DNA Marker May Predict Poor Outcomes, Treatment Resistance in Multiple Myeloma

New research has identified a certain type of DNA marker that may predict poor outcomes and treatment resistance in patients with multiple myeloma, according to a study published in Nature Communications.

Although many patients with multiple myeloma benefit from current therapies, 20% relapse or die within 2 years. These patients are deemed high risk, but many do not have known high-risk features at the time of diagnosis. Identifying patients with high-risk myeloma could help guide treatment and improve outcomes. The findings come from the CoMMPass study.

For the study, the researchers investigated the genomic landscape of 795 newly-diagnosed patients with multiple myeloma. Although 66.4% of these patients had recurrent translocations, very few of which were prognostic of outcome, according to the study authors.

However, the researchers found that translocations involving the immunoglobulin lambda (IgL) light chain locus were predictive of significantly worse progression-free survival and overall survival. This was most pronounced for IgL-MYC translocations. Various forms of IgL translocations were identified in 10% of the study participants and these patients were more than twice as likely to die within the first 3 years after diagnosis, according to the study.

Notably, the study also found that 78% of IgL-MYC translocations co-occur with hyperdipoid disease, which is a marker of standard risk. This indicates that IgL-MYC translocation can be misclassified. In comparison with other markers, IgL translocations are rarely tested for in the clinic, the researchers noted.

“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,” senior author 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, said in a press release.

Moreover, most patients with an IgL-translocation did not benefit from immunomodulatory drug therapies, such as lenalidomide. They noted that this may be because the IgL’s gene activity is resistant to the mechanism of action of these drugs.

“Several studies have reported IgL translocations, but to our knowledge this is the first study to report a frequency approaching 10% in newly diagnosed myeloma,” the researchers wrote in the study.

Overall, they concluded that IgL-MYC translocations are likely prognostic of poor outcomes in multiple myeloma, whereas the rarity of other types of IgL translocations make it difficult to assess which of those events also contribute to poor outcomes.

“As a result, IgL-MYC translocations represent an unrecognized high-risk marker prevalent in a subset of patients that are currently considered to be standard risk,” the authors wrote.

References

Barwick BG, Neri P, Bahlis NJ, et al. Multiple myeloma immunoglobulin lambda translocations portend poor prognosis. Nature Communications. 2019. https://www.nature.com/articles/s41467-019-09555-6#Abs1.

Multiple myeloma: DNA rearrangements may predict resistance, poor outcomes [news release]. Winship Cancer Institute of Emory University. http://news.emory.edu/stories/2019/04/winship_myeloma_transloc/index.html. Accessed April 23, 2019.