A Single Nucleotide Polymorphism (SNP) in the SLC22A3 Transporter Gene Is Associated With the Severity of Oral Mucositis in Multiple Myeloma Patients Receiving Autologous Stem Cell Transplant Followed by Melphalan Therapy

Abstract

Background: It has been reported that expressionof OCT3 enhanced the sensitivity to melphalan in cells, indicative of potential roles of OCT3 in melphalan transport. Herein we investigated the association of select single nucleotide polymorphisms in SLC22A3 (gene encoding OCT3) with clinical outcomes in multiple myeloma (MM) patients with hematopoietic autologous stem cell transplants followed by high-dose melphalan therapy. Materials and Methods: Melphlan concentrations in blood samples from 108 MM patients were measured using liquid chromatography-tandem mass spectrometry (LC-MS/ΜS); genotypes of rs2048327, rs1810126, and rs3088442 in these patients were determined using quatitive RT-PCR assays. Results: Rs3088442 A variantcarriers had a significantly increased risk of severe oral mucositis in comparison with homozygous rs3088442 G-carriers with adjusted odds ratio of 4.00 (95% CI=1. 25-14.7; p=0.027). Rs3088442 A carriers tended to have lower creatinine clearance (p=0.10) and higher maximum plasma concentration of melphalan (p=0.07). Conclusion: OCT3 might be involved in melphalan transport in MM patients.Multiple myeloma (MM) represents the 2 nd most common hematological malignancy characterized by a pattern of recurrent relapses and remains incurable due to resistance and relapse in almost all patients (1). Hematopoietic autologous stem cell transplant (HSCT) with high-dose intravenous melphalan (HDM) remains the "gold" standard of care and the most effective treatment for transplant-eligible patients (2-5). Notably, there are considerable variations among MM patients in regard to the efficacy of autoHSCT-HDM therapy and melphalan-induced side-effects. On one hand, about 20% of patients exhibit resistance to melphalan, as demonstrated by progression-free survival (PFS) much shorter than the PFS of the majority of MM patients, which is partially ascribed to inadequate dosing (6, 7). On the other hand, some patients suffered from severe adverse effects, such as oral mucositis, gastrointestinal toxicity, and infection, which arguably result from excessive dosing (8-12). Since the standard 200 mg/m 2 of melphalan is used in most MM patients (for some patients with severe renal dysfunction, 140 mg/m 2 ), the ability for melphalan to be metabolized in patients appears to be closely related to clinical outcomes (responses and adverse effects) (8,11). To date, it has been known that hydrolysis and renal 385 This article is freely accessible online. # Jasmine A. Johnson was an undergraduate student at the College of Pharmacy, The Ohio State University when this study was undertaken.