in the analysis. The median age at autoHCT was 61.5 years (range 40-77), 35% (n=25) were female and 16% identified as Black (n=11). Thirty-one percent of patients had Hematopoietic Cell Transplantation-specific Comorbidity Index (HCT-CI) of >3 (n=22), 22% (n=16) had HRCA, and 15% (n=10) had stage III Revised International Staging System (R-ISS) disease. 38% had high-risk disease by 2025 IMS/IMWG criteria. Patients received a median of 4 DVRD induction cycles (range 2-11). The maximum Len dose during induction was ≥20mg in 82%. Prior to transplant, 21% (n=15) of patients achieved complete response (CR) and 79% (n=57) achieved ≥very good partial response (VGPR); 49% had MRD negative status. At day 100 post-transplant, 44% (n=32) achieved CR and 94% (n=68) achieved ≥VGPR. At best post-transplant response, 72% (n=52) achieved CR and 98% (n=70) ≥VGPR, while 71% had MRD negative status. Median times to neutrophil (ANC>500) and platelet (>20K) engraftment were 12 (range, 12-14) and 13 (range, 9-19) days, respectively. With a median follow up of 22.1 months (range 3.9-47.4), the 1- and 2-year PFS rates for the entire cohort were 94% and 88%, respectively. In univariate analysis, there was a trend towards inferior PFS in patients with R-ISS stage III (hazard ratio (HR), 4.19; 95% confidence interval (CI), 0.82-21.48; p=0.09) and those with high-risk disease by the 2025 IMS/IMWG criteria (HR, 3.17; 95% CI, 0.82-12.34; p=0.10). For patients with high-risk disease per 2025 IMS/IMWG criteria the 1-year and 2-year PFS rates were 83% and 77%, respectively. Only two patients died during the follow up, therefore overall survival analysis was not performed. Conclusion: In this single-center analysis of MM patients who received DVRD induction, autoHCT and Len maintenance, we showed CR and MRDnegativity rates of 72% and 71%, respectively, and 2-year PFS of 88%. Patients with high-risk disease by the new IMS/IMWG criteria had a worse 2-year PFS of 77%, and these patients may need an alternative therapeutic approach, such as a doublet maintenance regimen.