A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis
Walker BA (1), Mavrommatis K (2), Wardell CP (1), Ashby TC (1), Bauer M (1), Davies F (1), Rosenthal A (3), Wang H (3), Qu P (3), Hoering A (3), Samur M (4), Towfic F (5), Ortiz M (6), Flynt E (5), Yu Z (5), Yang Z (5), Rozelle D (7), Obenauer J (7), Trotter M (6(, Auclair D (8), Keats J (9), Bolli N (10), Fulciniti M (4), Szalat R (4), Moreau P (11), Durie B (12), Stewart AK (13), Goldschmidt H (14), Raab MS (14,15), Einsele H (16), Sonneveld P (17), San Miguel J (18), Lonial S (19), Jackson GH (20), Anderson KC (4), Avet-Loiseau H (21,22), Munshi N (4), Thakurta A (5), Morgan G (23).
(1) Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
(2) Celgene Corporation, San Francisco, CA, USA.
(3) Cancer Research and Biostatistics, Seattle, WA, USA.
(4) Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
(5) Celgene Corporation, Summit, NJ, USA.
(6) Celgene Institute of Translational Research Europe, Sevilla, Spain.
(7) Rancho BioSciences, San Diego, CA, USA.
(8) Multiple Myeloma Research Foundation, Norwalk, CT, USA.
(9) Translational Genomics Research Institute, Phoenix, AZ, USA.
(10) University of Milan, Milano, Italy.
(11) University of Nantes, Nantes, France.
(12) Cedars-Sinai Samuel Oschin Cancer Center, Los Angeles, CA, USA.
(13) Department of Hematology, Mayo Clinic, Scottsdale, AZ, USA.
(14) Department of Medicine V, Hematology and Oncology, University Hospital of Heidelberg, Heidelberg, Germany.
(15) German Cancer Research Center (DKFZ), Heidelberg, Heidelberg, Germany.
(16) Department of Internal Medicine II, Wurzburg University, Wurzburg, Germany.
(17) Department of Hematology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.
(18) Clinica Universidad de Navarra, Centro Investigacion Medica Aplicada (CIMA), IDISNA, CIBERONC, Pamplona, Spain.
(19) Winship Cancer Institute, Emory University, Atlanta, GA, USA.
(20) Department of Haematology, Newcastle University, Newcastle, UK.
(21) Centre de Recherche en Cancérologie de Toulouse Institut National de a Santé et de la Recherche Médicale, U1037, Toulouse, France.
(22) L'Institut Universitaire du Cancer de Toulouse Oncopole, Centre Hospitalier Universitaire, Toulouse, France.
(23) Myeloma Institute, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
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.
CITATION Leukemia. 2018 Jul 2. doi: 10.1038/s41375-018-0196-8