Background
Randomized, multicenter phase 2 trial of 140 patients with previously untreated symptomatic multiple myeloma (regardless of transplant eligibility), comparing three- and four-drug bortezomib-based induction combinations. No formal statistical comparison across arms was prespecified.
Interventions and follow up
Arm A (VDCR): Bortezomib + dexamethasone + cyclophosphamide + lenalidomide, induction Q3W x8, then bortezomib maintenance Q6W x4
Arm B (VDR): Bortezomib + dexamethasone + lenalidomide, same schedule
Arm C (VDC): Bortezomib + dexamethasone + cyclophosphamide, same schedule
Arm D (VDC-mod): VDC plus additional D15 cyclophosphamide
Dosing: Bortezomib 1.3 mg/m2 D1,4,8,11 (induction); dexamethasone 40 mg D1,8,15; cyclophosphamide 500 mg/m2 D1,8; lenalidomide 15 mg (VDCR) or 25 mg (VDR) D1-14
Primary endpoint: CR + VGPR rate
Median follow-up: 20 months
Arm B (VDR): Bortezomib + dexamethasone + lenalidomide, same schedule
Arm C (VDC): Bortezomib + dexamethasone + cyclophosphamide, same schedule
Arm D (VDC-mod): VDC plus additional D15 cyclophosphamide
Dosing: Bortezomib 1.3 mg/m2 D1,4,8,11 (induction); dexamethasone 40 mg D1,8,15; cyclophosphamide 500 mg/m2 D1,8; lenalidomide 15 mg (VDCR) or 25 mg (VDR) D1-14
Primary endpoint: CR + VGPR rate
Median follow-up: 20 months
Results
VGPR or better: 58% (VDCR) vs 51% (VDR) vs 41% (VDC) vs 53% (VDC-mod)
Complete response: 25% vs 24% vs 22% vs 47%, respectively
1-year PFS: 86% vs 83% vs 93% vs 100%, respectively
Complete response: 25% vs 24% vs 22% vs 47%, respectively
1-year PFS: 86% vs 83% vs 93% vs 100%, respectively
Adverse events
Overall: Grade ≥3 adverse events 83% (VDCR) vs 76% (VDR) vs 79% (VDC) vs 88% (VDC-mod)
Neurologic: Peripheral neuropathy 13% vs 17% vs 9% vs 18%, respectively
Neurologic: Peripheral neuropathy 13% vs 17% vs 9% vs 18%, respectively
Conclusions
All bortezomib-based regimens were highly active and well tolerated in previously untreated multiple myeloma. No formal statistical comparison between the four arms was made; addition of lenalidomide to VDC (VDCR) did not clearly improve outcomes over the triplets, and VDR and VDC-mod were favored for further study.
Key Limitations
Small phase 2 trial with no prespecified statistical comparison between arms, limiting conclusions about relative efficacy. Short follow-up (20 months) precluded mature PFS/OS assessment. Heterogeneous transplant-eligible and -ineligible population.
Clinical Context
Bortezomib-based triplets (e.g., VRd, VCd) are standard induction options for newly diagnosed multiple myeloma. EVOLUTION helped establish that four-drug intensification with both cyclophosphamide and lenalidomide added little over triplets, informing subsequent regimen selection. ASCO and ESMO guidelines endorse proteasome inhibitor-based induction.
References