Myeloma :: Bank on a Cure researchers identify pathways mediating myeloma treatment side effects

Thalidomide is a widely prescribed treatment for multiple myeloma. However, an estimated 15 to 30 percent of patients suffer venous thromboembolisms (VTEs), blood clots, as a major complication. The Bank On A Cure DNA-bank researchers have identified four gene clusters associated with the VTEs. Identifying the associated single nucleotide polymorphisms (SNPs) for use as markers, may lead to the development of screenings and tailored interventions to prevent these side effects, as a major step toward personalized medicine.

Orlando, FL and North Hollywood, CA, December 11, 2006 ? Researchers with the International Myeloma Foundation’s Bank On A Cure? (BOAC), the world’s first repository of DNA samples created to advance the understanding of myeloma, today presented data identifying genetic pathways that may explain why some patients suffer from blood clots when undergoing treatment with thalidomide for multiple myeloma. The pathways may shed new light on individual differences in the response to cancer and its treatment, and may lead to the development of screenings and tailored interventions to prevent these side effects. The data were presented at the 48th Annual Meeting of the American Society of Hematology (ASH)1.

Thalidomide (Thalomid? from the Celgene Corporation in the U.S.) is a widely prescribed treatment for multiple myeloma that has been shown to extend and improve the quality of life for myeloma patients. However, an estimated 15% to 30% of patients treated with thalidomide suffer venous thromboembolisms (VTEs), blood clots, as a major complication. The BOAC team looked at genetic differences between patients who suffered from blood clots and those who remained event-free, and identified four gene clusters associated with the VTEs, as well as the specific changes within the genes, single nucleotide polymorphisms or SNPs, that can be used as markers to predict which patients are most likely to experience blood clots.

“We identified genes involved with drug metabolism, DNA repair and inflammation as differentiating factors predictive for which patients are more likely to experience VTEs,” said Gareth Morgan, M.D., of the Royal Marsden Hospital in London, and co-director of BOAC. “It is important to note that we did not find genes involved with the blood coagulation cascade as a differentiating risk factor for the blood clots, as might have been expected. These findings will help us better understand the mechanisms that cause this problem.”

Brian Van Ness, Ph.D., of the University of Minnesota, and co-director of BOAC, added, “Identifying these pathways is the first step toward telling us who is at risk. Our next step is to build this genetic data into a clinical risk model so we can develop screens to predict how an individual patient will respond to treatment, and apply appropriate intervention strategies.”

The genes identified are involved with inflammation, which has been shown to link the immune system to clotting mechanisms. Other genes identified are involved with the rapid tumor reduction achieved by thalidomide that can in turn release cytokines and other tissue factors, which increase the risk of thrombosis, or clots. The genes were validated using a custom panel of 3,404 SNPs developed by BOAC working with Affymetrix.

Brian G. M. Durie, M.D., chairman of the International Myeloma Foundation noted, “In a separate presentation2 from the Myeloma Working Group, we recommend aspirin as a prophylactic treatment for blood clots in these patients treated with thalidomide as well as myeloma patients who are treated with REVLIMID. The BOAC finding helps explain the mechanism by which aspirin works in these patients, even though aspirin’s familiar affect on platelets is not involved. However, at certain dose levels aspirin affects the inflammation pathways and the BOAC research shows that genes related to inflammation do contribute to the VTEs.”

While these are the most advanced findings from BOAC, the researchers are also using the custom chip to identify SNPs as potential prognostic markers to predict survival outcomes. Early analysis of this research, also presented at ASH,3 is showing there may be detectable genetic differences between short and long term survivors. From these findings it may be possible to better predict which patients will need more aggressive therapies when they start their treatment.

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