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

• Published in: Scientific reports 2019-10, Vol.9 (1), p.14884-7, Article 14884
• Main Authors: Huang, Phoebe A., Beedie, Shaunna L., Chau, Cindy H., Venzon, David J., Gere, Sheryl, Kazandjian, Dickran, Korde, Neha, Mailankody, Sham, Landgren, Ola, Figg, William D.
• Format: Article
• Language: English
• Subjects: 45/22; 45/23; 45/29; 45/77; 631/208/721; 631/67/1059/602; 631/67/1990/804; 692/53/2423; Adaptor Proteins, Signal Transducing - antagonists & inhibitors; Adaptor Proteins, Signal Transducing - genetics; Adaptor Proteins, Signal Transducing - metabolism; Antineoplastic Combined Chemotherapy Protocols - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - adverse effects; Clinical outcomes; Dexamethasone; Dexamethasone - administration & dosage; Dexamethasone - adverse effects; Drug Administration Schedule; Female; Gene Expression; Genotype; Humanities and Social Sciences; Humans; Hyperbilirubinemia; Hyperbilirubinemia - chemically induced; Hyperbilirubinemia - diagnosis; Hyperbilirubinemia - physiopathology; Hypoalbuminemia - chemically induced; Hypoalbuminemia - diagnosis; Hypoalbuminemia - physiopathology; Immunotherapy; Lenalidomide - administration & dosage; Lenalidomide - adverse effects; Male; Middle Aged; multidisciplinary; Multiple myeloma; Multiple Myeloma - drug therapy; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Oligopeptides - administration & dosage; Oligopeptides - adverse effects; Patients; Polymorphism, Single Nucleotide; Population studies; Prospective Studies; Science; Science (multidisciplinary); Targeted cancer therapy; Treatment Outcome; Ubiquitin-Protein Ligases
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-019-51446-9

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.