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Page 64 Sadaf et al. J Transl Genet Genom 2022;6:63-83 https://dx.doi.org/10.20517/jtgg.2021.36

[3]
Genomic aberrations are central to the development and progression of multiple myeloma . Genomic
[3]
instability affects all levels of the genome and leads to two types of aberrations: large-scale and small-scale .
[4]
Large-scale aberrations include insertions, deletions, translocations, and inversions . These aberrations can
be revealed in tumor cells during the metaphase of the mitotic cycle using traditional Giemsa banding and
spectral karyotyping . Similarly, fluorescence in situ hybridization and other molecular cytogenetic
[5]
approaches can identify large-scale aberrations in interphase cells . Small-scale aberrations include small
[6]
insertions and deletions (indels), loss of heterozygosity, copy number changes, and base substitution
mutations . Next-generation sequencing (NGS) is a collection of methods that can identify small-scale
[3]
aberrations and includes whole-genome sequencing and protein-encoding exome sequencing (WES) .
[7,8]
Recently, transcriptome-wide sequencing has allowed for the identification of subtypes stratified by cells of
[9]
origin and genomic/epigenetic alterations . To this end, analysis of a 70-gene prognostic signature
developed by the University of Arkansas for Medical Sciences has been used and validated to stratify risk for
relapse and survival . Furthermore, transcriptome sequencing-based stratification can predict response to
[10]
MM therapy, as shown with MCL1-M co-expression and bortezomib response .
[11]
In the cytogenetic approach, MM initiation and progression involve primary and secondary events. Primary
events responsible for plasma cell immortalization are further categorized into two subtypes: hyperdiploid
(HRD) and non-hyperdiploid (non-HRD). HRD subtype is correlated with trisomies of the odd-numbered
chromosomes (3, 5, 7, 9, 11, 15, 19, and 21). Non-HRD subtype involves balanced chromosomal
translocations, with more than 90% of non-HRD cases affecting the transcriptionally active IgH locus on
14q32. The primary translocations t(4;14), t(6;14), t(11;14), t(14;16), and t(14;20) cause over-expression of
oncogenes MMSET/FGFR3, CCND3, CCND1, MAF, and MAFB [12,13] . These primary translocations can be
found in about 50% monoclonal gammopathy of undetermined significance (MGUS) patients as an early
event, which takes place in the lymphoid germinal center during physiological class-switch recombination
[14]
and somatic hypermutation . Either directly or indirectly, HRD and non-HRD events can cause
dysregulation of the G1/S cell cycle transition point through the over-expression of cyclin D genes, which is
a key to an early molecular abnormality in myeloma . The secondary events involved in myeloma
[15]
progression occur later in the disease and include secondary translocations: t(8;14) linked with MYC
overexpression, loss of heterozygosity, copy number variations (CNV), acquired mutations, and epigenetic
modifications [1,14] .

One of the pivotal aspects of MM is the recognizable clinical phase linked to each step of MM development.
MGUS and smoldering multiple myeloma (SMM) are both early premalignant phases. MGUS is
asymptomatic and is characterized by a < 10% plasma cell count in the bone marrow and a progression rate
of 1% per year to MM. SMM follows MGUS; it is also an asymptomatic phase with > 10% intramedullary
clonal plasma cells and 10% per year progression risk to MM. Thirdly, overt MM presents clinical features
of hypercalcemia, renal dysfunction, anemia, and bone disease (the acronym CRAB). Lastly, plasma cell
leukemia (PCL) is characterized by extramedullary plasma cell clones and rapid progression to death.
Hence, the disease continuity between MGUS, SMM, and MM involves genomic hierarchy, including
germline events that increase predisposition to MM, followed by early initiating events, and later gaining of
genomic aberrations that ultimately trigger disease progression and treatment resistance .
[15]
GENETIC PREDISPOSITION
The inherited susceptibility to MM is well established, with an estimated heritability of about 15% and 17%
for MGUS and MM respectively . In 2010, a Swedish study comprising 13,896 MM patients revealed first-
[16]
degree relatives of MM patients having a higher relative risk (RR) to develop MM (RR = 2.1), MGUS (RR =
2.1), acute lymphoblastic leukemia (RR = 2.1) and, to a lesser extent, solid tumors (RR = 1.1) . There is a
[17]