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.
