Diagnostic criteria
In 2003, the IMG agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma, and MGUS, which was subsequently updated in 2009:
Symptomatic myeloma (all three criteria must be met):
Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma)
A monoclonal protein (myeloma protein) in either serum or urine and it has to be more than 3g/dL (except in cases of true nonsecretory myeloma)
Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, CRAB):
HyperCalcemia (corrected calcium >2.75 mmol/L, >11 mg/dL)
Renal failure (kidney insufficiency) attributable to myeloma
Anemia (hemoglobin <10 g/dL)
Bone lesions (lytic lesions or osteoporosis with compression fractures)Note: Recurrent infections alone in a person who has none of the CRAB features is not sufficient to make the diagnosis of myeloma. People who lack CRAB features, but have evidence of amyloidosis, should be considered as amyloidosis and not myeloma. CRAB-like abnormalities are common with numerous diseases, and these abnormalities must be felt to be directly attributable to the related plasma cell disorder and every attempt made to rule out other underlying causes of anemia, kidney failure, etc. In 2014, the IMWG updated their criteria further to include biomarkers of malignancy. These biomarkers are >60% clonal plasma cells, a serum involved / uninvolved free light chain ratio ≥ 100 (the concentration of the involved free light chain must be ≥ 100 mg/L) and more than one focal lesion ≥ 5 mm by MRI. Together, these biomarkers and the CRAB criteria are known as myeloma-defining events (MDEs).
The normal cell type most closely associated with MM cells is generally taken to be either an activated memory B cell or the precursor to plasma cells, the plasmablast.The immune system keeps the proliferation of B cells and the secretion of antibodies under tight control. When chromosomes and genes are damaged, often through rearrangement, this control is lost. Often, a promoter gene moves (or translocates) to a chromosome, where it stimulates an antibody gene to overproduction. A chromosomal translocation between the immunoglobulin heavy chain gene (on chromosome 14, locus q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11) is frequently observed in people with multiple myeloma. This mutation results in dysregulation of the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is a proliferation of a plasma cell clone and genomic instability that leads to further mutations and translocations. The chromosome 14 abnormality is observed in about 50% of all cases of myeloma. Deletion of (parts of) chromosome 13 is also observed in about 50% of cases. Production of cytokines (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the generation of new blood vessels) is increased. The produced antibodies are deposited in various organs, leading to kidney failure, polyneuropathy, and various other myeloma-associated symptoms.