A pharmacogenetic analysis of the Canadian Cancer Trials Group MY.10 clinical trial of maintenance therapy for multiple myeloma

Han, Ming; Murugesan, Alli; Bahlis, Nizar J.; Song, Kevin; White, Darrell; Chen, Christine; Seftel, Matthew D.; Howsen-Jan, Kang; Reece, Donna; Stewart, Keith; Xie, Yazhou; Hay, Annette E.; Shepherd, Lois E.; Djurfeldt, Marina; Zhu, Liting; Meyer, Ralph M.; Chen, Bingshu E.; Reiman, Tony

doi:10.1182/blood-2016-06-716902

Cited by 4 publications

(1 citation statement)

References 24 publications

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“…Two studies examining a SNV located at -29 nucleotides of the 5′-untranslated region (5′UTR) (rs1672753 C > T) yielded contradictory results on the predominance of each allele in myelodysplastic patients, as compared to healthy controls 16,27 . More recently, this SNV was found to have a significant impact on survival outcomes in patients with MM, conferring extended PFS (P = 0.005) and OS (P = 0.023) in patients with the variant genotypes compared to those with two major alleles, independent of thalidomide therapy 28 . Another study consisting of 68 thalidomide-treated patients with MM conversely identified the major allele to be associated with significantly shorter PFS (P = 0.0321), without significantly impacting OS 29 .…”

Section: Introductionmentioning

confidence: 98%

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

Huang

Beedie

Chau

et al. 2019

Sci Rep

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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.

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Section: Introductionmentioning

confidence: 98%

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

Huang

Beedie

Chau

et al. 2019

Sci Rep

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Machine learning‐guided covariate selection for time‐to‐event models developed from a small sample of real‐world patients receiving bevacizumab treatment

Karatza

Papachristos

Sivolapenko

et al. 2022

CPT Pharmacom & Syst Pharma

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Therapeutic outcomes in patients with metastatic colorectal cancer (mCRC) receiving bevacizumab treatment are highly variable, and a reliable predictive factor is not available. Progression‐free survival (PFS) and overall survival (OS) were recorded from an observational, prospective study after 5 years of follow‐up, including 46 patients with mCRC receiving bevacizumab treatment. Three vascular endothelial growth factor (VEGF)‐A and two intercellular adhesion molecule‐1 genes polymorphisms, age, gender, weight, dosing scheme, and co‐treatments were collected. Given the relatively small number of events (37 [80%] for the PFS and 26 [57%] for the OS), to study the effect of these covariates on PFS and OS, a covariate analysis was performed using statistical and supervised machine learning techniques, including Cox regression, penalized Cox regression techniques (least absolute shrinkage and selection operator [LASSO], ridge regression, and elastic net), survival trees, and survival forest. The predictive performance of each method was evaluated in bootstrapped samples, using prediction error curves and the area under the curve of the receiver operating characteristic. The LASSO penalized Cox‐regression model showed the best overall performance. Nonlinear mixed effects (NLME) models were developed, and a conventional stepwise covariate search was performed. Then, covariates identified as important by the LASSO model were included in the base NLME models developed for PFS and OS, resulting in improved models as compared to those obtained with the stepwise covariate search. It was shown that having gene polymorphisms in VEGFA (rs699947 and rs1570360) and ICAM1 (rs1799969) are associated with a favorable clinical outcome in patients with mCRC receiving bevacizumab treatment.

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Predisposing Factors for the Development of Chemotherapy-Induced Peripheral Neuropathy (CIPN)

Hertz

Tofthagen

Faithfull

2021

Diagnosis, Management and Emerging Strategies for Chemotherapy-Induced Neuropathy

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A pharmacogenetic analysis of the Canadian Cancer Trials Group MY.10 clinical trial of maintenance therapy for multiple myeloma

Cited by 4 publications

References 24 publications

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

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

Machine learning‐guided covariate selection for time‐to‐event models developed from a small sample of real‐world patients receiving bevacizumab treatment

Predisposing Factors for the Development of Chemotherapy-Induced Peripheral Neuropathy (CIPN)

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