Gene Translocation Marker Linked to Drug Resistance and Poor Prognosis

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.

To better understand the mechanisms that promote development of resistance to immunomodulatory drugs such as lenalidomide, investigators at Emory University School of Medicine (Atlanta, GA, USA) analyzed structural variants from 795 newly-diagnosed myeloma patients participating in the CoMMPass (Clinical Outcomes in Multiple Myeloma to Personal Assessment) study.

Results revealed that translocations involving the immunoglobulin lambda (IgL) gene locus were present in 10% of patients, and indicative of poor prognosis. This was particularly true for IgL-MYC gene translocations, which coincided with focal amplifications of enhancers at both loci. Importantly, 78% of IgL-MYC translocations co-occurred with hyperdiploid disease, a marker of standard risk, suggesting that IgL-MYC-translocated myelomas were being misclassified.

In addition, patients with myelomas carrying IgL translocations derived no survival benefit from immunomodulatory drugs such as lenalidomide. This may be because the IgL gene's activity was resistant to the mechanism of action of those drugs, or because the lenalidomide family of drugs promotes the destruction of Ikaros proteins, which bind especially tightly to the IgL gene locus.

"This [IgL translocation] could be different than other markers that we currently use in myeloma, because it may influence which drugs physicians may choose in both initial treatment as well as maintenance therapy," said senior author Dr. Lawrence Boise, professor of hematology and medical oncology at Emory University School of Medicine. "Most patients who have an IgL translocation are actually being diagnosed as having standard risk disease, so this study has helped explain why some patients who we think will do well end up relapsing and dying early."

The study was published in the April 23, 2019, online edition of the journal Nature Communications.

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Emory University School of Medicine