Cereblon gene variants and clinical outcome in multiple myeloma patients treated with lenalidomide

Abstract

Carfilzomib-lenalidomide-dexamethasone (KRd) therapy has yielded promising results in patients with newly diagnosed multiple myeloma (NDMM). Cereblon (CRBN) is the direct molecular target of lenalidomide and genetic polymorphisms in CRBN have been associated with lenalidomide efficacy. In this study, we assessed the correlation of five single nucleotide variants (SNVs) in the CRBN gene with clinical response and outcomes in patients with NDMM administered KRd therapy with lenalidomide maintenance, achieving favorable trial endpoints in a prospective Phase II study (NCT01402284). Of the observed SNVs, no associations with KRd therapy response were found in this patient cohort, although strong trends in hypoalbuminemia grade and hyperbilirubinemia grade emerged across the CRBN rs1672753 genotype (P = 0.0008) and the rs1714327 genotype (P = 0.0010), respectively. Our results do not provide conclusive support for the predictive utility of CRBN gene polymorphisms as potential biomarkers of clinical response to lenalidomide-based therapy in our patient population. However, these findings remain to be validated in prospective studies using larger patient populations.

ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment

“…Moreover, we and others (24) have also identified novel binding protein of IMiDs, such as TP53regulating kinase, which may broaden their clinical utility. However, most MM cells eventually acquire resistance to IMiDs, which has, to date, been attributed to decreased expression of CRBN and rarely CRBN mutations (50,51). Defining mechanisms underlying clinical resist ance to IMiDs is therefore essential to inform the design of novel strategies to restore and/or enhance IMiD sensistivity and improve patient outcome.…”

A Tangle of Genomic Aberrations Drives Multiple Myeloma and Correlates with Clinical Aggressiveness of the Disease: A Comprehensive Review from a Biological Perspective to Clinical Trial Results

“…Recent studies recognized an association between CRBN expression levels and response to IMIDs in MM. Therefore, SNVs in the CRBN gene have been investigated, but their role remains controversial due to the small number of patients [50,51].…”

Evaluation of the influence of genetic variants in Cereblon gene on the response to the treatment of ENL with thalidomide

“…This molecule is part of an E3-ubiquitin ligase complex (CRL4 CRBN ), acting as a substrate receptor that recognizes speci c targets for ubiquitination, leading to further degradation by the ubiquitin-proteasome system 14 . More recently, it was shown that CRBN is necessary for the e cacy of thalidomide and its analogs lenalidomide and pomalidomide (named immunomodulatory drugs -IMiDs) in the treatment of MM [15][16][17][18][19] . Several studies have investigated the Thalidomide-CRBN interaction with regard to the teratogenic, immunomodulatory and therapeutic effects of the drug.…”