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  • Early Detection of Aggressive Multiple Myeloma Using Advanced Proteogenomic Techniques

    Multiple myeloma, a common and incurable cancer of the bone marrow's immune cells, continues to pose significant challenges despite advancements in treatment. A collaborative study conducted by researchers at Charité – Universitätsmedizin Berlin, the Berlin Institute of Health at Charité (BIH), and the Max Delbrück Center aims to address this by exploring the disease at the molecular level. The findings, published in Nature Cancer, provide insights into how highly aggressive tumors can be detected early, potentially leading to more targeted interventions.

    Understanding Multiple Myeloma
    Multiple myeloma arises when plasma cells in the bone marrow, which are responsible for producing antibodies, mutate and proliferate uncontrollably. This unchecked growth forms a monoclonal cell population that produces non-functional antibodies. Over time, patients develop multiple tumors within the bone marrow, resulting in immunodeficiency, kidney failure, bone loss, and fractures.

    Despite new gene and cell therapies, there is currently no cure for multiple myeloma. The research team, led by Jan Krönke from Charité's Department of Hematology, Oncology, and Cancer Immunology and Philipp Mertins, head of the Proteomics technology platform at the Max Delbrück Center and BIH, sought new diagnostic and therapeutic approaches.

    Investigating Tumor Pathways
    The variability in tumor progression among multiple myeloma patients complicates treatment decisions. Some tumors remain localized, while others spread aggressively, worsening the prognosis. To understand this variability, the researchers conducted an in-depth study of genetic and molecular changes in tumor cells from over one hundred patients. The study included data from the German Multiple Myeloma Study Group (DSMM), coordinated by the University Hospital of Würzburg, providing clinical data on patients who received standardized treatment over eight years.

    Integrating Systems Medicine and Big Data
    This study represents the first detailed proteogenomic analysis of multiple myeloma. “Genetic data alone is 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 against the actual course of the disease in patients.” The team employed cutting-edge mass spectrometry methods to map the protein profiles of mutated plasma cells, comparing them with healthy plasma cells from individuals without the disease.

    The researchers discovered that changes in both genetic material and signaling pathways led to uncontrolled cancer cell activation, with regulatory processes at the protein level exerting a stronger influence. They identified a specific protein constellation indicative of a particularly aggressive disease course, independent of other known risk factors.

    Potential for New Therapeutic Approaches
    “Our findings will help subcategorize patients more effectively going forward, personalizing their treatment,” says Krönke. “We’ve identified key proteins and signaling pathways that can serve as the basis for even more effective, better tolerated treatments for multiple myeloma, for example for immune therapies such as CAR T-cell therapy.” The next steps involve studying which of the identified target structures are viable candidates for new therapeutic approaches.

    The study provides a valuable resource for both research and applied development. “To make the complex data set manageable, we programmed an interactive, freely available online tool,” says Dr. Evelyn Ramberger, first author of the study. This tool enables cancer researchers to access the results easily, facilitating the development of new therapies and tests to guide treatment. For instance, patients with particularly aggressive multiple myeloma might receive more intensive therapies from the outset based on these findings.

    Publication Details
    Ramberger, E., Sapozhnikova, V., Ng, Y.L.D. et al. The proteogenomic landscape of multiple myeloma reveals insights into disease biology and therapeutic opportunities. Nat Cancer (2024). https://doi.org/10.1038/s43018-024-00784-3

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