Study Identifies Gene Mutations Associated With Aggressive Multiple Myeloma
Using whole-exome sequencing on newly diagnosed patients with multiple myeloma, British researchers identified 15 genes that were significantly mutated in a subset of patients and mapped how these mutations related to long-term survival. They found 90% of patients with very aggressive disease who experienced relapse and died prematurely. Overall, a set of potential actionable mutations comprising 309 targets applicable in 53% of patients was identified.
In the future, according to the researchers, they may be able to increase the actionable targets to 440, applicable in 62% of patients. Detecting actionable mutations in high-risk patients could lead to more effective treatment strategies and improve patient outcome. The study by Walker et al was published in the Journal of Clinical Oncology.
Study Methodology
The researchers performed whole-exome sequencing on 463 newly diagnosed patients with multiple myeloma who were enrolled in the National Cancer Research Institute Myeloma XI trial, a phase III randomized trial investigating a triplet immunomodulatory drug induction of cyclophosphamide, thalidomide (Thalomid), and dexamethasone or cyclophosphamide, lenalidomide (Revlimid), and dexamethasone.
Patients with a suboptimal response were randomly assigned to pretransplant treatment with a proteasome inhibitor triplet. Older or less-fit patients did not receive an autologous stem cell transplant. All patients subsequently underwent further random assignment to no maintenance, lenalidomide maintenance, or lenalidomide and vorinostat (Zolinza) maintenance.
Progression-free survival and overall survival were measured from initial random assignment, and the median follow-up was 25 months (range = 0.09–42.97 months). The median progression-free survival was 26.6 months (95% confidence interval [CI] = 23.6–29.9 months), and the 3-year overall survival rate was 66% (95% CI = 60%–73%).
Study Findings
The researchers identified 15 significantly mutated genes (IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3) and then mapped how these mutations related to long-term survival. They found that the mutational spectrum is dominated by mutations in the RAS (43%) and nuclear factor kappa B (17%) pathways, but although they are prognostically neutral, they could be targeted therapeutically.
Mutations in CCND1 and DNA repair pathway alterations (TP53, ATM, ATR, and ZNFHX4 mutations) were associated with a negative impact on survival. Only 38% of patients with mutations in CCND1 survived longer than 2 years, compared with 80% of patients without mutations in this gene.
Conversely, all patients with mutations in IRF4 and EGR1 survived longer than 2 years, compared with 79% and 78% of patients with error-free copies of the genes, respectively.
The researchers then combined these novel mutation risk factors with the recurrent molecular adverse features and international staging system to generate an international staging system mutation score, which can identify a high-risk population of patients who experience relapse and die prematurely.
Long-Term Impact
“Our study has identified genetic features, which can identify those patients whose myeloma is likely to prove aggressive and to progress quickly,” said Gareth J. Morgan, MD, FRCP, FRCPath, PhD, Professor of Medicine and Director of the Myeloma Institute at the University of Arkansas for Medical Sciences (formerly, Professor of Hematology at The Institute of Cancer Research in London) and a coauthor of the study, in a statement. “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.”
Dr. Morgan is the corresponding author of this article published in the Journal of Clinical Oncology.
Funding for this study was provided by Myeloma UK, Cancer Research UK, Cancer Research UK Biomarkers and Imaging Discovery and Development, the National Institute of Health Biomedical Research Centre at the Royal Marsden Hospital, and the Fédération Française de Recherche sur le Myélome et les Gammapathies.
For full disclosures of the study authors, visit jco.ascopubs.org.
The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.
