Specific DNA Rearrangement Predicts Treatment Resistance, Poor Outcomes in Multiple Myeloma, Study Suggests

A genomic rearrangement involving the immunoglobulin lambda (IgL) gene is predictive of resistance to immunomodulatory agents and poor outcomes among multiple myeloma patients, a new study suggests.

Testing for this rearrangement of chromosomes may help better stratify patients according to their risk of disease progression and tailor their treatment regimens.

“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,” 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 the study’s lead author, said in a press release.

The study, “Multiple myeloma immunoglobulin lambda translocations portend poor prognosis,” was published in the journal Nature Communications.

In the last decade, new therapies — including stem cell transplants, proteasome inhibitors, antibodies, and immunomodulatory therapies — have improved the survival rates of multiple myeloma patients.

Despite these advances, 20% of patients will die or see their cancer return within two years. These patients are known as high risk, but many do not present high risk features at diagnosis.

To understand whether genetics plays a role in the risk of relapse, researchers at the Emory University School of Medicine investigated the genomic landscape of 795 newly diagnosed myeloma patients who took part in the CoMMpass study — a whole-genome sequencing project funded by the Multiple Myeloma Research Foundation (MMRF).

The researchers identified a type of genetic alteration called translocation — where chromosome segments and their genes change positions within the same chromosome or into another chromosome — in the IgL gene that was found in 10% of myeloma patients.

Patients with this genetic translocation were two times more likely to die within the first three years compared with patients without it. This risk was most pronounced for patients in which the translocation joined the IgL gene with the c-Myc gene, which drives uncontrolled cell proliferation.

Interestingly, most patients with this rearrangement had extra chromosomes, which is often associated with a better prognosis. Because patients are usually screened for genetic abnormalities such as extra chromosomes, but not IgL translocations, most of these high-risk patients are deemed standard risk, the researchers explained.

“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,” Boise said.

The study also found that patients with IgL translocations failed to benefit from immunomodulatory therapies such as Revlimid (lenalidomide), most likely due to a resistance of the IgL gene to the mechanism of action of these therapies.

Overall, “these data identify IgL-MYC translocations as a marker of poor prognosis, independent of other genetic abnormalities, with implications for diagnosis and treatment,” the researchers wrote.

With the support of the MMRF, the researchers are now working to develop genomic tests that identify several of these IgL translocations.

“This work is a perfect example of the benefits of broad access to CoMMPass data,” said Sagar Lonial, MD, FACP, an expert on multiple myeloma.

“This kind of work would not have been possible without the collaborative team of scientists and clinicians we have that focuses on myeloma-specific research every day, and is helping to change how we view and treat this disease,” he added.