Mymel: A Phase 1 Trial of AUC-Targeted High Dose Melphalan in Multiple Myeloma Patients Undergoing Autologous Transplant

Introduction Standard 200 mg/m2 high dose melphalan (HDM) yields a 500% variation in plasma melphalan exposure, i.e., area under the curve (AUC), leading to widely variable clinical responses. Test dose predictions fail to accurately represent melphalan AUC for doses >100 mg/m2. With a 2-day HDM regimen, a 24-hour turnaround for sample collection, shipping, processing and data analysis is a major challenge in practice. Here, we set out to perform the first phase 1 study of AUC-targeted HDM in ASCT (NCT04483206).This multicenter phase 1 trial (Fig 1) is designed to test 7 AUC ranges (13 - 21 mg x h/L) to determine the maximum tolerated systemic exposure. The feasibility portion focuses on the first 2 AUCs (phase A, n=20) in patients with at least 2L therapy, where we measure accuracy of achieving the narrow targeted AUC windows of 13-14 (cohort 1) and 14.1-15 (cohort 2) mg x h/L. Patients receive HDM 100 mg/m2 on day -3 with PK measurement and subsequent dose-adjustment on day -1 to achieve the total target AUC. PK parameter estimations are determined from noncompartmental analysis.16 patients are enrolled to date: Cohort 1 (n=10) and Cohort 2 (n=6). The median age of patients is 64.5 (49 - 75) years, with 11 (69%) male, 10 (62.5%) White and 6 (37.5%) Black patients. Median Day -3 HDM Clobs and AUC0-inf were 22.1 (16.3 - 38.2) L/hr and 9.4 (7.0 - 11.8) mg x h/L, respectively. Three patients whose samples were delayed a day during shipment received their Day -1 dose late in the day, resulting in only 4 (n=1) or 5 (n=2) of 7 samples collected. Notably, PK analyses predicted that Day -1 doses should be adjusted for all 16 patients, with a resulting median total BSA-based HDM dose of 146.0 (115.7-203.0) mg/m2. To evaluate the accuracy of dose adjustment, we analyzed 15 patients for whom LC-MS/MS results were available for both Day -3 and -1 samples. Two of these patients in whom the last 2 Day -1 samples were not collected were removed from analysis. After Day -1 dose adjustment, median Day -1 Clobs was 24.6 (17.5-35.8) L/hr, and median Day -1 AUC0-inf was 4.1 (1.7-7.0) mg x h/L and 5.3 (4.3-9.4) mg x h/L for Cohort 1 (n=9) and Cohort 2 (n=4), respectively. Across these 13 evaluable patients, total AUC was within a median of -0.6% of the target (range: -6.7% to +13.9%). Notably, 12 of 13 were within -6.7% to 3.3% and only patient #15 (Fig 2) had an unexplained large deviation from the target. No dose-limiting toxicities have been observed in either cohort.This is the first myeloma trial that uses a novel personalized melphalan dosing approach that results in cohorts of patients with narrowly targeted drug exposures. Despite the narrow target ranges set for these 2 cohorts, AUC attainment within 1% was achieved for all but one of 16 patients. Enrollment continues and updated results will be presented.