Multiple myeloma immunoglobulin lambda translocations portend poor prognosis

Benjamin G Barwick,Jonathan L Kaufman,Paula M Vertino,Sagar Lonial,Vikas A Gupta,Madhav V Dhodapkar,Lawrence H Boise,Daniel Auclair,Nizar J Bahlis,Jonathan J Keats,David L Jaye,Ajay K Nooka,Paola Neri,Craig C Hofmeister

doi:10.1038/s41467-019-09555-6

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.

Highlights

Multiple myeloma is a malignancy of antibody-secreting plasma cells
Modern combination therapies are mostly effective despite disease heterogeneity, with the majority of patients responding to frontline treatments that target plasma cell biology rather than specific genetic lesions17
To better understand the genetic basis of myeloma, and high-risk disease, we investigated the genomic landscape of 795 newly diagnosed myeloma patients using long-insert whole-genome sequencing as part of the Clinical Outcomes in Multiple Myeloma to Personal Assessment (CoMMpass) study

Summary

Introduction

Multiple myeloma is a malignancy of antibody-secreting plasma cells. Most patients benefit from current therapies, 20% of patients relapse or die within two years and are deemed high risk. There have been significant improvements in survival over the past decade, due to new therapies, which include autologous stem cell transplant, proteasome inhibitors, the immunomodulatory imide drugs (IMiDs), thalidomide, lenalidomide, and pomalidomide, and more recently monoclonal antibodies. There have been significant improvements in survival over the past decade, due to new therapies, which include autologous stem cell transplant, proteasome inhibitors, the immunomodulatory imide drugs (IMiDs), thalidomide, lenalidomide, and pomalidomide, and more recently monoclonal antibodies6,7 Despite these advances, ~20% of patients relapse or die within two years of diagnosis. Modern combination therapies are mostly effective despite disease heterogeneity, with the majority of patients responding to frontline treatments that target plasma cell biology rather than specific genetic lesions

Methods

Results

Conclusion