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MULTIPLE MYELOMA
Multiple myeloma (MM) is a neoplastic disorder characterized by the dysregulated proliferation of a
plasma cell clone that typically produces a monoclonal immunoglobulin, ultimately resulting in end-organ
[1-3]
damage . Clinical suspicion for active MM is often based on the presence of one or more laboratory/
imaging abnormalities, termed the CRAB criteria [hypercalcaemia (C), renal impairment (R), anaemia (A),
and osteolytic bone lesions (B)], particularly if occurring in a patient with a precursor plasma cell disorder
[4]
such as monoclonal gammopathy of undetermined significance (MGUS) or smoldering MM (SMM) . A
diagnosis of active MM requires the presence of greater than 10% clonal bone marrow (BM) plasma cells in
association with either one or more of the CRAB features or a biomarker of malignancy (BM plasmacytosis
equal or greater than 60%, ratio of involved vs. uninvolved light chain equal or greater than 100 or the
[5,6]
presence of more than 1 focal lesion on magnetic resonance imaging) . MM is generally preceded by
[6]
the asymptomatic precursor conditions MGUS and/or SMM . MGUS is characterized by low levels of
monoclonal protein (< 3 g/dL) and less than 10% clonal plasma cells in the BM while SMM is characterized
by the presence of > 3 g/dL of monoclonal protein with BM plasmacytosis exceeding 10% but less than
60% . Evidence of end organ damage related to the plasma cell disorder is an exclusion criteria for MGUS/
[6]
SMM diagnosis. Patients with MGUS and SMM progress to active MM at a rate of 1% and 10% per year,
[7]
respectively .

While single driver mutations have not been identified in MM, marked genomic instability is a hallmark
[8]
of the disease and contributes to elevated proteotoxic stress . The high frequency of genomic mutations
may confer a survival advantage by enabling MM cells to quickly adapt to stresses in the environment.
However, this comes at a cost. This deregulation of gene expression results in the accumulation of toxic
misfolded proteins that exerts additional stress on MM cells [9-13] . Furthermore, MM are highly secretory
cells, characterized by staggering rate of synthesis of clonal immunoglobulins which further contributes to
baseline ER stress. Therefore, protein quality control pathways are essential for MM survival .
[8]

AUTOPHAGY
Autophagy is a tightly regulated self-digestion mechanism that promotes the lysosomal degradation of
organelles, intracellular pathogens, and misfolded proteins. It is a key cellular mechanism to maintain
homeostasis and guarantee energy supply as products of autophagic digestion can be re-utilized in anabolic
processes [14-16] . Therefore, nutrient and energy deprivation, ER stress, and hypoxia can all induce autophagy
[17]
as a means to enable cell survival . In mammalian cells, there are three main types of autophagy, namely
macroautophagy, microautophagy, and chaperone-mediated autophagy .
[15]

Macroautophagy
Macroautophagy is a type of autophagy that delivers cellular contents to the lysosome via the formation
of double-membrane structures called autophagosomes which then fuse with lysosomes to form
[16]
autolysosomes [18,19] . Macroautophagy can be subdivided into non-selective (bulk) and selective autophagy .
During non-selective autophagy, bulk cytoplasm is randomly engulfed by a phagophore [Figure 1]. Notably,
[20]
the mammalian target of rapamycin (mTOR) pathway is a key inhibitor of autophagy . Subsequently,
the phagophore matures into an autophagosome and this process is mediated by autophagy-related protein 7
(ATG7), ATG8 (LC3), and ATG12 [21,22] . ATG7 functions as an E1-like enzyme by binding and activating ATG12
and ATG8 to facilitate the transfer of ATG12 to ATG5 via the E2 enzyme ATG10 [23-27] . The resultant ATG12-
ATG5 conjugate forms a large multimeric complex together with ATG16 (ATG12-ATG5-ATG16) which acts
as an E3 ligase to facilitate phosphatidylethanolamine (PE) and LC3 conjugation and conversion of LC3-I
to LC3-II. LC3-II stably associates with the autophagosome membrane and regulates autophagic membrane
expansion, recognition of autophagic cargo, and autolysosome formation [21,22] . Finally, autophagosome
and lysosome fusion occurs and the autophagic cargo is degraded by lysosomal hydrolases [21,22] . Selective