This study evaluated the efficacy and safety of lenalidomide maintenance therapy after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. Between April 2005 and July 2009, 460 patients were randomly assigned to receive either lenalidomide or placebo until disease progression. The primary endpoint was time to progression, defined as the time from transplantation to progressive disease or death. The study was unblinded after an interim analysis showed a significantly longer time to progression in the lenalidomide group. At unblinding, 20% of patients in the lenalidomide group and 44% of patients in the placebo group had progressive disease or died (P<0.001). At a median follow-up of 34 months, 37% of patients in the lenalidomide group and 58% of patients in the placebo group had disease progression or died (hazard ratio, 0.48; 95% CI, 0.36 to 0.63). The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). The 3-year freedom from progression or death rate was 66% in the lenalidomide group and 39% in the placebo group. The 3-year overall survival rate was 88% in the lenalidomide group and 80% in the placebo group (hazard ratio, 0.62; 95% CI, 0.40 to 0.95). Lenalidomide maintenance therapy was associated with more grade 3 or 4 hematologic adverse events and grade 3 non-hematologic adverse events but also with a significantly longer time to progression and improved overall survival. The study concluded that lenalidomide maintenance therapy is feasible and beneficial for patients with multiple myeloma who have undergone stem-cell transplantation.This study evaluated the efficacy and safety of lenalidomide maintenance therapy after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. Between April 2005 and July 2009, 460 patients were randomly assigned to receive either lenalidomide or placebo until disease progression. The primary endpoint was time to progression, defined as the time from transplantation to progressive disease or death. The study was unblinded after an interim analysis showed a significantly longer time to progression in the lenalidomide group. At unblinding, 20% of patients in the lenalidomide group and 44% of patients in the placebo group had progressive disease or died (P<0.001). At a median follow-up of 34 months, 37% of patients in the lenalidomide group and 58% of patients in the placebo group had disease progression or died (hazard ratio, 0.48; 95% CI, 0.36 to 0.63). The median time to progression was 46 months in the lenalidomide group and 27 months in the placebo group (P<0.001). The 3-year freedom from progression or death rate was 66% in the lenalidomide group and 39% in the placebo group. The 3-year overall survival rate was 88% in the lenalidomide group and 80% in the placebo group (hazard ratio, 0.62; 95% CI, 0.40 to 0.95). Lenalidomide maintenance therapy was associated with more grade 3 or 4 hematologic adverse events and grade 3 non-hematologic adverse events but also with a significantly longer time to progression and improved overall survival. The study concluded that lenalidomide maintenance therapy is feasible and beneficial for patients with multiple myeloma who have undergone stem-cell transplantation.