Genetic associations with thalidomide mediated venous thrombotic events in myeloma identified using targeted genotyping

Abstract

A venous thromboembolism (VTE) with the subsequent risk of pulmonary embolism is a major concern in the treatment of patients with multiple myeloma with thalidomide. The susceptibility to developing a VTE in response to thalidomide therapy is likely to be influenced by both genetic and environmental factors. To test genetic variation associated with treatment related VTE in patient peripheral blood DNA, we used a custom-built molecular inversion probe (MIP)-based single nucleotide polymorphism (SNP) chip containing 3404 SNPs. SNPs on the chip were selected in "functional regions" within 964 genes spanning 67 molecular pathways thought to be involved in the pathogenesis, treatment response, and side effects associated with myeloma therapy. Patients and controls were taken from 3 large clinical trials: Medical Research Council (MRC) Myeloma IX, Hovon-50, and Eastern Cooperative Oncology Group (ECOG) EA100, which compared conventional treatments with thalidomide in patients with myeloma. Our analysis showed that the set of SNPs associated with thalidomide-related VTE were enriched in genes and pathways important in drug transport/metabolism, DNA repair, and cytokine balance. The effects of the SNPs associated with thalidomide-related VTE may be functional at the level of the tumor cell, the tumor-related microenvironment, and the endothelium. The clinical trials described in this paper have been registered as follows: MRC Myeloma IX: ISRCTN68454111; Hovon-50: NCT00028886; and ECOG EA100: NCT00033332.

Figure 1

Simplified treatment arms of ECOG EA100, Hovon-50, and Myeloma IX studies.

Figure 2

Venn diagram showing overlapping VTE-associated genes between thalidomide Myeloma IX, non-thalidomide Myeloma IX, and thalidomide Hovon-50/ECOG EA100 analyses.

Figure 3

Forest plots showing distribution of validated SNPs associated with thalidomide-related VTEs across the Myeloma IX, Hovon-50, and ECOG EA100 trials. Error bars indicate upper and lower 95% CIs.

Figure 4

Predictive tree of thalidomide-related thrombosis in myeloma patients following recursive partitioning analysis.

Figure 5

Thalidomide treatment in combination with alkylating agents in myeloma promotes prothrombotic conditions at the endothelium surface via a combination of mechanisms. Mechanisms include rapid apoptosis of myeloma cells leading to circulating tissue factor (TF), exposed TF by endothelium cells salvaged from apoptosis, increased circulating cytokines (eg, TNFα) with T-cell activation by antigen-presenting cells (APCs), and activated platelets in response to increased circulating cytokines.