Background. Melphalan-prednisone-thalidomide (MPT) improves outcome in multiple myeloma (MM) patients, and it is now considered a standard of care for patients not eligible for transplantation. However, this treatment is a major source of morbidity. Design and Methods. An individual patient data meta-analysis (N=1680) of all the six randomized trials comparing MPT vs melphalan-prednisone (MP) was performed. The main objective was to estimate the risk of serious adverse events (AEs) and their impact on outcome. The primary endpoints were the 2-year cumulative incidence of grade 3-4 hematologic and non-hematologic AEs. Results. At least 75% of the grade 3-4 AEs occurred during the first six months of treatment in both MPT and MP groups. A higher cumulative incidence of grade 3-4 hematologic (28% vs 22%, HR 1.32, 95%CI 1.05-1.66) and non-hematologic (39% vs 17%, HR 2.78, 95%CI 2.21-3.50) AEs was documented in patients treated with MPT vs MP. Grade 3-4 non-hematologic AEs were significantly increased in patients with poor performance status. Occurrence of grade 3-4 non-hematologic AEs negatively impacted on progression-free survival (PFS) (HR 1.24, 95%CI 1.07-1.45) and overall survival (OS), (HR 1.23, 95%CI 1.03-1.47). In addition to the occurrence of AEs, PFS and OS were also negatively affected by advanced ISS stage, high creatinine levels and poor performance status. Age had a negative impact on OS as well. Conclusions. Although MPT improved outcome, it increased the incidence of toxicities, especially non-hematologic. Serious non-hematologic AEs, older age, poor performance status, and high creatinine levels have a negative impact on survival.