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54-402: The Multiple Myeloma Research Foundation ( MMRF ) is a charitable organization dedicated to multiple myeloma , an incurable blood cancer. The MMRF runs as if it were a for-profit business, expecting high returns from the money the organization raises from donors. MMRF was founded in 1998 by twin sisters Kathy Giusti and Karen Andrews, following Kathy's diagnosis with multiple myeloma. Giusti,

108-488: 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 multiple myeloma. This myeloma

162-466: A fundamental genetic instability in plasma cells or their precursors leads to the progression: Monoclonal gammopathy of undetermined significance → smoldering multiple myeloma → multiple myeloma → plasma cell leukemia Being asymptomatic, monoclonal gammopathy of undetermined significance and smoldering multiple myeloma are typically diagnosed fortuitously by detecting a myeloma protein on serum protein electrophoresis tests done for other purposes. MGUS

216-520: A large cell two or three times the size of a peripheral lymphocyte. Because they are actively producing antibodies, the Golgi apparatus typically produces a light-colored area adjacent to the nucleus, called a perinuclear halo. The single nucleus (with inside a single nucleolus with vesicular nuclear chromatin) is eccentric, displaced by an abundant cytoplasm. Other common morphologies seen, but which are not usual in normal plasma cells, include: Historically,

270-507: A multiple myeloma specific gene silencing pattern associated with abnormal histone modifications caused by dysregulation of the polycomb repressive complex 2 (PRC2). Increased expression of the PRC2 subunit, EZH2 have been described to be a common feature in multiple myeloma, resulting in an accumulation and redistribution of histone H3 lysine 27 trimethylation which advances with disease severity. Genetic abnormalities in multiple myeloma divide

324-431: A pathologic fracture is diagnostic of osteoporosis irrespective of bone mineral density . Based on Mirel's score (if the score is more than 8), bone fixation should be done prophylactically. Fixation is done by internal fixation rather than conservatively, along with treatment of the underlying cause. Once a fracture has occurred, intramedullary fixation is the usual surgical management for certain long bones, such as

378-482: A person's immune response is typically performed by a lab test that measures the levels of different immunoglobulins in the blood. There are five varieties of immunoglobulins, indicated by the suffices -A, -D, -E, -G and -M. In the aggregate, the immunoglobulin level may be elevated with the disease, but the majority of such increased antibodies are of a monoclonal variety due to the clonal plasma cell and are thus ineffective. Such ineffective antibodies are commonly of

432-603: A pharmaceutical company executive and Harvard Business School Alum, wanted to encourage researchers to develop treatments for multiple myeloma by using business models rather than academic models of drug development . MMRF is a private funder of multiple myeloma research, having raised over $ 120 million since its inception to contribute funding to more than 120 laboratories worldwide. MMRF funding contributes to diverse research strategies to yield long-, mid-, and short-term results in an effort to deliver better treatments to patients faster: basic science programs to better understand

486-426: A result of an injury that would be insufficient to cause fracture in a normal bone. There are three fracture sites said to be typical of fragility fractures: vertebral fractures, fractures of the neck of the femur, and Colles fracture of the wrist. This definition arises because a normal human being ought to be able to fall from standing height without breaking any bones, and a fracture, therefore, suggests weakness of

540-452: A specific set of "CRAB" symptoms, which are the basis for diagnosing malignant multiple myeloma and treating the disease. In a small percentage of multiple myeloma 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,

594-468: 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. Recently, new approaches utilizing CAR-T cell therapy have been included in the treatment regimes. Globally, about 175,000 people were diagnosed with

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648-626: 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 ). Collateral infections are common with multiple myeloma, since the disease impairs functioning of blood components that normally resist pathogens. The most common infections are pneumonias, urinary tract infections, and sepsis. The greatest risk period for

702-545: Is a relatively stable condition afflicting 3% of people aged 50 and 5% of people aged 70; it progresses to multiple myeloma at a rate of 0.5–1% cases per year; smoldering multiple myeloma 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 multiple myeloma cases eventually progress to plasma cell leukemia . The globulin level may be normal in established disease. A doctor may request protein electrophoresis of

756-595: 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

810-457: 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

864-545: Is commonly seen, though this is not specific. The recent introduction of a commercial immunoassay for measurement of free light chains potentially offers an improvement in monitoring disease progression and response to treatment, particularly where the paraprotein is difficult to measure accurately by electrophoresis (for example in light chain myeloma, or where the paraprotein level is very low). Initial research also suggests that measurement of free light chains may also be used, in conjunction with other markers, for assessment of

918-537: 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

972-664: 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

1026-424: 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

1080-486: Is generally unknown. 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-Americans with myeloma and may contribute to the higher rates of myeloma in this group. In a study to investigate

1134-402: 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

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1188-416: Is mainly due to casts of paraprotein deposition in the kidney, although the cast may also contain complete immunoglobulins, Tamm-Horsfall protein and albumin . Other useful laboratory tests include quantitative measurement of IgA, IgG, and IgM to look for immune paresis, and beta-2 microglobulin, which provides prognostic information. On peripheral blood smear, the rouleaux formation of red blood cells

1242-584: 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 lymphoproliferative diseases, its role in multiple myeloma

1296-616: 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. 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 (cell surface antigens). When they are activated to secrete antibodies, they are known as plasma cells. Multiple myeloma develops in B lymphocytes after they have left

1350-426: 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 antibody proteins (often using electrophoretic techniques revealing the presence of a monoclonal spike in the results, termed an m-spike), bone marrow biopsy finding cancerous plasma cells, and medical imaging finding bone lesions. Another common finding

1404-419: Is unknown. Risk factors include obesity , radiation exposure, family history, age 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 is the result of a multi-step malignant transformation, and almost universally originates from

1458-399: The diagnostic criteria for myeloma. Immunohistochemistry (staining particular cell types using antibodies against surface proteins) can detect plasma cells that express immunoglobulin in the cytoplasm and occasionally on the cell surface; myeloma cells are often CD56 , CD38 , CD138 , and CD319 positive and CD19 , CD20 , and CD45 negative. Flow cytometry is often used to establish

1512-481: The CD138 has been used to isolate myeloma cells for diagnostic purposes. However, this antigen disappears rapidly ex vivo . Recently, however, the surface antigen CD319 (SLAMF7) was discovered to be considerably more stable and allows robust isolation of malignant plasma cells from delayed or even cryopreserved samples. Pathological fracture Fragility fracture is a type of pathologic fracture that occurs as

1566-520: The CRAB criteria appears, thereby making more people eligible for treatment with myeloma drugs earlier. Bone pain affects almost 70% of people with multiple myeloma and is one of the most common symptoms. 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

1620-462: The activation of specific oncogenes and repression of specific tumor suppressor genes . The observed methylation pattern of CpG within intronic regions with enhancer-related chromatin marks in multiple myeloma is similar to undifferentiated precursor and stem cells. These results may represent a de novo epigenetic reprogramming in multiple myeloma, leading to the acquisition of a methylation pattern related to stemness. Other studies have identified

1674-458: The association between occupational exposure to aromatic hydrocarbon solvents ( Benzene and its many derivatives), 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

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1728-478: The blood and urine, which might show the presence of a paraprotein (monoclonal protein, or M protein ) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis). One type of paraprotein is the Bence Jones protein , which is a urinary paraprotein composed of free light chains. Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor

1782-410: The clonal nature of the plasma cells, which will generally express only kappa or lambda light chain. Cytogenetics may also be performed in myeloma for prognostic purposes, including a myeloma-specific fluorescent in situ hybridization and virtual karyotype . The plasma cells seen in multiple myeloma have several possible morphologies. First, they could have the appearance of a normal plasma cell,

1836-480: The disease and identify new druggable targets through genomics and proteomics research; validation programs to prioritize new compounds and combinations based on key targets; and clinical trials conducted at a number of myeloma centers. In 2009, the MMRF funded research into 30 compounds at the pre-clinical stage. By 2013 it had raised more than $ 250 million and its work has helped gain approval of six new drugs to treat

1890-473: The disease between 2013 and 2019, about 60% lived five years or more post-diagnosis, with about 34% living ten years or more. People newly diagnosed with the disease now have a better outlook, due to improved treatments. The disease usually occurs around the age of 60 and is more common in men than women. It is uncommon before the age of 40. The word myeloma is from Greek myelo- 'marrow' and -oma 'tumor'. Because many organs can be affected by myeloma,

1944-497: The disease establishment and progression. In a study that investigated the DNA methylation profile of multiple myeloma cells and normal plasma cells , a gradual demethylation from stem cells to plasma cells was observed, with site-specific gain of methylation. Loss of methylation is associated with gene activation and gain of methylation is correlated with gene silencing. The dysregulated methylation pattern in multiple myeloma results in

1998-474: The disease in 2020, while about 117,000 people died from the disease that year. In the U.S., forecasts suggest about 35,000 people will be diagnosed with the disease in 2023, and about 12,000 people will die from the disease that year. In 2020, there were an estimated 170,405 people living with myeloma in the U.S. It is difficult to judge mortality statistics because treatments for the disease are advancing rapidly. Based on data concerning people diagnosed with

2052-816: The disease in two main groups, hyperdiploid multiple myeloma and non-hyperdiploid multiple myeloma. Hyperdiploid MM is associated with good prognosis and includes trisomies of odd-numbered chromosomes. Non-hyperdiploid MM has worse outcome and is characterized by translocations on chromosome 14, which lead to the expression of oncogenes. These translocations can be t(11;14), t(6;14), t(4;14), t(14;16), t(14;20). Other genetic alterations are 1q amplification, deletion 1p, deletion 17, deletion 13, MYC overexpression, and point mutations in key pathways. Associated genetic mutations include ATM , BRAF , CCND1 , DIS3 , FAM46C , KRAS , NRAS and TP53 . The genetic and epigenetic changes occur progressively. The initial change, often involving one chromosome 14 translocation, establishes

2106-554: 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. 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. The cause of multiple myeloma

2160-454: The disease. 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 , renal insufficiency , and infections may occur. Complications may include hypercalcemia and amyloidosis . The cause of multiple myeloma

2214-550: The disease. The paraprotein is a specific immunoglobulin (or fragment of immunoglobulin) originally produced by the mutated plasma cell which began to multiply, and which is now produced by the entire line of malignant cells. In theory, multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM . IgD and IgE myeloma are very rare. In addition, light and or heavy chains (the building blocks of antibodies) may be secreted in isolation: κ- or λ-light chains or any of

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2268-451: The five types of heavy chains (α-, γ-, δ-, ε- or μ-heavy chains). People without evidence of a monoclonal protein may have "nonsecretory" myeloma (not producing immunoglobulins); this represents about 3% of all people with multiple myeloma. Additional findings may include a raised calcium level (when osteoclasts are breaking down bone, releasing it into the bloodstream), raised serum creatinine level due to reduced kidney function , which

2322-421: The immunoglobulin -A and -G varieties. When the measure of effective antibodies drops below a threshold (a condition termed hypogammaglobulinemia ), supplemental immunoglobulins may be provided by periodic infusions to reduce the risk of collateral infections. Some symptoms (e.g., weakness , confusion , and fatigue ) may be due to anemia or hypercalcemia. Headache , visual changes, and retinopathy may be

2376-598: The occurrence of infection is in the initial few months after the start of a new drug therapy, since many drug therapies further suppress the normal immune response. Infections (and "adverse events" for all diseases) are graded by a standardized scale. With some myeloma drug therapies, over 30% of people experience a "Grade 3" or higher infection (many people experience multiple such infections), calling for intervention at least by antibiotics. Of people who die within 6 months of their myeloma diagnosis, between 20% and 50% die from collateral infections. Clinical evaluation of

2430-437: 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

2484-422: 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

2538-455: The plasma cells causes much of their localized 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 modifications , as DNA methylation or histone modifications , are key for

2592-412: The pre-malignant stage monoclonal gammopathy of undetermined significance (MGUS). As MGUS evolves into MM, another pre-stage of the disease is reached, known as smoldering myeloma (SMM) . In MM, 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

2646-516: The release of calcium ions into the blood, leading to hypercalcemia and its associated symptoms. 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 may develop, either acutely or chronically , and with any degree of severity. The most common cause of kidney failure in multiple myeloma

2700-414: 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

2754-496: The risk of progression from MGUS to multiple myeloma. This assay, the serum free light chain assay, has recently been recommended by the International Myeloma Working Group for the screening, diagnosis, prognosis, and monitoring of plasma cell dyscrasias . A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in

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2808-588: The skeleton. Pathological fractures present as a chalkstick fracture in long bones, and appear as a transverse fractures nearly 90 degrees to the long axis of the bone. In a pathological compression fracture of a spinal vertebra fractures will commonly appear to collapse the entire body of vertebra . Pathologic fractures in children and adolescents can result from a diverse array of disorders namely; metabolic, endocrine, neoplastic, infectious, immunologic, and genetic skeletal dysplasias . In circumstances where other pathologies are excluded (for example, cancer),

2862-638: The symptoms and signs vary greatly. Fatigue and bone pain are the most common symptoms at presentation. The CRAB criteria were formerly the benchmark used to establish presence of active multiple myeloma (as opposed to an earlier, generally asymptomatic, "smoldering" form of the disease). The CRAB criteria are: As of 2014 the diagnostic criteria were expanded and updated by the IMWG (International Myeloma Working Group) to add three myeloma defining events, any one of which indicates presence of active multiple myeloma. Each of these three events may occur before any of

2916-492: 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. Rarely, Epstein–Barr virus (EBV)

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