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transporters leading to an acidification of the bone marrow microenvironment. This results in inhibition of
MCTs in T-cells and thus accumulation of intracellular lactate and H+, which-together with their reduced
[92]
access to glucose by overconsuming tumor cells-leads to decreased T-cell activation .
OXPHOS in multiple myeloma
Since oxidative phosphorylation is the last step in ATP synthesis for aerobic respiration it has been a
particular focus of research in cancer metabolism. Given the increase in glycolysis during the progression of
myeloma reviewed above, it might be predicted that OXPHOS increases as well. However, it has been found
that OXPHOS activity is decreased during increased glycolysis in MM. This is thought to occur because
the TCA cycle is not producing enough electron carriers to supply the OXPHOS mechanism to operate at a
[90]
normal rate of ATP production . Given these conditions, energy production shifts to anaerobic respiration
since other mechanisms, like ketosis, are evolutionarily reserved for starvation and extreme cases, meaning
that lactate is the main source of energy in myeloma cells.

While many groups have investigated the role of metabolism in myeloma, relatively few have focused on the
role of oxidative phosphorylation in MM. The complex 1 inhibitor, IACS-010759, has been tested in leukemia
cells where it led to decreased proliferation and increased apoptosis in leukemia cells [93,94] . This compound
is actively being tested in clinical trials of relapsed AML (NCT02882321), and advanced solid tumors and
lymphomas (NCT03291938).

Similarly, inhibitors of complex III have been explored as possible anti-cancer agents. Inhibition of complex
III leads to an increase in ROS which can combat tumor proliferation and metastasis as well as induce
[95]
apoptosis in MM. Previously, Arihara et al. demonstrated that reactive oxygen species have antimyeloma
activity. Using CP-31398, an activator of p53 which also induces the formation of ROS, the investigators
demonstrated decreased MM proliferation and increased apoptosis in a p53 independent fashion, and this
effect was synergistic with carfilzomib. Notably, no additional hematologic toxicity was seen with the agent
[96]
in animal studies .

Fatty acid research
It is established that resistant MM cells can increase lipogenesis as a mechanism of chemotherapy
resistance [42,79,97] . PUFAs have previously been shown to enhance chemotherapeutic drug effects by
selectively inducing apoptosis in multiple cancer cell lines [98-103] . Specifically, administration of two PUFAs,
eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) to four MM cells (L363, OPM-1, OPM-
2 and U266) resulted in induction of apoptosis through increased caspase-3 activation, and mitochondrial
[104]
membrane perturbation with no effect on normal human peripheral mononuclear cells . Similarly, studies
[105]
by Dai et al. examined the effects of EPA and DHA on the myeloma cell lines MM1S and MM1R and
found that treatment with these agents resulted in increased apoptosis which was enhanced by the addition
of dexamethasone. Notably, this synergy with dexamethasone was observed in the MM1R cell line which
is inherently dexamethasone resistant. As glucocorticoids are known to increase lipogenesis, and remain
a mainstay of MM therapy, these data suggest that EPA and DHA may resensitize cells that have acquired
resistance to glucocorticoids. Additional studies on MM cell lines showed that treatment with EPA or
DHA decreased MM cell proliferation through induction of lipid peroxidation. This effect was inhibited
by superoxide dismutase, or cyclooxygenase/lipooxygenase inhibitors suggesting a role for superoxides,
[107]
[106]
prostaglandins, and leukotrienes in MM proliferation . Similarly, Wang et al. examined the expression of
FAS in bone marrow from MM patients and matched healthy volunteers and found 70% of MM patients had
elevated FAS while none of the healthy volunteers had detectable levels. Treatment of the FAS expressing MM
cell lines U266 and RPMI8226 with the FAS inhibitor cerulenin resulted in induction of apoptosis evidenced
by increased Annexin V staining suggesting FAS as a possible target of anti-myeloma therapy. These studies
are admittedly preliminary but warrant additional research in this area.