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Objective There is no strong evidence to guide therapeutic approach to multiple myeloma ( MM) patients who experience first relapse. The treatment choice can be difficult since currently all patients are exposed to novel agents as thalidomide, bortezomib and lenalidomide. Methods In this retrospective analysis, we evaluated the best therapeutic sequence, the role of retreatment, and the most beneficial cutoff of first remission in order to choose retreatment, analyzing 476 patients relapsed after first-line therapy. Results Bortezomib-based regimens upfront followed by lenalidomide-based regimens at first relapse resulted in significantly better second progression-free survival (2nd PFS), PFS2, and overall survival ( OS) compared to the opposite sequence. Changing therapy resulted in significantly better 2nd PFS in the whole population, whereas PFS2 was significantly longer only in patients who underwent maintenance therapy. Moreover, until PFS1 was shorter than 27 months, changing therapy at first relapse significantly extended 2nd PFS and PFS2 compared to retreatment, whereas similar outcomes were observed between the two strategies, when PFS1 was longer than 27 months. Conclusion Lacking randomized trials, our study could help to choose the most appropriate therapy algorithm in patients with MM. [ABSTRACT FROM AUTHOR]