Evaluating the Impacts of CYP3A41B and CYP3A53 Variations on Pharmacokinetic Behavior and Clinical Outcomes in Multiple Myeloma Patients With Autologous Stem Cell Transplant

• Published in: Cancer genomics & proteomics Vol. 20; no. 1; pp. 9 - 17
• Main Authors: Li, Junan, Cho, Yu Kyoung, Sborov, Douglas W, Phelps, Mitch A, Hofmeister, Craig C, Poi, Ming J
• Format: Journal Article
• Language: English
• Published: Greece International Institute of Anticancer Research 01.01.2023
• Subjects: Autografts; Carrier density; Chromatography, Liquid; Cytochrome P-450 CYP3A - genetics; Deoxyribonucleic acid; DNA; Genotype; Genotypes; Humans; Liquid chromatography; Mass spectrometry; Mass spectroscopy; Melphalan; Melphalan - therapeutic use; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Pharmacokinetics; Pharmacology; Polymerase chain reaction; Stem Cell Transplantation; Stem cells; Tandem Mass Spectrometry; Transplantation; Variation; pharmacokinetics; melphalan; CYP3A53; CYP3A41B; Multiple myeloma
• ISSN: 1109-6535; 1790-6245
• DOI: 10.21873/cgp.20360

There exists considerably large interpatient variability in pharmacokinetic exposure of high dose melphalan in multiple myeloma patients with hematopoietic stem-cell transplantation. In this study, we aimed to evaluate the potential impacts of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) variations on pharmacokinetic properties of melphalan and clinical outcomes in multiple myeloma (MM) patients. Genotypes of CYP3A4*1B (rs2940574) and CYP3A5*3 (rs776746) were determined by validated gene-specific real-time PCR (RT-PCR) assays using DNA samples from 108 MM patients; plasma concentrations of melphalan at different time points were quantified using liquid chromatography-tandem mass spectrometry (LC-MS/MS). CYP3A4*1B/*1B and CYP3A5*3/*3 carriers appeared to have a short median progression-free survival time and a higher maximum melphalan plasma concentration than non-carriers [792 vs. over 950 days, p=0.08; 9.91 (2.67, 34.03) vs. 8.66 (4.46, 17.61) mg/l, p=0.039]. CYP3A4*1B/*1B and CYP3A5*3/*3 variations might influence melphalan therapy in MM patients through yet-to-be-identified mechanisms.