INTRODUCTION — Multiple myeloma (MM) is a plasma cell neoplasm that accounts for approximately 10 percent of all hematologic malignancies. It is an incurable disease and the cause of about 20 percent of deaths from hematologic malignancy and 2 percent of deaths from all cancers.
MM evolves from an asymptomatic premalignant stage of clonal plasma cell proliferation termed monoclonal gammopathy of undetermined significance (MGUS). MGUS is present in over 3 percent of the population above the age of 50 and progresses to MM or a related malignancy at a rate of 1 percent per year.
While MGUS is asymptomatic, MM is characterized by end-organ damage, which includes hypercalcemia, renal dysfunction, anemia, or lytic bone lesions. In some patients, an intermediate asymptomatic but more advanced premalignant stage referred to as smoldering multiple myeloma (SMM) can be recognized clinically.
The pathobiology of MM will be reviewed here. The clinical and laboratory manifestations, diagnosis, and management of MGUS, SMM, and MM are discussed separately.
●(See "Smoldering multiple myeloma".)
CELL OF ORIGIN — In general, MM arises from the malignant transformation of post-germinal center plasma cells [1,2]. The post-germinal ancestry of these cells is principally supported by the identification of somatic mutations in the variable region of the immunoglobulin (Ig) genes, which serve as a marker of germinal center transit. These cells also display ongoing somatic mutations, which reflect the pressure of antigen selection encountered by post-germinal center lymphocytes. By definition, class switching is demonstrated in IgG and IgA MM, but not in IgM MM. IgM MM is a very rare disease which appears to arise from a pre-germinal center plasma cell with translocations characterized by VDJ recombination-induced breakpoints . (See "Immunoglobulin genetics", section on 'Class-switching'.)
The malignant plasma cells of MM have a low proliferative rate and have generally been unable to sustain tumor growth in vivo, suggesting that precursor cells are responsible for proliferation of the malignant cell population [2,4-6]. It has been proposed that these abnormal precursor B cells originate in the lymph nodes and migrate to the bone marrow, which provides a microenvironment conducive to terminal plasma cell differentiation . This could explain the observation that the malignant plasma cells appear to be restricted to the microenvironment of the bone marrow, even though the disease is widely disseminated throughout the axial skeleton. (See 'Bone marrow microenvironment' below.)
OVERVIEW OF PATHOGENESIS — The pathobiology of MM is a complex process leading to the replication of a malignant clone of plasma cell origin. While some steps in this pathway have been elucidated, many remain unknown. Virtually all MM cases are preceded by a premalignant plasma cell proliferative disorder known as monoclonal gammopathy of undetermined significance (MGUS) . MGUS can be detected by standard assays in over 3 percent of the population above the age of 50, and it progresses to MM or a related malignancy at a rate of 1 percent per year. High sensitivity techniques such as mass spectrometry are able to detect MGUS in an even greater percentage of the population . (See "Diagnosis of monoclonal gammopathy of undetermined significance" and "Laboratory methods for analyzing monoclonal proteins".)
The pathogenesis of MM can be conceptualized as two sequential processes (figure 1):
●Establishment of MGUS – While the inciting event is unknown, MGUS appears to develop as the result of cytogenetic abnormalities, many of which are thought to be the product of an abnormal plasma cell response to antigenic stimulation. The result is a plasma cell clone producing monoclonal immunoglobulin.
●Progression from MGUS to MM – Further insults to the plasma cell clone, either through additional genetic abnormalities or changes in the bone marrow microenvironment, result in the progression of MGUS to MM.
In some patients, an intermediate asymptomatic but more advanced premalignant stage referred to as smoldering multiple myeloma (SMM) can be recognized clinically. These patients may have been diagnosed in the midst of progressing from MGUS to MM, or they may represent biologic MGUS with a higher baseline clonal plasma cell burden. (See "Smoldering multiple myeloma".)
Once the clonal plasma cell population is created and progresses to MM, patients develop symptoms (eg, hypercalcemia, lytic bone lesions, renal dysfunction, and anemia) related to the infiltration of plasma cells into the bone or other organs or to kidney damage from excess light chains. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Clinical presentation'.)
ESTABLISHMENT OF MGUS — The first step in the pathway to the development of MM is the establishment of the premalignant plasma cell proliferative disorder known as monoclonal gammopathy of undetermined significance (MGUS). Patient-related and environmental risk factors for MGUS have been proposed, but the exact cause of MGUS development remains elusive.
Similar patterns of certain cytogenetic abnormalities can be found in the clonal plasma cells of MGUS and MM. These cytogenetic abnormalities are thought to lead to the creation of a plasma cell clone. (see 'Cytogenetic abnormalities' below)
While the event leading to these genetic changes likely varies, the most likely process is abnormal plasma cell response to antigenic stimulation. (See 'Abnormal response to antigenic stimulation' below.)
Risk factors — Epidemiologic data suggest a genetic predisposition as well as other potential risk factors including older age, immunosuppression, and environmental exposures [10-14]. Hormonal factors may play a role, since women have lower age-specific prevalence rates when compared with men.
A genetic predisposition is predominantly supported by the findings that the incidence of MGUS varies by ethnicity and that a small, but unknown, fraction of cases is familial. Such cases may be due to either shared genes or environmental factors. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Epidemiology'.)
Exposure to radiation, benzene, and other organic solvents, herbicides, and insecticides may also play a role. However, the number of cases reported for each of these risk factors is small [10-15].
Cytogenetic abnormalities — Primary cytogenetic abnormalities appear to play a major role in the development of MGUS. Most, if not all, cases of MGUS and MM have chromosomal abnormalities that can be detected by fluorescence in situ hybridization (FISH), multicolor spectral karyotyping, comparative genomic hybridization, or gene expression profiling [16-20]. The percentage of cases demonstrating each abnormality varies by the detection method used and disease stage.
Most cases of MGUS appear to be initiated in conjunction with either translocation events involving the immunoglobulin heavy chain (IgH) locus (approximately 40 percent) or genetic instability manifested by trisomies (approximately 40 percent) or both translocations and trisomies (approximately 10 percent) [21,22].
Immunoglobulin heavy chain translocations — The initial immune response (primary immune response) results in formation of IgM antibodies targeting the offending antigen. When exposed to the same antigen again, there may be a "class switch" that occurs wherein the genes coding for the variable portion of the IgH switch from the gene coding for the constant region of IgM to move next to the gene coding for the constant region of IgG (or IgA). As a result of this "switch recombination" or "class switching," the antibody made by the plasma cell changes from IgM type to IgG or IgA (secondary immune response). (See "Immunoglobulin genetics".)
Approximately one-half of MGUS cases are likely caused by translocation events (errors) that occur at the time of immunoglobulin switch recombination. These translocations affect the IgH locus on chromosome 14q32, and result in the juxtaposition of an oncogene next to the IgH locus. This results in the aberrant expression of the affected oncogene and is thought to be a critical step in the development of MGUS. Cases that include these rearrangements are referred to as "IgH translocated MGUS" or "non-hyperdiploid MGUS." The most common partner chromosome loci and genes dysregulated in these translocations are (table 1) [23-26]:
●11q13 – cyclin D1 (CCND1)
●6p21 – cyclin D3 (CCND3)
●4p16.3 – multiple myeloma set domain (MMSET/WHSC1)
●16q23 – musculoaponeurotic fibrosarcoma (C-MAF)
●20q11 – musculoaponeurotic fibrosarcoma oncology family, protein B (MAFB)
The juxtaposition of these oncogenes next to the IgH locus results in overexpression of the oncogene induced by the active promoter region of the IgH genes. The products of this translocation then act as transcription factors, growth factor receptors, and cell cycle mediators to promote growth and replication. In many cases, the translocations are not simple reciprocal events but involve complex rearrangements with changes in copy numbers of important gene drivers, oncogenes, and tumor suppressor genes. Additionally, complex genomic rearrangements can lead to overexpression/underexpression of sets of genes based on their proximity to topologically associating transcriptional domains . (See 'Mechanisms resulting in complex structural variants' below.)
The percentage of cases displaying IgH translocations increases as the disease progresses from MGUS to MM. IgH translocations are found in nearly 50 percent of patients with MGUS or smoldering MM, 55 to 73 percent of those with MM, 85 percent of plasma cell leukemias, and >90 percent of in vitro human myeloma cell lines [28,29]. This may reflect the fact that certain types of IgH translocated MGUS and MM (eg, t(14;16), t(14;20)) may be more aggressive than the hyperdiploid type of MGUS.
Trisomies/hyperdiploidy — The majority of MGUS cases that do not have translocations involving IgH demonstrate genetic instability manifested by the gain of chromosomes (trisomies) [23,30-35]. This subset of MGUS is referred to as "IgH nontranslocated MGUS" or "hyperdiploid MGUS."
Hyperdiploid MGUS and MM typically demonstrate trisomies of one or more odd numbered chromosomes, with the exception of chromosomes 1, 13, and 21. These trisomies are not acquired from a single event, but are rather a result of a consecutive accumulation of multiple genetic events . Trisomies can result in the overexpression of genes located on the affected chromosomes, and these genes may promote growth and replication leading to the MGUS clone.
Other genomic copy number variations — Complex genomic rearrangements in MGUS often lead to other losses and/or gains of whole chromosomes and smaller chromosome regions, such as loss of chromosome 13 and gain of the whole arm of chromosome 1q .
Mechanisms resulting in complex structural variants — The genomic complexity of MM is similar to that of lymphomas (less complex than solid tumors, more complex than leukemias). Complex structural variants are primarily caused by:
●Chromothripsis – Shattering of whole chromosomes with subsequent random reassembly and oscillating copy number changes.
●Chromoplexy – Multiple simultaneous double-stranded DNA breaks with incorrect rejoining, resulting in regional DNA copy number losses.
●Templated insertions – Similar to chromoplexy but with insertions of copied DNA material into the new genomic region, resulting in DNA copy number gains.
Aberrant cyclin D expression dysregulates cell cycle progression — Cyclin D genes appear to be universally dysregulated in early stages of MM development, promoting cell cycle progression and tumor proliferation [37,38]. Aberrant cyclin D expression can occur through several mechanisms, including translocations involving CCND1 (11q23), CCND2 (12p13), and CCND3 (6p21) genes, MAF-induced upregulation of CCND2 transcription, and point mutations in the CCND1 gene [39,40].
Abnormal response to antigenic stimulation — The cytogenetic abnormalities described above are thought to be the result of an abnormal, sustained response to antigenic stimulation.
The nature of the antigenic stimulus is unknown and likely differs between cases. As an example, one study found that a high percentage of patients (17 of 20 patients) with Gaucher disease-associated MM had monoclonal immunoglobulins with reactivity against the lysolipid LGL-1 . In contrast, monoclonal immunoglobulins with reactivity against LGL-1 or another lysolipid, lysophosphatidylcholine (LPC), were found in only a minority of patients with sporadic MM (22 of 66 patients). Polyclonal serum free light chain elevation is associated with an increased risk of MGUS, providing further support for prolonged immune stimulation as a contributing factor to the development of plasma cell neoplasms .
The reason why an antigenic stimulus produces an abnormal, sustained, proliferative signal for plasma cells is unclear. One likely contributing factor is re-entry/persistence of a plasma cell precursor in germinal centers and the resulting exposure to the mutagenic effect of activation-induced cytidine deaminase (AID). During normal germinal center reactions, AID mediates somatic hypermutation and class switching. Typical signatures of early/clonal (as opposed to late/subclonal) AID mutational activity are seen in the vast majority of myelomas . Based on the frequency of age-related mutations in symptomatic MM, it appears that the initial cytogenetic events causing MGUS occur in early adulthood .
Homing of premalignant plasma cell in bone marrow — Having acquired primary cytogenetic abnormalities, premalignant plasma cells travel to the bone marrow, a homing mechanism which is shared with their normal counterparts. The survival and growth of these cells depends on complex interactions with the bone marrow microenvironment. (See 'Bone marrow microenvironment' below.)
PROGRESSION OF MGUS TO MM — The main driver for progression of monoclonal gammopathy of undetermined significance (MGUS) to MM is accumulation of additional genetic changes, both structural variants and single nucleotide variants. These changes confer proliferative and/or survival benefit to the plasma cell clone in the context of bone marrow microenvironment.
There are two important concepts to keep in mind when thinking about the progression of MGUS to MM:
●Although there is a sequential accumulation of genetic changes, the risk of progressing from MGUS to MM is remarkably constant over time in an individual (1 percent per year), suggesting that a single or a small number of "catastrophic" events is likely responsible.
●The clinical classification of MGUS, smoldering MM, and MM is based on a tumor burden assessment using widely available technologies, rather than on the biology of the disease. In contrast, whole-genome sequencing suggests that there are two different types of MM precursors (stable versus progressive) that may be identified based on the presence of specific genetic changes, regardless of the percentage of plasma cells in the bone marrow . Further studies of these stable versus progressive precursors may help us better understand progression.
Mechanism of secondary changes — The same large genomic events responsible for clone initiation (chromothripsis, chromoplexy, templated insertions) can occur at the MGUS to MM transition. Multiple single nucleotide mutational signatures are observed, the most important of which appears to be the mutagenic activity of APOBEC cytidine deaminase [39,46]. In addition, epigenetic changes such as DNA methylation and histone modifications contribute to dysregulation of gene expression [47,48].
Drivers of progression from MGUS to MM — Genetic changes driving the progression from MGUS to MM dysregulate intracellular pathways involved in cell proliferation, survival, and DNA repair. The most important genes/pathways for progression include:
●MYC activation, mostly by structural rearrangements 
●TP53 deletion, both by 17p deletion and point mutations 
●Activation of RAS/MAPK pathway by point mutations in NRAS, KRAS, BRAF, or genes encoding downstream signaling molecules 
●Activation of NFkB pathway by mutations in TRAF3, CYLD, NIK, or other genes 
●Dysregulation of apoptosis, including MCL1 overexpression 
●Hyperdiploid myelomas are enriched in NRAS mutations
●t(11;14) is associated with KRAS, IRF4, and CCND1 mutations
●t(4;14) often has mutations in FGFR3, DIS3, and PRKD2
During this process, a number of different branching subclones are formed, with high temporal and spatial heterogeneity [50,51]. Additional subclones frequently emerge post-therapy, at disease relapse. One study showed that incorporating genomic alterations from high-sensitivity studies can improve clinical stratification and potential management of newly diagnosed MM .
Bone marrow microenvironment — The bone microenvironment is a complex 3D structure composed of:
●Various cells (mesenchymal stem cells, osteoclasts, osteoblasts, adipose cells, hematopoietic cells, immune cells)
●Extracellular matrix (collagens, fibronectin, laminin, thrombospondin, proteoglycans)
●Soluble factors (growth factors, cytokines, chemokines)
Numerous changes in the bone marrow microenvironment support the survival of the abnormal plasma cell clone in MGUS and enable the progression of MGUS to MM. These include:
●Induction of angiogenesis [53,54]
●Immune dysregulation [55-59]
●Paracrine loops involving cytokines such as interleukin (IL)-6 and vascular endothelial growth factor (VEGF) 
●Modulation of tumor growth by bone marrow stromal cell [61,62]
Pathobiology of end organ damage — Once the clonal plasma cell population is created and progresses to MM, patients develop symptoms (eg, hypercalcemia, lytic bone lesions, renal dysfunction, and anemia) related to the infiltration of plasma cells into the bone or other organs or to kidney damage from excess light chains. (See "Multiple myeloma: Clinical features, laboratory manifestations, and diagnosis", section on 'Clinical presentation'.)
Osteolytic bone lesions — Osteolytic bone lesions are the hallmark of MM. Although there are some data suggesting abnormalities in bone metabolism in MGUS, the presence of osteolytic bone lesions signals the onset of active malignancy. The pathogenesis of lytic bone lesions characteristic of MM is thought to be mediated by an imbalance between the activity of osteoclasts and osteoblasts. This imbalance is caused both by enhanced osteoclastic activity as well as (in contrast to other malignancies) a marked suppression of osteoblastic activity. As a result, MM bone lesions tend to be purely osteolytic and better visualized on plain radiographs compared with other bone metastases from solid tumors that tend to have an osteoblastic component and are better visualized on radionucleotide bone scans.
●Increased osteolytic activity – Increased osteolytic activity is mediated by an increase in RANKL (receptor activator of nuclear factor kappa-B ligand) expression by osteoblasts (and possibly plasma cells) accompanied by a reduction in the level of its decoy receptor, osteoprotegerin (OPG) [63,64]. This leads to an increase in RANKL/OPG ratio, which causes osteoclast activation and bone resorption. Increased levels of macrophage inflammatory protein-1 alpha (MIP-1alpha, CCL3), IL-3, and IL-6 produced by marrow stromal cells also contribute to the overactivity of osteoclasts. Finally, there is increased expression of stromal derived factor 1 alpha (SDF-1alpha) by stromal cells and myeloma cells . SDF-1alpha causes osteoclast activation by binding to CXCR4 on osteoclast precursors.
●Osteoblast suppression – Active suppression of osteoblasts is most likely related to increased levels of IL-3, IL-7, and dickkopf 1 (DKK1), which inhibit osteoblast differentiation in MM . MM cells express DKK1, an inhibitor of Wnt signaling, and increased expression of DKK1 by these cells has been associated with presence of focal bone lesions in MM . Increased IL-3 and IL-7 levels may also play a role.
Hypercalcemia — Hypercalcemia appears to be a product of osteoclast activating factors such as lymphotoxin, IL-6, hepatocyte growth factor, and RANKL. (See "Etiology of hypercalcemia", section on 'Malignancy'.)
Kidney impairment — Kidney involvement in MM is usually the result of monoclonal immunoglobulin light chains. However, in rare occasions, monoclonal heavy chains or the entire immunoglobulins may be involved. Non-monoclonal protein-related kidney injury may also occur. (See "Kidney disease in multiple myeloma and other monoclonal gammopathies: Etiology and evaluation".)
Anemia — Involvement of the bone marrow in MM can result in anemia thought to be due to both the replacement of normal hematopoietic tissue by tumor (myelophthisis) and by the disruption of the bone marrow microenvironment. (See "Causes of anemia in patients with cancer", section on 'Bone marrow infiltration'.)
The relatively common occurrence of anemia in the setting of limited bone marrow infiltration suggests that MM-associated anemia is not entirely due to bone marrow replacement by malignant cells. Importantly, the bone marrow of patients with MM contains lower than normal numbers of hematopoietic stem and progenitor cells . This reduction in hematopoietic precursors appears to be at least partially due to changes in the bone marrow microenvironment. Elimination of myeloma cells and restoration of the normal bone marrow environment may result in repopulation with these precursors and reversal of the anemia.
Other frequent causes of anemia in patients with MM include relative erythropoietin deficiency (in part due to kidney damage) and therapeutic (cytotoxic) drugs.
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●Scope of disease – Multiple myeloma (MM) is a plasma cell neoplasm that accounts for approximately 10 percent of all hematologic malignancies and evolves from an asymptomatic premalignant stage of clonal plasma cell proliferation termed monoclonal gammopathy of undetermined significance (MGUS). (See 'Overview of pathogenesis' above.)
●Cell of origin – Most cases of MM arise from the malignant transformation of post-germinal center plasma cells, whereas rare instances of IgM MM arise from a pre-germinal center plasma cell. (See 'Cell of origin' above.)
●Step-wise evolution – The pathogenesis of MM is complex and poorly understood. However, a two-step model of progression best describes clinical presentation (figure 1):
•Establishment of MGUS – Primary cytogenetic abnormalities play a major role in the establishment of a limited stage of clonal proliferation, clinically recognized as MGUS. These include immunoglobulin heavy chain (IgH) translocations, hyperdiploidy, and copy number variations, including complex structural changes. (See 'Establishment of MGUS' above.)
These abnormalities may be the product of an abnormal, sustained response to antigenic stimulation, and errors that occur at the time of immunoglobulin switch recombination.
•Progression of MGUS to MM – A single or a small number of additional (secondary) genetic events results in progression to MM. Interaction of plasma cells with bone marrow microenvironment is an important part of disease pathogenesis. (See 'Progression of MGUS to MM' above.)
•End-organ damage – Symptoms (eg, hypercalcemia, lytic bone lesions, kidney impairment, and anemia) are related to the infiltration of plasma cells into the bone or other organs or to kidney damage from excess light chains. (See 'Pathobiology of end organ damage' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges extensive contributions of Robert A Kyle, MD to earlier versions of this topic review.
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