The myeloma cell is a post‐germinal centre plasma cell that has undergone immunoglobulin class switching and somatic hypermutation and secretes the paraprotein that is present in serum.

Epidemiology

• MM accounts for 1.8% of all malignancies.
• International mortality data reveal that the highest rates of MM occur in Northern Europe, North America, Australia, and New Zealand, and the lowest rates are in Japan, Yugoslavia, and Greece.

Pathogenesis

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• The paraprotein is IgG in 60% of cases, IgA in 20% and light chain only in almost all the rest. Less than 1% have IgD or IgE paraprotein and a similar number are non‐secretory.
• Most IgM monoclonal proteins are associated with diagnoses of MGUS, lymphoma, Waldenström macroglobulinemia, or immunoglobulin lightchain amyloidosis.

• Analysis of stored serum samples has shown that almost all cases of myeloma develop from a pre‐existing monoclonal gammopathy of undetermined significance (MGUS). Most of the early genetic changes are present at the MGUS stage but the size of the clone is considerably smaller.
• Nearly all MM patients have abnormal chromosomes by FISH, including deletions, aneuploidy, and translocations, although abnormal karyotypes are seen in only 18% to 30% of cases due to the generally low proliferative rate of MM cells and the requirement of obtaining plasma cells (and not just the rapidly dividing normal myeloid precursors) in metaphase to generate conventional cytogenetics. Therefore, any abnormality in conventional cytogenetics identifies a group with a higher proliferative rate159 and poorer prognosis.

• Cytogenetic analysis shows that aneuploidy (more or less than 46 chromosomes) is almost universal. There is also a high incidence of translocations involving the immunoglobulin heavy‐chain gene (IGH) on chromosome 14. The D‐cyclin genes, D1 , D2 or D3 , are often involved in the translocations.

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• Early chromosomal abnormalities (immunoglobulin heavy chain translocations or trisomies) are shared by plasma cells in multiple myeloma and in monoclonal gammopathy of undetermined clinical significance (MGUS). Secondary translocations involving MYC (8q24), MAFB (20q12), and IRF4 (6p25) are common in multiple myeloma but quite rare in MGUS. Mutations of RAS or FGFR3, MYC dysregulation, deletion in p18, or loss of expression or mutation in TP53 are found only in multiple myeloma and play a key role in determining tumor progression and drug resistance. Also, changes in gene expression, in particular the up-regulation of transcription factors, have been reported in plasma cells from patients with MGUS but not in those from patients with multiple myeloma. Besides molecular alterations of plasma cells, abnormal interactions between plasma cells and bone marrow, as well as aberrant angiogenesis, are hallmarks of disease progression.

• Primary trisomies typically lead to a hyperdiploid karyotype.
• Primary cytogenetic abnormalities are nonoverlapping.