A phase 3 clinical trial evaluated lenalidomide maintenance therapy after autologous hematopoietic stem-cell transplantation (HSCT) in patients with multiple myeloma. The study enrolled 460 patients aged 18–70 years who had stable disease or a partial, complete, or marginal response after HSCT. Patients were randomly assigned to receive lenalidomide (10 mg/day) or placebo until disease progression. The primary endpoint was time to progression (TP), defined as progression of disease or death. The study was unblinded in 2009 after an interim analysis showed significantly longer TP in the lenalidomide group. At unblinding, 20% of lenalidomide recipients and 44% of placebo recipients had disease progression or death (P<0.001). Of the remaining 128 placebo recipients without progression, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 37% of lenalidomide recipients and 58% of placebo recipients had progression or death (P<0.001). The median TP was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). Overall survival was 88% in the lenalidomide group and 80% in the placebo group at 3 years (P=0.62). Lenalidomide was associated with more grade 3 or 4 hematologic adverse events and grade 3 non-hematologic adverse events compared to placebo (P<0.001 for both). Second primary cancers occurred in 15% of lenalidomide recipients and 23% of placebo recipients (P=0.03). Despite increased toxicity and second cancers, lenalidomide significantly prolonged TP and improved overall survival. The study was funded by the National Cancer Institute and registered at ClinicalTrials.gov (NCT00114101). The results suggest that lenalidomide maintenance therapy is feasible for prolonged use, with benefits in progression and survival, particularly in patients who received lenalidomide-based induction therapy. Further studies are needed to determine if combining lenalidomide with other agents will further improve outcomes.A phase 3 clinical trial evaluated lenalidomide maintenance therapy after autologous hematopoietic stem-cell transplantation (HSCT) in patients with multiple myeloma. The study enrolled 460 patients aged 18–70 years who had stable disease or a partial, complete, or marginal response after HSCT. Patients were randomly assigned to receive lenalidomide (10 mg/day) or placebo until disease progression. The primary endpoint was time to progression (TP), defined as progression of disease or death. The study was unblinded in 2009 after an interim analysis showed significantly longer TP in the lenalidomide group. At unblinding, 20% of lenalidomide recipients and 44% of placebo recipients had disease progression or death (P<0.001). Of the remaining 128 placebo recipients without progression, 86 crossed over to lenalidomide. At a median follow-up of 34 months, 37% of lenalidomide recipients and 58% of placebo recipients had progression or death (P<0.001). The median TP was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). Overall survival was 88% in the lenalidomide group and 80% in the placebo group at 3 years (P=0.62). Lenalidomide was associated with more grade 3 or 4 hematologic adverse events and grade 3 non-hematologic adverse events compared to placebo (P<0.001 for both). Second primary cancers occurred in 15% of lenalidomide recipients and 23% of placebo recipients (P=0.03). Despite increased toxicity and second cancers, lenalidomide significantly prolonged TP and improved overall survival. The study was funded by the National Cancer Institute and registered at ClinicalTrials.gov (NCT00114101). The results suggest that lenalidomide maintenance therapy is feasible for prolonged use, with benefits in progression and survival, particularly in patients who received lenalidomide-based induction therapy. Further studies are needed to determine if combining lenalidomide with other agents will further improve outcomes.