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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 insuficiency, and infections may occur. Complications may include hypercalcemia and amyloidosis.

The cause of multiple myeloma 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 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 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 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 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 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'.

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 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:
 *  C alcium: serum calcium >0.25 mmol/L (>1 mg/dL) higher than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
 *  R enal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >1.77 mol/L (>2 mg/dL)
 *  A nemia: hemoglobin value of >2g/dL below the lowest limit of normal, or a hemoglobin value <10g/dL
 *  B one lesions: osteolytic lesions on skeletal radiography, CT, or PET/CT

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 the CRAB criteria appears, thereby making more people eligible for treatment with myeloma drugs earlier.

Bone pain
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 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
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 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 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 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.

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%. In addition, studies have shown a positive correlation between BMI and adhesion of multiple myeloma cells.

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.

Occupations
In a study to investigate 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 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 lymphoproliferative 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
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 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 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.

Epigenetics
Epigenetic modifications, as DNA methylation or histone modifications, are key for 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 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 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.

Genetics
Genetic abnormlaities in multiple myeloma divide 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.

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 multiple myeloma. 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 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, 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 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.

Blood tests

The globulin level may be normal in established disease. A doctor may request protein electrophoresis of 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 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 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 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 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 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.

Histopathology
A bone marrow biopsy is usually performed to estimate the percentage of bone marrow occupied by plasma cells. This percentage is used in 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 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, 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:
 * Bizarre cells, which are multinucleated
 * Mott cells, containing multiple clustered cytoplasmic droplets or other inclusions (sometimes confused with Auer rods, commonly seen in myeloid blasts)
 * Flame cells, having a fiery red cytoplasm

Historically, 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.

The prognosis varies widely depending upon various risk factors. The Mayo Clinic has developed a risk-stratification model termed Mayo Stratification for Myeloma and Risk-adapted Therapy (mSMART), which divides people into high-risk and standard-risk categories. People with deletion of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), t(14;20) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or more) are considered to have high-risk myeloma.

Medical imaging
The diagnostic examination of a person with suspected multiple myeloma typically includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton, and proximal long bones. Myeloma activity sometimes appears as "lytic lesions" (with local disappearance of normal bone due to resorption) or as "punched-out lesions" on the skull X-ray ("raindrop skull"). Lesions may also be sclerotic, which is seen as radiodense. Overall, the radiodensity of myeloma is between −30 and 120 Hounsfield units (HU). Magnetic resonance imaging is more sensitive than simple X-rays in the detection of lytic lesions, and may supersede a skeletal survey, especially when vertebral disease is suspected. Occasionally, a CT scan is performed to measure the size of soft-tissue plasmacytomas. Nuclear Medicine Bone scans are typically not of any additional value in the workup of people with myeloma (no new bone formation; lytic lesions not well visualized on nuclear bone scan).

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). A person must have >10 % clonal plasma cells and any MDE to be diagnosed with myeloma. The biomarker criteria were added so that smouldering people with multiple myeloma at high risk of developing multiple myeloma could be diagnosed before organ damage occurred, so they would therefore have a better prognosis.
 * Asymptomatic/smoldering myeloma:
 * Serum M protein >30 g/L (3 g/dL) or
 * Clonal plasma cells >10% on bone marrow biopsy and
 * No myeloma-related organ or tissue impairment
 * Monoclonal gammopathy of undetermined significance (MGUS):
 * Serum paraprotein <30 g/L (3 g/dL) and
 * Clonal plasma cells <10% on bone marrow biopsy and
 * No myeloma-related organ or tissue impairment or a related B-cell lymphoproliferative disorder

Related conditions include solitary plasmacytoma (a single tumor of plasma cells, typically treated with irradiation), plasma cell dyscrasia (where only the antibodies produce symptoms, e.g., AL amyloidosis), and peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes.

Staging
In multiple myeloma, staging helps with prognostication but does not guide treatment decisions. The Durie-Salmon staging system was used historically and was replaced by the International Staging System (ISS), published by the International Myeloma Working Group In 2005. The revised ISS (R-ISS) was published in 2015 and incorporates cytogenetics and lactate dehydrogenase (LDH).
 * Stage I: β2 microglobulin (β2M) < 3.5 mg/L, albumin ≥ 3.5 g/dL, normal cytogenetics, no elevated LDH
 * Stage II: Not classified under Stage I or Stage III
 * Stage III: β2M ≥ 5.5 mg/L and either elevated LDH or high-risk cytogenetics [t(4,14), t(14,16), and/or del(17p)]

Prevention
The risk of multiple myeloma can be reduced slightly by maintaining a normal body weight.

Treatment
Most drug therapies employ multiple agents, e.g., so-called "triplet" or "quadruplet" therapies. Many such groupings include one or more of a monoclonal antibody (e.g., isatuximab or daratumumab), an immunomodulatory agent (e.g., lenalidomide or pomalidomide), and a proteasome inhibitor (e.g., or bortezomib, carfilzomib or ixazomib), in combination with a steroid (e.g., dexamethasone).

While triplet therapies were the standard of care for many years, current practice more commonly applies quadruplets of drugs. Such combination therapies are commonly referenced by initials, employing upper-case letters for drug brandnames and lower-case letters for generic drug names, e.g., VRd for Velcade (brandname for bortezomib), Revlimid (brandname for lenalidomide) and dexamethasone. Similarly with DKRd, with the D representing Darzalex (brandname for daratumumab), and K representing Kyprolis (brandname for carfilzomib). (Emerging practice is not to call such drugs "chemotherapy" because they are not the traditional non-specific intracellular poisons that operate in the classic "chemo" fashion of inhibiting mitosis or inducing DNA damage. )

Commonly, the efficacy of each drug diminishes over time, as the cancer develops drug resistance mechanisms, such as by clonal evolution or genetic mutations. In part for this reason, multiple myeloma has not historically been treated when in its "smoldering" stage, since the drug(s) utilized may then be of diminished efficacy if the disease progresses to a symptomatic stage. Thus, the standard of care was "watchful waiting" while the disease smoldered. Increasingly, however, efforts are underway to study whether drug therapies applied during the smoldering stage might prevent the disease from ever advancing to the active stage. Exemplary are the GEM-CESAR, ASCENT and Immuno-PRISM clinical trials.

After drug therapy has reduced a patient's cancer burden, some patients undergo a bone marrow transplant (more properly termed a autologous hematopoietic stem cell transplant, or ASCT) to further suppress the disease. However, this procedure is not available for frail patients, as it essentially resets aspects of the immune system and requires redevelopment of natural defenses, such as by administering childhood vaccines.

Increasingly, precision medicine therapies are being explored, with research indicating that certain variants and genetic sub-types of the disease respond more favorably to some drug therapies than others. For example, some research indicates that patients with the t(11,14) genetic translocation (present in about 15-20% of multiple myeloma patients) may particularly benefit from Venetoclax therapy (which is FDA approved for other blood cancers but not yet available for multiple myeloma patients except through clinical trials).

While drug therapies commonly entail months or years of treatment, CAR-T therapy offers the alternative of a single treatment (albeit involving a prolonged hospital stay). Moreover, CAR-T treatment seems to provide a deeper, longer lasting disease remission than existing drugs. Presently, however, such therapy is FDA-approved only for patients in later stages of the disease, and is available only at certain medical centers.

An upcoming therapy that also leverages T-cell immune response is the class of drugs termed bispecific T-cell engagers (BITE), or sometimes simply bispecific antibodies. The first drug in this class approved for multiple myeloma is Teclistamab, but again its use is presently reserved for patients in later stages of the disease. Another BITE drug,Talquetamab, is under study; others are in the pipeline. (Ongoing clinical trials are investigating BITE therapy for smoldering and newly diagnosed patients. )

Some patients seek out clinical drug trials, as these provide a degree of medical oversight not present in most other clinical settings – not to mention access to new drugs that seem to hold promise over existing therapies. Some patients temporarily relocate to urban areas where such trials are available.

The major cancer research institutes offer the most clinical trials, but some trials (particularly later-stage, Phase 3, trials) are available at satellite networks that extend to hundreds of hospitals. The U.S. National Institutes of Health maintains a directory of clinical trials. In the U.S., cities such as New York, Boston, Houston and Rochester host leading multiple myeloma research efforts; globally, other top-tier myeloma research programs are found at the University of Salamanca, Spain, and at Vrije Universiteit Brussels, amongst others.

Medical information soon becomes outdated in fast-moving medical arenas, such as therapies for multiple myeloma, so oncologists at smaller medical centers may not be able to stay up-to-date with the literature in all relevant disciplines. This has given rise to organizations that work to educate patients on latest developments in the disease, e.g., by offering webinars featuring prominent researchers and practitioners who focus on multiple myeloma; examples of such organisations are the International Myeloma Foundation and the Multiple Myeloma Research Foundation. Some patients interested in following latest developments review proceedings from major hematologic cancer conferences, such as the American Society of Hematologists (ASH) Conference, the American Society of Clinical Oncology (ASCO) Conference, the IMF IMWG Summit, and the European Hematology Association (EHA) Annual Conference.

Treatment is indicated in myeloma with symptoms. If there are no symptoms, but a paraprotein typical of myeloma and diagnostic bone marrow is present without end-organ damage, treatment is usually deferred or restricted to clinical trials. Treatment for multiple myeloma is focused on decreasing the clonal plasma cell population and consequently decrease the symptoms of disease.

Initial
The preferred treatment for those under the age of 65 is high-dose chemotherapy, commonly with bortezomib-based regimens, and lenalidomide–dexamethasone, to be followed by a stem cell transplant. A 2016 study concluded that stem cell transplant is the preferred treatment of multiple myeloma. There are two types of stem cell transplants to treat multiple myeloma. In autologous hematopoietic stem-cell transplantation (ASCT) – the patient's own stem cells are collected from the patient's own blood. The patient is given high-dose chemotherapy, and the patient's stem cells are then transplanted back into the patient. The process is not curative, but does prolong overall survival and complete remission. In allogeneic stem-cell transplantation, a healthy donor's stem cells are transplanted into the affected person. Allogenic stem-cell transplantation has the potential for a cure, but is used in a very small percentage of people (and in the relapsed setting, not as part of initial treatment). Furthermore, a 5–10% treatment-associated mortality rate is associated with allogeneic stem-cell transplant.

People over age 65 and people with significant concurrent illnesses often cannot tolerate stem-cell transplantation. For these people, the standard of care has been chemotherapy with melphalan and prednisone. Recent studies among this population suggest improved outcomes with new chemotherapy regimens, e.g., with bortezomib. Treatment with bortezomib, melphalan, and prednisone had an estimated overall survival of 83% at 30 months, lenalidomide plus low-dose dexamethasone an 82% survival at 2 years, and melphalan, prednisone, and lenalidomide had a 90% survival at 2 years. Head-to-head studies comparing these regimens have not been performed.

There is support for continuous therapies with multiple drug combinations of antimyeloma drugs bortezomib, lenalidomide, and thalidomide as initial treatment for transplant-ineligible multiple myeloma. Further clinical studies are required to determine the potential harms of these drugs and the effect on the person's quality of life. A 2009 review noted, "Deep venous thrombosis and pulmonary embolism are the major side effects of thalidomide and lenalidomide. Lenalidomide causes more myelosuppression, and thalidomide causes more sedation. Chemotherapy-induced peripheral neuropathy and thrombocytopenia are major side effects of bortezomib." The addition of subcutaneous daratumumab to induction and consolidation therapy with bortezomib, lenalidomide, and dexamethasone, and to lenalidomide maintenance therapy, conferred improved progression-free survival among transplantation-eligible patients with newly diagnosed multiple myeloma.

Treatment of related hyperviscosity syndrome may be required to prevent neurologic symptoms or kidney failure.

Maintenance
Most people, including those treated with ASCT, relapse after initial treatment. Maintenance therapy using a prolonged course of low-toxicity medications is often used to prevent relapse. A 2017 meta-analysis showed that post-ASCT maintenance therapy with lenalidomide improved progression-free survival and overall survival in people at standard risk. A 2012 clinical trial showed that people with intermediate- and high-risk disease benefit from a bortezomib-based maintenance regimen.

Relapse
Reasons for relapse include disease evolution, either from the selective pressure applied by treatment or by de novo mutations and/or if disease was inadequately represented in the initial biopsy. Relapse within the first 18 months of diagnosis is considered as functional high-risk multiple myeloma. Depending on the person's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include retreatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide, or dexamethasone, alone or in combination), and a second ASCT.

Later in the course of the disease, it becomes refractory (resistant) to formerly effective treatment. This stage is referred to as relapsed/refractory multiple myeloma (RRMM). Treatment modalities that are commonly use to treat RRMM include dexamethasone, proteasome inhibitors (e.g. bortezomib and carfilzomib), immunomodulatory imide drugs (e.g. thalidomide, lenalidomide, and pomalidomide), and certain monoclonal antibodies (e.g. isatuximab against CD38 or antibodies targeting CD319). Survival expectancy has risen in recent years, and new treatments are under development.

Kidney failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute kidney failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic kidney failure is dependent on the type of kidney failure and may involve dialysis.

Several newer options are approved for the management of advanced disease:
 * belantamab mafodotin: a monoclonal antibody against B-cell maturation antigen (BCMA), also known as CD269, indicated for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.
 * carfilzomib: a proteasome inhibitor that is indicated:
 * as a single agent in people who have received one or more lines of therapy
 * in combination with dexamethasone or with lenalidomide and dexamethasone in people who have received one to three lines of therapy
 * daratumumab: a monoclonal antibody against CD38 indicated in people who have received at least three prior lines of therapy including a proteasome inhibitor and an immunomodulatory agent or who are double refractory to a proteasome inhibitor and an immunomodulatory agent
 * elotuzumab: an immunostimulatory humanized monoclonal antibody against SLAMF7 (also known as CD319) indicated in combination with lenalidomide and dexamethasone in people who have received one to three prior therapies
 * isatuximab: a monoclonal antibody against CD38 indicated in combination with pomalidomide and dexamethasone for the treatment of adults with multiple myeloma who have received at least two prior therapies including lenalidomide and a proteasome inhibitor.
 * ixazomib: an orally available proteasome inhibitor indicated in combination with lenalidomide and dexamethasone in people who have received at least one prior therapy
 * panobinostat: an orally available histone deacetylase inhibitor used in combination with bortezomib and dexamethasone in people who have received at least two prior chemotherapy regimens, including bortezomib and an immunomodulatory agent
 * selinexor: an orally available selective inhibitor of nuclear export indicated in combination with dexamethasone in people who have received at least four prior therapies and whose disease does not respond to at least two proteasome inhibitors, two immunomodulatory agents and an anti-CD38 monoclonal antibody
 * idecabtagene vicleucel: first cell-based gene therapy was approved by FDA in 2021 for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies

Talquetamab (Talvey) and elranatamab (Elrexfio) were approved for medical use in the United States in August 2023.

Stem cell transplant
Stem cell transplant can be used to treat multiple myeloma. Stem cell transplants come with a risk of a graft-versus-host-disease. Mesenchymal stromal cells may reduce the all-cause mortality if they are used for a therapeutic reason and the therapeutic use of MSCs may increase the complete response of acute and chronic GvHD, but the evidence is very uncertain. The evidence suggests that MSCs for prophylactic reason result in little to no difference in the all-cause mortality, in the relapse of malignant diseases and in the incidence of acute GvHD. The evidence suggests that MSCs for prophylactic reason reduce the incidence of chronic GvHD.

Bone marrow transplant
Plerixafor (Mozobil) was approved for medical use in the United States in 2008.

Motixafortide (Aphexda) was approved for medical use in the United States in September 2023.

Gene therapy

 * Idecabtagene vicleucel (Abecma) – first cell-based gene therapy was approved by FDA in 2021 for the treatment of adults with relapsed or refractory multiple myeloma who have received at least four prior therapies
 * Ciltacabtagene autoleucel (Carvykti) was approved for medical use in the United States in February 2022. Ciltacabtagene autoleucel is indicated for the treatment of adults with relapsed or refractory multiple myeloma after four or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Other measures
In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g., pamidronate or zoledronic acid) are routinely administered to prevent fractures; they have also been observed to have a direct antitumor effect even in people without known skeletal disease. If needed, red blood cell transfusions or erythropoietin can be used for management of anemia.

Side effects
Chemotherapies and stem cell transplants can cause unwanted bleedings and may require platelet transfusions. It was seen that platelet transfusions for people undergoing a chemotherapy or a stem cell transplantation for the prevention of bleeding events had different effects on the number of participants with a bleeding event, the number of days on which a bleeding occurred, the mortality secondary to bleeding and the number of platelet transfusions depending on the way they were used (therapeutic, depending on a threshold, different dose schedules or prophylactic).

Supportive treatment
Adding physical exercises to the standard treatment for adult patients with haematological malignancies like multiple myeloma may result in little to no difference in the mortality, in the quality of life and in the physical functioning. These exercises may result in a slight reduction in depression. Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect and serious adverse events

Palliative care
Multiple national cancer treatment guidelines recommend early palliative care for people with advanced multiple myeloma at the time of diagnosis and for anyone who has significant symptoms.

Palliative care is appropriate at any stage of multiple myeloma and can be provided alongside curative treatment. In addition to addressing symptoms of cancer, palliative care helps manage unwanted side effects, such as pain and nausea related to treatments.

Teeth
Oral prophylaxis, hygiene instruction and elimination of sources of infection within the mouth before beginning cancer treatment, can reduce the risk of infectious complications. Before starting bisphosphonates therapy, the person's dental health should be evaluated to assess the risk factors to prevent the development of medication-related osteonecrosis of the jaw (MRONJ). If there are any symptoms or radiographic appearance of MRONJ like jaw pain, loose tooth, mucosal swelling, early referral to an oral surgeon is recommended. Dental extractions should be avoided during the active period of treatment and treat the tooth with nonsurgical root canal treatment instead.

Prognosis
Overall the 5-year survival rate is around 54% in the United States. With high-dose therapy followed by ASCT, the median survival has been estimated in 2003 to be about 4.5 years, compared to a median around 3.5 years with "standard" therapy.

The international staging system can help to predict survival, with a median survival (in 2005) of 62 months for stage-1 disease, 45 months for stage-2 disease, and 29 months for stage-3 disease. The median age at diagnosis is 69 years.

Genetic testing
SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel.

The following table outlines the prognostic effect of various genetic findings in multiple myeloma, with chromosomal translocations designated t, followed by standard nomenclature thereof:

Epidemiology

Globally, multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015. This is up from 49,000 in 1990.

United States
In the United States in 2016, an estimated 30,330 new cases and 12,650 deaths were reported. These numbers are based on assumptions made using data from 2011, which estimated the number of people affected as 83,367 people, the number of new cases as 6.1 per 100,000 people per year, and the mortality as 3.4 per 100,000 people per year.

Multiple myeloma is the second-most prevalent blood cancer (10%) after non-Hodgkin's lymphoma. It represents about 1.8% of all new cancers and 2.1% of all cancer deaths.

Multiple myeloma affects slightly more men than women. African Americans and native Pacific Islanders have the highest reported number of new cases of this disease in the United States and Asians the lowest. Results of one study found the number of new cases of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top-10 causes of cancer death.

UK
Myeloma is the 17th-most common cancer in the UK: around 4,800 people were diagnosed with the disease in 2011. It is the 16th-most common cause of cancer death: around 2,700 people died of it in 2012.

Other animals
Multiple myeloma has been diagnosed in dogs, cats, and horses.

In dogs, multiple myeloma accounts for around 8% of all haemopoietic tumors. Multiple myeloma occurs in older dogs and is not particularly associated with either males or females. No breeds appear overrepresented in case reviews that have been conducted. Diagnosis in dogs is usually delayed due to the initial nonspecificity and range of clinical signs possible. Diagnosis usually involves bone-marrow studies, X-rays, and plasma-protein studies. In dogs, protein studies usually reveal the monoclonal gammaglobulin elevation to be IgA or IgG in equal number of cases. In rare cases the globulin elevation is IgM, which is referred to as Waldenström's macroglobulinemia. The prognosis for initial control and return to good quality of life in dogs is good; 43% of dogs started on a combination chemotherapeutic protocol achieved complete remission. Long-term survival is normal, with a median of 540 days reported. The disease eventually recurs, becoming resistant to available therapies. The complications of kidney failure, sepsis, or pain can lead to an animal's death, frequently by euthanasia.

title: Multiple myeloma


text:
Moondog

Louis Thomas Hardin (May 26, 1916 – September 8, 1999), known professionally as Moondog, was an American composer, musician, performer, music theoretician, poet and inventor of musical instruments. Largely self-taught as a composer, his prolific work widely drew inspiration from jazz, classical, Native American music which he had become familiar with as a child, and Latin American music. His strongly rhythmic, contrapuntal pieces and arrangements later influenced composers of minimal music, in particular American composers Steve Reich and Philip Glass.

Due to an accident, Moondog was blind from the age of 16. He lived in New York City from the late 1940s until 1972, during which time he was often found on Sixth Avenue, between 52nd and 55th Streets, selling records, composing, and performing poetry. He briefly appeared in a cloak and horned helmet during the 1960s and was hence recognized as "the Viking of Sixth Avenue" by passersby and residents who were not aware of his musical career.

Early life
Hardin was born in Marysville, Kansas, to Louis Thomas Hardin, an Episcopalian minister, and Norma Alves. Hardin started playing a set of drums that he made from a cardboard box at the age of five. His family relocated to Wyoming, where his father opened a trading post at Fort Bridger. At one point, his father took him to an Arapaho Sun Dance where he sat on the lap of Chief Yellow Calf and played a tom-tom made from buffalo skin. He also played drums for the high school band in Hurley, Missouri.

On July 4, 1932, the 16-year-old Hardin found an object in a field which he did not realise was a dynamite cap. While he was handling it, the explosive detonated in his face and permanently blinded him. His older sister, Ruth, would read to him daily after the accident for many years. Here he had his first encounters with philosophy, science and myth that formed his character. One book in particular, The First Violin by Jessie Fothergill, inspired him to pursue music. Up to that point he had been interested mainly in percussion instruments, but from then on, he became obsessed with the desire to become a composer.

After learning the principles of music in several schools for blind young men across middle America, he taught himself the skills of ear training and composition. He studied with Burnet Tuthill at the Iowa School for the Blind.

He then moved to Batesville, Arkansas, where he lived until 1942, when he obtained a scholarship to study in Memphis, Tennessee. Although he was largely self-taught in music, learning predominantly by ear, he learned some music theory from books in braille during his time in Memphis.

In 1943, Hardin moved to New York, where he met classical musicians including Leonard Bernstein and Arturo Toscanini, as well as jazz performers such as Charlie Parker and Benny Goodman, whose upbeat tempos and often humorous compositions would influence Hardin's later work. One of his early street posts was near the 52nd Street nightclub strip, and he was known to jazz musicians. By 1947, Hardin had adopted the name "Moondog" in honor of a dog "who used to howl at the moon more than any dog I knew of."

New York City
From the late 1940s until 1972, Moondog lived as a composer and poet in New York City, occasionally playing in midtown Manhattan, eventually settling on the corner of 53rd or 54th Street and Sixth Avenue in Manhattan. He was rarely if ever homeless, and maintained an apartment in upper Manhattan and had a country retreat in Candor, New York, to which he moved full-time in 1972. He partially supported himself by selling copies of his poetry, sheet music, records, and his musical philosophy. In addition to his music and poetry, he was also known for a distinctive "Viking" garb that he briefly wore during the 1960s. Already bearded and long-haired, he added a Viking-style horned helmet to avoid the occasional comparisons of his appearance with that of Christ or a monk, as he had rejected Christianity in his late teens. He developed a lifelong interest in Nordic mythology, and maintained an altar to Thor in his country home in Candor.

In 1949, he traveled to a Blackfoot Sun Dance in Idaho where he performed on percussion and flute, returning to the Native American music he had first come in contact with as a child. It was this Native music, along with contemporary jazz and classical, mixed with the ambient sounds from his environment (city traffic, ocean waves, babies crying, etc.) that created the foundation of Moondog's music.

In 1954, he won a case in the New York State Supreme Court against disc jockey Alan Freed, who had branded his radio show, "The Moondog Rock and Roll Matinee", around the name "Moondog", using "Moondog's Symphony" (the first record that Moondog ever cut) as his "calling card". Moondog believed he would not have won the case had it not been for the help of musicians such as Benny Goodman and Arturo Toscanini, who testified that he was a serious composer. Freed had to apologize and stop using the nickname "Moondog" on air, on the basis that Hardin was known by the name long before Freed began using it.

Germany
Along with his passion for Nordic culture, Moondog had an idealised view of Germany ("The Holy Land with the Holy River" — the Rhine), where he settled in 1974.

Moondog revisited the United States briefly in 1989, for a tribute at the New Music America Festival in Brooklyn, in which festival director Yale Evelev asked him to conduct the Brooklyn Philharmonic Chamber Orchestra, stimulating a renewed interest in his music.

Eventually, a young German student named Ilona Goebel (later known as Ilona Sommer) helped Moondog set up the primary holding company for his artistic endeavors and hosted him, first in Oer-Erkenschwick, and later on in Münster in Westphalia. Moondog lived with Sommer's family and they spent time together in Münster. During that period, Moondog created hundreds of compositions which were transferred from Braille to sheet music by Sommer. Moondog spent the remainder of his life in Germany.

On 8 September 1999, he died in Münster from heart failure. He is buried at the Central Cemetery Münster. His tomb was designed by the artist Ernst Fuchs after the death mask.

He recorded many albums and toured both in the U.S. and in Europe—France, Germany and Sweden.

Music
In the process of establishing himself as a composer, Moondog drew inspiration from a wide variety of styles of music. His first works were immediately inspired by the music of pow wow gatherings that he had attended as a child; as his career progressed, his music encompassed influences from bebop, swing, rumba, modernism and Renaissance music. It was characterized by what he called "snaketime" and described as "a slithery rhythm, in times that are not ordinary [...] I'm not gonna die in 4/4 time". During the 1950s, he began to incorporate city sounds such as cars, subway trains, human speech, and foghorns into his work.

Inventions
Moondog invented several musical instruments, some of which were played on studio albums or in live performances by him and his subsequent ensembles. They include the "oo", a small triangular-shaped harp, a larger harp which he named the "ooo-ya-tsu", a triangular stringed instrument played with a bow that he called the "hüs" (after the Norwegian hus, meaning house), the "dragon's teeth", the "tuji, the "uni", the "utsu", the "hexagonal drums", and the "troubador harp". His best known instrument is the trimba, a triangular percussion instrument that the composer invented in the late 1940s. The original trimba was played by Moondog's friend and only student Stefan Lakatos, a Swedish percussionist, to whom Moondog also explained the methods for building such an instrument. Prior to Stefan's passing on February 10 of 2023 he shared his teachings from Moondog with American composer Julian Calv.

Legacy
Moondog's music from the 1940s and '50s has been cited by American composers Philip Glass and Steve Reich as a major influence on their styles, saying they took Moondog's work "very seriously and understood and appreciated it much more than what we were exposed to at Juilliard". Moondog was also admired by Charlie Parker, whom he mutually admired and paid tribute to with the piece "Bird's Lament", Frank Zappa and Igor Stravinsky, and met on several occasions with Lenny Bruce, William S. Burroughs and Allen Ginsberg.

Moondog inspired other musicians with several songs dedicated to him. These include "Moondog" on Pentangle's 1968 album Sweet Child and "Spear for Moondog" (parts I and II) by jazz organist Jimmy McGriff on his 1968 Electric Funk album. Glam rock musician Marc Bolan and T. Rex referenced him in the song "Rabbit Fighter" with the line "Moondog's just a prophet to the end...". The English pop group Prefab Sprout included the song "Moondog" on their album Jordan: The Comeback released in 1990. Big Brother and the Holding Company featuring Janis Joplin covered his song "All Is Loneliness" on their 1967 self-titled album. The song was also covered by Antony and the Johnsons during their 2005 tour. Mr. Scruff's single "Get a Move On" from his album Keep It Unreal is structured around samples from "Bird's Lament". New York band The Insect Trust play a cover of Moondog's song "Be a Hobo" on their album Hoboken Saturday Night. The track "Stamping Ground", with its preamble of Moondog reciting one of his epigrams, was featured on the sampler double album Fill Your Head with Rock (CBS, 1970). Canadian composer and producer Daniel Lanois included a track called "Moondog" on his album/video-documentary Here Is What Is.

Between 1970 and 1980, a blind bearded mystic called "Moondog" appeared as the title character in a four issue series of Underground comix written and illustrated by George Metzger.

Since the early 1970s, a number of professional wrestlers have been named The Moondogs, taking inspiration from the artist.

Personal life
Moondog was married briefly to Virginia Sledge in 1943, but the marriage was dissolved in 1947.

In 1952, he married Mary Suzuko Whiteing, a single mother of mixed American-Japanese heritage. She had grown up in Japan then came to New York with her mother that year. Suzuko and Hardin met on the streets of New York. According to his daughter, June, Mary was struck by his appearance and moved by his music; Moondog was stirred by the sound of her voice.

The June 4, 1952 issue of the New York Journal-American features a photograph of Moondog playing a flute on a rooftop while Mary looks on endearingly: the caption indicates it is a "skyline serenade" to a "June bride". The marriage lasted eight years. They had one daughter, June Hardin, born June 1, 1953. On the Prestige (1956) Moondog LP, Moondog's wife, Suzuko is credited in "Lullaby", singing to June, their six-week-old daughter. Hardin later fathered another daughter, Lisa Colins, out of wedlock.

Singles

 * "Snaketime Rhythms (5 Beat) / Snaketime Rhythms (7 Beat)" (1949), SMC
 * "Moondog's Symphony" (1949–1950), SMC
 * "Organ Rounds" (1949–1950), SMC
 * "Oboe Rounds" (1949–1950), SMC
 * "Surf Session" (c. 1953), SMC
 * "Caribea Sextet"/"Oo Debut" (1956), Moondog Records
 * "Stamping Ground Theme" (from the Kralingen Music Festival) (1970), CBS

EPs

 * 1953 Improvisations at a Jazz Concert, Brunswick
 * 1953 Moondog on the Streets of New York, Decca/Mars
 * 1953 Pastoral Suite / Surf Session, SMC
 * 1955 Moondog & His Honking Geese Playing Moondog's Music, Moondog Records

Albums

 * 1953 Moondog and His Friends, Epic
 * 1956 Snaketime Series (not the same as the 1954 LP), Moondog Records
 * 1956 Moondog, Prestige
 * 1956 More Moondog, Prestige
 * 1957 The Story of Moondog, Prestige
 * 1969 Moondog (not the same as the 1956 LP), Columbia
 * 1971 Moondog 2, Columbia (with insert: Round the World of Sound: Moondog Madrigals with scores)
 * 1977 Moondog in Europe, Kopf
 * 1978 H'art Songs, Kopf
 * 1978 Moondog: Instrumental Music by Louis Hardin, Musical Heritage Society
 * 1979 A New Sound of an Old Instrument, Kopf
 * 1981 Facets, Managarm
 * 1986 Bracelli, Kakaphone
 * 1992 Elpmas, Kopf
 * 1994 Sax Pax for a Sax with the London Saxophonic, Kopf/Atlantic
 * 1995 Big Band, Trimba
 * 2005 Bracelli und Moondog, Laska Records

With Julie Andrews and Martyn Green

 * 1957 Songs of Sense and Nonsense - Tell it Again, Angel/Capitol

Compilations

 * 1991 More Moondog/The Story of Moondog, Original Jazz Classics (reissue of Prestige albums listed above)
 * 2001 Moondog/Moondog 2, Beat Goes On (reissue of the two Columbia albums issued above)
 * 2004 The Viking of Sixth Avenue, Honest Jon's
 * 2005 The German Years 1977–1999, ROOF Music
 * 2005 Un hommage à Moondog tribute album, trAce label
 * 2006 Rare Material, ROOF Music
 * 2007 The Viking Of 6th Avenue(disc inside biographical book), Process (ISBN 978-0-9760822-8-6). Reissue, Honest Jon, 2008
 * 2017 The Viking of Sixth Ave., Manimal

Various artist compilations

 * 1954 New York 19 (recorded and edited by Tony Schwartz), Folkways
 * 1954 Music in the Streets (recorded and edited by Tony Schwartz), Folkways
 * 1958 Rosey 4 Blocks (arrangement by Andy Forsythe), Rosey
 * 1970 Fill Your Head With Rock, CBS
 * 1998 The Big Lebowski motion picture soundtrack, Mercury
 * 2000 Miniatures 2, Cherry Red
 * 2006 DJ-Kicks: Henrik Schwarz, K7 Records
 * 2006 The Trip: Curated By Jarvis Cocker and Steve Mackey, Disc 1 Track 19: "Pastoral"
 * 2008 Pineapple Express Motion Picture Sound Track, Track 9 "Birds Lament," Moondog & The London Saxophonic.

Performed by other musicians

 * 1957 Moondog and Suncat Suite by British jazz musician Kenny Graham features one side of interpretations of the work of Moondog
 * 1967 "All Is Loneliness" by Big Brother and the Holding Company, featuring Janis Joplin, on their self-titled first album
 * 1968 "Moon Dog" by Pentangle on Sweet Child
 * 1968 "Spear for Moondog (parts 1 and 2)" by jazz organist Jimmy McGriff on Electric Funk
 * 1970 "Be a Hobo" by The Insect Trust on Hoboken Saturday Night
 * 1978 Canons on the Keys by Paul Jordan, unreleased
 * 1983 Here's to John Wesley Hardin by R. Stevie Moore, unreleased
 * 1985 "Theme and Variations" performed by John Fahey on the album Rain Forests, Oceans and Other Themes
 * 1990 Love Child Plays Moondog, EP, Forced Exposure
 * 1990 "Moondog" by Prefab Sprout on Jordan: The Comeback
 * 1993 "All is Loneliness" by Motorpsycho on Demon Box (album) and Roadwork Vol. 4: Intrepid Skronk
 * 1995 Alphorn of Plenty by Hans Kennel, Hat Art
 * 1997 "Synchrony Nr. 2" by Kronos Quartet
 * 1998 Trees Against the Sky compilation album, SHI-RA-Nui 360°
 * 1998 "Paris" by NRBQ, live, on You Gotta Be Loose and NRBQ: High Noon - A 50-Year Retrospective
 * 1999 "Get a Move On" (structured around samples from "Bird's Lament (In Memory of Charlie Parker)") by Mr. Scruff on Keep It Unreal
 * 2004 Bracelli und Moondog CD Ensemble Bracelli, Germany w Stefan Lakatos. LASKA records
 * 2005 "All Is Loneliness" by Antony and the Johnsons, live
 * 2005 Sidewalk Dances by Joanna MacGregor & Britten Sinfonia, Sound Circus SC010
 * 2006 Moondog Sharp Harp by Xenia Narati, Ars Musici
 * 2007 "Paris" by Jens Lekman, live
 * 2009 "Rabbit Hop" by Hypnotic Brass Ensemble
 * 2009 "New Amsterdam" by Pink Martini on Splendor in the Grass
 * 2010 The Orastorios - Moondog rounds by Stefan Lakatos/Andreas Heuser, Makro
 * 2011 Making Moonshine - Moondog Songs by Moondog Fans by Various Artists, SL Records
 * 2011 Chaconne 1 & Viking 1 by R. Stevie Moore, unreleased
 * 2013 Seeds of Immortality Spirit of Moondog w Stefan Lakatos. Moondog music for saxophones.
 * 2013 tRío lucas - homage to Moondog in the introduction of the song desintegración de la antimateria by tRío lucas
 * 2013 Moondog Mask by Hobocombo
 * 2014 Perpetual Motion (A Celebration of Moondog) by Sylvain Rifflet & Jon Irabagon
 * 2015 Beyond Horizons Moondog Piano/Percussion by Mariam Tonoyan and Stefan Lakatos and friends. CD Moondogscorner.de/Rockwerk records
 * 2015 Cabaret Contemporain Plays Moondog by Cabaret Contemporain
 * 2016 A Tribute To Moondog by Condor Gruppe (2016) on Condor Men Records – Format: Vinyl, LP, Mini-Album
 * 2017 New Sound by Ensemble Minisym (2017) on Association Bongo Joe Records (Genève) – Format : Vinyl, CD, LP
 * 2018 Moondog by Katia Labèque & Triple Sun
 * 2018 Erk-Moondog Ensemble Bracelli w Stefan Lakatos. CD Moondogscorner.de/Rockwerk records Germany
 * 2019 The Witch of Endor by Kreiz Breizh Akademi #7 "Hed" (Brittany, France)
 * 2019 Moondog Piano Trimba by Dominique Ponty and Stefan Lakatos, SHIIN Records CD (France)
 * 2019 Moondog - The Stockholm 1981 Recordings Moondog & Stefan Lakatos w friends. Vinyl LP brus&knaster KNASTER 048. Sweden
 * 2022 Seahorse by Moondog. Album: Lost & Found by Sean Shibe
 * 2022 Pastoral by Moondog. Album: Lost & Found by Sean Shibe
 * 2022 High on a Rocky Ledge (Second Movement) by Moondog. Album: Lost & Found by Sean Shibe
 * 2023 New Amsterdam by Moondog. Album: An American Rhapsody by Calefax Reed Quintet. Music video: https://www.youtube.com/watch?v=OTt8QFvfYPY
 * 2023 Songs and Symphoniques: The Music of Moondog by Kronos Quartet and Ghost Train Orchestra

license: Creative Commons - Attribution Share-Alike - https://creativecommons.org/licenses/by-sa/4.0/

title: Moondog


text:
Sarvadaman Chowla

Sarvadaman D. S. Chowla (22 October 1907 – 10 December 1995) was an Indian American mathematician, specializing in number theory.

Early life
He was born in London, since his father, Gopal Chowla, a professor of mathematics in Lahore, was then studying in Cambridge. His family returned to India, where he received his master's degree in 1928 from the Government College in Lahore. In 1931 he received his doctorate from the University of Cambridge, where he studied under J. E. Littlewood.

Career and awards
Chowla then returned to India, where he taught at several universities, becoming head of mathematics at Government College, Lahore in 1936. During the difficulties arising from the partition of India in 1947, he left for the United States. There he visited the Institute for Advanced Study until the fall of 1949, then taught at the University of Kansas in Lawrence until moving to the University of Colorado in 1952. He moved to Penn State in 1963 as a research professor, where he remained until his retirement in 1976. He was a member of the Indian National Science Academy.

Among his contributions are a number of results which bear his name. These include the Bruck–Ryser–Chowla theorem, the Ankeny–Artin–Chowla congruence, the Chowla–Mordell theorem, and the Chowla–Selberg formula, and the Mian–Chowla sequence.

title: Sarvadaman Chowla


text:
Talk:List of lakes

I note this list is by continent and appears to make no provision for lakes on islands that are not continents. Also as Oceania is not a continent but a region of continental islands, I have subdivided the New Zealand portion of Oceania, on the assumption that the other lakes are in Australia. It would be helpful if the country or countries around each lake were also indicated as this would assist locating the lake. -- kiwiinapanic 00:34, 9 Aug 2003 (UTC)

If you include man-made lakes from dams, please add Lake Karapiro to the North Island of New Zealand, and Lake Oberon to Australia (in the state of New South Wales). Actually there's also a natural? Lake Oberon in Tasmania, Australia, containing the endangered Pedder galaxias (Galaxias pedderensis) from Lake Pedder.
 * zig 01:16, 7 Feb 2004 (UTC)

It would probably be better to also arrange the U.S. lakes by state before the list gets too unwieldy. --Our Bold Hero 18:29, 30 May 2005 (UTC)

Organized the lakes with their states...
I organized the lakes with their states, but should each state be separated into their own sections or is the list fine? It wouldn't be a hard thing to do (especially since I've done all the work of organizing the states). All that needs to be done is a simple surrounding the states with a few equal signs and that'd be that. DannyMac

Does This Include Underground Lakes?
Scallop 19:08, 22 March 2006 (UTC)

Reorganization
Grouped lakes by country and, for the U.S., by state. Hopefully I didn't step on anyone's toes adding those plusses. I've linked to "main articles" listing lakes for individual areas whenever possible, but if I've missed one (or there should be one) add it in. I also thought it would be wise to add something about "major or important" at the top to keep this under control. Now should we cull some of these dead links (specifically the U.S. state ones) or leave them be? --Our Bold Hero 02:22, 3 May 2006 (UTC)

Greek lakes
I removed a list of Greek lakes from the middle of the African section - this list seems to be identical with List of lakes in Greece which is linked from the European section, so no information was lost. It looks as if the major Greek lakes are listed in this article already (under Europe!). Walkerma 02:36, 24 August 2006 (UTC)

lake ronkonkama
there is a lake in long island new york called "lake ronkonkoma" shouldn't that be added?-hotspot

US lakes
Since the List of US Lakes was taking up a third of the article and making it too unwieldy, I've moved them off into a new article List of lakes in the United States. I'll make that a List of Lists page and eventually pull each state's lakes into a page of it's own (and probably tabulate it). I'd like to keep a few US lakes on the List of lakes page as the most notable (biggest, deepest, longest etc), but my US geography knowledge is restricted to the inside of LAX so some assitance in that respect would be appreciated. Malathos 06:28, 22 August 2007 (UTC)

Quick note
I went through and cleaned up/removed the lists from the countries that have their own article, keeping in place the link to that main list. This is similar to what we did with the List of castles and keeps the list organized to avoid a long, unnecessarily detailed article. Rarelibra (talk) 13:58, 18 August 2008 (UTC)

Wheres African Lakes
What happened to the section for African lakes??? —Preceding unsigned comment added by 71.182.138.162 (talk) 01:19, 20 June 2009 (UTC)

Vandalism
Why would the List of Lakes page be vandalized so many times? —Preceding unsigned comment added by ABickerstaff (talk • contribs) 18:19, 5 May 2010 (UTC)

Clarifying Scope of List of lakes and format
The scope of this article according to WP:Lakes is "major" lakes, but doesn't define what classifies a lake as a major lake or the context in which "major" is considered. To bring some clarification to the criteria for inclusion. Level 1 listing - bullet point and reason for listing Level 2 listing - no bullet point - convert to section and description like seen in Caspian Sea, Lake Baikal, and Aral Sea of International lakes of Asia
 * 1) I propose the scope of "major" to be per sovereign state, States with limited recognition, Dependencies and other territories as listed in the "Lakes of Africa, Lakes of Asia, Lakes of Europe, etc" nav boxes at the end of the article, Antarctica to provide emphasis on a balanced representation of the major lakes of each region. If there is a case there are no lakes in a region that should be stated in the section as it is of equal value.
 * 2) Defining what is a "major" lake - largest area of water, deepest, volume. Aim for one of each and the other two could be significant notability (depth of news coverage/historic events, research focus and citations). The listed lakes should also have high or top rating in WP Lakes (which a request for reassessment with reason of which criteria it meets should be noted in the reassessment request.). Those not making the top lakes should appear in the List of lakes for the country or lower list of a subregion meeting the inclusion criteria.
 * 3) Limit to number of "major" lakes - due to the potential length we could limit this top level list to 5 "major" lakes per region.
 * 4) Phases of lake listing maturity:

These are my first thoughts on how to make the inclusion criteria clear and when to put a on a sublist. Obviously if the top 5 have been reached then staring a section on this talk page would help bring to consensus what should be included. Wolfgang8741 says: If not you, then who? (talk) 07:03, 26 June 2020 (UTC)

English
Lake name 2400:1A00:B1C0:EA40:5976:B013:9493:9D17 (talk) 14:24, 10 October 2022 (UTC)

title: Talk:List of lakes