Genetic test helps identify risk for more aggressive disease, improving myeloma treatment

Testing for genetic risk factors could improve treatment for myeloma by helping doctors identify patients at risk of developing more aggressive disease. New research, published in the Journal of Clinical Oncology (2015; doi:10.1200/JCO.2014.59.1503), found as few as nine genetic features would need to be tested to identify high-risk patients who might benefit from intensive treatment.

The study, led by researchers at The Institute of Cancer Research, London, United Kingdom, is the first to link genetic mutations in myeloma cells to the chances of surviving the disease. Myeloma is a cancer of the blood and bone marrow.

Funding for this research was provided by Myeloma UK, Cancer Research UK, the NIHR Biomedical Research Centre at The Royal Marsden NHS Foundation Trust, and The Institute of Cancer Research (ICR).

Researchers used genetic sequencing to analyze all of the genes of 463 patients enrolled in the Myeloma XI clinical trial. The study identified 15 genes that were significantly mutated in a subset of patients with myeloma and mapped how having these mutations related to long-term survival.

The researchers found that testing for nine of these mutated genes, in combination with a test to determine the stage of myeloma, identified 90% of patients with very aggressive disease who died prematurely.

Myeloma patients with mutations within their cancers in the CCND1 gene, which helps control cell division, were more likely to have severe forms of disease than those without. Only 38% of patients with mutations in CCND1 survived longer than 2 years, compared with 80% of patients without faults in this gene.

DNA repair gene TP53 was found to be faulty in 11% of the patients, and was also associated with a shorter survival time, as 54% of patients with TP53 mutations survived more than 2 years.

The most common genetic faults in myeloma were found to be errors in members of the RAS gene family, one of which was discovered at the ICR, and which are defective in many cancer types. The researchers discovered mutations in the genes NRAS and KRAS in 43% of patients, which suggests that in myeloma RAS mutations drive cells to become cancerous, and potentially opening up new avenues for treatment.

Strikingly, more than 50% of the mutations identified in this study can be targets of new cancer drugs or existing drugs developed for other cancer types, which opens up potential new avenues for targeted treatment.

The scientists also found that patients with myeloma who had errors in some genes had a more favorable outlook. All the patients in the study with mutations in the genes IRF4 and EGR1 survived more than 2 years, compared with 79% and 78% of patients with error-free copies of the genes, respectively.

"Our study has identified genetic features which can identify those patients whose myeloma is likely to prove aggressive and to progress quickly,” said study leader Professor Gareth Morgan, MD, PhD, of The Institute of Cancer Research. "We hope our study ultimately paves the way for genetic testing to pick out the minority of patients with myeloma with a poor prognosis, who might benefit from the most intensive possible treatment."

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