Obesity is a possible risk factor for multiple myeloma, but could Myeloma be prevented by Metformin treatment?

MGUS and its low-risk (but possible) transformation into myeloma
Epidemiological data are clear : 5% of population above 70 years of age has an MGUS!
MGUS stays for Monoclonal Gammopathy of Undetermined Significance. It is usually an asymptomatic condition. However, there is a low risk(1% per year) for its transformation into more aggressive conditions, such as multiple myeloma.
One of the questions is the following one: will it be possible to stop this dangerous transformation of the calm MGUS into the aggressive multiple myeloma?                                                                                              
Some studies about this topic have been presented by scientists.

The article of the day
Today I would like to present you a review article that comes from Brazil and summarizes the current knowledge of the possible implications of obesity in the progression from MGUS to multiple myeloma. This article also includes a hopeful and intriguing hope to halt this progression.
How could it be possible to stop this progression? Simply with the metformin, a common and low-cost drug commonly used in Type 2- Diabetes Mellitus!
Ademar Dantas da Cunha and his colleagues explain that with an interesting and detailed summary of the current scientific literature. (1)

There are some interesting connections between obesity and myeloma
The first paragraph of the article analyses the possible connections between obesity and multiple myeloma.
Some studies have demonstrated that obesity might act as a risk factor for the occurrence of myeloma, for example affecting the transformation of MGUS into multiple myeloma. (2)                                         
The authors focused their attention first on pathological mechanisms that obesity and cancer have in common: they include the release of cytokines and the action of insulin.

Cytokines and their role in multiple myeloma
What are Cytokines? Cytokines are microscopic molecules produced in this situation by bone marrow cells
They are typically produced by some cells in bone marrow, for example the so-called bone marrow stromal cells (BMSC).  
IGF-1 is an important cytokine that  promotes the growth and the survival of myeloma cells in the bone marrow environment.                                                                                                                                              
IL-6 is another actor of this process, an important cytokine that can act with other molecules: for example a molecule produced by blood vessels, namely Vascular Endothelial Growth Factor(VEGF). All these molecules can act synergically and stimulate the production of new vessels in the bone marrow. Vessels which could help the typical ambiguous MGUS cells to receive nutrients and oxygen in order to evolve in a possible dangerous way! 

Insulin: its role in obesity and inflammatory processes
Insulin is a hormone produced by pancreas, that has an important role on carbohydrates taken during the meal. 
Scientists demonstrated that obesity can really stimulate the production and secretion in our body of insulin and cytokines. All this would contribute to create an inflammatory state that could be dangerous for our bone marrow but (unfortunately) very positive for the malignant transformation of an MGUS into myeloma.  
The question is: Could a drug strike these dangerous processes? Could this drug perform a preventive and protective action in this malignant  transformation?

Metformin as one of the possible future solutions
In the following paragraph, the authors analyse the possible role of metformin in order to stop a malignant evolution of MGUS into myeloma.                                                                                                         
We can start to evaluate the general role of metformin, one of the most common drugs used to treat type 2-diabetes in order to reduce carbohydrates in the blood!                                                                  
Metformin can help to reduce body weight over time and improve factors linked to the obesity, such as the so-called Body Mass Index (BMI). (3)

BMI is a value derived from the weight and height of a person. It is used to categorize a person as underweightnormal weightoverweight, or obese based on tissue mass (muscle, fat, and bone) and height. The BMI is defined as the body mass divided by the square of the body height, and is expressed in units of Kg/m2.

The role of metformin in myeloma
Metformin could be a potential therapy in patients with haematological conditions, such as multiple myeloma. It has indeed many effects: 
Metformin could conduct to a reduction of the inflammatory process mediated by cytokines produced in bone marrow of people with myeloma. In myeloma patients metformin sure enough could specifically decrease the expression of IL-6R, the receptor of  the cytokine IL-6. This action is probably synergic with the action of some common antimyeloma drugs.
Starting with this concept, a subsequent question arrives among the scientists:  Could IL6-R serve as a biomarker for metformin action in multiple myeloma? (4)

Metformin could influence the immune response(mediated by specific cells of the immune system) and also the role of microbiota and its systemic impacts on body metabolism. (5)
Metformin could influence the bone turnover. This mechanism is complicated. However, we could say that metformin activates the molecule AMPK which can stop (through others molecules) the differentiation of osteoclasts.                                                                                                                                   
Osteoclasts are important actors in the destruction of bone tissue in myeloma, which for example creates fractures.                                                                                                                                                                
It means that metformin, through an accurate mechanism, could indirectly stop the typical and painful myelomatous-bone destruction. (6-7)
Furthermore, Metformin work can be  evaluated well by detecting of some substances in the blood, such as circulating insulin and glucose levels.

The few studies about the relationships between Metformin and MGUS
Metformin has demonstrated incredible advantages in terms of myeloma incidence and  mortality in diabetic patients who received metformin. (8-9)
However many could be the technical mistakes (the so-called biases) in the scientific studies  performed until now. So, it is necessary to plan further studies in the future, in order to use this low-cost and safe drug among the therapeutic  myeloma-arsenal.  
Currently, there are a reduced number of epidemiological studies focused on obesity as a risk factor for MGUS and myeloma, despite the potential clinical importance of obesity in myeloma. (10)

Conclusions
5% of adults over the age of 70 have MGUS. There is furthermore an increasing number of patients that have diabetes and obesity in the world . So, less toxic approaches are needed to minimize the risk of progression from MGUS into myeloma.
Antidiabetic drugs such as metformin are low-cost and safe, and studies have demonstrated their potentially protective roles in cancer, including myeloma.
Metformin has various direct and indirect effects also on the bone marrow environment: so, it is essential to investigate how metformin can stop the progression from MGUS into multiple myeloma. 
Finally, we can affirm that also obesity and diabetes are risk factors for myeloma, but in this context metformin might represent a potential protective therapy in order to halt the development of this disease.

Bibliography

(1) 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? – PubMed (nih.gov)

(2) S. H. Chang, S. Luo, T. S. Thomas et al., “Obesity and the transformation of monoclonal gammopathy of undetermined significance to multiple myeloma: a population-based cohort study,” Journal of the National Cancer Institute, vol. 109, no. 5, 2017.

(3) Diabetes Prevention Program Outcomes Study Research Group, T. J. Orchard, M. Temprosa et al., “Long-term effects of the diabetes prevention program interventions on cardiovascular risk factors: a report from the DPP outcomes study,” Diabetic Medicine, vol. 30, no. 1, pp. 46–55, 2013.

(4) A. K. Mishra and D. Dingli, “Metformin inhibits IL-6 signaling by decreasing IL-6R expression on multiple myeloma cells,” Leukemia, vol. 33, no. 11, pp. 2695–2709, 2019.

(5) S. Verdura, E. Cuyas, B. Martin-Castillo, and J. A. Menendez, “Metformin as an archetype immuno-metabolic adjuvant for cancer immunotherapy,” Oncoimmunology, vol. 8, no. 10, Article ID e1633235, 2019.

(6) Y.-S. Lee, Y.-S. Kim, S.-Y. Lee et al., “AMP kinase acts as a negative regulator of RANKL in the differentiation of osteoclasts,” Bone, vol. 47, no. 5, pp. 926–937, 2010.

(7) Q.-G. Mai, Z.-M. Zhang, S. Xu et al., “Metformin stimulates osteoprotegerin and reduces RANKL expression in osteoblasts and ovariectomized rats,” Journal of Cellular Biochemistry, vol. 112, no. 10, pp. 2902–2909, 2011.

(8) J. M. M. Evans, L. A. Donnelly, A. M. Emslie-Smith, D. R. Alessi, and A. D. Morris, “Metformin and reduced risk of cancer in diabetic patients,” BMJ, vol. 330, no. 7503, pp. 1304-1305, 2005.

(9) S. Gandini, M. Puntoni, B. M. Heckman-Stoddard et al., “Metformin and cancer risk and mortality: a systematic review and meta-analysis taking into account biases and confounders,” Cancer Prevention Research, vol. 7, no. 9, pp. 867–885, 2014.

(10) B. Boursi, B. M. Weiss, K. Haynes, R. Mamtani, and Y.-X. Yang, “Reappraisal of risk factors for monoclonal gammopathy of undetermined significance,” American Journal of Hematology, vol. 91, no. 6, pp. 581–584, 2016.

About the author: Walter Bertolami

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