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A second autologous stem-cell transplantation (ASCT2) is considered for relapsed multiple myeloma (RMM) patients showing prolonged response after a first ASCT. However, given breakthrough treatments like anti-CD38 and immunotherapy, its role remains debated. We conducted a real-life study in 10 French centers (1996-2017) involving 267 RMM patients receiving ASCT2. The median age was 61 years, with 49% females. Most patients received melphalan 200 mg/m² before ASCT2, with low early mortality (1%). Very good partial response or better (VGPR+) rate post ASCT2 was 78%. Post ASCT2, 48% received consolidation therapy and 40% maintenance therapy. Median event-free survival (EFS) after ASCT2 was 2.6 years (95% confidence interval [CI]: 2.3-2.8), and 2-year EFS estimate was 63% (95% CI: 57-70). Median overall survival (OS) was 8.1 years (95% CI: 5.9-NA), and 2-year OS estimate was 92% (95% CI: 88-95). Multivariate analysis revealed that VGPR+ status and maintenance therapy post ASCT2 were associated with better EFS (hazard ratio [HR]: 0.6; 95% CI: 0.3-0.9, p  = 0.012 and HR: 0.4; 95% CI: 0.3-0.6, p  < 0.001, respectively) and OS (HR: 0.4; 95% CI: 0.2-0.9, p  = 0.017 and HR: 0.2; 95% CI: 0.1-0.4, p  < 0.001, respectively), while male sex correlated with poorer outcomes for EFS (HR: 2.5; 95% CI: 1.7-3.7, p  < 0.001) and OS (HR: 2.7; 95% CI: 1.4-4.9, p  = 0.002). Overall, ASCT2 appeared efficient with low toxicity in RMM. Maintenance therapy was associated with extended EFS and OS, particularly in patients with VGPR+ status post ASCT2. These findings underscore ASCT2's potential in RMM when coupled with maintenance therapy in selected patients., Competing Interests: The authors declare no conflict of interest., (© 2024 The Author(s). HemaSphere published by John Wiley & Sons Ltd on behalf of European Hematology Association.)