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The first comprehensive molecular analysis of patients in a clinical trial with myeloma has identified key copy number and structural abnormalities (CNSAs) and mutations that may help target high risk patients for more appropriate treatments, according to a new study published online in the Journal of Clinical Oncology.
“The detection of mutations can improve our ability to detect high-risk patients who experience relapse and die early, but who may benefit from specific therapeutic interventions,” said Dr. Brian Walker, from the Institute of Cancer Research, London, UK, and his colleagues (J Clin Oncol. 2015 Aug 17. doi:10.1200/JCO.2014.59.1503).
Samples were taken from 463 patients who were newly diagnosed with symptomatic myeloma and enrolled onto the National Cancer Research Institute Myeloma XI trial. This was a phase III, open-label trial in which patients were randomized to triplet immunomodulatory drug induction of either cyclophosphamide, thalidomide, and dexamethasone, or cyclophosphamide, lenalidomide, and dexamethasone.
Whole-exome sequencing of the patients identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3.
With the exception of NRAS and KRAS, all of the genes are mutated at a low percentage. The finding could be of importance, as it indicates that key pathways are deregulated, instead of mutations arising in single genes.
A number of the mutations appear to have an effect on survival. CCND1 mutations were associated with a negative impact on overall survival (2-year OS, 38%; [95% confidence interval, 14%-100%] vs. 80% [95% CI, 76%-84%]; P = .005). TP53 mutations and deletions were also associated with a significant negative impact on progression-free survival (PFS) and overall survival, as were ATM and ATR mutations.
In contrast, mutations in IRF4 had a positive impact on survival, with a trend toward an improvement in progression free survival (2-year PFS, 71%; [95% CI, 50%-100%] vs. 54% [95% CI, 49%-60%]; P = .09) and a significant impact on overall survival (2-year OS, 100% vs. 79% [95% CI, 75%-83%]; P = .05).
Aside from being prognostic for outcomes, some of these mutations are potential therapeutic targets. The deregulation of the RAS/MAPK pathway with the most common mutations being in NRAS and KRAS is a major therapeutic target, while the other targetable pathway is NF-kappa-B.
“Overall, we identified a set of potential actionable mutations comprising 309 targets applicable to 53% of patients,” the researchers wrote. “In the years to come, we foresee this to increase to 440 targets applicable to 62% of patients.”
The study was supported by several U.K. government grants, as well as funds from the National Institute of Health Biomedical Research Centre at the Royal Marsden Hospital. Coauthor Dr. Boyle was supported by the Fédération Française de Recherche sur le Myélome et les Gammapathies grant. Dr. Walker reports receiving honoraria from Celgene and Onyx Pharmaceuticals.
The first comprehensive molecular analysis of patients in a clinical trial with myeloma has identified key copy number and structural abnormalities (CNSAs) and mutations that may help target high risk patients for more appropriate treatments, according to a new study published online in the Journal of Clinical Oncology.
“The detection of mutations can improve our ability to detect high-risk patients who experience relapse and die early, but who may benefit from specific therapeutic interventions,” said Dr. Brian Walker, from the Institute of Cancer Research, London, UK, and his colleagues (J Clin Oncol. 2015 Aug 17. doi:10.1200/JCO.2014.59.1503).
Samples were taken from 463 patients who were newly diagnosed with symptomatic myeloma and enrolled onto the National Cancer Research Institute Myeloma XI trial. This was a phase III, open-label trial in which patients were randomized to triplet immunomodulatory drug induction of either cyclophosphamide, thalidomide, and dexamethasone, or cyclophosphamide, lenalidomide, and dexamethasone.
Whole-exome sequencing of the patients identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3.
With the exception of NRAS and KRAS, all of the genes are mutated at a low percentage. The finding could be of importance, as it indicates that key pathways are deregulated, instead of mutations arising in single genes.
A number of the mutations appear to have an effect on survival. CCND1 mutations were associated with a negative impact on overall survival (2-year OS, 38%; [95% confidence interval, 14%-100%] vs. 80% [95% CI, 76%-84%]; P = .005). TP53 mutations and deletions were also associated with a significant negative impact on progression-free survival (PFS) and overall survival, as were ATM and ATR mutations.
In contrast, mutations in IRF4 had a positive impact on survival, with a trend toward an improvement in progression free survival (2-year PFS, 71%; [95% CI, 50%-100%] vs. 54% [95% CI, 49%-60%]; P = .09) and a significant impact on overall survival (2-year OS, 100% vs. 79% [95% CI, 75%-83%]; P = .05).
Aside from being prognostic for outcomes, some of these mutations are potential therapeutic targets. The deregulation of the RAS/MAPK pathway with the most common mutations being in NRAS and KRAS is a major therapeutic target, while the other targetable pathway is NF-kappa-B.
“Overall, we identified a set of potential actionable mutations comprising 309 targets applicable to 53% of patients,” the researchers wrote. “In the years to come, we foresee this to increase to 440 targets applicable to 62% of patients.”
The study was supported by several U.K. government grants, as well as funds from the National Institute of Health Biomedical Research Centre at the Royal Marsden Hospital. Coauthor Dr. Boyle was supported by the Fédération Française de Recherche sur le Myélome et les Gammapathies grant. Dr. Walker reports receiving honoraria from Celgene and Onyx Pharmaceuticals.
The first comprehensive molecular analysis of patients in a clinical trial with myeloma has identified key copy number and structural abnormalities (CNSAs) and mutations that may help target high risk patients for more appropriate treatments, according to a new study published online in the Journal of Clinical Oncology.
“The detection of mutations can improve our ability to detect high-risk patients who experience relapse and die early, but who may benefit from specific therapeutic interventions,” said Dr. Brian Walker, from the Institute of Cancer Research, London, UK, and his colleagues (J Clin Oncol. 2015 Aug 17. doi:10.1200/JCO.2014.59.1503).
Samples were taken from 463 patients who were newly diagnosed with symptomatic myeloma and enrolled onto the National Cancer Research Institute Myeloma XI trial. This was a phase III, open-label trial in which patients were randomized to triplet immunomodulatory drug induction of either cyclophosphamide, thalidomide, and dexamethasone, or cyclophosphamide, lenalidomide, and dexamethasone.
Whole-exome sequencing of the patients identified 15 significantly mutated genes: IRF4, KRAS, NRAS, MAX, HIST1H1E, RB1, EGR1, TP53, TRAF3, FAM46C, DIS3, BRAF, LTB, CYLD, and FGFR3.
With the exception of NRAS and KRAS, all of the genes are mutated at a low percentage. The finding could be of importance, as it indicates that key pathways are deregulated, instead of mutations arising in single genes.
A number of the mutations appear to have an effect on survival. CCND1 mutations were associated with a negative impact on overall survival (2-year OS, 38%; [95% confidence interval, 14%-100%] vs. 80% [95% CI, 76%-84%]; P = .005). TP53 mutations and deletions were also associated with a significant negative impact on progression-free survival (PFS) and overall survival, as were ATM and ATR mutations.
In contrast, mutations in IRF4 had a positive impact on survival, with a trend toward an improvement in progression free survival (2-year PFS, 71%; [95% CI, 50%-100%] vs. 54% [95% CI, 49%-60%]; P = .09) and a significant impact on overall survival (2-year OS, 100% vs. 79% [95% CI, 75%-83%]; P = .05).
Aside from being prognostic for outcomes, some of these mutations are potential therapeutic targets. The deregulation of the RAS/MAPK pathway with the most common mutations being in NRAS and KRAS is a major therapeutic target, while the other targetable pathway is NF-kappa-B.
“Overall, we identified a set of potential actionable mutations comprising 309 targets applicable to 53% of patients,” the researchers wrote. “In the years to come, we foresee this to increase to 440 targets applicable to 62% of patients.”
The study was supported by several U.K. government grants, as well as funds from the National Institute of Health Biomedical Research Centre at the Royal Marsden Hospital. Coauthor Dr. Boyle was supported by the Fédération Française de Recherche sur le Myélome et les Gammapathies grant. Dr. Walker reports receiving honoraria from Celgene and Onyx Pharmaceuticals.
FROM JOURNAL OF CLINICAL ONCOLOGY
Key clinical point: A comprehensive analysis identified key copy number and structural abnormalities (CNSAs) and mutations in multiple myeloma.
Major finding: Fifteen significantly mutated genes were identified, primarily mutations in the RAS (43%) and nuclear factor kB pathway (17%).
Data source: Whole-exome sequencing for 463 patients who presented with myeloma and were enrolled onto the National Cancer Research Institute Myeloma XI trial.
Disclosures: The study was supported by several U.K. government grants, as well as funds from the National Institute of Health Biomedical Research Centre at the Royal Marsden Hospital, London. Coauthor Dr. Boyle was supported by the Fédération Française de Recherche sur le Myélome et les Gammapathies grant. Dr. Walker reports receiving honoraria from Celgene and Onyx Pharmaceuticals.
