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contributor of carbon substrates to the TCA cycle whereas glucose is an important contributor of carbon
[37]
substrates for the formation of lactate in clonal plasma cells . This was also supported by the finding
that clonal bone marrow plasma cells in MM patients have higher glutamine uptake compared with the
remainder of bone marrow mononuclear cells. Additionally, 2-hydroxyglutarate (2-HG) - an oncometabolite
of glutaminolysis - is significantly increased in the bone marrow supernatant of MM patients compared to
that of MGUS patients. Similarly, levels of 2-HG in the bone marrow supernatant or in the peripheral blood
plasma of patients with smoldering multiple myeloma was associated with higher risk of progression to
[37]
MM, and correlates with the percentage of bone marrow plasma cells expressing c-MYC . These results
demonstrate the utility of measuring 2-HG levels in BM supernatant or peripheral blood plasma of SMM
patients as a potential biomarker for disease progression and for identification of patients who may benefit
from early therapeutic intervention.

[38]
To characterize the lipid profile of MM cells, Hossen et al. sorted single MM and normal plasma cells
using flow cytometry and performed matrix-assisted laser desorption/ionization-imaging mass spectrometry.
They found that PC (16:0/20:4) was significantly decreased in MM cells compared to normal plasma cells,
which is likely due to the decrease of its integrated fatty acids or to increased metabolism of C .
16:0
[39]
The development of drug resistance is also associated with metabolic alterations in MM. Zub et al.
performed global proteomic and transcriptomic profiling on melphalan sensitive and resistant RPMI8226
MM cell lines. Glycolysis was found to be the most significantly altered pathway. Gluconeogenesis, glutaryl-
CoA degradation, isoleucine and tryptophan degradation, TCA cycle, ketolysis and ketogenesis were also
significantly altered when MM cells develop resistance to melphalan. Specifically, the glycolytic and pentose
phosphate pathway enzymes were up-regulated in the melphalan resistant cells, whereas the TCA cycle and
ETC proteins were down-regulated. Additionally, the melphalan-resistant cells displayed increased tolerance
to overall oxidative stress, but were sensitive to mitochondrial electron transport inhibitors. It was further
demonstrated that lactate accumulation, Interleukin-8 and vascular endothelial growth factor (VEGF)
signaling, as well as aldo-keto reductase played a role in the development of drug resistance to melphalan in
[39]
MM cell lines . Similarly, in MM cell lines resistant to proteasome inhibitors (bortezomib and carfilzomib),
[40]
complex proteomic changes, particularly in redox and energy metabolism were observed . Proteins
involved in metabolic regulation, redox homeostasis, and protein folding and destruction were upregulated
in proteasome inhibitor-resistant MM cell lines, which exhibited metabolic adaptations that favored the
[40]
generation of reducing equivalents such as NADPH . The glucose metabolism was rewired in bortezomib-
resistant MM cells, leading to higher activity of both the pentose phosphate pathway and serine synthesis
[41]
pathway and an increased anti-oxidant capacity in bortezomib-resistant cells . Interestingly, the expression
of 3-phosphoglycerate dehydrogenase (PHGDH), which catalyzes the rate-limiting step of serine synthesis,
was up-regulated in bortezomib-resistant MM cells. Consistent with increased serine synthesis observed
in bortezomib-resistant MM cells, serine starvation enhances the cytotoxicity of bortezomib. These data
suggest that interfering with serine metabolism could be a novel strategy to improve bortezomib therapy and
[41]
PHGDH could be a potential biomarker for bortezomib resistance .
[42]
To identify therapeutic targets for the prevention and treatment of drug resistance, Maiso et al. performed
metabolic profiling of multiple myeloma cells in normoxic and hypoxic conditions. It was found that in
hypoxic conditions, intermediates of the TCA cycle and the ETC were reduced whereas intermediates of
glycolysis were elevated. Specifically, glucose 6-phosphate, fructose 6-phosphate, fructose 1,6-bisphosphate,
pyruvate, and lactate were significantly increased in hypoxic cells. Gene expression profiling further
demonstrated that the main pathways altered by hypoxic culture were those involved in glucose metabolism
and the TCA cycle including key metabolic genes such as hexokinase 2 (HK2) and lactate dehydrogenase
A (LDHA). Interestingly, bortezomib treatment inhibited HK2 activity but not lactate activity, suggesting
LDHA may play a role in modulating drug resistance of MM cells in hypoxic conditions.