B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surfaces. When they are activated to secrete antibodies, they are known as plasma cells.<unk>  develops in B lymphocytes after they have left the part of the lymph node known as the germinal center. The normal cell type most closely associated with<unk>  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<unk> . 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. Epigenetic In a study that investigated the DNA methylation profile of<unk>  cells and normal plasma cells, a gradual demethylation from stem cells to plasma cells was observed. The observed methylation pattern of CpG within intronic regions with enhancer-related chromatin marks in<unk>  is similar to undifferentiated precursor and stem cells. These results may represent a de novo epigenetic reprogramming in<unk> , leading to the acquisition of a methylation pattern related to stemness. Other studies have identified a<unk>  specific gene silencing pattern associated with the polycomb repressive complex 2 (PRC2). Increased expression of the PRC2 subunit, EZH2 have been described to be a common feature in<unk> , resulting in an accumulation and redistribution of histone H3 lysine 27 trimethylation which advances with disease severity. Genetics Chromosomal abnormalities commonly found in this disease, like trisomy of<unk>  odd-numbered chromosomes, t(11;14), and del(13q), are not associated with a worse prognosis. However, about 25% of patients with newly diagnosed disease have abnormalities associated with a worse prognosis, like t(4;14), t(14;16), and del(17p). Other less common abnormalities associated with a worse prognosis include t(14;20) and ≥4 copies of 1q. Associated genetic mutations include ATM, BRAF, CCND1, DIS3, FAM46C, KRAS, NRAS and TP53. Development The genetic and epigenetic changes occur progressively. The initial change, often involving one chromosome 14 translocation, establishes a clone of bone marrow plasma cells that causes the asymptomatic disorder MGUS, which is a premalignant disorder characterized by increased numbers of plasma cells in the bone marrow or the circulation of a myeloma protein immunoglobulin. Further genetic or epigenic changes produce a new clone of bone marrow plasma cells, usually descendant from the original clone, that causes the more serious, but still asymptomatic premalignant disorder smoldering<unk> . This myeloma is characterized by a rise in the number of bone marrow plasma cells or levels of the circulating myeloma protein above that seen in MGUS. Subsequent genetic and epigenetic changes lead to a new, more aggressive clone of plasma cells, which cause further rises in the level of the circulating myeloma protein, further rises in the number of bone marrow plasma cells, or the development of one or more of a specific set of "CRAB" symptoms, which are the basis for diagnosing malignant<unk>  and treating the disease. In a small percentage of<unk>  cases, further genetic and epigenetic changes lead to the development of a plasma cell clone that moves from the bone marrow into the circulatory system, invades distant tissues, and thereby causes the most malignant of all plasma cell dyscrasias, plasma cell leukemia. Thus, a fundamental genetic instability in plasma cells or their precursors leads to the progression: Monoclonal gammopathy of undetermined significance → smoldering<unk>  →<unk>  → plasma cell leukemia Being asymptomatic, monoclonal gammopathy of undetermined significance and smoldering<unk>  are typically diagnosed fortuitously by detecting a myeloma protein on serum protein electrophoresis tests done for other purposes. MGUS is a relatively stable condition afflicting 3% of people aged 50 and 5% of people aged 70; it progresses to<unk>  at a rate of 0.5–1% cases per year; smoldering<unk>  does so at a rate of 10% per year for the first 5 years, but then falls off sharply to 3% per year for the next 5 years and thereafter to 1% per year. Overall, some 2–4% of<unk>  cases eventually progress to plasma cell leukemia.
Multiple myeloma
Monoclonal gammopathy of renal significance  Monoclonal gammopathy of renal significance  1
Monoclonal gammopathy of undetermined significance
Monoclonal gammopathy of renal significance
Smouldering myeloma
Waldenström macroglobulinemia
AL amyloidosis
Plasma cell leukemia