multiple myeloma multiple myeloma multiple myeloma (mm), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibodies. often, no symptoms are noticed initially. as it progresses, bone pain, anemia, kidney dysfunction, and infections may occur. complications may include amyloidosis. not to be confused with melanoma. multiple myelomaother namesplasma cell myeloma, myelomatosis, kahler's disease, myelomaan artist’s 3d depiction of myeloma cells producing monoclonal proteins of varying typesspecialtyhematology and oncologysymptomsbone pain, fatigue: 653 complicationsamyloidosis, kidney problems, bone fractures, hyperviscosity syndrome, infections, anemia: 653 usual onsetaround 60durationlong termcausesunknownrisk factorsobesitydiagnostic methodblood or urine tests, bone marrow biopsy, medical imagingtreatmentsteroids, chemotherapy, thalidomide, stem cell transplant, bisphosphonates, radiation therapyprognosisfive-year survival rate 54% / life expectancy 6 years (usa)frequency488,200 (affected during 2015)deaths101,100 (2015) the cause of multiple myeloma is unknown. risk factors include obesity, radiation exposure, family history, and certain chemicals. there is an increased risk of multiple myeloma in certain occupations. this is due to the occupational exposure to aromatic hydrocarbon solvents having a role in causation of multiple myeloma. multiple myeloma may develop from monoclonal gammopathy of undetermined significance that progresses to smoldering myeloma. the abnormal plasma cells produce abnormal antibodies, which can cause kidney problems and overly thick blood. the plasma cells can also form a mass in the bone marrow or soft tissue. when one tumor is present, it is called a plasmacytoma; more than one is called multiple myeloma. multiple myeloma is diagnosed based on blood or urine tests finding abnormal antibodies, bone marrow biopsy finding cancerous plasma cells, and medical imaging finding bone lesions. another common finding is high blood calcium levels. multiple myeloma is considered treatable, but generally incurable. remissions may be brought about with steroids, chemotherapy, targeted therapy, and stem cell transplant. bisphosphonates and radiation therapy are sometimes used to reduce pain from bone lesions. globally, multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015. in the united states, it develops in 6.5 per 100,000 people per year and 0.7% of people are affected at some point in their lives. it usually occurs around the age of 60 and is more common in men than women. it is uncommon before the age of 40. without treatment, the median survival in the prechemotherapy era was about 7 months. after the introduction of chemotherapy, prognosis improved significantly with a median survival of 24 to 30 months and a 10-year survival rate of 3%. even further improvements in prognosis have occurred because of the introduction of newer biologic therapies and better salvage options, with median survivals now exceeding 60 to 90 months. with current treatments, survival is usually 4–5 years. the five-year survival rate is about 54%. the word myeloma is from the greek myelo- meaning "marrow" and -oma meaning "tumor". signs and symptoms because many organs can be affected by myeloma, the symptoms and signs vary greatly. fatigue and bone pain are the most common symptoms at presentation. the crab criteria encompass the most common signs of multiple myeloma:: 651 calcium: 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 >1.77 mol/l (>2 mg/dl) anemia: hemoglobin value of >2g/dl below the lowest limit of normal, or a hemoglobin value <10g/dl bone lesions: osteolytic lesions on skeletal radiography, ct, or pet/ct bone pain illustration showing the most common site of bone lesions in vertebrae bone pain affects almost 70% of people with multiple myeloma and is one of the most common symptoms.: 653 myeloma bone pain usually involves the spine and ribs, and worsens with activity. persistent, localized pain may indicate a pathological bone fracture. involvement of the vertebrae may lead to spinal cord compression or kyphosis. myeloma bone disease is due to the overexpression of receptor activator for nuclear factor κ b ligand (rankl) by bone marrow stroma. rankl activates osteoclasts, which resorb bone. the resultant bone lesions are lytic (cause breakdown) in nature, and are best seen in plain radiographs, which may show "punched-out" resorptive lesions (including the "raindrop" appearance of the skull on radiography). the breakdown of bone also leads to the release of calcium ions into the blood, leading to hypercalcemia and its associated symptoms. anemia the anemia found in myeloma is usually normocytic and normochromic. it results from the replacement of normal bone marrow by infiltrating tumor cells and inhibition of normal red blood cell production (hematopoiesis) by cytokines. impaired kidney function impaired kidney function may develop, either acutely or chronically, and with any degree of severity. the most common cause of kidney failure in multiple myeloma is due to proteins secreted by the malignant cells. myeloma cells produce monoclonal proteins of varying types, most commonly immunoglobulins (antibodies) and free light chains, resulting in abnormally high levels of these proteins in the blood. depending on the size of these proteins, they may be excreted through the kidneys. kidneys can be damaged by the effects of proteins or light chains. increased bone resorption leads to hypercalcemia and causes nephrocalcinosis, thereby contributing to kidney failure. amyloidosis is a distant third in the causation. people with amyloidosis have high levels of amyloid protein that can be excreted through the kidneys and cause damage to the kidneys and other organs. light chains produce myriad effects that can manifest as the fanconi syndrome (type ii kidney tubular acidosis). infection the most common infections are pneumonias and pyelonephritis. common pneumonia pathogens include s. pneumoniae, s. aureus, and k. pneumoniae, while common pathogens causing pyelonephritis include e. coli and other gram-negative organisms. the greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy. the increased risk of infection is due to immune deficiency. although the total immunoglobulin level is typically elevated in multiple myeloma, the majority of the antibodies are ineffective monoclonal antibodies from the clonal plasma cell. a selected group of people with documented hypogammaglobulinemia may benefit from replacement immunoglobulin therapy to reduce the risk of infection. neurological symptoms some symptoms (e.g., weakness, confusion, and fatigue) may be due to anemia or hypercalcemia. headache, visual changes, and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. finally, radicular pain, loss of bowel or bladder control (due to involvement of spinal cord leading to cord compression) or carpal tunnel syndrome, and other neuropathies (due to infiltration of peripheral nerves by amyloid) may occur. it may give rise to paraplegia in late-presenting cases. when the disease is well-controlled, neurological symptoms may result from current treatments, some of which may cause peripheral neuropathy, manifesting itself as numbness or pain in the hands, feet, and lower legs. mouth the initial symptoms may involve pain, numbness, swelling, expansion of the jaw, tooth mobility, and radiolucency. multiple myeloma in the mouth can mimic common tooth problems such as periapical abscess or periodontal abscess, gingivitis, periodontitis, or other gingival enlargement or masses. cause the cause of multiple myeloma is generally unknown. risk factors monoclonal gammopathy of undetermined significance (mgus) increases the risk of developing multiple myeloma. mgus transforms to multiple myeloma at the rate of 1% to 2% per year, and almost all cases of multiple myeloma are preceded by mgus. smoldering multiple myeloma increases the risk of developing multiple myeloma. individuals diagnosed with this premalignant disorder develop multiple myeloma at a rate of 10% per year for the first 5 years, 3% per year for the next 5 years, and then 1% per year. obesity is related to multiple myeloma with each increase of body mass index by five increasing the relative risk by 11%. studies have reported a familial predisposition to myeloma. hyperphosphorylation of a number of proteins—the paratarg proteins—a tendency that is inherited in an autosomal dominant manner, appears a common mechanism in these families. this tendency is more common in african-american with myeloma and may contribute to the higher rates of myeloma in this group. occupations in a study to investigate the association between occupational exposure to aromatic hydrocarbon solvents, evidence has shown that these solvents have a role in causation of multiple myeloma. the occurrence of multiple myeloma may occur more in certain occupations. the risk of multiple myeloma occurring is greater in occupations as a firefighter, as a hairdresser, and in agricultural and industrial occupations. the risk in certain occupations is due to the exposure of different chemicals. repeated exposure to chemicals increases risk of multiple myeloma. the use of pesticides and hazardous chemicals in occupations, like firefighting and agriculture have been seen to cause an increase of risk for multiple myeloma. other occupations, such as the industrial occupations, are also at increased risk for multiple myeloma. industrial workers are exposed to chemicals that have aromatic hydrocarbon solvents in them. exposure to aromatic hydrocarbon solvents, benzene, toluene, and xylene, can increase risk of multiple myeloma. increased duration, high intensity of exposure, or repeated exposure was associated with an increased risk of multiple myeloma by up to 63%. the time from exposure to diagnosis was studied, and diagnosis after exposure lagged at least 20 years. when exposure to one chemical was identified, there was usually exposure to another hydrocarbon solvent identified. multiple myeloma affects more men, older adults, and african americans. these populations also have higher exposure frequencies than their female counterparts. epstein–barr virus rarely, epstein–barr virus (ebv) is associated with multiple myeloma, particularly in individuals who have an immunodeficiency due to e.g. hiv/aids, organ transplantation, or a chronic inflammatory condition such as rheumatoid arthritis. ebv-positive multiple myeloma is classified by the world health organization (2016) as one form of the epstein–barr virus-associated lymphoproliferative diseases and termed epstein–barr virus-associated plasma cell myeloma. ebv-positive disease is more common in the plasmacytoma rather than multiple myeloma form of plasma cell cancer. tissues involved in ebv+ disease typically show foci of ebv+ cells with the appearance of rapidly proliferating immature or poorly differentiated plasma cells. the cells express products of ebv genes such as eber1 and eber2. while the ebv contributes to the development and/or progression of most epstein–barr virus-associated lymphoproliferatve diseases, its role in multiple myeloma is not known. however, people who are ebv-positive with localized plasmacytoma(s) are more likely to progress to multiple myeloma compared to people with ebv-negative plasmacytoma(s). this suggest that ebv may have a role in the progression of plasmacytomas to systemic multiple myeloma. pathophysiology plasmablast, wright stain, in a case of multiple myeloma of plasmablastic type. 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. multiple myeloma 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 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. epigenetics in a study that