Background and Objectives: The treatment of Myeloma after the second relapse is still challenging. The aim of the study was to investigate the outcomes of the POM-DEX regimen in real clinical practice. Materials and Methods: We retrospectively and prospectively analyzed 121 patients with MM treated with POM-DEX in three Italian sites in Tuscany. We assessed the efficacy based on IMWG Uniform Response Criteria in 106 patients who had received at least two courses of the POM-DEX regimen. The median time from diagnosis to use of POM-DEX was 65 months. POM-DEX median use was in the fourth-line therapy. 63.6% were exposed to lenalidomide or thalidomide, 40.5% to bortezomib or carfilzomib or ixazomib, 5.8% to mAbs in the immediately preceding line of therapy. Results: ORR was 43.4%. Median PFS and OS were 8.5 and 14 months. Eighty-nine patients received more than two courses: their median PFS and OS were 11 and 16 months. When used as the third line of therapy, median PFS and OS were 9 and 20 months and, when patients received POM-DEX for more than two courses, median PFS and OS were 14.5 and 22.5 months. Conclusions: POM-DEX is effective in RRMM, regardless of the latest exposure to IMiDs, PIs, and mAbs in the previous line of therapy.