Salvage or Second Autologous SCT in Relapsed Multiple Myeloma (2016-2026): A Decade in Review

Background: The role of second or salvage autologous stem cell transplantation (ASCT2) in relapsed multiple myeloma (MM) has evolved substantially over the past decade with the introduction of novel agents, maintenance strategies, and cellular immunotherapies. The clinical value of ASCT2 in the contemporary era requires reappraisal based on modern real-world and prospective data. Methods: We conducted a targeted literature review of PubMed-indexed studies published between January 2016 and January 2026 evaluating second or salvage autologous transplantation in adult patients with relapsed or refractory multiple myeloma. Retrospective registry analyses, real-world cohorts, and prospective randomized trials were included, focusing on feasibility, toxicity, progression-free survival (PFS), overall survival (OS), and prognostic determinants. Fourteen key studies formed the core evidence base, supplemented by guideline statements and comparative immunotherapy data. Results: Across large registry and institutional series, ASCT2 was consistently feasible with low non-relapse mortality (≤5% at day 100-1 year). The median PFS ranged from 9.8 to 30.2 months and the median OS from approximately 30 to >80 months, with outcomes strongly influenced by duration of remission after first ASCT. Patients relapsing ≥24 months after ASCT1 derived the greatest benefit, achieving a median PFS of 17-45 months and OS exceeding 60 months in favorable-risk subgroups. Post-ASCT2 maintenance, particularly with lenalidomide or carfilzomib-based regimens, significantly prolonged disease control in randomized and real-world studies. Conversely, the phase III GMMG ReLApsE trial did not demonstrate a survival advantage for routine salvage ASCT over continuous lenalidomide-based therapy, highlighting the importance of patient selection. In heavily refractory or cytopenic populations, ASCT2 provided modest disease control but enabled hematopoietic recovery and access to subsequent therapies. Conclusions: In the modern treatment landscape, second or salvage autologous transplantation remains a valid, safe, and effective strategy for carefully selected patients with relapsed multiple myeloma, particularly those with chemosensitive disease and prolonged initial remissions. ASCT2 should be integrated in a risk-adapted manner alongside maintenance therapy and emerging immunotherapies, serving as a durable consolidation or bridging approach rather than routine therapy for all relapsed patients.