Cereblon (CRBN) Gene Polymorphisms Predict Clinical Response and Progression-Free Survival in Multiple Myeloma Patients Treated with Lenalidomide: A Pharmacogenetic Study of Immense Consortium

Abstract

Background: Cereblon (CRBN), a subunit of cullin 4-based E3 ubiquitine ligase complex, has been characterized as the main immunomodulatory drugs (IMiDs), thalidomide, lenalidomide and pomalidomide, binding protein that is crucial for their antiproliferative and immunomodulatory properties. Several recent reports have suggested that CRBN gene and protein expression or alternative splicing affect sensitivity to IMiDs in multiple myeloma (MM). It can be speculated that CRBN expression level, alternative splicing or CRBN-E3 ubiquitine ligase substrate specificity in MM and microenvironment cells may be partially determined by inherited genetic background including functional single nucleotide polymorphisms (SNPs). Aim: The objective of this study was to verify whether naturally occurring SNPs in CRBN encoding CRBNgene (locus chromosome 3p26.2) may influence outcome of lenalidomide-based therapy in patients with MM. Methods: We genotyped 14 tagging SNPs in CRBN gene in 169 Polish Caucasian patients with refractory/relapsed MM treated with lenalidomide-based therapy. Among these patients 151 (89%) received lenalidomide/dexamethasone (Len-Dex) regimen while the remaining patients were treated with lenalidomide-based three drug combinations. Genomic DNA samples were collected and genotyped in the context of the IMMEnSE consortium. The influence of CRBNallelic variants on probability to achieve clinical response (at least partial response, PR) to lenalidomide-based therapy, achievement of complete response (CR), duration of progression-free survival (PFS) and overall survival (OS) were tested in regard to established clinical and laboratory predictive factors using logistic regression and proportional-hazards regression models. For all genotyped SNPs co-dominant, dominant and recessive inheritance modes were tested. Results: We found that carriers of minor alleles of two studied SNPs, namely CRBN rs1714327G>C and CRBN rs1705814T>C significantly associated with lower probability of achievement of clinical response (≥PR) to lenalidomide-based therapy using dominant inheritance model (OR=0.25, 95%CI 0.10-0.63; p=0.0033, Bonferroni corrected p=0.019 and OR=0.21, 95%CI 0.07-0.61; p=0.0041, Bonferroni corrected p=0.024, respectively). Moreover, in concordance with these findings one of these two SNPs, namely CRBN rs1705814T>C, was also significantly associated with shorter PFS in the analyzed group of lenalidomide treated MM patients (OR=2.49; 95%CI 1.31-4.74; P=0.0054, Bonferroni corrected p=0.032). In contrast, none of the tested allelic variants of CRBN showed significant influence on OS. Conclusions: Taken together, our observations suggest that selected germline CRBN SNPs (rs1714327G>C and rs1705814T>C) affect lenalidomide efficacy in relapsed/refractory MM. Further studies are needed to explain functional mechanisms underlying these associations as well as to establish whether CRBN genetic variants may be useful as potential biomarkers for IMiDs-based therapy. Acknowledgments: This work was supported by the grants of Polish Young Heamatologists Club and Polish Myeloma Consortium. The work of Pawe³ Gaj was supported by a grant from the European Commission 7th Framework Programme: FP7-REGPOT-2012-CT2012-316254-BASTION Disclosures No relevant conflicts of interest to declare.

Polymorphisms in the promotor region of the CRBN gene as a predictive factor for peripheral neuropathy in the course of thalidomide‐based chemotherapy in multiple myeloma patients

“…There are a few similar studies performed on MM patients. At the 56th American Society of Hematology Conference, Iskierka‐Jazdzewska et al () presented data describing 169 relapsed/refractory multiple myeloma (RRMM) patients treated with lenalidomide‐based regimen. Patients were evaluated for the effect of 14 selected SNPs located in the CRBN gene coding region.…”

“…The rs1714327 G>C and rs1705814 T>C polymorphisms were associated with significantly lower probability of response to treatment ≥ partial response (OR = 0·25, P = 0·0033 and OR = 0·21, P = 0·0041). In addition, one of these genotypes (rs1705814 T>C) was also associated with shorter PFS (OR = 2·49, P = 0·0054) (Iskierka‐Jazdzewska et al , ). Butrym et al () did not find an association between the CRBN rs121918368 C>T polymorphism and response to immunomodulating therapy in patients diagnosed with MM.…”

Polymorphisms in the promoter region of the CRBN gene as a predictive factor for the first-line CTD therapy in multiple myeloma patients

“…Two of the polymorphisms (rs1714327G>C and rs1705814T>C) were associated with significantly lower probability of response to treatment ≥ PR (OR = 0.25, 95% CI 0.10-0.63; p = 0.0033 and OR = 0.21, 95% CI 0.07- 0.61; p = 0.0041). In addition, one of these SNPs, namely rs1705814T>C, was also associated with shorter PFS (OR = 2.49; 95% CI 1.31-4.74; p = 0.0054) [ 36 ]. Butrym et al analyzed two selected SNPs found in the non-coding regions of the CRBN gene (rs711613, rs1045433) in the context of response to treatment in patients diagnosed with MM.…”

Vertebrate embryos as tools for anti-angiogenic drug screening and function

“…Zebrafish with non-functional cereblon do not produce the fin defects when exposed to thalidomide, suggesting that thalidomide-induced teratogenicity may occur by binding to the cereblon complex [71]. Since this finding, several clinical reports have shown a correlation between cereblon expression and the response to thalidomide, and its analogs lenalidomide and pomalidomide in the adult condition, multiple myeloma [72–75].…”