Obesity-associated Metaflammation as Driver in the Transition from Myeloma Precursor States to Symptomatic Disease

• Applicant: Dr. David Manuel Cordas dos Santos
• Subject Area: Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 525171148

Multiple myeloma (MM) is a monoclonal plasma cell disease and compromises 10-15% of hematologic neoplasias in adults. The disease is characterized by an infiltration of monoclonal, malign myeloma cells into the bone marrow and an aberrant production of immune globulins (or parts), and leads to end organ damages if not treated. In almost all cases, symptomatic MM develops from the precursor diseases monoclonal gammopathy of unclear significance (MGUS) and smouldering multiple myeloma (SMM). In these precursor diseases monoclonal protein and an increase of plasma cells can be detected without clinical symptoms. Whereas in earlier times, the accumulation of genetic mutations within myeloma cells were solely thought to foster progression to symptomatic disease, recent evidence shows that myeloma-specific driver mutations are already existent at early precursor stages. It is therefore assumed, that alterations within the bone marrow microenvironment significantly contribute to the progression from MGUS and SMM to overt disease. Overweight and obesity are among the clinical risk factors for disease progression. The pathophysiologic mechanisms underlying this association are complex and not fully understood. Next to direct cell-cell interactions between bone marrow adipocytes and myeloma cells as well as a disruption of obesity-associated hormone homeostasis, obesity also affects the immune system. In recent years, it was shown that obesity leads to a low-grade, chronic and systemic inflammatory status, called metaflammation, through an infiltration of inflammatory active immune cells with the production of pro-inflammatory cytokines into the adipose tissues. By this continuous cell stress, metaflammation can lead to an impairment of the immune system and subsequently foster immune evasion of myeloma cells. However, the various adipose tissue deposits contribute to the metaflammation process in different extent. In the present project, we therefore want to analyze, if the obesity-associated effects on the (local) immune system based on different adipose tissue deposits including the bone marrow adipose tissue is a driver for the progression from MGUS and SMM to overt disease. The planned analyses will make use of patient records and biomaterials from patients with MGUS and SMM previously collected. For in-depth mechanistic analyses of the interaction of obesity, immune system and myeloma development, we will use in-vivo myeloma models.

• DFG Programme: WBP Fellowship
• International Connection: USA
• Host: Professorin Dr. Irene M. Ghobrial