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A high-risk, Double-Hit, group of newly diagnosed myeloma identified by genomic analysis

Lookup NU author(s): Professor Graham Jackson

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2018 The Author(s) 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.

Publication metadata

Author(s): Walker BA, Mavrommatis K, Wardell CP, Ashby TC, Bauer M, Davies F, Rosenthal A, Wang H, Qu P, Hoering A, Samur M, Towfic F, Ortiz M, Flynt E, Yu Z, Yang Z, Rozelle D, Obenauer J, Trotter M, Auclair D, Keats J, Bolli N, Fulciniti M, Szalat R, Moreau P, Durie B, Stewart AK, Goldschmidt H, Raab MS, Einsele H, Sonneveld P, San Miguel J, Lonial S, Jackson GH, Anderson KC, Avet-Loiseau H, Munshi N, Thakurta A, Morgan G

Publication type: Article

Publication status: Published

Journal: Leukemia

Year: 2018

Volume: 33

Issue: 1

Pages: 159-170

Print publication date: 01/01/2019

Online publication date: 02/07/2018

Acceptance date: 07/06/2018

Date deposited: 16/07/2018

ISSN (print): 0887-6924

ISSN (electronic): 1476-5551

Publisher: Nature Publishing Group

URL: https://doi.org/10.1038/s41375-018-0196-8

DOI: 10.1038/s41375-018-0196-8

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