Статья

Genomic Profiling of Smoldering Multiple Myeloma Identifies Patients at a High Risk of Disease Progression

Mark BustorosBroad Institute of MIT and Harvard, Cambridge, MARomanos Sklavenitis‐PistofidisBroad Institute of MIT and Harvard, Cambridge, MAJihye ParkBroad Institute of MIT and Harvard, Cambridge, MARobert ReddDepartment of Data Sciences, Dana-Farber Cancer Institute, Boston, MABenny ZhitomirskyBroad Institute of MIT and Harvard, Cambridge, MAAndrew DunfordBroad Institute of MIT and Harvard, Cambridge, MAKarma Z. SalemDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MAYu‐Tzu TaiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MAShankara AnandBroad Institute of MIT and Harvard, Cambridge, MATarek H. MouhieddineBroad Institute of MIT and Harvard, Cambridge, MASelina J ChavdaDepartment of Hematology, University College London, London, United KingdomCody J. BoehnerCenter for Prevention of Progression of Blood Cancers, Dana-Farber Cancer Institute, Boston, MALiudmila ElaginaBroad Institute of MIT and Harvard, Cambridge, MACarl Jannes NeuseDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MAJustin ChaBroad Institute of MIT and Harvard, Cambridge, MAMahshid RahmatBroad Institute of MIT and Harvard, Cambridge, MAAmaro Taylor‐WeinerBroad Institute of MIT and Harvard, Cambridge, MAEliezer M. Van AllenBroad Institute of MIT and Harvard, Cambridge, MAShaji KumarDivision of Hematology, Mayo Clinic, Rochester, MNEfstathis KastritisDepartment of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, GreeceIgnaty LeshchinerBroad Institute of MIT and Harvard, Cambridge, MAElizabeth A. MorganDepartment of Pathology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MAJacob P. LaubachDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MATineke CasneufJanssen Research and Development, Beerse, BelgiumPaul G. RichardsonDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MANikhil C. MunshiDepartment of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MAKenneth C. AndersonDana-Farber Cancer InstituteLorenzo TrippaDepartment of Data Sciences, Dana-Farber Cancer Institute, Boston, MAFrançois AguetBroad Institute of MIT and Harvard, Cambridge, MAChip StewartBroad Institute of MIT and Harvard, Cambridge, MAMeletios Α. DimopoulosDepartment of Clinical Therapeutics, National and Kapodistrian University of Athens School of Medicine, Athens, GreeceKwee YongDepartment of Hematology, University College London, London, United KingdomP. Leif BergsagelDivision of Hematology, Mayo Clinic, Scottsdale, AZSalomon ManierDepartment of Hematology, CHU Lille, University of Lille, Lille, FranceGad GetzBroad Institute of MIT and Harvard, Cambridge, MAIrene M. GhobrialBroad Institute of MIT and Harvard, Cambridge, MA

2020en

ABI

Аннотация

PURPOSE Smoldering multiple myeloma (SMM) is a precursor condition of multiple myeloma (MM) with a 10% annual risk of progression. Various prognostic models exist for risk stratification; however, those are based on solely clinical metrics. The discovery of genomic alterations that underlie disease progression to MM could improve current risk models. METHODS We used next-generation sequencing to study 214 patients with SMM. We performed whole-exome sequencing on 166 tumors, including 5 with serial samples, and deep targeted sequencing on 48 tumors. RESULTS We observed that most of the genetic alterations necessary for progression have already been acquired by the diagnosis of SMM. Particularly, we found that alterations of the mitogen-activated protein kinase pathway ( KRAS and NRAS single nucleotide variants [SNVs]), the DNA repair pathway (deletion 17p, TP53, and ATM SNVs), and MYC (translocations or copy number variations) were all independent risk factors of progression after accounting for clinical risk staging. We validated these findings in an external SMM cohort by showing that patients who have any of these three features have a higher risk of progressing to MM. Moreover, APOBEC associated mutations were enriched in patients who progressed and were associated with a shorter time to progression in our cohort. CONCLUSION SMM is a genetically mature entity whereby most driver genetic alterations have already occurred, which suggests the existence of a right-skewed model of genetic evolution from monoclonal gammopathy of undetermined significance to MM. We identified and externally validated genomic predictors of progression that could distinguish patients at high risk of progression to MM and, thus, improve on the precision of current clinical models.

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Идентификаторы

DOI: 10.1200/jco.20.00437

Цитирования и источники

Цитирований: 2Использованных источников: 0

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