Daratumumab Quadruplet Improves Depth of Response in Older Myeloma
Key Clinical Summary
- Population/Design: Post hoc pooled analysis of transplant-eligible patients aged ≥65 years from GRIFFIN (phase 2, US) and PERSEUS (phase 3, Europe/Australia); D-VRd (daratumumab+bortezomib/lenalidomide/dexamethasone) vs VRd with lenalidomide maintenance.
- Efficacy: Trend toward longer PFS with D-VRd (HR, 0.56; 95% CI, 0.31–1.01) and higher rates of ≥CR (82.8% vs 67.0%) and minimal residual disease (MRD)-negativity at 10⁻⁵ (66.4% vs 41.7%).
- Safety/Transplant: No new safety concerns; stem cell mobilization, engraftment, and transplant proceeded without detriment in older adults.
A pooled, patient-level analysis from the GRIFFIN and PERSEUS trials evaluated daratumumab added to VRd induction/consolidation followed by daratumumab-lenalidomide maintenance (D-VRd/D-R) in transplant-eligible (TE) older adults (≥65 years) with newly diagnosed multiple myeloma (NDMM). Conducted across the United States and Europe/Australia, the analysis addresses prior uncertainty in this age subgroup by harmonizing methods and removing censoring of certain progression events.
Study Findings
The pooled cohort included 237 patients aged ≥65 years (D-VRd, n = 122; VRd, n = 115). Median follow-up was 49.6 months (GRIFFIN) and 47.5 months (PERSEUS). Progression-free survival (PFS) favored D-VRd, with a hazard ratio of 0.56 (95% CI, 0.31–1.01; P = 0.05); 48-month PFS rates were 79.1% (D-VRd) versus 71.6% (VRd).
Depth of response improved with D-VRd: ≥CR 82.8% vs 67.0% (OR, 2.37; P = .0046) and MRD-negativity at 10⁻⁵ 66.4% vs 41.7% (OR, 2.75; P = .0002). Sustained MRD-negativity (10⁻⁵ for ≥12 months) was also higher (52.5% vs 26.1%; OR, 3.20; P < .0001). End-of-consolidation MRD-negativity (10⁻⁵) favored D-VRd (49.2% vs 29.6%; P = .003).
Safety in patients ≥65 years showed no new concerns; the overall profile was consistent with prior reports. Importantly, stem cell mobilization and transplant metrics were comparable between groups: high proportions proceeded to mobilization and transplant, CD34+ yields were adequate, time to neutrophil and platelet engraftment was similar, and melphalan dosing was maintained.
Clinical Implications
Older, transplant-eligible adults remain underrepresented in NDMM trials and often pose treatment challenges due to frailty and comorbidities. In this pooled analysis, adding daratumumab to VRd consistently deepened responses and increased MRD-negativity, endpoints associated with favorable long-term outcomes in myeloma. The trend toward improved PFS (HR, 0.56) supports clinical use, particularly given the absence of new safety signals and the preserved feasibility of autologous transplant after quadruplet induction.
These results help reconcile earlier subgroup variability by addressing methodological issues (eg, event censoring) and cytogenetic imbalances. For clinicians in the US and Europe managing TE patients aged ≥65 years, D-VRd followed by D-R maintenance emerges as a viable, age-inclusive standard option up to age 70 years.
Conclusion
In transplant-eligible older adults with NDMM across the US and Europe, D-VRd induction/consolidation followed by D-R maintenance deepens response quality and improves MRD-negativity with a favorable safety profile. These findings support D-VRd/D-R as a standard regimen regardless of age up to 70 years and underscore the need for continued follow-up to confirm PFS benefits.
Reference
Rodriguez-Otero P, Voorhees P M, Boccadoro M, et al. Daratumumab for newly diagnosed multiple myeloma: Pooled analysis of patients aged ≥65 years from GRIFFIN and PERSEUS. Clin Lymphoma Myeloma Leuk. 2025;25(10):746-758.e6. doi: 0.1016/j.clml.2025.04.007
