Early detection of aggressive multiple myeloma by molecular analysis

Multiple myeloma is one of the most common forms of immune cell cancer in the bone marrow. It is considered incurable. Even when patients respond to initial treatment, the cancer returns. To be able to intervene more quickly and on a more targeted basis, researchers at Charité – Universitätsmedizin Berlin, the Berlin Institute of Health at Charité (BIH) and the Max Delbrück Center joined with other partners for a comprehensive study of this disease at the molecular level. The team now describes how very aggressive types of tumors can be detected early in an article published in the journal Nature Cancer. They show how changes in the genetic material affect the protein profile of tumor cells, and thus the mechanisms involved in the disease.

Multiple myeloma is a form of cancer in which immune cells in the bone marrow, known as plasma cells, mutate and become cancerous. Plasma cells are responsible for the production of antibodies. All people have many different types of plasma cells that form a large number of different antibodies. This allows the body to recognize and fight various pathogens. In multiple myeloma, a single plasma cell changes into a tumor cell. That cell reproduces uncontrollably, forming a monoclonal cell population. This means that many cells are formed, all of them exactly the same and genetically identical to begin with. Mutated cells often also produce large volumes of antibodies or fragments of them – but they don’t work properly.

During the course of the disease, most patients develop tumors in different places in the bone marrow, hence the name of the disease is “multiple”. Immune deficiency, kidney failure, bone loss and bone fractures are just some of the consequences of this uncontrolled cell growth. Despite advances in treatment and the introduction of new gene and cell therapies, there is currently no cure for multiple myeloma. With this issue in mind, a team of researchers led by Jan Krönke from the Department of Hematology, Oncology and Cancer Immunology at Charité and Dr. Philipp Mertins, head of the Proteomics technology platform of the Max Delbrück Center and BIH, set out in search. of new approaches to diagnosis and treatment.

What path does the tumor take?

No two cancer cases are alike, and multiple myeloma is no exception. Tumors develop differently in different individuals, including at different rates. This makes it more difficult to predict how the disease will progress and to choose the optimal treatment. While the mutated plasma cells do not spread much in some cases, in others they are extremely aggressive, leading to a poor prognosis.

But what causes so much divergence in the course of multiple myeloma? In collaboration with protein analysis experts from the Max Delbrück Center and BIH, the researchers conducted a detailed study of the genetic and molecular changes occurring in tumor cells in a group of more than a hundred patients. The study included data from patients in the German Multiple Myeloma Study Group (DSMM), which is coordinated by the University Hospital of Würzburg. This allowed the researchers to include clinical data on patients who had received standardized treatment over a period of eight years or more after initial diagnosis.

Systems medicine and big data

While changes in the genome and their effects on the proteome are already well described for other cancer types, this is the first detailed proteo-genomic study of multiple myeloma.

“Genetic data alone are insufficient to explain the mechanisms involved in this disease,” says Mertins. “We wanted to know the consequences of genetic changes at the protein level and compare this molecular biology data with the actual course of the disease in patients.” The team relied on the collection and analysis of large volumes of data by experts at Charité, BIH, and the German Cancer Consortium (DKTK).

Recent mass spectrometry methods have made it possible to map the protein profile of mutated plasma cells and compare it with that of healthy plasma cells in people without the disease. The researchers found that genetic changes and changes in signaling pathways lead to the uncontrolled activation of cancer cells. Regulatory processes at the protein level had the strongest impact. The researchers identified a group of proteins that suggests the disease will take a particularly aggressive course, regardless of other known risk factors.

Unlocking new therapies

“Our findings will help subcategorize patients more effectively going forward, personalizing their treatment,” concludes Krönke. “We have identified key proteins and signaling pathways that may serve as the basis for even more effective and tolerable treatments for multiple myeloma, for example immune therapies such as CAR T-cell therapy.” In the next steps, the researchers plan to study which of the target structures they have identified are actually good candidates for new therapeutic approaches.

The study is an essential resource for applied research and development, says Dr. Evelyn Ramberger, first author of the study: “To make the complex data set manageable, we programmed an interactive tool, freely available online.” This has given cancer researchers easy access to the results, so they can use the information to develop new therapies and tests to help guide treatment. For example, it may be possible to treat patients with a particularly aggressive form of multiple myeloma with more intensive therapy early on.