Feasibility and Target AUC Accuracy of Personalized High Dose Melphalan in Myeloma

• Published in: Blood 2024-11, Vol.144, p.1993-1993
• Main Authors: Sweiss, Karen, Kim, Kyeongmin, Guo, Yizhen, Hill, Kasey, Abbott, Nicole, Sanchez, Matias Eugenio, Uzoka, Chukwuemeka, Avila Rodriguez, Ana Maria, Quigley, John G, Mahmud, Nadim, Rondelli, Damiano, Sborov, Douglas W, Harvey, Donald, Nooka, Ajay K., Dhodapkar, Madhav V., Kaufman, Jonathan L., Joseph, Nisha S., Lonial, Sagar, Patel, Pritesh, Phelps, Mitch A., Hofmeister, Craig C.
• Format: Article
• Language: English
• ISSN: 0006-4971
• DOI: 10.1182/blood-2024-205614

Background: Autologous transplant remains standard first line treatment in multiple myeloma (MM) yet melphalan 200 mg/m2 leads to 500% variation in systemic exposure (Nath CE et al, 2010, PMID 20573084), as measured by area under the curve (AUC). Unfortunately, PK-targeted melphalan dosing has been unsuccessful with test dose strategies failing to reliably estimate melphalan AUC for doses >100 mg/m2. We developed a PK-based dosing regimen whereby the first 100 mg/m2 is used to generate PK data in real-time, allowing us to adjust the second dose within 48 hours (Sweiss K et al, 2020, PMID 32285957). Here we report final results of the Phase A portion of our multicenter Phase 1 trial aimed at demonstrating feasibility and success of this first ever personalized melphalan dosing strategy (NCT04483206). Methods: Phase A was a pre-planned run-in required by the FDA to show feasibility and accuracy of achieving narrow AUC targets of 13-14 (cohort 1) and 14.1-15 (cohort 2) mg*h/L. Eligible patients who had received two or more lines of therapy (Rajkumar V et al, 2015, PMID 26272048) received day-3 melphalan 100 mg/m2 and 7 blood samples were collected and shipped overnight for LC-MS/MS analysis. Using noncompartmental analysis (NCA), day -3 AUC estimation was used to determine day -1 dosing to achieve the target AUC. For comparison, we performed a Bayesian post-hoc estimation of clearance (CL) and AUC with nonlinear mixed effects modeling (NLME) using our developed population PK model. Results: Target enrollment of 20 patients was achieved. Median age was 64 (49-75) years, with 6 (30%) ≥70 years. 14 (70%) were male and 15 (75%) were Black. Median day -3 CrCl was 97.6 (44.8-185.8) ml/min and median body weight was 91.7 (65-142.4) kg. Our real-time workflow was feasible and adopted at both centers, with 273 (97.5%) of the prescribed blood samples collected, processed, and shipped overnight successfully to the PK laboratory, and dose adjustment was performed in all patients. 7 samples not collected on day -1 were due to unexpected overnight shipping delays which resulted in delayed drug administration. After day -3 melphalan 100 mg/m2, the median day -3 CL and AUC was 22.1 (16.3-38.2) L/hr and 9.4 (7.0-11.8) mg ´ h/L in Cohort 1, and 21.4 (17.8-25.5) L/hr and 9.8 (7.1-10.8) mg ´ h/L in Cohort 2, respectively, resulting in all but 1 (95%) patient needing a lower day -1 adjusted dose for both cohorts. Based on the PK data observed, a BSA-based dose, 200 mg/m2, would h