Associations of High-Dose Melphalan Pharmacokinetics and Outcomes in the Setting of a Randomized Cryotherapy Trial.
High-dose melphalan followed by autologous stem cell transplantation remains the 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 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2-h is at least as effective as 6-h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat-free mass, hematocrit, and creatinine clearance were significant covariates, as 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.
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Y K
YK
Cho
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
D W
DW
Sborov
Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
M
M
Lamprecht
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
J
J
Li
Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
J
J
Wang
Center for Biostatistics, Department of Biomedical Informatics, The Ohio State University, Columbus, Ohio, USA.
E M
EM
Hade
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
Y
Y
Gao
Wexner Medical Center, The Ohio State University, Columbus, Ohio, USA.
K
K
Tackett
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
N
N
Williams
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
D M
DM
Benson
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
Y A
YA
Efebera
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
A E
AE
Rosko
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
S M
SM
Devine
Division of Pharmacy Practice and Science, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.
M
M
Poi
Division of Hematology, Department of Internal Medicine, The Ohio State University, Columbus, Ohio, USA.
C C
CC
Hofmeister
Division of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, Ohio, USA.|Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio, USA.
M A
MA
Phelps
D000328:Adult; D000368:Aged; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D003131:Combined Modality Therapy; D003404:Creatinine / Q000378:metabolism; D017679:Cryotherapy / Q000379:methods*; D018572:Disease-Free Survival; D004305:Dose-Response Relationship, Drug; D005260:Female; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D027283:Large Neutral Amino Acid-Transporter 1 / Q000235:genetics; D008297:Male; D008558:Melphalan / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D008875:Middle Aged; D009101:Multiple Myeloma / Q000628:therapy*; D011110:Polymorphism, Genetic; D013280:Stomatitis / Q000139:chemically induced / Q000517:prevention & control*; D015996:Survival Rate; D013997:Time Factors
D018906:Antineoplastic Agents, Alkylating; D027283:Large Neutral Amino Acid-Transporter 1; D003404:Creatinine; D008558:Melphalan