Phase I/II Trial of Evomela for Autologous Transplant in Myeloma: Schedule Optimization and Matched Comparison with MEL200

Melphalan 200 mg/m² is the standard conditioning regimen for autologous hematopoietic stem cell transplantation (ASCT) in multiple myeloma, but further dose escalation is limited by toxicity. Evomela, a propylene‑glycol-free melphalan with enhanced stability, enables safer dose intensification and pharmacokinetic (PK) optimization. We conducted a prospective phase I/II trial to optimize Evomela dosing and infusion schedule in newly diagnosed myeloma patients undergoing ASCT. Primary objectives included dose/schedule optimization using a Bayesian design and PK characterization; secondary objectives included minimal residual disease (MRD)‑negative complete response (CR) at day 90, toxicity, and progression‑free survival (PFS). Sixty patients were randomized to short (30-60 mins) or long (8-9 hrs) Evomela infusions at 200 or 225 mg/m². No grade ≥4 non‑hematologic toxicities or day‑100 non‑relapse mortality occurred. MRD-negative stringent (s)CR/CR at day 90 was 45% (43% in the short infusion arm and 47% in the long infusion arm), with similar toxicity and PFS between the schedules. A higher melphalan area under the concentration-time curve (AUC) was strongly associated with MRD‑negative sCR/CR (posterior probability of benefit [PBE] = 0.99) without increased toxicity, but not with PFS. In propensity‑matched comparisons, Evomela was associated with longer PFS than melphalan 200 mg/m² (MEL200) (PBE = 0.90). These results support Evomela as a platform for safe dose intensification and AUC‑guided conditioning in newly diagnosed myeloma patients undergoing ASCT. (NCT03417284)