Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

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. Keats, Sagar Lonial, Paula M. Vertino () and Lawrence H. Boise ()
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Benjamin G. Barwick: Emory University School of Medicine
Paola Neri: University of Calgary
Nizar J. Bahlis: University of Calgary
Ajay K. Nooka: Emory University School of Medicine
Madhav V. Dhodapkar: Emory University School of Medicine
David L. Jaye: Emory University
Craig C. Hofmeister: Emory University School of Medicine
Jonathan L. Kaufman: Emory University School of Medicine
Vikas A. Gupta: Emory University School of Medicine
Daniel Auclair: Multiple Myeloma Research Foundation
Jonathan J. Keats: Translational Genomics Research Institute
Sagar Lonial: Emory University School of Medicine
Paula M. Vertino: Emory University School of Medicine
Lawrence H. Boise: Emory University School of Medicine

Nature Communications, 2019, vol. 10, issue 1, 1-13

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-09555-6

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