Combinations of bortezomib (V) and dexamethasone (D) with either lenalidomide (R) or cyclophosphamide (C) have shown significant efficacy. This randomized phase 2 trial evaluated VDC, VDR, and VDCR in previously untreated multiple myeloma (MM). Patients received V 1.3 mg/m2 (days 1, 4, 8, 11) and D 40 mg (days 1, 8, 15), with either C 500 mg/m2 (days 1, 8) and R 15 mg (days 1-14; VDCR), R 25 mg (days 1-14; VDR), C 500 mg/m2 (days 1, 8; VDC) or C 500 mg/m2 (days 1, 8, 15; VDC-mod) in 3-week cycles (maximum 8 cycles), followed by maintenance with V 1.3 mg/m2 (days 1, 8, 15, 22) for four 6-week cycles (all arms)≥very good partial response was seen in 58%, 51%, 41%, and 53% (complete response rate of 25%, 24%, 22%, and 47%) of patients (VDCR, VDR, VCD, and VCD-mod, respectively); the corresponding 1-year progression-free survival was 86%, 83%, 93%, and 100%, respectively. Common adverse events included hematologic toxicities, peripheral neuropathy, fatigue, and gastrointestinal disturbances. All regimens were highly active and well tolerated in previously untreated MM, and, based on this trial, VDR and VCD-mod are preferred for clinical practice and further comparative testing. No substantial advantage was noted with VDCR over the 3-drug combinations. This trial is registered at www.clinicaltrials.gov (NCT00507442).