Analyses identify proteins tied to multiple myeloma disease course

Researchers in Germany have identified proteins that could help identify multiple myeloma patients who at high risk for an aggressive disease course and worse prognosis.

Across a series of experiments, the scientists uncovered protein-level molecular changes that appeared specific to myeloma and correlated with disease progression patterns and myeloma stage.

“Our findings will help subcategorize patients more effectively going forward, personalizing their treatment,” Jan Krönke, MD, one of the study’s senior authors and a professor at Charité Universitätsmedizin Berlin, said in a press release. “We’ve identified key proteins and signaling pathways that can serve as the basis for even more effective, better tolerated treatments for multiple myeloma.”

The study, “The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities,” was published in Nature Cancer.

In multiple myeloma, plasma cells in the bone marrow mutate and grow uncontrollably, taking over the bone marrow from healthy immune cells. New treatment options for multiple myeloma have emerged in recent years, but the cancer is still considered incurable.

Different responses to treatment

Some patients have a more slowly progressing disease that’s more responsive to treatment, while others have aggressively advancing myeloma and are at a high risk of a poor prognosis. A better understanding of the molecular underpinnings for why this is so could help scientists develop more personalized and effective treatment strategies.

A range of mutations in genes involved in promoting or regulating cell growth have been identified as risk factors for myeloma, and may also influence its progression.

However, “genetic data alone is insufficient to explain the mechanisms involved in this disease,” said Philipp Mertins, PhD, another of the study’s senior authors and group leader in proteomics at the Max Delbrück Center for Molecular Medicine and the Berlin Institute of Health.

“We wanted to know the consequences of genetic changes at the protein level and compare this molecular biology data against the actual course of the disease in patients,” said Mertins.

To that end, the scientists performed molecular analyses of plasma cells from a group of 114 newly diagnosed and treatment-naive multiple myeloma patients who had participated in previous myeloma clinical trials, as well as from healthy people.

They also looked at plasma cells from seven people with monoclonal gammopathy of undetermined significance (MGUS) and 17 with plasma cell leukemia (PCL).

MUGS is a condition that can precede multiple myeloma in which plasma cells exhibit some abnormal behavior, but they do not form a tumor and there are no overt signs of cancer. PCL is an aggressive form of multiple myeloma in which the cancer extends beyond the bone marrow and into the bloodstream.

Patient data came from the German Multiple Myeloma Study Group, which is coordinated by the University Hospital of Würzburg, whose researchers also participated in the study.

The scientists observed a range of molecular changes in cells from myeloma patients relative to healthy people. In particular, they saw evidence that there is disruption to the cell cycle, or the series of events that take place when a cell is growing and dividing to make new cells.

Few protein-level differences were observed between plasma cells of myeloma patients and MGUS patients. On the other hand, newly diagnosed myeloma patients had a distinct protein profile from plasma cell leukemia patients.

Recommended Reading

Risk profile based on protein levels

Ultimately, the scientists identified a risk profile based on the levels of eight different proteins that could predict a more aggressive multiple myeloma course, independent of other known disease risk factors.

The selected proteins are not targets of current multiple myeloma therapies, the scientists noted.

Patients found to be at high risk based on this protein profile had a median survival time without cancer progression of a little over a year, compared with 2.5 years for people with a median score and more than seven years for those with low risk scores.

The median risk score progressively increased from MGUS, to newly diagnosed myeloma, to PCL.

In a series of additional experiments, the team identified myeloma cell proteins that could potentially be targeted with immunotherapy approaches, such as CAR T-cell therapy.

The researchers said they will work to identify which proteins might actually be good therapeutic targets for multiple myeloma.

“Collectively, the [protein-related] landscape of plasma cell malignancies described here provides a powerful resource … to promote research on [multiple myeloma] biology, risk stratification and novel therapies,” the team wrote.

The researchers have programmed the dataset from the study into a free online tool that other cancer scientists can use in their own studies.