Obesity as a Possible Risk Factor for Progression from Monoclonal Gammopathy of Undetermined Significance Progression into Multiple Myeloma: Could Myeloma Be Prevented with Metformin Treatment?
Clinical studies have revealed a remarkable prevalence of diabetes, obesity and cancer in adults over time and with a progressive expansion in the last years. Diabetes mellitus type 2 and cancer share many risk factors, especially obesity and metabolic syndrome, with potential biological connections between the two diseases, as meta-analysis data from prospective cohort studies suggest a modest but consistent direct effect of body mass index (BMI) on the incidence of lymphoma, Multiple Myeloma, increased risk of leukaemia in adults, increased risk of Monoclonal Gammopathy Of Undetermined Significance transformation into Multiple Myeloma, and increased risk of death in Multiple Myeloma patients.
The Diabetes Prevention Program study showed that metformin constantly reduced body weight over time, which could explain the diabetes prevention effects of the drug.
Metformin also significantly improved fasting insulin and proinsulin and other adiposity parameters such as BMI, waist circumference, and waist-hip ratio.
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Epidemiological and preclinical research studies indicate that metformin is a potential therapeutic target in patients with leukaemia, lymphomas and Multiple Myeloma. It is expected that the diverse pleiotropic effects of the drug act on multiple targets, specifically in myeloma, in which there is a strong interaction between the clonal plasma cells and the bone marrow microenvironment.
Finally, metformin influences bone turnover because it activates AMP-activated protein kinase, which, in turn, acts as a negative regulator of Receptor Activator of Nuclear Factor Κb Ligand in the differentiation of osteoclasts. Furthermore, metformin might also significantly suppress bone resorption
New epidemiological and preclinical research points to metformin as a potential therapeutic target in patients with Multiple Myeloma. Although epidemiological studies have reasonably and consistently reported reduced Multiple Myeloma incidence and/or mortality in diabetic patients who receive metformin, many sampled their case study retrospectively from the hospital or clinical registries rather than population-based registries, restricting external validity and inserting potential selection biases. Some studies did not exclude individuals with a prior cancer diagnosis, thus presenting a possible reverse causation bias. Many studies included patients exposed to various treatments for diabetes, complicating the analysis of metformin associations. Self-reporting of crucial data such as concomitant medication use and cancer risk factors such as obesity, tobacco use, and family history may have provided exposure biases.
Assuming that 3% of adults over the age of 50 have Monoclonal Gammopathy of Undetermined Significance and the increasing numbers of diabetes and obesity in the world population, less toxic approaches are needed to minimize the chances of Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma progression. Antidiabetic drugs such as metformin are low-cost and safe, and studies have demonstrated their potentially protective roles in cancer, Multiple Myeloma, and Monoclonal Gammopathy of Undetermined Significance to Multiple Myeloma progression. Interventions with minor results may have a meaningful influence on the cumulative disease load. Considering the pleiotropic effects (direct and indirect) of metformin on the bone marrow milieu, it is essential to investigate the mechanisms involved in the preventive effects of the drug in the progression of Multiple Myeloma, in order to indicate its proper use in this context.
Journal of Medical Research & Health Education