A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis
Brian A Walker,Konstantinos Mavrommatis,Christopher P. Wardell,T. Cody Ashby,Michael A Bauer,Faith E. Davies,Adam Rosenthal,Hongwei Wang,Pingping Qu,Antje Hoering,Mehmet Kemal Samur,Fadi Towfic,Maria Ortiz,Erin Flynt,Zhinuan Yu,Zhihong Yang,Dan Rozelle,John C. Obenauer,Matthew Trotter,Daniel Auclair,Jonathan J Keats,Niccolo Bolli,Mariateresa Fulciniti,Raphael Szalat,P. Moreau,Brian G.M. Durie,A. Keith Stewart,Hartmut Goldschmidt,Marc S. Raab,Hermann Einsele,Pieter Sonneveld,Jesús F. San Miguel,Sagar Lonial,Graham Jackson,Kenneth C. Anderson,Hervé Avet-Loiseau,Nikhil C. Munshi,Anjan Thakurta,Gareth J. Morgan +38 more
TLDR
In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, DNA drivers of aggressive clinical behavior are defined and Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.Abstract:
Patients with newly diagnosed multiple myeloma (NDMM) with high-risk disease are in need of new treatment strategies to improve the outcomes. Multiple clinical, cytogenetic, or gene expression features have been used to identify high-risk patients, each of which has significant weaknesses. Inclusion of molecular features into risk stratification could resolve the current challenges. In a genome-wide analysis of the largest set of molecular and clinical data established to date from NDMM, as part of the Myeloma Genome Project, we have defined DNA drivers of aggressive clinical behavior. Whole-genome and exome data from 1273 NDMM patients identified genetic factors that contribute significantly to progression free survival (PFS) and overall survival (OS) (cumulative R2 = 18.4% and 25.2%, respectively). Integrating DNA drivers and clinical data into a Cox model using 784 patients with ISS, age, PFS, OS, and genomic data, the model has a cumlative R2 of 34.3% for PFS and 46.5% for OS. A high-risk subgroup was defined by recursive partitioning using either a) bi-allelic TP53 inactivation or b) amplification (≥4 copies) of CKS1B (1q21) on the background of International Staging System III, comprising 6.1% of the population (median PFS = 15.4 months; OS = 20.7 months) that was validated in an independent dataset. Double-Hit patients have a dire prognosis despite modern therapies and should be considered for novel therapeutic approaches.read more
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Journal ArticleDOI
Identification of novel mutational drivers reveals oncogene dependencies in multiple myeloma.
Brian A Walker,Konstantinos Mavrommatis,Christopher P. Wardell,T. Cody Ashby,Michael A Bauer,Faith E. Davies,Adam Rosenthal,Hongwei Wang,Pingping Qu,Antje Hoering,Mehmet Kemal Samur,Fadi Towfic,Maria Ortiz,Erin Flynt,Zhinuan Yu,Zhihong Yang,Dan Rozelle,John C. Obenauer,Matthew Trotter,Daniel Auclair,Jonathan J Keats,Niccolo Bolli,Mariateresa Fulciniti,Raphael Szalat,Philippe Moreau,Brian G.M. Durie,A. Keith Stewart,Hartmut Goldschmidt,Marc-Steffen Raab,Hermann Einsele,Pieter Sonneveld,Jesús F. San Miguel,Sagar Lonial,Graham Jackson,Kenneth C. Anderson,Hervé Avet-Loiseau,Nikhil C. Munshi,Anjan Thakurta,Gareth J. Morgan +38 more
TL;DR: Using integrated genomics of 1273 newly diagnosed patients with MM, associations indicate that the genomic landscape of myeloma is predetermined by the primary events upon which further dependencies are built, giving rise to a nonrandom accumulation of genetic hits.
Journal ArticleDOI
Diagnosis and Management of Multiple Myeloma: A Review.
Andrew J. Cowan,Damian J. Green,Mary Kwok,Sarah S. Lee,David C. Coffey,Leona Holmberg,Sherilyn A. Tuazon,Ajay K. Gopal,Edward N. Libby +8 more
TL;DR: The Revised International Staging System combines data from the serum biomarkers β2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization to assess estimated progression-free survival and overall survival.
Journal ArticleDOI
Genomic landscape and chronological reconstruction of driver events in multiple myeloma
Francesco Maura,Francesco Maura,Francesco Maura,Niccolo Bolli,Nicos Angelopoulos,Nicos Angelopoulos,Kevin J. Dawson,Daniel Leongamornlert,Inigo Martincorena,Thomas J. Mitchell,Anthony Fullam,Santiago Gonzalez,Raphael Szalat,Federico Abascal,Bernardo Rodriguez-Martin,Mehmet Kemal Samur,Dominik Glodzik,Dominik Glodzik,Marco Roncador,Mariateresa Fulciniti,Yu-Tzu Tai,Stephane Minvielle,Florence Magrangeas,Philippe Moreau,Paolo Corradini,Kenneth C. Anderson,Jose M. C. Tubio,Jose M. C. Tubio,David C. Wedge,Moritz Gerstung,Hervé Avet-Loiseau,Nikhil C. Munshi,Nikhil C. Munshi,Peter J. Campbell +33 more
TL;DR: A catalog and hierarchy of driver lesions using sequences from 67 MM genomes serially collected from 30 patients together with public exome datasets is reported, noting a limited repertoire of initiating driver events that shape the evolutionary trajectory of the disease.
Journal ArticleDOI
Toward personalized treatment in multiple myeloma based on molecular characteristics.
Charlotte Pawlyn,Faith E. Davies +1 more
TL;DR: It is argued that in order to continue to improve multiple myeloma patient outcomes incorporating such biomarkers into the routine diagnostic workup of patients will allow for the use of personalized, biologically based treatments.
Journal ArticleDOI
Gain of Chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone.
Timothy M. Schmidt,Benjamin G. Barwick,Nisha Joseph,Leonard T. Heffner,Craig C. Hofmeister,Leon Bernal,Madhav V. Dhodapkar,Vikas Gupta,David L. Jaye,Jiayi Wu,Subir Goyal,Zhengjia Chen,Lawrence H. Boise,Sagar Lonial,Ajay K. Nooka,Jonathan L. Kaufman +15 more
TL;DR: Patients with +1q should be considered at very high risk for early progression in multiple myeloma when ≥4 copies are detected or in the context of other high-risk cytogenetic abnormalities.
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TL;DR: The R-ISS is a simple and powerful prognostic staging system, and it is recommended for use in future clinical studies to stratify patients with NDMM effectively with respect to the relative risk to their survival.
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