Background
Italian open-label randomized phase II trial evaluating carfilzomib-based induction and consolidation with or without transplant, then maintenance, in 474 transplant-eligible patients ≤65 years with newly diagnosed multiple myeloma. Two randomizations: induction/consolidation strategy, then maintenance.
Interventions and follow up
1st randomization Arm A: KRd x4 + MEL200-ASCT + KRd x4 consolidation
Arm B: KRd x12 (no transplant)
Arm C: KCd x4 + MEL200-ASCT + KCd x4 consolidation
2nd randomization maintenance: carfilzomib + lenalidomide (KR) vs lenalidomide (R)
Primary endpoint: 1st randomization – pre-maintenance VGPR rate; 2nd randomization – PFS
mFollow up: 50.9mo (1st randomization), 37.3mo (2nd randomization)
Arm B: KRd x12 (no transplant)
Arm C: KCd x4 + MEL200-ASCT + KCd x4 consolidation
2nd randomization maintenance: carfilzomib + lenalidomide (KR) vs lenalidomide (R)
Primary endpoint: 1st randomization – pre-maintenance VGPR rate; 2nd randomization – PFS
mFollow up: 50.9mo (1st randomization), 37.3mo (2nd randomization)
Results
VGPR rate at end of induction: KRd 70% vs KCd 53%; OR 2.14, 95% CI 1.44–3.19, P=.0002
4yr PFS (ITT, 1st randomization, A vs B vs C): 69% vs 56% vs 51%
3yr PFS (2nd randomization, KR vs R): 75% vs 65%; HR 0.64, 95% CI 0.44–0.94, P=.023
4yr PFS (ITT, 1st randomization, A vs B vs C): 69% vs 56% vs 51%
3yr PFS (2nd randomization, KR vs R): 75% vs 65%; HR 0.64, 95% CI 0.44–0.94, P=.023
Adverse events
Induction grade 3-4 (KRd+ASCT vs KRd12 vs KCd+ASCT): neutropenia 13% vs 15% vs 11%; dermatologic 6% vs 8% vs 1%; hepatic 8% vs 8% vs 0%; pneumonia 4% vs 3% vs 3%; treatment discontinuation 7% vs 8% vs 8%
Maintenance grade 3-4 (KR vs R): neutropenia 20% vs 23%; infection 5% vs 7%; vascular events 7% vs 1%; pneumonia 3% vs 3%; deaths 1 vs 0
Maintenance grade 3-4 (KR vs R): neutropenia 20% vs 23%; infection 5% vs 7%; vascular events 7% vs 1%; pneumonia 3% vs 3%; deaths 1 vs 0
Conclusions
ASCT retains an important consolidation role in young transplant-eligible newly diagnosed MM, with longer PFS than KRd12 alone. KRd induction yields deeper response than KCd. Maintenance with carfilzomib plus lenalidomide improves PFS over lenalidomide alone, with modestly higher toxicity.
Key Limitations
Phase II design, not powered for OS. Three-arm 1st randomization compared across heterogeneous strategies. Maintenance benefit reported at 3yr; longer follow-up needed. No daratumumab-containing comparator.
Clinical Context
Supports carfilzomib-based induction and ASCT in transplant-eligible NDMM. ESMO and ASCO guidelines endorse ASCT consolidation and continuous maintenance in eligible patients. KRd is an accepted alternative induction triplet. Doublet (regimen details: KRd carfilzomib 36 mg/m2 IV D1,2,8,9,15,16; lenalidomide 25 mg PO D1–21; dexamethasone 20 mg D1,2,8,9,15,16,22,23. KCd substitutes cyclophosphamide 300 mg/m2 PO D1,8,15. KR maintenance: carfilzomib 36 mg/m2 D1–2 and 15–16 q28d up to 2yr plus lenalidomide 10 mg D1–21).
References