Open AccessGenome-Wide Somatic Alterations in Multiple Myeloma Reveal a Superior Outcome Group
Author(s) -
Mehmet K. Samur,
Anıl Aktaş Samur,
Mariateresa Fulciniti,
Raphaël Szalat,
Tessa Han,
Masood A. Shammas,
Paul G. Richardson,
Florence Magrangeas,
Stéphane Minvielle,
Jill Corre,
Philippe Moreau,
Anjan Thakurta,
Kenneth C. Anderson,
Giovanni Parmigiani,
Hervé AvetLoiseau,
Nikhil C. Munshi
Publication year - 2020
Publication title -
journal of clinical oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 10.482
H-Index - 548
eISSN - 1527-7755
pISSN - 0732-183X
DOI - 10.1200/jco.20.00461
Subject(s) - medicine , multiple myeloma , neuroblastoma ras viral oncogene homolog , somatic evolution in cancer , oncology , lenalidomide , bioinformatics , kras , cancer , biology , colorectal cancer
PURPOSE Multiple myeloma (MM) is accompanied by heterogeneous somatic alterations. The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing (WGS) and develop a model that identifies patients with long survival.METHODS We analyzed deep WGS data from 183 newly diagnosed patients with MM treated with lenalidomide, bortezomib, and dexamethasone (RVD) alone or RVD + autologous stem cell transplant (ASCT) in the IFM/DFCI 2009 study (ClinicalTrials.gov identifier: NCT01191060 ). We integrated genomic markers with clinical data.RESULTS We report significant variability in mutational load and processes within MM subgroups. The timeline of observed activation of mutational processes provides the basis for 2 distinct models of acquisition of mutational changes detected at the time of diagnosis of myeloma. Virtually all MM subgroups have activated DNA repair–associated signature as a prominent late mutational process, whereas APOBEC signature targeting C>G is activated in the intermediate phase of disease progression in high-risk MM. Importantly, we identify a genomically defined MM subgroup (17% of newly diagnosed patients) with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort. This subgroup allowed us to distinguish patients with low- and high-risk hyperdiploid MM and identify patients with prolongation of progression-free survival. Genomic characteristics of this subgroup included lower mutational load with significant contribution from age-related mutations as well as frequent NRAS mutation. Surprisingly, their overall survival was independent of International Staging System and minimal residual disease status.CONCLUSION This is a comprehensive study identifying genomic markers of a good-risk group with prolonged survival. Identification of this patient subgroup will affect future therapeutic algorithms and research planning.