Real-world stratified treatment strategies in transplant-eligible newly diagnosed multiple myeloma: A multicohort study

Abstract

Abstract Introduction Transplant-eligible NDMM (TE-NDMM) exhibits heterogeneous risk profiles requiring tailored approaches. We evaluated three stratified strategies:Ultra-high-risk (UHiR): ≥2 high-risk cytogenetic abnormalities (HRCAs: t(4;14), t(14;16), t(14;20), del(17p), gain(1q) or circulating plasma cells (CPC≥1%).Extramedullary disease (EMD)Non-UHiRnor EMD Each strategy was implemented based on patient-specific profiles, ensuring precise treatment alignment. UHiR patients received aggressive therapies, EMD cases received quadruplet, while non-UHiR/EMD followed standard protocols, optimizing outcomes across diverse risk groups. Methods Real-world cohorts from First Affiliated Hospital of Sun Yat-sen University (2024–2025): - UHiR cohort (n=26): Dara-KAD (daratumumab, carfilzomib, liposomal doxorubicin, dexamethasone) induction → tandem ASCT → carfilzomib/pomalidomide maintenance. Primary endpoint: 2-year PFS. - EMD cohort (n=22): KAPD (carfilzomib, liposomal doxorubicin, pomalidomide, dexamethasone) induction ± ASCT. Primary endpoint: dual-negativity rate (bone marrow multi-colour flow MRD<10⁻⁵ + PET-CT CR post-4 cycles). - Non-UHiR nor EMD cohort (n=403): Suboptimal responders (SOR) was difined as ≥minimal response (MR) but <complete response (CR) to first-line (1L) induction. Retrospective/prospective analysis of: - Cohort A: SOR who received 2L intensified induction → ASCT (n=41) - Cohort B: SOR who received direct ASCT without 2L (n=214) - Cohort C: 1L CR → ASCT (n=148). Primary endpoints: PFS, OS. Results UHiR cohort (median follow-up 12.5months): - Post-induction response: CR 57%, VGPR 38%, MRD negativity 43%. - Median PFS: 25 months. - Mobilization success: 100% (15/16 required plerixafor; 9/16 collected ≥6×10⁶ CD34⁺/kg). - Grade ≥3 AEs: Neutropenia (23.1%), infections (23.1%).EMD cohort (15 evaluable): - Dual-negativity rate: 40% (6/15). - Extramedullary ORR: 80% (CR 20%, PR 60%). - Mobilization: 100% success (9/9 collected >4×10⁶ CD34⁺/kg; 66.7% used plerixafor). - Two year PFS: 70%.Non-UHiRnor EMD cohort cohort(median follow-up 10.0 months): - 2L induction (Cohort A): 91.7% (37/41) deepened responses (Dara-based: 52.4% CR). - Post-ASCT CR rates: Cohort A 63.4% (vs. Cohort B 48.1%, p=0.08). - PFS: SOR without 2L (Cohort B) had inferior PFS vs. OR (Cohort C) (HR 1.72, p<0.01); 2L intensified induction (Cohort A) bridged this gap (PFS comparable to Cohort C, HR 0.93, p=0.64). - Mobilization: Plerixafor use higher in Cohort A (58.5% vs. 40.2% overall) but CD34⁺yield comparable (median 5.1×10⁶/kg). Conclusion Stratified approaches improved outcomes in high-risk TE-NDMM: - UHiR: Dara-KAD + tandem ASCT achieved 95% ORR and 25 months median PFS. - EMD: KAPd induced 40% dual-negativity. - SOR: 2L intensified induction (particularly Dara-based regimens) rescued survival disparity vs. optimal responders. Mobilization remained feasible across all cohorts with proactive plerixafor use. Real-world evidence supports risk-adapted induction, transplantation, and mobilization strategies.