Population Pharmacokinetic Estimation of Melphalan Exposure Predicts Disease Control and Toxicity after Autologous Hematopoietic Cell Transplantation for Multiple Myeloma.

High-dose therapy (HDT) with melphalan followed by autologous hematopoietic cell transplantation (AHCT) remains standard for multiple myeloma (MM) consolidation. However, body surface area-based dosing results in interpatient variability in exposure, which may affect efficacy and toxicity. We retrospectively studied patients with MM who underwent AHCT and had serial melphalan concentrations measured after HDT. Melphalan area under the concentration-time curve (AUC) was calculated using non-compartmental analysis (NCA) and estimated using a two-compartment population pharmacokinetic (pop PK) model. 148 patients were included; median follow-up was 6.3 years. Median melphalan AUC was 12.7 mg*h/L by NCA and 14.0 mg*h/L by pop PK, with significant correlation between methods (r=0.64, P<0.001). Patients with NCA AUC equal to or above the median had superior 12- and 24-month progression-free survival compared with those below the median (75% vs 62% and 60% vs 44%, P=0.019). Pop PK AUC showed a similar trend (76% vs 61% and 57% vs 47%, P=0.11). Overall survival and non-relapse mortality did not differ by exposure. Higher exposure was associated with longer hospitalization, neutropenic fever days and more CTCAE v5.0 grade ≥3 nonhematologic toxicities. Higher pop PK AUC was associated with overall response at day 100 (OR 2.94, 95% CI, 1.04-9.60, P=0.041). Higher exposure by NCA and pop PK was also associated with day 100 measurable residual disease negativity (OR 0.47, 95% CI 0.23-0.96, P=0.038 and OR 0.40, 95% CI 0.19-0.81, P=0.011, respectively). These findings support prospective evaluation of pop PK-guided melphalan dosing to define an exposure range that optimizes efficacy while limiting toxicity.