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Secondly, studies have revealed that miRNAs may act as both tumor suppressors and oncogenes in various
cancers. Substantial work has been done to investigate the role of miRNAs in MM. Studies indicate that
miRNAs can negatively regulate genes and pathways relevant to myelomagenesis via transcriptional control
[14]
through promoter methylation . For example, miR-137 maintains genomic instability in an aurora kinase
A (AURKA)-dependent manner, while miR-22 regulates DNA ligase III in MM [109,110] . In short, miRNA
deregulation is a key contributor to malignancy, and further research will unravel potential treatment
targets.

Third, DNA methylation regulates gene expression and contributes to MM progression from MGUS to
PCL. DNA methylation is found at higher frequencies in promoter regions, repeat sequences, and
transposable elements of genes. MM has a recognized pattern of global DNA hypomethylation and gene-
specific hypermethylation affecting cell adhesion, proliferation, the stromal-clone relationship, cell cycle
progression, and transcription, predominantly in t(4;14) tumors, resulting in MMSET gene over-
[111]
expression .

CLONAL HETEROGENEITY
Intraclonal heterogeneity is a common feature of MM and occurs in the milieu of selection events in the
tumor microenvironment . The clonal evolution in MM follows the Darwinian model, which involves the
[1]
random acquisition of genetic changes that offer a survival advantage . WES sequencing analysis shows
[14]
that clonal heterogeneity begins from a premalignant stage and follows either linear or branching evolution
patterns. Linear evolution involves the emergence of a new subclone or predominance of a pre-existing
subclone, resulting in the stepwise acquisition of driver mutations. Branching evolution involves the
emergence of one or more subclones via divergent mutational pathways, while other subclones decline in
[2]
frequency or disappear . Another factor is clonal stability, where similar clonal and subclonal heterogeneity
is found before and after treatment, which would equally repopulate the tumor. The study of intraclonal
heterogeneity is important to improve the understanding of disease pathogenesis, as the genetic aberrations
in the predominant clonal population at the time of sampling may not apply to all subclonal populations.
Thus, such heterogeneity may explain relapse and drug resistance to anticancer treatments .
[14]

BONE MARROW MICROENVIRONMENT
A complex interaction exists between malignant plasma cells and non-malignant stromal cells in the bone
marrow microenvironment. This interaction involves adhesion molecules and autocrine/paracrine cytokine
signaling. The cytokines secreted by the stromal cells include IL-6, VEGF, IL-1b, IL-10, TNF-a, TGF-b,
MMP-1, osteoprotegerin (OPG)/RANKL MIP-1a, FGFs, and IGFs . IL-6 is the most significant with a
[112]
role in B cell differentiation; however, in MM, it induces proliferation and apoptosis inhibition. The IL-6
receptor has two subunits: IL-6Ra and gp130 (a transmembrane signal transducer). IL-6 combines with IL-
Ra, which then mediates signals via gp130. IL-Ra subunit has an agonist action. In contrast, gp130 may
[113]
competitively inhibit the growth-promoting effects of IL-6/IL-6R complex at higher concentrations .
IL-6-IL-6R interaction activates 3 downstream pathways: STAT1/STAT3 pathway, STAT3/STAT3 pathway,
[114]
and Ras/MAPK pathway .
Similarly, VEGF, FGFs, and HGFs play a role in angiogenesis and IL-1b, RANKL, and HGFs in osteoclast
[75]
activation. TNF-a, IGFs, IL-1b, and VEGF have a direct effect on MM cells . Some factors secreted by bone
marrow are known to influence the efficacy of chemo and radiation therapy and have a role in disease
progression. For example, MM cell interaction with fibronectin in the extracellular matrix up-regulates p27,
which induces drug resistance . Likewise, the binding of MM cells to hyaluronic acid synergizes IL-6
[115]
signaling and reduction in adhesion molecules CD56; very late antigen 4 facilitates the transition to the