IgL Translocation May Predict Poor Outcomes in Multiple Myeloma

Although most people with multiple myeloma benefit from current therapies, approximately 20% of patients relapse or die within 2 years, and many of these high-risk patients don’t have known high-risk features at the time of diagnosis. For these patients, DNA rearrangement may be the key to predicting poor outcomes, according to a new study.

By studying genome sequencing information from 795 newly diagnosed patients, researchers identified that translocations involving the immunoglobulin lambda (IgL) locus may predict such outcomes. The marker, according to the researchers, is a kind of rearrangement of chromosomes that is rarely tested for but may dictate resistance to immunomodulatory drugs such as lenalidomide.

These translocations were present in 10% of patients, who were more than twice as likely to die within the first 3 years following diagnosis.

“This 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 Lawrence Boise, PhD, professor and vice chair for basic research in the Department of Hematology and Medical Oncology at Winship Cancer Institute and Emory University School of Medicine, and senior author of the study, in a statement.

The researchers were able to study patients’ genome sequencing information from the Clinical Outcomes in Multiple Myeloma to Personal Assessment (CoMMPass) study, which included patients from medical centers across North America and Europe. Among the patients, recurrent translocations were present in 66.4%, with CCND1, WHSC1, MYC, MAF, and other immunoglobin translocations being the most common. These translocations resulted in aberrant oncogene expression, although few had any bearing on outcome, with the exception of translocations involving the IgL locus.

According to the researchers, these findings indicate that patients with IgL translocations reap no survival benefit from immunomodulatory drugs, which could be because the IgL gene’s activity is resistant to the mechanism of actions of these drugs.

The researchers noted that these findings will need to be validated in a clinical trial setting in which treatment options can be standardized. They added that it will be important to better understand how IKZF1 regulates the IgL enhancer in myeloma.

Reference

Barwick B, Neri P, Bahlis N, et al. Multiple myeloma immunoglobin lambda translocations portend poor prognosis [published online April 23, 2019]. Nat Commun. doi: 10.1038/s41467-019-09555-6.