Simple SummaryTreatment consolidation using high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has relevantly contributed to achieving durable remissions in multiple myeloma (MM) patients. The optimization of HDCT regimens can, therefore, essentially contribute to further improving the depth and duration of tumor remissions. In our previous work, we showed that the combination of treosulfan and melphalan (TreoMel) was effective and safe as a conditioning regimen in acute myeloid leukemia (AML) patients undergoing ASCT. Based on these data, TreoMel has been adopted as the standard of care for fit MM patients at our institution. In the current work, we analyzed data from 115 MM patients who underwent consolidation via TreoMel and ASCT between 01/2020 and 08/2022 at the University Hospital of Bern. We report a promising complete response (CR) rate of 84%, which is comparable to the CR rate achieved for the quadruplet combination. The median progression-free survival (PFS) was 30 months (95% CI: 20.4—not reached) and the 31-month overall survival (OS) rate was 83%. The results from our study suggest that TreoMel should be further explored as a conditioning regimen for first-line HDCT consolidation in MM.Abstract(1) Background: Upfront treatment consolidation with high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) has relevantly contributed to achieving durable remissions following induction treatment in multiple myeloma (MM) patients. The optimization of HDCT regimens can, therefore, essentially contribute to improving the depth and duration of tumor remissions. To date, melphalan at 200 mg/m2is the standard HDCT regimen for fit MM patients. In our previous work, we showed promising efficacy and safety results for treosulfan (14 g/m2) and melphalan (200 mg/m2) (TreoMel) in acute myeloid leukemia (AML) patients receiving ASCT. Based on these data, TreoMel became the standard of care for fit MM patients at our institution. (2) Methods: We identified 115 consecutive MM patients who underwent consolidation with TreoMel between 01/2020 and 08/2022 at the University Hospital of Bern. We analyzed the safety and efficacy data, as well as the treosulfan pharmacokinetics, correlating them with tumor responses. (3) Results: A complete response (CR) rate of 84% was achieved, which is comparable to the CR rate reported for the quadruplet combination. The median PFS was 30 months (95% CI: 20.4—not reached), and the 31-month OS rate was 83%. The median area under the curve (AUC) for treosulfan was 952.5 mg*h/L (range: 527.4–1781.4), and the median peak level was 332.3 mg/L (range: 168–554). The treosulfan pharmacokinetics showed no significant correlation with MM responses after HDCT and ASCT. However, female patients had a significantly higher AUC (p= 0.007) and peak value (p= 0.001), and the higher values were associated with longer hospitalizations. (4) Conclusions: Treatment consolidation with TreoMel HDCT demonstrated a promising efficacy and safety profile in our cohort of MM patients and deserves further investigation in prospective studies.