Lenalidomide-dexamethasone improved outcome in newly diagnosed elderly multiple myeloma (MM) patients. We randomized 662 patients ≥65 years or transplant-ineligible to receive induction with melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd). The primary endpoint was progression-free survival (PFS) in triplet (MPR+CPR) vs doublet (Rd) lenalidomide-containing regimens. After a median follow-up of 39 months, the median PFS was 22 months for the triplet combinations and 21 months for the doublet (p=0.284). The median overall survival (OS) was not reached in both groups, and the 4-year OS was 67% for the triplet and 58% for the doublet (p=0.709). By considering the three treatment arms separately, no difference in outcome was detected between MPR, CPR and Rd. The most common grade ≥3 toxicity was neutropenia: 64% in MPR, 29% in CPR and 25% in Rd patients (p<0.0001). Grade ≥3 non-hematologic toxicities were similar among groups and were mainly infections (6.5-11%), constitutional (3.5-9.5%) and cardiac (4.5-6%), with no difference between the arms. In conclusion, in the overall population, the alkylator-containing triplets MPR and CPR were not superior to the alkylator-free doublet Rd, which was associated with lower toxicity. This study was registered at www.clinicaltrials.gov #NCT01093196.