Melphalan (M) has been the most significant drug in myeloma treatment for over 30 years and, in combination with prednisone (MP), has been the backbone of new combinations, including bortezomib plus MP (VMP). However, new alkylator-free schemes, such as lenalidomide plus low-dose dex, are challenging the role of alkylators in the treatment of elderly patients. Here we have updated, after a long follow-up (median 6 years), the results of the GEM2005 study that addressed this question by comparing VMP with VTP as induction. Between April 2005 and October 2008, 260 patients were randomized to receive 6 cycles of VMP or VTP as induction. Those who completed the induction therapy were subsequently randomly assigned to maintenance therapy with VT or VP. The median progression-free survival was 32 months for the VMP and 23 months for the VTP arms (p=0.09). VMP significantly prolonged the overall survival (OS) compared with VTP (median of 63 and 43 months, respectively; HR: 0.67, p=0.01). In multivariate analysis, receiving VMP as induction (HR: 1.3), having standard-risk cytogenetic abnormalities (HR: 1.85) and achieving CR (HR=2.14) were independent factors associated with significantly longer OS. Achieving CR and immunophenotypic response were associated with a significantly longer OS and this was particularly evident in the VMP arm (66% remain alive after 8 years). Melphalan, in combination with bortezomib, should be maintained as one of the standards of care for the treatment of elderly MM patients. The trial is registered with www.ClinicalTrials.gov, number NCT00443235.