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Genetic testing may improve myeloma risk stratification, treatment
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Researchers have identified significantly mutated genes in patients with newly diagnosed myeloma that may be used to improve risk stratification and treatment at disease presentation.
These findings mark the first time cell mutations in myeloma have been linked to survival.
“Our study has identified genetic features which can identify those patients whose myeloma is likely to prove aggressive and to progress quickly,” Gareth Morgan, MD, professor of hematology at The Institute of Cancer Research, said in a press release. “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.”
The investigators performed whole-exome sequencing on 463 patients with newly diagnosed myeloma who were enrolled into the United Kingdom’s National Cancer Research Institute Myeloma XI trial.
Overall, the researchers found 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD and FGFR3.
The most common genetic mutations occurred in the RAS pathway (43.2%), which includes KRAS (21.2%), NRAS (19.4%) and BRAF (6.7%).
Seventeen percent of patients had mutational activation of the nuclear factor-kappa B pathway genes, which include TRAF3, CYLD and LTB.
Patients with cancer cells in the CCND1 gene, a gene that controls cell division, were more likely to have aggressive disease. Thirty-eight percent (95% CI, 14-100) of the patients with CCND1 achieved 2-year OS compared with 80% (95% CI, 76-84) of the patients who did not have this mutation.
Other DNA repair pathway alterations that appeared associated with worse outcomes included TP53, ATM, ATR and ZNFHX4.
The researchers also found that IRF4 and EGR1 mutations improved survival, and every patient who harbored one of these mutations remained alive at 2 years. Compared with patients without these mutations, a significantly greater proportion of patients with IRF4 mutations (100% vs. 79%; P = .05) and EGR1 mutations (100% vs. 78%; P = .04) achieved 2-year OS.
The investigators created an international staging system mutation score by combining these new risk factors with recurrent molecular adverse features and the existing international staging system. Results showed the new score — which creates three prognostic groups — is more sensitive to the detection of early progression (80.5% vs. 65%) and early mortality (90% vs. 75%).
“We now know that cancer is much more complex than had once been thought and that each individual form of cancer can, in fact, be divided up into many different subtypes, each with different sets of genetic drivers,” Paul Workman, FMedSci, chief executive of The Institute of Cancer Research, said in a press release. “This new study has found that testing for a particular set of mutations seems to pick out patients whose myeloma is likely to prove particularly aggressive and who will need the most intensive possible treatment to maximize their chances at survival.” – by Anthony SanFilippo
Reference:
Walker BA, et al. J Clin Oncol. 2015;doi:10.1200/JCO.2014.59.1503.
Disclosure: Morgan reports consultant/advisory and speakers bureau roles with and research funding from Celgene, Janssen, Millennium and Onyx. Please see the full study for a list of all other researchers’ relevant financial disclosures.
Perspective
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Damian J. Green, MD
In the words of world champion race car driver Mario Andretti, “If everything is under control, you aren’t going fast enough.”This seems an appropriate aphorism when applied to the pace of new discovery in the management of multiple myeloma. Things are happening fast and it is a challenge to manage and control all of the data.
At least six new agents have been approved by the FDA over the past 12 years in this setting, monoclonal antibodies appear poised to enter the panoply of treatment options soon, and dramatic improvements in outcome are being reported, with standard-risk patients now achieving a median OS approaching 8 years.
Discovery is being accelerated through the integration of powerful sequencing technology capable of further defining risk and potentially enabling us to tailor therapy based on a personalized mutational snapshot.
In their Journal of Clinical Oncology article, Walker and colleagues use whole-exome sequencing to identify prognostically important genetic abnormalities in tissue specimens from 463 patients enrolled in the phase 3 Myeloma XI trial.
They report 15 significantly mutated genes, with the highest frequency seen in RAS and NF-KB (43% and 17%), although mutations in neither pathway turn out to have prognostic significance.
Patients carrying the “high-risk” marker TP53 and concomitant ATM or ATR mutations were found to have very poor outcomes, potentially explaining the spectrum of aggressiveness — from bad to worse — among TP53-positive patients seen in the clinic. Another member of the DNA repair pathway, ZFHX4, also is independently associated with a poor outcome.
These findings lead the authors to suggest that patients with mutations impacting the DNA repair pathway may not represent good candidates for alkylating agent therapy. This requires further validation, but if true, it may have significant prognostic importance in determining appropriate patients for high-dose melphalan therapy and autologous stem cell rescue.
The authors also propose a new refinement — based on incorporation of a mutational score — for the dated International Staging System (ISS) risk scheme (which they call ISS-MUT).
Although compelling, this arrives on the heels of the recently published Revised ISS (R-ISS) score proposed by the International Myeloma Working Group in the same journal 2 weeks earlier. The myeloma community has been slow to adopt any changes to the original ISS criteria in part because of the impact such change would have on the management of clinical trials and interpretation of trial data.
Further modifications to the ISS/R-ISS based on sequencing technologies that are not universally employed may not be currently feasible, even though the findings are informative.
Overall, Walker and colleagues’ paper deepens our understanding of the risk for progression and early death among multiple myeloma patients at presentation. They provide important insights into both passenger and driver mutations that will enable us to maintain control as we move rapidly down the road of discovery in multiple myeloma.
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