Qaiser Bashir, Peter F. Thall, Jitesh Kawedia, Xun Xu, Cristina Knape, Ruby Delgado, Yago Nieto, Neeraj Saini, Yosra Aljawai, Samer A Srour, Jeremy L. Ramdial, Chitra Hosing, Uday Popat, Betül Oran, Partow Kebriaei, Sairah Ahmed, Oren Pasvolsky, Krina K. Patel, Sheeba K. Thomas, Mahmoud R. Gaballa, Jing Christine Ye, Robert Z. Orlowski, Richard E. Champlin, Elizabeth J. Shpall, Muzaffar H. Qazilbash
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).