Accuracy of Real-Time PK-Guided Melphalan Dosing in Achieving Target Exposure in Myeloma Patients Undergoing...

Background: High-dose melphalan 140-200 mg/m² (HDM) with autologous stem cell transplant (ASCT) is standard first-line treatment in multiple myeloma (MM), yet standard BSA-based dosing results in wide variation in systemic exposure (AUC). We developed a pharmacokinetic (PK)-guided dosing strategy using a 100 mg/m² first dose, enabling real-time PK assessment and individualized adjustment for the second dose. We report final results of Phase A of our multi-center Phase 1 trial (NCT04483206, MyMel) evaluating feasibility and accuracy of this personalized approach. Methods: Patients received melphalan 100 mg/m² on Day -3, and seven PK samples were collected and shipped overnight for LC-MS/MS analysis. Real-time AUC estimation using noncompartmental analysis (NCA) guided Day -1 dosing to achieve pre-specified AUC targets (13.5 or 14.5 mg × h/L). For comparison, post hoc Bayesian estimation using a nonlinear mixed effects (NLME) model was performed. Sparse sampling designs were evaluated using NONMEM. Results: All 20 patients successfully received PK-guided dosing, with Day -1 doses determined within 48 h. PK-guided dosing reduced AUC variability (CV 4.20-5.62%), with 19 of 20 achieving AUCs within ±10% of the target, compared to what would have been achieved by BSA dosing (CV 9.74-15.34%). NLME improved accuracy, particularly in patients with missing samples, and maintained performance using only four PK time points. Conclusions: This study demonstrates that PK-guided dosing is accurate and feasible with HDM-ASCT. NLME enhances accuracy and enables simplified sampling. Phase B will identify maximum tolerated systemic exposure of seven additional AUC cohorts using the NLME model and a four-sample design.