PMID- 29177954
OWN - NLM
STAT- MEDLINE
DCOM- 20190204
LR  - 20190215
IS  - 1432-0843 (Electronic)
IS  - 0344-5704 (Print)
IS  - 0344-5704 (Linking)
VI  - 81
IP  - 1
DP  - 2018 Jan
TI  - 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.
PG  - 183-193
LID - 10.1007/s00280-017-3481-8 [doi]
AB  - 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>A (Ser400Asn, rs2229109), 1236C>T (silent, 
      rs1128503), 2677G>T/A (Ala893Ser, rs2032582), and 3435C>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>T, 
      2677G>T or 3435C>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>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.
FAU - Jakobsen Falk, Ingrid
AU  - Jakobsen Falk I
AUID- ORCID: 0000-0003-4450-0333
AD  - Division of Drug Research, Department of Medical and Health Sciences, Linkoping 
      University, Linkoping, Sweden. Ingrid.jakobsen.falk@liu.se.
FAU - Lund, Johan
AU  - Lund J
AD  - Unit for Hematology, Department of Medicine, Karolinska Institute, Huddinge, 
      Sweden.
FAU - Green, Henrik
AU  - Green H
AD  - Division of Drug Research, Department of Medical and Health Sciences, Linkoping 
      University, Linkoping, Sweden.
AD  - Department of Forensic Genetics and Forensic Toxicology, National Board of 
      Forensic Medicine, Linkoping, Sweden.
FAU - Gruber, Astrid
AU  - Gruber A
AD  - Unit for Hematology, Department of Medicine, Karolinska Institute, Huddinge, 
      Sweden.
FAU - Alici, Evren
AU  - Alici E
AD  - Unit for Hematology, Department of Medicine, Karolinska Institute, Huddinge, 
      Sweden.
FAU - Lauri, Birgitta
AU  - Lauri B
AD  - Department of Internal Medicine, Sunderby Hospital, Lulea, Sweden.
FAU - Blimark, Cecilie
AU  - Blimark C
AD  - Hematology Department, Sahlgrenska University Hospital, Gothenburg, Sweden.
FAU - Mellqvist, Ulf-Henrik
AU  - Mellqvist UH
AD  - Division for Haematology, Oncology and Lung, Department of Medicine, South 
      Elvsborg Hospital, Boras, Sweden.
FAU - Swedin, Agneta
AU  - Swedin A
AD  - Hematology Department, Skane University Hospital, Lund, Sweden.
FAU - Forsberg, Karin
AU  - Forsberg K
AD  - Department of Hematology, Norrland University Hospital, Umea, Sweden.
FAU - Carlsson, Conny
AU  - Carlsson C
AD  - Department of Internal Medicine, Hallands Hospital, Halmstad, Sweden.
FAU - Hardling, Mats
AU  - Hardling M
AD  - Department of Hematology, Uddevalla Hospital, Uddevalla, Sweden.
FAU - Ahlberg, Lucia
AU  - Ahlberg L
AD  - Department of Hematology, Linkoping University Hospital, Linkoping, Sweden.
FAU - Lotfi, Kourosh
AU  - Lotfi K
AD  - Division of Drug Research, Department of Medical and Health Sciences, Linkoping 
      University, Linkoping, Sweden.
AD  - Department of Hematology, Linkoping University Hospital, Linkoping, Sweden.
FAU - Nahi, Hareth
AU  - Nahi H
AD  - Unit for Hematology, Department of Medicine, Karolinska Institute, Huddinge, 
      Sweden.
LA  - eng
PT  - Clinical Trial, Phase II
PT  - Clinical Trial, Phase IV
PT  - Journal Article
PT  - Multicenter Study
PT  - Observational Study
PT  - Research Support, Non-U.S. Gov't
DEP - 20171125
PL  - Germany
TA  - Cancer Chemother Pharmacol
JT  - Cancer chemotherapy and pharmacology
JID - 7806519
RN  - 0 (ABCB1 protein, human)
RN  - 0 (ATP Binding Cassette Transporter, Subfamily B)
RN  - 0 (Antineoplastic Agents)
RN  - F0P408N6V4 (Lenalidomide)
SB  - IM
MH  - ATP Binding Cassette Transporter, Subfamily B/genetics
MH  - Adult
MH  - Aged
MH  - Aged, 80 and over
MH  - Antineoplastic Agents/adverse effects/*therapeutic use
MH  - Disease Progression
MH  - Female
MH  - Humans
MH  - Lenalidomide/adverse effects/*therapeutic use
MH  - Male
MH  - Middle Aged
MH  - Multiple Myeloma/*drug therapy/*genetics
MH  - *Pharmacogenomic Testing
MH  - *Polymorphism, Single Nucleotide
MH  - Prospective Studies
MH  - Skin Diseases/chemically induced
MH  - Treatment Outcome
PMC - PMC5754426
OTO - NOTNLM
OT  - Genetic markers
OT  - Lenalidomide
OT  - Multiple myeloma
OT  - P-Glycoprotein
OT  - Single-nucleotide polymorphisms
COIS- CONFLICT OF INTEREST: MH has received personal fees from Celgene, Janssen, Amgen, 
      and Takeda. U-HM has received honoraria from Amgen, Novartis, Celgene, and 
      Mundipharma, and has served on advisory boards for Amgen and Takeda. The 
      remaining authors declare no competing financial interests. ETHICAL APPROVAL: All 
      procedures performed in studies involving human participants were in accordance 
      with the ethical standards of the institutional and/or national research 
      committee and with the 1964 Helsinki declaration and its later amendments or 
      comparable ethical standards.
EDAT- 2017/11/28 06:00
MHDA- 2019/02/05 06:00
PMCR- 2017/11/25
CRDT- 2017/11/28 06:00
PHST- 2017/05/29 00:00 [received]
PHST- 2017/11/12 00:00 [accepted]
PHST- 2017/11/28 06:00 [pubmed]
PHST- 2019/02/05 06:00 [medline]
PHST- 2017/11/28 06:00 [entrez]
PHST- 2017/11/25 00:00 [pmc-release]
AID - 10.1007/s00280-017-3481-8 [pii]
AID - 3481 [pii]
AID - 10.1007/s00280-017-3481-8 [doi]
PST - ppublish
SO  - Cancer Chemother Pharmacol. 2018 Jan;81(1):183-193. doi: 
      10.1007/s00280-017-3481-8. Epub 2017 Nov 25.