Multiple myeloma is a prevalent type of cancer affecting the immune cells in the bone marrow, making it incurable as it tends to reoccur even after initial treatment. To enable earlier and more targeted intervention, a group of researchers embarked on an in-depth study of this disease at the molecular level.
Multiple myeloma is a common cancer affecting the immune cells in the bone marrow. It is considered incurable and often reoccurs after treatment. Researchers from Charité–Universitätsmedizin Berlin, the Berlin Institute of Health at Charité (BIH), and the Max Delbrück Center collaborated with other partners to conduct an extensive study of this disease at the molecular level. They have revealed how aggressive types of tumors can be detected early on, and their findings have been published in the journal Nature Cancer.* The study explores how genetic changes influence the protein profile of tumor cells and the underlying disease mechanisms.
Multiple myeloma occurs when plasma cells in the bone marrow, responsible for antibody production, undergo mutations and transform into cancerous cells. In this condition, a single plasma cell mutates into a tumor cell that replicates uncontrollably, forming a population of identical cells initially. These mutated cells often produce excessive antibodies or fragments that fail to function properly.
Over time, most patients develop tumors in various areas of the bone marrow, leading to the disease’s name. Common consequences include immunodeficiency, kidney failure, bone loss, and fractures due to uncontrolled cell growth. Despite advancements in treatment and the introduction of new therapies, multiple myeloma remains incurable. To address this challenge, Jan Krönke from the Department of Hematology, Oncology, and Cancer Immunology at Charité, along with Dr. Philipp Mertins from the Proteomics technology platform of the Max Delbrück Center and BIH, spearheaded research to explore novel approaches to diagnosis and treatment.
Understanding Tumor Progression
Cancer cases, including multiple myeloma, are highly individualized and can progress at different rates, making prognosis and treatment selection challenging. While some mutated plasma cells do not spread significantly, others exhibit aggressive behavior, leading to a poor outlook.
To investigate the varying nature of multiple myeloma, the researchers collaborated with protein analysis experts from the Max Delbrück Center and BIH to scrutinize genetic and molecular changes in tumor cells across a group of over one hundred patients. The study incorporated data from the German Multiple Myeloma Study Group (DSMM), managed by the University Hospital of Würzburg, including clinical information on patients who underwent standardized treatment for over eight years post-initial diagnosis.
Integration of Systems Medicine and Big Data
While genetic alterations and their impact on the proteome are well-documented in other cancers, this study represents the first comprehensive proteo-genomic investigation of multiple myeloma. Mertins emphasizes that genetic data alone cannot elucidate disease mechanisms, necessitating an analysis of protein-level consequences of genetic changes to understand disease progression. Charité, BIH, and the German Cancer Consortium (DKTK) provided crucial support in data collection and analysis.
Advanced mass spectrometry techniques facilitated the mapping of the protein profiles of mutated plasma cells, enabling a comparison with healthy plasma cells from unaffected individuals. The researchers discovered that genetic modifications and altered signaling pathways drive uncontrolled cancer cell activation, with protein-level regulatory processes exerting a stronger influence. They identified a protein constellation indicating a highly aggressive disease course, independent of known risk factors.
Implications for Therapeutic Innovation
Krönke emphasizes that their discoveries will improve patient subcategorization for personalized treatment, pinpointing key proteins and signaling pathways that can underpin more effective and tolerable therapies for multiple myeloma, such as immune therapies like CAR T-cell therapy. The team plans to further investigate the identified target structures for new therapeutic avenues.
As the study’s lead author, Dr. Evelyn Ramberger, notes the significance of the study in research and applied development, highlighting the creation of an interactive online tool to manage the complex dataset. This tool allows easy access to the findings for cancer researchers, aiding in the development of new therapies and diagnostic tests for enhanced treatment strategies, including early intensive intervention for patients with aggressive multiple myeloma.
Understanding Mass Spectrometry
Mass spectrometry is a methodology for analyzing the mass of molecules and atoms by ionizing the substance under study and converting it to a gas phase. The formed ions are accelerated and sorted by mass-to-charge ratio, providing insights into molecular composition. This technique is valuable for identifying, characterizing, and quantifying various biomolecules, like proteins and metabolites, which exhibit diverse behaviors based on the disease and individual biological characteristics.
