Associations of High‐Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial

Abstract

High dose melphalan followed by autologous stem cell transplantation remains standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 hours) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate 2-hour is at least as effective as 6-hour cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified fat free mass, hematocrit, and creatinine clearance were significant covariates, as had been reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.

Pharmacogenetics‐based population pharmacokinetic analysis of gabapentin in patients with chronic pain: Effect of OCT2 and OCTN1 gene polymorphisms

“…The SNP rs1060250 (N230K) did not change the transport of phenylalanine . On the other hand, the SNP rs4240803 was associated with melphalan toxicity and had a significant effect on melphalan distribution to the peripheral compartment …”

Pharmacokinetic‐Pharmacodynamic Model of Neutropenia in Patients With Myeloma Receiving High‐Dose Melphalan for Autologous Stem Cell Transplant

“…The clinical and PK portions of this study were recently published . Briefly, blood samples and peripheral blood mononuclear cells (PBMCs) were collected from 119 patients (69 men and 50 women) enrolled on OSU11055 (NCT01653106).…”

“…SLC7A5 genotype (coded as 0 or 1 if patients had AA/AG or GG genotype, respectively) data were collected from PBMCs, as described previously …”

XRCC1‐mediated DNA repair is associated with progression‐free survival of multiple myeloma patients after autologous stem cell transplant

“…As effective drug concentration may also affect treatment response, further clinical studies to assess pharmacokinetics‐pharmacodynamics of melphalan and genetic alterations in these DNA repair/damage response genes in ASCT‐HDM setting in a larger patient cohort are imperative to verify the findings observed in this study. Once these observations are validated, a personalized melphalan dose in ASCT based on the patient's genetic susceptibility and PK/PD models of melphalan may improve the current “one‐size fits all” dosing approach for ASCT in MM, thus providing a platform for risk stratification and optimal dosing for this critical yet highly toxic treatment modality. New knowledge gained to understand and predict favorable response to ASCT‐HDM may enable patients who are otherwise deemed unfit or avoiding ASCT to receive an effective treatment for MM.…”

“…PBMCs from 108 MM patients who underwent melphalan‐based autologous stem cell transplant as part of a prospective clinical trial were procured following approval from the Cancer Institutional Research Board's guidance (IRB#2011C0080, NCT01653106) . Briefly, approximately 24 mL of venous blood were obtained in green top (heparin) tubes within 2 hours before the intravenous infusion of high‐dose melphalan (200 or 140 mg/m 2 ), and autologous stem cell transplant occurred 1 day afterward.…”