Background
Phase 3, open-label, randomized controlled trial. N=706 patients with newly diagnosed, transplant-ineligible multiple myeloma. Randomized 1:1. Key eligibility: ECOG PS ≤2, creatinine clearance ≥30 mL/min, not eligible for high-dose therapy and ASCT.
Interventions and follow up
Arm A: Daratumumab 16 mg/kg IV weekly (cycle 1), then every 3 weeks (cycles 2–9) + bortezomib 1.3 mg/m² SC + melphalan 9 mg/m² PO + prednisone 60 mg/m² PO (D-VMP), 9 cycles
Arm B: Bortezomib 1.3 mg/m² SC + melphalan 9 mg/m² PO + prednisone 60 mg/m² PO (VMP), 9 cycles
Primary endpoint: 18-month progression-free survival rate
Median follow up: 16.5 months
Arm B: Bortezomib 1.3 mg/m² SC + melphalan 9 mg/m² PO + prednisone 60 mg/m² PO (VMP), 9 cycles
Primary endpoint: 18-month progression-free survival rate
Median follow up: 16.5 months
Results
18-mo PFS rate: 71.6% vs 50.2%, HR 0.50 (95% CI 0.38–0.65), P<.001
ORR: 90.9% vs 73.9%
≥CR rate: 42.6% vs 24.4%
MRD-negativity (10⁻⁵): 22.3% vs 6.2%
OS: Immature at primary analysis; subsequent updates confirmed OS benefit (HR 0.60 at 40-month follow-up)
ORR: 90.9% vs 73.9%
≥CR rate: 42.6% vs 24.4%
MRD-negativity (10⁻⁵): 22.3% vs 6.2%
OS: Immature at primary analysis; subsequent updates confirmed OS benefit (HR 0.60 at 40-month follow-up)
Adverse events
Hematologic (grade ≥3): Neutropenia 39.9% vs 38.7%; thrombocytopenia 34.4% vs 37.6%
Non-hematologic: Infusion-related reactions 27.7% (grade ≥3 3.0%); peripheral neuropathy any grade 34.0% vs 33.7%; treatment discontinuation 7.5% vs 4.5%
Non-hematologic: Infusion-related reactions 27.7% (grade ≥3 3.0%); peripheral neuropathy any grade 34.0% vs 33.7%; treatment discontinuation 7.5% vs 4.5%
Conclusions
Daratumumab added to VMP significantly improved PFS, response depth, and MRD-negativity in transplant-ineligible NDMM, with a PFS hazard ratio of 0.50. The trial established D-VMP as the first anti-CD38–based regimen approved in the frontline setting for this population.
Key Limitations
Median follow-up was only 16.5 months at primary analysis; OS data were immature. Open-label design may have introduced response-assessment bias. The VMP schedule was adapted from the VISTA trial, differing from some contemporary European and US practices. Updated analyses suggest OS benefit, though confirmatory phase 3 OS data specifically in this regimen context remain limited.
Clinical Context
D-VMP was FDA-approved in 2018 for transplant-ineligible NDMM and became the first anti-CD38 combination in the frontline setting. It has been partly superseded by D-VRd (CEPHEUS) and D-Rd (MAIA) and Isa-VRd (IMROZ) as lenalidomide-based quadruplets/triplets have become preferred for eligible patients. D-VMP remains relevant in countries with restricted lenalidomide access or in frail patients where melphalan-based therapy is standard. ESMO endorses anti-CD38–based frontline regimens for transplant-ineligible NDMM.