Studies looking at the epigenetic, genetic, transcriptional, and phenotypic changes within the transforming plasma cell as well as the microenvironment have improved our understanding of this process. The process of transformation, from a normal plasma cell to the premalignant MGUS/SMM state and finally to symptomatic multiple myeloma, involves several oncogenic events within the plasma cell as well as in the bone marrow microenvironment ().
Figure 1 Biology of myelomagenesis. Progression from a normal post germinal center B cell to symptomatic myeloma involves a series of genetic and phenotypic changes. Early genetic events can be categorized into two major types – hyperdiploid type and non-hyperdiploid (more ...)
A recent study using SNP-based arrays compared MGUS, SMM and MM samples (21
). They found copy number abnormalities in all stages. The incidence of genomic imbalance did increase from a median of 5/case for MGUS to 7.5/case for SMM and 12/case for MM. The study also noted certain genomic changes that were exclusive to MM including 11q and 21q gains and 16q and 22q deletions. Interestingly, the study found these abnormalities in a small subclone in MGUS patients indicating that most if not all of the chromosomal changes may be already present at the MGUS state.
Several studies have found varying rates of the different translocations between MGUS, SMM and MM () (22
). The rate of t(11;14) appears to be uniform from MGUS to MM, but there is some discrepancy in the rate of the other IgH translocations- t(4;14) and t(14;16) as well as del13q. Some studies have suggested that the incidence of these changes increases from MGUS to MM while other studies have indicated that the rate is the same among MGUS and MM patients. The role of 13q deletion is also not completely clear and some studies have suggested that it may be an early event while others point to del13q as the next step in the pathogenesis of myeloma especially following IgH translocations (25
). The presence of these translocations in MGUS and SMM does not seem to affect the rate of progression in either condition, while in multiple myeloma, some of these translocations are associated with adverse outcomes (24
). A recent study has shown that there is a clonal expansion of these genetically abnormal plasma cells from MGUS to SMM and MM (26
). IgH translocations and 13q deletion were seen in a higher proportion of plasma cells in SMM compared to MGUS and in MM compared to SMM.
Table 2 Common cytogenetic abnormalities and their incidence seen in MGUS, SMM and MM (22, 24–27)*.
Cyclin D overexpression as an unifying early event
Using gene expression analyses, overexpression of the cyclin D genes appears to be one possible unifying event which is seen in almost all MM cases with or without an immunoglobulin translocation as compared to normal plasma cells (30
). IgH translocations directly dysregulate Cyclin D1 or D3 (t(11;14) and t(6;14) respectively) and the C-MAF or MAFB transcription factors dysregulate Cyclin D2 (t(14;16) and t(14;20)) (31
). In this study, 12 MGUS samples had a similar pattern of cyclin D dysregulation despite a lower proliferative index suggesting that cyclin D perturbation may indeed be an early and unifying event in plasma cell dyscrasias.
MicroRNAs are single stranded RNA molecules that regulate gene expression posttranscriptionally and are being implicated in a large number of cancers (32
). A study comparing miRNA profiles of normal PC, MGUS, SMM and MM found overexpression of mir-21, mir-106~25 and mir181a and mir181b in MGUS and MM compared to normal PCs (33
). The study also found mir-32 and mir17~92 clusters to be upregulated only in MM and not in any other forms. Mir 17~92 and Mir 106~25 are known to have a role in B cell development as well as B cell lymphomas targeting PTEN, E2F1, Bcl2 and BIM (32
). The mir17 cluster has been shown to upregulated by the transcription factor c-Myc, which is considered a late event in myeloma progression (34
Cytogenetic and gene expression studies in myeloma precursor disease are limited by technical limitations in the ability to sort out the abnormal plasma cells for evaluation. The ratio of abnormal cells to normal plasma cells will be lower in a MGUS sample as compared to a MM sample if CD 138+ sorting is used.
With the advances in deep sequencing techniques, we are now able to study the whole genome of myeloma cells and compare that to the normal human genome. Several studies employing these techniques are beginning to shift our understanding of the pathogenesis of myeloma. These studies have revealed that the previously held dogma that cancer progression occurred through a linear cumulative acquisition of mutational changes may be too simplistic. A new model of clonal heterogeneity is beginning to emerge (36
). In this model various subclones exist in a dynamic equilibrium and over time the subclonal populations flow under environmental evolutionary pressures with alternating dominance of various subclones (37
). Most of these studies were done on patients with symptomatic MM and as similar studies involving MGUS and SMM emerge, our understanding of the pathogenesis of myeloma from these precursor states will continue to evolve.
Role of microenvironment in progression of MGUS to MM
The transition from MGUS to MM involves changes to the complex interaction with the microenvironment along with the genetic changes described above. In MM there is an upregulation of osteoblast RANK-L expression and a decrease in osteoprotegerin (OPG) a decoy for RANK-L which inhibits osteoclast differentiation. This increases the ratio of RANK-L/OPG, which leads to osteoclast activation and development of the characteristic lytic lesions (41
). Interestingly, although lytic bone lesions are not seen in MGUS, the RANK-L/OPG ratio is higher in MGUS subjects and they are at a higher risk of fractures compared to healthy controls (42
). The role of other pathways including Wnt/β-catenin involving activation of FRZB and Dickkopf 1 (DKK1), a Wnt inhibitor, is also being studied (44
). The homing of MM cells to bone marrow (BM) stromal cell niches is essential for their survival. A recent study suggests that these BM stromal cell niches are limited and a progressive competition and replacement of normal BM cells by clonal plasma cells is associated with more advanced disease (45
). The evasion of the immune system is an important step in the progression from MGUS to MM. Oligoclonal T cell expansion can be found in both MGUS and MM with lower disease burden states demonstrating a more robust T cell expansion (46
). A defect in the T cell function is seen during progression from MGUS to multiple myeloma (48
). Several cytokines and growth factors including IL-6, SDF-1, MIP-1α, IGF-1, VEGF and HGF have been implicated in myeloma pathogenesis and transition from MGUS (50