In the EMN01 trial, the addition of an alkylator (melphalan or cyclophosphamide) to lenalidomide-steroid induction has been prospectively evaluated in transplant-ineligible multiple myeloma patients. After induction, patients were randomly assigned to maintenance treatment with lenalidomide alone or with prednisone continuously. This analysis (median follow-up of 71 months) focused on maintenance treatment and on subgroup analyses according to the International Myeloma Working Group Frailty Score. 217 patients in lenalidomide-dexamethasone, 217 in melphalan-prednisone-lenalidomide and 220 in cyclophosphamide-prednisone-lenalidomide arms were evaluable. 284 (43%) patients were fit, 205 (31%) intermediate-fit and 165 (25%) frail. After induction, 402 patients were eligible for maintenance, (lenalidomide arm: 204; lenalidomide-prednisone: 198). After a median duration of maintenance of 22.0 months, progression-free survival from start of maintenance was 22.2 months with lenalidomide-prednisone vs 18.6 months with lenalidomide (HR 0.85,p=0.14), with no differences across frailty subgroups. The most frequent grade ≥3 toxicity was neutropenia (10% of lenalidomide-prednisone and 21% of lenalidomide patients; p=0.001). Grade ≥3 non-hematologic adverse events were rare (<15%). In fit patients, melphalan-prednisone-lenalidomide significantly prolonged progression-free survival compared to cyclophosphamide-prednisone-lenalidomide (HR 0.72,p=0.05) and lenalidomide-dexamethasone (HR 0.72, p=0.04). Likewise, a trend towards a better overall survival was noted for melphalan-prednisone-lenalidomide and cyclophosphamide-prednisone-lenalidomide, as compared to lenalidomide-dexamethasone. No differences were observed in intermediate-fit and frail patients. This analysis showed positive outcomes of maintenance with lenalidomide-based regimens, with a good safety profile. For the first time, we showed that fit patients benefit from a triplet full-dose regimen, while intermediate-fit and frail patients from gentler regimens. ClinicalTrials.gov registration number: NCT01093196.