BACKGROUND: Despite therapeutic advances, multiple myeloma (MM) remains challenging to treat effectively. High-dose melphalan (Mel200) with autologous stem cell transplantation (ASCT) is the standard treatment for transplant-eligible patients. Reduced-dose melphalan (Mel140) is an alternative for older or frail patients, yet its efficacy data remain unclear. METHODS: We retrospectively analyzed 233 MM patients undergoing first ASCT between 2014 and 2022, comparing outcomes between Mel140 (n = 82) and Mel200 (n = 151). We assessed patient demographics, disease characteristics, progression-free survival (PFS), and overall survival (OS). In an exploratory subset analysis achievement of MRD from bone marrow samples after ASCT was compared between the 2 groups. RESULTS: As expected, patients who received Mel 140 were significantly older with a higher KPS. Median follow-up was 47.7 months. Both groups had similar rates of readmissions and infections within the first 100 days after transplant despite Mel140 group being older with more comorbidities. No significant difference in PFS or OS was observed between Mel140 and Mel200 groups (P >
.05). MRD negativity rates at sensitivity levels of 10 CONCLUSION: Our findings suggest equivalent efficacy and safety profiles between Mel140 and Mel200, supporting Mel140 as a viable option for older or frail MM patients. In a subset analysis equivalent rates of MRD were achieved between the groups and remained a highly significant predictor of PFS, highlighting its relevance regardless of dosing strategies.