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Pharmacogenetic study of the impact of ABCB1 single-nucleotide polymorphisms on lenalidomide treatment outcomes in patients with multiple myeloma: results from a phase IV observational study and subsequent phase II clinical trial
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences.ORCID iD: 0000-0003-4450-0333
Karolinska Institute, Sweden.
Linköping University, Department of Medical and Health Sciences, Division of Drug Research. Linköping University, Faculty of Medicine and Health Sciences. National Board Forens Med, Department Forens Genet and Forens Toxicol, Linkoping, Sweden.
Karolinska Institute, Sweden.
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2018 (English)In: Cancer Chemotherapy and Pharmacology, ISSN 0344-5704, E-ISSN 1432-0843, Vol. 81, no 1, p. 183-193Article in journal (Refereed) Published
Abstract [en]

Purpose Despite therapeutic advances, patients with multiple myeloma (MM) continue to experience disease relapse and treatment resistance. The gene ABCB1 encodes the drug transporter P-glycoprotein, which confers resistance through drug extrusion across the cell membrane. Lenalidomide (Len) is excreted mainly via the kidneys, and, given the expression of P-gp in the renal tubuli, single-nucleotide polymorphisms (SNPs) in the ABCB1 gene may influence Len plasma concentrations and, subsequently, the outcome of treatment. We, therefore, investigated the influence of ABCB1 genetic variants on Len treatment outcomes and adverse events (AEs). Methods Ninety patients with relapsed or refractory MM, who received the second-line Len plus dexamethasone in the Rev II trial, were genotyped for the ABCB1 SNPs 1199G amp;gt; A (Ser400Asn, rs2229109), 1236C amp;gt; T (silent, rs1128503), 2677G amp;gt; T/A (Ala893Ser, rs2032582), and 3435C amp;gt; T (silent, rs1045642) using pyrosequencing, and correlations to response parameters, outcomes, and AEs were investigated. Results No significant associations were found between genotype and either best response rates or hematological AEs, and 1236C amp;gt; T, 2677G amp;gt; T or 3435C amp;gt; T genotypes had no impact on survival. There was a trend towards increased time to progression (TTP) in patients carrying the 1199A variant, and a significant difference in TTP between genotypes in patients with standard-risk cytogenetics. Conclusions Our findings show a limited influence of ABCB1 genotype on lenalidomide treatment efficacy and safety. The results suggest that 1199G amp;gt; A may be a marker of TTP following Len treatment in standard-risk patients; however, larger studies are needed to validate and clarify the relationship.

Place, publisher, year, edition, pages
SPRINGER , 2018. Vol. 81, no 1, p. 183-193
Keywords [en]
Lenalidomide; Multiple myeloma; Genetic markers; Single-nucleotide polymorphisms; P-Glycoprotein
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:liu:diva-144446DOI: 10.1007/s00280-017-3481-8ISI: 000419437500019PubMedID: 29177954OAI: oai:DiVA.org:liu-144446DiVA, id: diva2:1176583
Note

Funding Agencies|Swedish Cancer Society; Swedish Research Council; AFA Insurance; Linkoping University; ALF Grants, Region Ostergotland; Celgene Corporation

Available from: 2018-01-22 Created: 2018-01-22 Last updated: 2018-02-21

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Jakobsen Falk, IngridGreen, HenrikAhlberg, LuciaLotfi, Kourosh
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