Background
Multicenter, single-arm phase 2 trial of 123 patients with newly diagnosed multiple myeloma (enriched for high-risk cytogenetics) using next-generation sequencing MRD to guide the duration of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) after autologous HCT, with treatment cessation after two consecutive MRD-negative assessments.
Interventions and follow up
Regimen: Dara-KRd induction x4, autologous HCT, then Dara-KRd consolidation; MRD-adapted treatment cessation after 2 consecutive MRD-negative results (10^-5)
Dosing: Daratumumab 16 mg/kg (QW C1-2, Q2W C3-6, Q4W C7-12); carfilzomib 56 mg/m2 D1,8,15 (20 mg/m2 first dose); lenalidomide 25 mg D1-21; dexamethasone 40 mg weekly
Primary endpoint: MRD-negative response rate
Median follow-up: 25.1 months
Dosing: Daratumumab 16 mg/kg (QW C1-2, Q2W C3-6, Q4W C7-12); carfilzomib 56 mg/m2 D1,8,15 (20 mg/m2 first dose); lenalidomide 25 mg D1-21; dexamethasone 40 mg weekly
Primary endpoint: MRD-negative response rate
Median follow-up: 25.1 months
Results
MRD negativity (10^-5): 80% overall; 71% reached two consecutive MRD-negative assessments
CR or better (by high-risk cytogenetic abnormalities 0/1/≥2): 90.6% vs 89.1% vs 70.8%
2-year PFS: 87% overall
CR or better (by high-risk cytogenetic abnormalities 0/1/≥2): 90.6% vs 89.1% vs 70.8%
2-year PFS: 87% overall
Adverse events
Infectious: Pneumonia 6%
Thrombotic: Venous thromboembolism 3%
Thrombotic: Venous thromboembolism 3%
Conclusions
Dara-KRd with autologous HCT and MRD response-adapted consolidation produced high rates of MRD negativity in newly diagnosed multiple myeloma. For patients with 0 or 1 high-risk cytogenetic abnormalities, MRD-guided treatment cessation with surveillance may be an alternative to indefinite maintenance, whereas patients with ≥2 abnormalities had higher rates of MRD resurgence.
Key Limitations
Single-arm design without a maintenance-continuation comparator, so the safety of treatment cessation cannot be definitively established. Limited follow-up for MRD resurgence, especially in high-risk patients. Modest sample size enriched for high-risk disease.
Clinical Context
MASTER demonstrated the feasibility of MRD-adapted, response-driven therapy with quadruplet Dara-KRd in newly diagnosed multiple myeloma, informing ongoing efforts to incorporate MRD as a treatment-decision tool. Daratumumab-based quadruplet induction is endorsed for transplant-eligible patients per ASCO and ESMO guidance.
References