Researchers discovered that changes in the bone marrow needed for multiple myeloma to grow have already taken hold in patients with monoclonal gammopathy of undetermined significance (MGUS).1
Increased expression of peptidyl arginine deiminase 2 (PADI2) in patients with MGUS and multiple myeloma alters the malignant cell phenotype, and PADI2 activity directly leads to bortezomib resistance. Since the changes in the bone marrow are already present in MGUS, this study raises the possibility that early medical intervention could prevent this incurable cancer from taking root.
“It is now clear that the bone marrow of patients with MGUS, traditionally thought of as a benign condition, is significantly different to that of healthy individuals. The bone marrow environment in these patients appears capable of supporting cancer growth, even though the majority of patients will not progress to myeloma. While this research is in the early stages, it offers the exciting possibility that early intervention could potentially delay or even prevent cancer development,” said Daniel Tennant, PhD, who led the research at the University of Birmingham, United Kingdom.
Multiple myeloma affects the plasma cells. The American Cancer Society states an estimated 30,330 new cases will be diagnosed in the United States in 2016. Fewer than half of patients survive longer than 5 years after diagnosis. Symptoms include debilitating and painful bone damage, anemia, and nausea.
The disease almost always progresses from MGUS, an apparently benign condition. MGUS is present in up to 7% of people older than 85 years; yet only approximately 1 in 100 patients with MGUS will develop myeloma each year. Currently, there is no way to accurately predict which patients will do so, or when.
Myeloma never spreads to other organs, suggesting that myeloma cells rely on support from other cells in the bone marrow environment to survive. Early on in the development of MGUS, the cells that compose bone marrow connective tissue undergo a change in behavior that makes them more supportive of cancer growth. The key gene PADI1 becomes particularly active in these connective tissue cells, leading to the overproduction of interleukin-6 (IL-6), a signaling molecule.
IL-6 released into the bone marrow by connective tissue cells binds with receptors on the surface of cancerous plasma cells prompting them to multiply rapidly and resist cell death signals. Furthermore, high levels of IL-6 in a patient’s bone marrow are known to significantly reduce the effectiveness of bortezomib.
Drugs designed to target PADI2 in patients with MGUS and multiple myeloma could significantly reduce the supportive signaling that myeloma cells depend on, which could possibly increase the effectiveness of current treatments. In addition, PADI2 is also linked with the development of other types of cancer, rheumatoid arthritis, Alzheimer disease, and autoimmune disease, so any drug developed could have wider indications beyond treatment of multiple myeloma.
“There is an urgent need for new treatments for myeloma, which, as well as being largely incurable, can have a devastating impact on quality of life. With an increasing elderly population, MGUS and myeloma are only going to become more common. Drugs designed to remove the support system myeloma uses to grow could be an effective way of treating the disease, or even preventing it altogether,” said Dr Alasdair Rankin, director of research at Bloodwise, a British blood cancer charity that funded this research.
1. McNee G, Eales KL, Wei W, et al. Citrullination of histone H3 drives IL-6 production by bone marrow mesenchymal stem cells in MGUS and multiple myeloma. Leukemia. 2016 Jul 11. doi:10.1038/leu.2016.187. [Epub ahead of print]