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Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

Author

Listed:
  • Benjamin G. Barwick

    (Emory University School of Medicine
    Emory University School of Medicine
    Emory University)

  • Paola Neri

    (University of Calgary)

  • Nizar J. Bahlis

    (University of Calgary)

  • Ajay K. Nooka

    (Emory University School of Medicine
    Emory University)

  • Madhav V. Dhodapkar

    (Emory University School of Medicine
    Emory University)

  • David L. Jaye

    (Emory University
    Emory University School of Medicine)

  • Craig C. Hofmeister

    (Emory University School of Medicine
    Emory University)

  • Jonathan L. Kaufman

    (Emory University School of Medicine
    Emory University)

  • Vikas A. Gupta

    (Emory University School of Medicine
    Emory University)

  • Daniel Auclair

    (Multiple Myeloma Research Foundation)

  • Jonathan J. Keats

    (Translational Genomics Research Institute)

  • Sagar Lonial

    (Emory University School of Medicine
    Emory University)

  • Paula M. Vertino

    (Emory University School of Medicine
    Emory University
    University of Rochester School of Medicine and Dentistry)

  • Lawrence H. Boise

    (Emory University School of Medicine
    Emory University)

Abstract

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, however, 20% of patients relapse or die within two years and are deemed high risk. Here we analyze structural variants from 795 newly-diagnosed patients as part of the CoMMpass study. We report translocations involving the immunoglobulin lambda (IgL) locus are present in 10% of patients, and indicative of poor prognosis. This is particularly true for IgL-MYC translocations, which coincide with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occur with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myeloma is being misclassified. Patients with IgL-translocations fail to benefit from IMiDs, which target IKZF1, a transcription factor that binds the IgL enhancer at some of the highest levels in the myeloma epigenome. These data implicate IgL translocation as a driver of poor prognosis which may be due to IMiD resistance.

Suggested Citation

  • Benjamin G. Barwick & Paola Neri & Nizar J. Bahlis & Ajay K. Nooka & Madhav V. Dhodapkar & David L. Jaye & Craig C. Hofmeister & Jonathan L. Kaufman & Vikas A. Gupta & Daniel Auclair & Jonathan J. Kea, 2019. "Multiple myeloma immunoglobulin lambda translocations portend poor prognosis," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-09555-6
    DOI: 10.1038/s41467-019-09555-6
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