Background
Phase 3, open-label, randomized controlled trial. N=395 patients with newly diagnosed, transplant-ineligible or transplant-deferred multiple myeloma. Randomized 1:1 to D-VRd vs VRd. Key eligibility: ECOG PS ≤2, transplant-ineligible (per investigator) or transplant-deferred. Stratified by MRD testing feasibility, International Staging System (ISS) stage, and region.
Interventions and follow up
Arm A: Daratumumab 1800 mg SC (weekly cycles 1–2, every 2 weeks cycles 3–6, monthly cycles 7+) + bortezomib 1.3 mg/m² SC + lenalidomide 25 mg PO (days 1–14 q21d) + dexamethasone 20 mg PO/IV (D-VRd), until progression or unacceptable toxicity
Arm B: Bortezomib 1.3 mg/m² SC + lenalidomide 25 mg PO + dexamethasone 20 mg PO/IV (VRd), until progression or unacceptable toxicity
Primary endpoint: MRD-negativity rate (10⁻⁵ sensitivity by NGS) at 12 months from randomization
Median follow up: 58.7 months
Arm B: Bortezomib 1.3 mg/m² SC + lenalidomide 25 mg PO + dexamethasone 20 mg PO/IV (VRd), until progression or unacceptable toxicity
Primary endpoint: MRD-negativity rate (10⁻⁵ sensitivity by NGS) at 12 months from randomization
Median follow up: 58.7 months
Results
MRD-negativity (10⁻⁵) at 12 mo: 60.9% vs 39.4%, OR 2.37 (95% CI 1.58–3.58), P<.001
ORR: 91.2% vs 82.2%
≥CR rate: 56.6% vs 36.7%
PFS: HR 0.57 (95% CI 0.41–0.79), medians not reached at primary analysis
ORR: 91.2% vs 82.2%
≥CR rate: 56.6% vs 36.7%
PFS: HR 0.57 (95% CI 0.41–0.79), medians not reached at primary analysis
Adverse events
Hematologic (grade ≥3): Neutropenia 24.9% vs 11.7%
Non-hematologic: Grade ≥3 infections 19.3% vs 10.1%; infusion/injection-site reactions any grade 17.3% (D-VRd); treatment discontinuation 6.6% vs 9.1%
Non-hematologic: Grade ≥3 infections 19.3% vs 10.1%; infusion/injection-site reactions any grade 17.3% (D-VRd); treatment discontinuation 6.6% vs 9.1%
Conclusions
D-VRd significantly improved MRD-negativity rates and response depth compared with VRd alone in transplant-ineligible or transplant-deferred NDMM, with a clinically meaningful PFS benefit, supporting D-VRd as a new standard of care for this population.
Key Limitations
The population included both transplant-ineligible and transplant-deferred patients — a heterogeneous group that complicates comparisons with other NDMM-TI trials. MRD-negativity at 12 months is a surrogate endpoint; mature PFS and OS data were limited at primary analysis. Subcutaneous daratumumab was used, differing from earlier IV-daratumumab trials. The VRd schedule used 21-day cycles, differing from some US-practice 28-day cycle VRd.
Clinical Context
CEPHEUS contributed to FDA approval of daratumumab + VRd for transplant-ineligible NDMM in 2024. Together with IMROZ (isatuximab + VRd), this trial establishes anti-CD38 quadruplet therapy as a standard for fit transplant-ineligible NDMM. CEPHEUS is particularly notable for including transplant-deferred patients, a group for whom prospective data were previously lacking. ESMO supports anti-CD38–based quadruplets as a frontline option.