Aetiology
The exact cause of multiple myeloma (MM) is unknown. Studies suggest that genetic and hereditary factors may play a role.[11][12][13]
A possible association with exposure to ionising radiation and petroleum products has been suggested, but there is no evidence for causality.[14][15][16][17][18]
Most cases of MM evolve from monoclonal gammopathy of undetermined significance (MGUS), a benign pre-malignant condition.[19] The risk of progression of MGUS to MM (or related disorders) is approximately 1% per year.[20][21][22][23]
Pathophysiology
Oncogenic events (e.g., chromosome translocations) occurring in the germinal centre and bone marrow are involved in transforming normal B cells (plasma cells) to myeloma cells.[24][25]
Myeloma cells usually secrete monoclonal immunoglobulins or immunoglobulin fragments (known as a paraprotein or M-protein), which can be detected in serum and urine. Normal immunoglobulin production is impaired, resulting in a relative hypogammaglobulinaemia and predisposing patients to infections.
Chromosomal abnormalities
Chromosome translocations involving the immunoglobulin heavy chain (IgH) region at chromosome 14q32 are common in MM.[26][27] Certain 14q32 translocations result in upregulation of specific oncogenes located on the translocation partner chromosome (e.g., MMSET, FGFR3, MAF, cyclin D1, cyclin D3). The following are the main 14q32 translocations reported in MM, accounting for a prevalence of nearly 40%:[28]
t(4;14)(p15;q32): MMSET and FGFR3 (15%)
t(14;16)(q32;q23): c-maf (5%)
t(14;20)(q32;q11): MAFB (2%)
t(11;14)(q13;q32): cyclin D1 (15%)
t(6;14)(p21;q32): cyclin D3 (2%)
High levels of cyclin D1, D2, and D3 are reported in MM and monoclonal gammopathy of undetermined significance (MGUS), suggesting a unifying early oncogenic event.[29]
Chromosome 17p deletion, which is associated with a poor prognosis, may be detected in 10% of patients with MM at diagnosis.[30] Chromosome 13 deletions are predominant with conventional cytogenetics and associated with a poor prognosis. Chromosome 1 abnormalities (e.g., chromosome 1q gain or amplification; 1p deletion) are also frequently observed in MM and may increase the risk of progression.[31][32][33]
A molecular classification has been proposed that categorises patients with MM based on chromosomal abnormalities (e.g., translocations and hyperdiploidy).[34][35]
Deep sequencing of MM genomes has identified several mutations of genes involved in protein translations and signal transductions.[36]
Bone disease pathogenesis
Adhesion molecules are involved in the homing of myeloma cells (which arise from the germinal centre of lymph nodes) to the bone marrow and adhesion to bone marrow stromal cells (BMSC) and extracellular matrix. The role of adhesion molecules and the bone marrow microenvironment is critical for tumour cell growth, survival, and resistance to chemotherapy. Moreover, such binding stimulates cytokine secretion from BMSCs. Interleukin-6 and insulin-like growth factor-1 confer a growth and survival advantage to myeloma cells, regulating the mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT kinase pathways and activating the survival Janus kinase/signal transducer and activator of transcription pathway. Cytokines such as macrophage inflammatory protein-1alpha, receptor activator of nuclear factor-kappaB ligand, and Dickkopf-1 stimulate osteoclastogenesis and osteoclast activity and impair osteoblast formation, inducing osteolytic bone disease and hypercalcaemia.
Classification
International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma[3][4]
Multiple myeloma
Clonal bone marrow plasma cells ≥10%, or biopsy-proven bony or extramedullary plasmacytoma, and any one or more of the following myeloma-defining events:
Evidence of end-organ damage that can be attributed to the underlying plasma cell proliferative disorder, specifically:
Hypercalcaemia: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >177 micromol/L (>2 mg/dL)
Anaemia: haemoglobin value of >20 g/L (>2 g/dL) below the lower limit of normal, or a haemoglobin value <100 g/L (<10 g/dL)
Bone lesions: one or more osteolytic lesions on skeletal radiography, computed tomography (CT), or positron emission tomography (PET)-CT
Any one or more of the following biomarkers of malignancy:
Clonal bone marrow plasma cells ≥60%
Involved:uninvolved serum free light-chain ratio ≥100 (involved serum free light-chain level must be ≥100 mg/L [≥10 mg/dL])
Two or more focal lesions (each ≥5 mm) on magnetic resonance imaging (MRI) studies
Smouldering (asymptomatic) multiple myeloma
Both of the following criteria must be met:
M-protein (IgG or IgA) in serum ≥30 g/L, or urinary monoclonal protein ≥500 mg/24 hours, and/or clonal bone marrow plasma cells 10% to 60%
Absence of myeloma-defining events or amyloidosis
Non-IgM monoclonal gammopathy of undetermined significance (MGUS)
Serum monoclonal protein (non-IgM type) <30 g/L
Clonal bone marrow plasma cells <10%
Absence of end-organ damage such as hypercalcaemia, renal insufficiency, anaemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
IgM MGUS
Serum IgM monoclonal protein <30 g/L
Bone marrow lymphoplasmacytic infiltration <10%
Absence of anaemia, constitutional symptoms, hyperviscosity, lymphadenopathy, hepatosplenomegaly, or other end-organ damage that can be attributed to the underlying lymphoproliferative disorder
Light-chain MGUS
Abnormal free light-chain ratio (<0.26 or >1.65)
Increased level of the involved light chain
No immunoglobulin heavy chain on immunofixation
Absence of end-organ damage such as CRAB or amyloidosis that can be attributed to the plasma cell proliferative disorder
Clonal bone marrow plasma cells <10%
Urinary monoclonal protein <500 mg/24 hours
Use of this content is subject to our disclaimer