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Page 2 of 16 Rizzieri et al. J Cancer Metastasis Treat 2019;5:26 I http://dx.doi.org/10.20517/2394-4722.2019.05

(Ig) produced by the transformed plasma cells. Production of this aberrant Ig results in several of the
[2,3]
complications associated with MM such as renal dysfunction, neuropathy, and hyperviscosity syndrome .
However, in approximately 15%-20% of patients the abnormal plasma cells secrete only monoclonal free light
chains, and in approximately 2%-3% of cases these cells secrete no monoclonal protein at all resulting in the
[4,5]
so-called non-secretory myeloma . Myeloma cell growth in the bone marrow and the resultant cytokines
produced by these transformed cells and/or other cells in the bone marrow microenvironment lead to the
[6]
classic symptoms of active MM: osteolytic bone lesions, hypercalcemia, and anemia .
The underlying epidemiology of MM remains largely undefined. Previously, exposure to ionizing radiation
was thought to be a risk factor, but this was subsequently refuted in a large cohort of atomic bomb
[7]
survivors in Japan . More recent data suggest a 2-3 fold increased risk for development of MM among
[8,9]
African Americans which is thought to be related to increased rates of MGUS among this population .
Interestingly, in contrast to most other malignancies, African Americans with MM tend to have a better
[10]
prognosis compared to age-matched Caucasians with the disorder . Several meta-analyses have suggested
obesity is associated with increased risk of myeloma with a relative risk ranging from 1.11-1.82 [11-14] , and it
has been shown that obesity significantly increases the risk of myeloma associated mortality [15,16] .

[1]
MM is primarily a disease of the elderly, with the median age at diagnosis being 69 in the United States .
This population often suffers from significant co-morbidities making management of myeloma more
[17]
challenging. Specifically, approximately 40% of this population meets criteria for obesity (BMI ≥ 30) ,
and the rates of several obesity associated metabolic disorders such as diabetes and hyperlipidemia already
approach 25% and 50% respectively, and continue to rise [18,19] . Given these associations it is reasonable
to wonder if these metabolic changes are significantly participating in MM pathogenesis. As this area
has largely been uncharacterized, in this review we aim to highlight the metabolic changes that occur in
myeloma patients, summarize how these changes are affected by myeloma directed therapy, and suggest
possible interventions to enhance anti-myeloma based therapies by taking advantage of metabolic pathways
which are often dysregulated in MM patients.

OVERVIEW OF METABOLISM
Glycolysis
Glycolysis is the primary process by which cells break down glucose releasing stored energy in the process
[20]
which can be used to generate ATP . This process begins when membrane bound insulin receptors bind
insulin resulting in autophosphorylation of the tyrosine residues. Subsequent phosphorylation of insulin
[21]
receptor substrates, and activation of the PI3K and MAPK pathways promote cellular uptake of glucose .
Insulin also regulates fructose 2,6-bisphosphate, a key regulator of glycolysis. In glycolysis, a single glucose
molecule is phosphorylated by hexokinase (HK) to yield glucose-6-phosphate (a reaction which requires
ATP), which then undergoes isomeric change by the enzyme glucose 6-phosphate isomerase to become
fructose 6-phosphate. Fructose 6-phosphate is then irreversibly phosphorylated by phosphofructokinase
(PFK) in a reaction that requires ATP to yield fructose 1,6-bisphosphate; this reaction is the rate-
limiting and committed step of glycolysis. Fructose 1,6-bisphosphate is then cleaved by aldolase into two
triose phosphates: glycerolaldehyde-3-phosphate and dihydroxyacetone phosphate. Glycerolaldehyde
3-phosphate is oxidized by glycerolaldehyde 3-phosphate dehydrogenase using NAD+ as an electron
donor to yield 1,3-bisphosphoglycerate (1,3-BPG). 1,3-BPG is then dephosphorylated at carbon-1 by
phosphoglycerate kinase to yield 3-phosphoglycerate, and then reversibly converted to 2-phosphoglycerate
by phosphoglycerate mutase. 2- phosphoglycerate undergoes a dehydration reaction catalyzed by enolase to
form phosphoenolpyruvate (PEP) which is then irreversibly converted to pyruvate by pyruvate kinase (PK)
in a reaction that also generates ATP [22,23] .

In eukaryotic cells, pyruvate can be reduced to produce ATP through two different pathways depending
on the presence of mitochondria and appropriate blood and oxygen supply in the tissue of need: aerobic