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cells survives glucose deprivation or ritonavir treatment likely by engagement of mitochondrial oxidative
phosphorylation. Metformin is an FDA approved anti-diabetic medication that targets mitochondrial complex
1. The combination of ritonavir and metformin effectively elicited apoptosis in vitro in MM cell lines and
[59]
primary human myeloma cells and showed anti-myeloma activity in vivo in a xenograft model of MM .
Further analysis of the combination showed that it suppressed AKT and mTORC1 phosphorylation, and
[59]
down-regulated the expression of Mcl-1 in myeloma models .
Hexokinases catalyze the first irreversible step of glycolysis and play a critical role in the regulation of
glycolytic activity. HK2 interacts with the voltage dependent anion channel in the outer membrane of
[60]
mitochondria, where it catalyzes the conversion of glucose to glucose 6-phosphate . HK2 has been shown to
be overexpressed in a variety of cancers including MM [61,62] , suggesting that HK2 could be a viable target for
inhibiting the proliferation of multiple myeloma cells [62-65] . Notably, treatment with bortezomib or vincristine,
[66]
downregulated the expression of GLUT-1 and hexokinase, and induced apoptosis in OPM2 MM cells .
An additional approach to targeting glucose consumption has been with the use of the novel purine
[67]
analogue 8-aminoadenosine (8-NH(2)-Ado). Shanmugam et al. showed that treatment of the MM1S
myeloma cell line with 8-NH(2)-Ado reduced glucose consumption through regulation of the GLUT4
transporter.

Targeting amino acid metabolism for the treatment of MM
In addition to MM cells being dependent on glucose, myeloma cells are also dependent on glutamine for
energy equivalents through a process known as glutaminolysis. This process is especially prevalent in
[68]
chemotherapy resistant myeloma cells. Bajpai et al. showed that when glucose metabolism is inhibited
in myeloma cells exposed to various anti-myeloma agents, (bortezomib, melphalan, or carfilzomib), the
resistant myeloma cells became preferentially dependent on glutamine and thus less likely to undergo
apoptosis. Using glutamine as a primary energy source also affects the bone marrow microenvironment in
MM patients. Specifically, the T-cells and NK cells in the tumor microenvironment are suppressed by the
nutrient deprivation, hypoxia, and decreased pH that results from increased dependence on glutamine as an
[69]
energy source .
Glutaminolysis breaks down glutamine into alpha-ketoglutarate which then enters TCA cycle. Glutamine
can be converted to glutamate, a reaction termed glutamine anaplerosis. Alpha-ketoglutarate can be further
broken down to 2-HG which is associated with c-MYC overexpression [37,70] . 2-HG is an oncometabolite,
and elevated levels of 2-HG in smoldering MM patients are associated with increased risk of progression
[37]
to MM . Glutamine is crucial for the survival and proliferation of certain cancer cells, and starvation of
[72]
[71]
glutamine induces cancer cell death . Effenberger et al. recently showed that in vitro cultures of MM cells
are dependent on glutamine for survival and that this is dependent on MYC protein expression. Notably,
when these cells were treated with the glutaminase inhibitor benzophenanthridinone 968 apoptosis was
induced. Additionally, MM cells show high expression of the glutamine transporters SNAT1, ASCT2, and
L-type amino acid transporter 1 (LAT1); and inhibition of the ASCT2 transporter exhibits anti-myeloma
[73]
activity . Furthermore, high expression of LAT1 is associated with high proliferation and poor prognosis
in newly diagnosed MM patients, and predicts poor overall survival independent of the International
[74]
Staging System . These data demonstrate that inhibition of glutaminolysis serves as a potential therapeutic
approach in the treatment of MM [71,72] .

Targeting fatty acid metabolism for the treatment of MM
Fatty acids and lipids play important roles in the development and pathogenesis of MM through direct
influence on the metabolism of myeloma cells, functioning as intercellular messengers, or acting as
[75]
mediators of the pathological immunologic pathways . Analysis of plasma or erythrocyte membrane lipid