Abstract 5030: The impact of ABCB1 single nucleotide polymorphisms on the outcome in lenalidomide treated multiple myeloma patients
Authors: Falk Ingrid Jakobsen , Lund Johan , Gréen Henrik , Gruber Astrid , Alici Evren , Lauri Birgitta , Blimark Cecilie , Mellqvist Ulf-Henrik , Swedin Agneta , Forsberg Karin , Carlsson Conny , Hardling Mats , Ahlberg Lucia , Nahi Hareth , Lotfi Kourosh 
Published: July 2017

Abstract
Introduction: Multiple myeloma (MM) is an incurable plasma cell malignancy with high mortality rate. Treatment outcomes have improved since the introduction of new drugs such as the IMiD lenalidomide, but relapse rates and resistance is still a problem. The gene ABCB1 encodes the drug transporter p-glycoprotein (p-gp) which confers resistance through extrusion of drugs over the cell membrane. Lenalidomide is subject to limited metabolism and excreted mainly via the kidneys. In vitro studies have shown lenalidomide to be an ABCB1 substrate, and single nucleotide polymorphisms (SNPs) affecting gene expression, transporter function and/or activity may affect drug distribution and the subsequent outcome and risk of adverse events. However, in vivo studies of the effect of ABCB1 on lenalidomide pharmacokinetics are contradictory. Our aim was to investigate the influence of ABCB1 SNPs on lenalidomide treatment outcome and adverse events (AE).
Materials & Methods: In the observational part of two connected studies, 133 Lenalidomide naïve patients at 1st relapse/refractory MM were treated with lenalidomide and dexamethasone for up to 9 cycles of 4 weeks. In the prospective 2nd part, 62 patients that had achieved at least partial response according to IMWG-criteria followed by at least two additional treatment cycles were randomized to either lenalidomide/dexamethasone or lenalidomide as a single drug. 90 patients (of which 47 was further randomized to the 2nd part) had samples available for genotyping of the ABCB1 SNPs 1199G&gt;A (Ser400Asn, rs2229109), 1236C&gt;T (rs1128503), 2677G&gt;T/A (Ala893Ser, rs2032582) and 3435C&gt;T (rs1045642) using Pyrosequencing. Correlations to overall survival, time to progression (TTP), response parameters and AE were investigated, and a p-value of 0.05 was considered significant.
Results: No significant correlations to hematological AE or response rates were found, and no impact on survival for 1236C&gt;T, 2677G&gt;T/A or 3435C&gt;T, neither in the whole population nor in patients randomized to the 2nd part. The results were similar also when risk (according to FISH) was considered. There was a trend towards improved TTP for patients carrying the 1199A variant; mean TTP 3.2 years (95%CI 2.3-4.1) vs 2.2 years (95%CI 1.8-2.6) for G/A and G/G, respectively (p=0.076). This trend was confirmed in the multivariable cox regression analysis; HR=0.280 (95%CI 0.74-1.054), p=0.06. The difference in TTP was significant in the non-high risk subgroup; mean TTP 4.3 years (95%CI 3.7-4.9) vs 2.3 years (95%CI 1.8-2.8), p=0.034, for G/A and G/G, respectively.
Conclusion: No evidence was found for a large impact of 1236C&gt;T, 2677G&gt;T/A or 3435C&gt;T on lenalidomide treatment outcome or risk of hematological AE. 1199G&gt;A may be a potential marker of TTP in non-high risk MM but further studies in a larger cohort is needed to clarify the relationship and whether this is due to altered drug transport or efflux independent mechanisms.
Citation Format: Ingrid Jakobsen Falk, Johan Lund, Henrik Gréen, Astrid Gruber, Evren Alici, Birgitta Lauri, Cecilie Blimark, Ulf-Henrik Mellqvist, Agneta Swedin, Karin Forsberg, Conny Carlsson, Mats Hardling, Lucia Ahlberg, Hareth Nahi, Kourosh Lotfi. The impact of ABCB1 single nucleotide polymorphisms on the outcome in lenalidomide treated multiple myeloma patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5030. doi:10.1158/1538-7445.AM2017-5030