Phase 1/2 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 1/2 trial to optimize Evomela dosing and infusion schedule in patients with newly diagnosed myeloma 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 minutes) or long (8-9 hours) Evomela infusions at 200 or 225 mg/m2. No grade ≥4 nonhematologic toxicities or day-100 nonrelapse mortality occurred. MRD-negative stringent CR (sCR)/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] of 0.99) without increased toxicity but not with PFS. In propensity-matched comparisons, Evomela was associated with longer PFS than melphalan 200 mg/m2 (PBE of 0.90). These results support Evomela as a platform for safe dose intensification and AUC-guided conditioning for patients with newly diagnosed myeloma undergoing ASCT. This trial was registered at www.clinicaltrials.gov as NCT03417284.