Multiple myeloma

Last updated

Multiple myeloma
Other namesPlasma cell myeloma, myelomatosis, Kahler's disease, myeloma [1]
Multiple myeloma (1) MG stain.jpg
Bone marrow sample from a patient with multiple myeloma
Specialty Hematology and oncology
Symptoms Bone pain, fatigue [2] : 653 
Complications Amyloidosis, kidney problems, bone fractures, hyperviscosity syndrome, infections, anemia [3] [2] : 653 
Usual onsetAround 60
DurationLong term [3]
CausesUnknown [4]
Risk factors Obesity [5]
Diagnostic method Blood or urine tests, bone marrow biopsy, medical imaging [6]
Treatment Steroids, chemotherapy, thalidomide, stem cell transplant, bisphosphonates, radiation therapy [3] [6]
Prognosis Five-year survival rate 54% / life expectancy 6 years (USA) [7]
Frequency488,200 (affected during 2015) [8]
Deaths101,100 (2015) [9]

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. [6] Often, no symptoms are noticed initially. [10] As it progresses, bone pain, anemia, renal insufficiency, and infections may occur. [10] Complications may include hypercalcemia and amyloidosis. [3]

Contents

The cause of multiple myeloma is unknown. [4] Risk factors include obesity, radiation exposure, family history, age and certain chemicals. [5] [11] [12] There is an increased risk of multiple myeloma in certain occupations. [13] This is due to the occupational exposure to aromatic hydrocarbon solvents having a role in causation of multiple myeloma. [14] 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). [15]

In MM, the abnormal plasma cells produce abnormal antibodies, which can cause kidney problems and overly thick blood. [10] The plasma cells can also form a mass in the bone marrow or soft tissue. [10] When one tumor is present, it is called a plasmacytoma; more than one is called multiple myeloma. [10] 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. [6] Another common finding is high blood calcium levels. [6]

Multiple myeloma is considered treatable, but generally incurable. [3] Remissions may be brought about with steroids, chemotherapy, targeted therapy, and stem cell transplant. [3] Bisphosphonates and radiation therapy are sometimes used to reduce pain from bone lesions. [3] [6] Recently, new approaches utilizing CAR-T cell therapy have been included in the treatment regimes. [16]

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. [17] In 2020, there were an estimated 170,405 people living with myeloma in the U.S. [18]

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. [18] People newly diagnosed with the disease now have a better outlook, due to improved treatments. [19]

The disease usually occurs around the age of 60 and is more common in men than women. [6] It is uncommon before the age of 40. [6] The word myeloma is from Greek myelo- 'marrow' and -oma 'tumor'. [20]

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: [21] [2] [22]

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 the CRAB criteria appears, thereby making more people eligible for treatment with myeloma drugs earlier. [22]

Bone pain

Illustration showing the most common site of bone lesions in vertebrae Blausen 0656 MultipleMyeloma.png
Illustration showing the most common site of bone lesions in vertebrae

Bone pain affects almost 70% of people with multiple myeloma and is one of the most common symptoms. [2] : 653  [23] 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. [24]

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. [25]

Impaired kidney function

Impaired kidney function may develop, either acutely or chronically, and with any degree of severity. [26] [27] 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. [28] [29]

Light chains produce myriad effects that can manifest as the Fanconi syndrome (type II kidney tubular acidosis). [28]

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. [30] 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. [31]

Infections (and "adverse events" for all diseases) are graded by a standardized scale. [32] With some myeloma drug therapies, over 30% of people experience a "Grade 3" or higher infection (many people experience multiple such infections), [33] calling for intervention at least by antibiotics. [32] Of people who die within 6 months of their myeloma diagnosis, between 20% and 50% die from collateral infections. [30]

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. [34] 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. [34] When the measure of effective antibodies drops below a threshold (a condition termed hypogammaglobulinemia), [35] supplemental immunoglobulins may be provided by periodic infusions to reduce the risk of collateral infections. [33]

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.[ citation needed ]

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.[ citation needed ]

Mouth

The initial symptoms may involve pain, numbness, swelling, expansion of the jaw, tooth mobility, and radiolucency. [36] 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. [37]

Cause

The cause of multiple myeloma is generally unknown. [4]

Risk factors

Studies have reported a familial predisposition to myeloma. [42] [43] 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. [42]

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. [14] 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. [44] 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. [13] 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. [14] [13]

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%. [14] The time from exposure to diagnosis was studied, and diagnosis after exposure lagged at least 20 years. [14] When exposure to one chemical was identified, there was usually exposure to another hydrocarbon solvent identified. [14] Multiple myeloma affects more men, older adults, and African Americans. These populations also have higher exposure frequencies than their female counterparts. [14]

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. [45] 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. [46] Tissues involved in EBV+ disease typically show foci of EBV+ cells with the appearance of rapidly proliferating immature or poorly differentiated plasma cells. [46] The cells express products of EBV genes such as EBER1 and EBER2. [47] 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. [48] 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. [47]

Pathophysiology

Plasmablast, Wright stain, in a case of multiple myeloma of plasmablastic type. Plasmablast, Wright stain.png
Plasmablast, Wright stain, in a case of multiple myeloma of plasmablastic type.

B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surfaces (cell surface antigens). When they are activated to secrete antibodies, they are known as plasma cells. [49]

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. [50]

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.[ citation needed ]

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 [51] ) 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. [52] 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 [53] (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.[ citation needed ]

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. [54] 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. [55] 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. [56]

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). [57] [58] 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. [59]

Genetics

Genetic abnormalities 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). [60] 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. [61]

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. [62]

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. [63]

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. [39] [64] [65] 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. [39] [40]

Overall, some 2–4% of multiple myeloma cases eventually progress to plasma cell leukemia. [64]

Diagnosis

Blood tests

Serum protein electropherogram showing a paraprotein (peak in the gamma zone) in a person with multiple myeloma Monoclonal gammopathy Multiple Myeloma.png
Serum protein electropherogram showing a paraprotein (peak in the gamma zone) in a person with multiple myeloma

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. [66]

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. [67]

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. [68]

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. [69]

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. [70]

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. [21] 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.[ citation needed ]

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:

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. [73]

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. [74] 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. [75]

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. [76] Overall, the radiodensity of myeloma is between −30 and 120 Hounsfield units (HU). [77] 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 [21] agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma, and MGUS, which was subsequently updated in 2009: [78]

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. [70] [79] 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. [70] [79] 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. [70] 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. [79]

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. [80] The revised ISS (R-ISS) was published in 2015 and incorporates cytogenetics and lactate dehydrogenase (LDH). [81] : 1730–1  [82] [83] : 732–3 

Prevention

The risk of multiple myeloma can be reduced slightly by maintaining a normal body weight. [84]

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). [85]

While triplet therapies were the standard of care for many years, current practice more commonly applies quadruplets of drugs. [85] 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). [86] (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. [87] [88] )

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. [89] 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, [90] ASCENT [91] and Immuno-PRISM [92] 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, [93] as it essentially resets aspects of the immune system and requires redevelopment of natural defenses, such as by administering childhood vaccines. [94]

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. [95] 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). [95] [96]

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. [97] Presently, however, such therapy is FDA-approved only for patients in later stages of the disease, and is available only at certain medical centers. [98]

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. [99] Another BITE drug,Talquetamab, is under study; others are in the pipeline. [100] (Ongoing clinical trials are investigating BITE therapy for smoldering and newly diagnosed patients. [92] )

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. [101] 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, [102] the American Society of Clinical Oncology (ASCO) Conference, [103] the IMF IMWG Summit, and the European Hematology Association (EHA) Annual Conference. [104]

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. [105] Treatment for multiple myeloma is focused on decreasing the clonal plasma cell population and consequently decrease the symptoms of disease.

Chemotherapy

Initial

The preferred treatment for those under the age of 65 is high-dose chemotherapy, commonly with bortezomib-based regimens, and lenalidomide–dexamethasone, [106] to be followed by a stem cell transplant. A 2016 study concluded that stem cell transplant is the preferred treatment of multiple myeloma. [107] There are two types of stem cell transplants to treat multiple myeloma. [108] 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). [51] 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. [109] [110] 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 as of 2008. [111]

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. [112] Further clinical studies are required to determine the potential harms of these drugs and the effect on the person's quality of life. [112] 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." [113] 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. [114]

Treatment of related hyperviscosity syndrome may be required to prevent neurologic symptoms or kidney failure. [115] [116]

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. [117] A 2012 clinical trial showed that people with intermediate- and high-risk disease benefit from a bortezomib-based maintenance regimen. [118]

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. [81] Relapse within the first 18 months of diagnosis is considered as functional high-risk multiple myeloma. [81] 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, [119] and new treatments are under development.[ medical citation needed ]

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. [120] [121]
  • 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 [122]
  • 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 [123]
  • 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 [124]
  • 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. [125] [126]
  • ixazomib: an orally available proteasome inhibitor indicated in combination with lenalidomide and dexamethasone in people who have received at least one prior therapy [127]
  • 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 [128]
  • 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 [129]
  • 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 [130]

Talquetamab (Talvey) and elranatamab (Elrexfio) were approved for medical use in the United States in August 2023. [131] [132] [133] [134]

Stem cell transplant

Stem cell transplant can be used to treat multiple myeloma. [3] 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. [135] 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. [135] The evidence suggests that MSCs for prophylactic reason reduce the incidence of chronic GvHD. [135]

Bone marrow transplant

Plerixafor (Mozobil) was approved for medical use in the United States in 2008. [136]

Motixafortide (Aphexda) was approved for medical use in the United States in September 2023. [137]

Gene therapy

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.[ citation needed ] 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). [139] [140]

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. [141] These exercises may result in a slight reduction in depression. [141] Furthermore, aerobic physical exercises probably reduce fatigue. The evidence is very uncertain about the effect and serious adverse events [141]

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. [142] [143]

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. [144] [145]

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, such as jaw pain, loose tooth, or mucosal swelling, early referral to an oral surgeon is recommended. Dental extractions should be avoided during the active period of treatment, and the affected tooth should be treated with nonsurgical root canal therapies instead. [146]

Prognosis

Overall the 5-year survival rate is around 54% in the United States. [147] 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. [148]

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. [80] The median age at diagnosis is 69 years. [147]

Genetic testing

SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel. [149]

The following table outlines the prognostic effect of various genetic findings in multiple myeloma, with chromosomal translocations designated t, followed by standard nomenclature thereof: [150]

Genetic abnormalityGene(s)Incidence among myelomasPrognostic impact
Deletion/isolated monosomy 13RB1, DIS345–50%Effect on prognosis is unclear
Trisomies 40–50%Median overall survival: 7–10 years
1q21 gain, as an addition to another abnormalityCKS1B, ANP32E35–40%Median overall survival: 5 years
t(11;14)(q13;q32) IgH and CCND115–20%Median overall survival: 7–10 years
Trisomies plus any one IgH translocation15%May neutralize high risk IgH and del 17p translocations
Hypodiploidy 13–20%Unfavorable prognosis, high risk of progression
t(4:14)(p16;q32)IgH and FGFR3/MMSET10–15%Median overall survival: 5 years
17p deletion, as an addition to another abnormalityTP5310%Median overall survival: 5 years
t(14;16)IgH and C-MAF2–5%Median overall survival: 5 years
t(6;14)(p21;q32)IgH and CCND32%Median overall survival: 7–10 years
t(14;20)(q32;q12)MAFB1%Median overall survival: 5 years

Epidemiology

Deaths from lymphomas and multiple myeloma per million persons in 2012 .mw-parser-output .div-col{margin-top:0.3em;column-width:30em}.mw-parser-output .div-col-small{font-size:90%}.mw-parser-output .div-col-rules{column-rule:1px solid #aaa}.mw-parser-output .div-col dl,.mw-parser-output .div-col ol,.mw-parser-output .div-col ul{margin-top:0}.mw-parser-output .div-col li,.mw-parser-output .div-col dd{page-break-inside:avoid;break-inside:avoid-column} .mw-parser-output .legend{page-break-inside:avoid;break-inside:avoid-column}.mw-parser-output .legend-color{display:inline-block;min-width:1.25em;height:1.25em;line-height:1.25;margin:1px 0;text-align:center;border:1px solid black;background-color:transparent;color:black}.mw-parser-output .legend-text{} 0-13 14-18 19-22 23-28 29-34 35-42 43-57 58-88 89-121 122-184 Lymphomas, multiple myeloma world map-Deaths per million persons-WHO2012.svg
Deaths from lymphomas and multiple myeloma per million persons in 2012
  0–13
  14–18
  19–22
  23–28
  29–34
  35–42
  43–57
  58–88
  89–121
  122–184
Age-standardized death from lymphomas and multiple myeloma per 100,000 inhabitants in 2004. no data less than 1.8 1.8-3.6 3.6-5.4 5.4-7.2 7.2-9 9-10.8 10.8-12.6 12.6-14.4 14.4-16.2 16.2-18 18-19.8 more than 19.8 Lymphomas, multiple myeloma world map - Death - WHO2004.svg
Age-standardized death from lymphomas and multiple myeloma per 100,000 inhabitants in 2004.
  no data
  less than 1.8
  1.8–3.6
  3.6–5.4
  5.4–7.2
  7.2–9
  9–10.8
  10.8–12.6
  12.6–14.4
  14.4–16.2
  16.2–18
  18–19.8
  more than 19.8

Globally, multiple myeloma affected 488,000 people and resulted in 101,100 deaths in 2015. [8] [9] This is up from 49,000 in 1990. [152]

United Kingdom

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. [153]

United States

In the United States in 2016, an estimated 30,330 new cases and 12,650 deaths were reported. [7] 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. [154] It represents about 1.8% of all new cancers and 2.1% of all cancer deaths. [7]

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. [155] Among African Americans, myeloma is one of the top-10 causes of cancer death. [156]

Other animals

Multiple myeloma has been diagnosed in dogs, [157] cats, and horses. [158]

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. [159] 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. [159] In rare cases the globulin elevation is IgM, which is referred to as Waldenström's macroglobulinemia. [160] 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. [159] The disease eventually recurs, becoming resistant to available therapies.[ medical citation needed ] The complications of kidney failure, sepsis, or pain can lead to an animal's death, frequently by euthanasia.[ medical citation needed ]

See also

Related Research Articles

<span class="mw-page-title-main">POEMS syndrome</span> Paraneoplastic syndrome

POEMS syndrome is a rare paraneoplastic syndrome caused by a clone of aberrant plasma cells. The name POEMS is an acronym for some of the disease's major signs and symptoms, as is PEP.

<span class="mw-page-title-main">Lenalidomide</span> Pair of enantiomers

Lenalidomide, sold under the brand name Revlimid among others, is a medication used to treat multiple myeloma, smoldering myeloma, and myelodysplastic syndromes (MDS). For multiple myeloma, it is a first line treatment, and is given with dexamethasone. It is taken by mouth.

<span class="mw-page-title-main">Bortezomib</span> Chemical compound

Bortezomib, sold under the brand name Velcade among others, is an anti-cancer medication used to treat multiple myeloma and mantle cell lymphoma. This includes multiple myeloma in those who have and have not previously received treatment. It is generally used together with other medications. It is given by injection.

<span class="mw-page-title-main">Monoclonal gammopathy of undetermined significance</span> Medical condition

Monoclonal gammopathy of undetermined significance (MGUS) is a plasma cell dyscrasia in which plasma cells or other types of antibody-producing cells secrete a myeloma protein, i.e. an abnormal antibody, into the blood; this abnormal protein is usually found during standard laboratory blood or urine tests. MGUS resembles multiple myeloma and similar diseases, but the levels of antibodies are lower, the number of plasma cells in the bone marrow is lower, and it rarely has symptoms or major problems. However, since MGUS can lead to multiple myeloma, which develops at the rate of about 1.5% a year, or other symptomatic conditions, yearly monitoring is recommended.

Waldenström macroglobulinemia is a type of cancer affecting two types of B cells: lymphoplasmacytoid cells and plasma cells. Both cell types are white blood cells. It is characterized by having high levels of a circulating antibody, immunoglobulin M (IgM), which is made and secreted by the cells involved in the disease. Waldenström macroglobulinemia is an "indolent lymphoma" and a type of lymphoproliferative disease which shares clinical characteristics with the indolent non-Hodgkin lymphomas. It is commonly classified as a form of plasma cell dyscrasia, similar to other plasma cell dyscrasias that, for example, lead to multiple myeloma. Waldenström macroglobulinemia is commonly preceded by two clinically asymptomatic but progressively more pre-malignant phases, IgM monoclonal gammopathy of undetermined significance and smoldering Waldenström macroglobulinemia. The Waldenström macroglobulinemia spectrum of dysplasias differs from other spectrums of plasma cell dyscrasias in that it involves not only aberrant plasma cells but also aberrant lymphoplasmacytoid cells and that it involves IgM while other plasma dyscrasias involve other antibody isoforms.

<span class="mw-page-title-main">Plasmacytoma</span> Growth of a plasma cell tumour within soft tissue or the axial skeleton

Plasmacytoma is a plasma cell dyscrasia in which a plasma cell tumour grows within soft tissue or within the axial skeleton.

In hematology, plasma cell dyscrasias are a spectrum of progressively more severe monoclonal gammopathies in which a clone or multiple clones of pre-malignant or malignant plasma cells over-produce and secrete into the blood stream a myeloma protein, i.e. an abnormal monoclonal antibody or portion thereof. The exception to this rule is the disorder termed non-secretory multiple myeloma; this disorder is a form of plasma cell dyscrasia in which no myeloma protein is detected in serum or urine of individuals who have clear evidence of an increase in clonal bone marrow plasma cells and/or evidence of clonal plasma cell-mediated tissue injury. Here, a clone of plasma cells refers to group of plasma cells that are abnormal in that they have an identical genetic identity and therefore are descendants of a single genetically distinct ancestor cell.

Amyloid light-chain (AL) amyloidosis, also known as primary amyloidosis, is the most common form of systemic amyloidosis. The disease is caused when a person's antibody-producing cells do not function properly and produce abnormal protein fibers made of components of antibodies called light chains. These light chains come together to form amyloid deposits which can cause serious damage to different organs. An abnormal light chain in urine is known as Bence Jones protein.

Elotuzumab, sold under the brand name Empliciti, is a humanized IgG1 monoclonal antibody medication used in combination with lenalidomide and dexamethasone, for adults that have received 1 to 3 prior therapies for the treatment of multiple myeloma. It is also indicated for adult patients in combination with pomalidomide and dexamethasone, who have received 2 prior therapies including lenalidomide and a protease inhibitor. Administration of elotuzumab is done intravenously. Each intravenous injection of elotuzumab should be premedicated with dexamethasone, diphenhydramine, ranitidine and acetaminophen. It is being developed by Bristol Myers Squibb and AbbVie.

<span class="mw-page-title-main">Plasma cell leukemia</span> Medical condition

Plasma cell leukemia (PCL) is a plasma cell dyscrasia, i.e. a disease involving the malignant degeneration of a subtype of white blood cells called plasma cells. It is the terminal stage and most aggressive form of these dyscrasias, constituting 2% to 4% of all cases of plasma cell malignancies. PCL may present as primary plasma cell leukemia, i.e. in patients without prior history of a plasma cell dyscrasia or as secondary plasma cell dyscrasia, i.e. in patients previously diagnosed with a history of its predecessor dyscrasia, multiple myeloma. The two forms of PCL appear to be at least partially distinct from each other. In all cases, however, PCL is an extremely serious, life-threatening, and therapeutically challenging disease.

<span class="mw-page-title-main">Carfilzomib</span> Chemical compound

Carfilzomib, sold under the brand name Kyprolis, is an anti-cancer medication acting as a selective proteasome inhibitor. Chemically, it is a tetrapeptide epoxyketone and an analog of epoxomicin. It was developed by Onyx Pharmaceuticals.

<span class="mw-page-title-main">Daratumumab</span> Monoclonal antibody

Daratumumab, sold under the brand name Darzalex among others, is an anti-cancer monoclonal antibody medication. It binds to CD38, which is overexpressed in multiple myeloma cells. Daratumumab was originally developed by Genmab, but it is now being jointly developed by Genmab along with the Johnson & Johnson subsidiary Janssen Biotech, which acquired worldwide commercialization rights to the drug from Genmab.

Smouldering myeloma is a disease classified as intermediate in a spectrum of step-wise progressive diseases termed plasma cell dyscrasias. In this spectrum of diseases, a clone of plasma cells secreting monoclonal paraprotein causes the relatively benign disease of monoclonal gammopathy of undetermined significance. This clone proliferates and may slowly evolve into more aggressive sub-clones that cause smouldering multiple myeloma. Further and more rapid evolution causes the overtly malignant stage of multiple myeloma and can subsequently lead to the extremely malignant stage of secondary plasma cell leukemia. Thus, some patients with smouldering myeloma progress to multiple myeloma and plasma cell leukemia. Smouldering myeloma, however, is not a malignant disease. It is characterised as a pre-malignant disease that lacks symptoms but is associated with bone marrow biopsy showing the presence of an abnormal number of clonal myeloma cells, blood and/or urine containing a myeloma protein, and a significant risk of developing into a malignant disease.

MDX-1097 is a monoclonal antibody therapy that in 2023 has been assessed in a Phase IIb clinical trial in conjunction with lenalidomide and dexamethasone as a treatment for multiple myeloma, a type of white blood cell cancer. MDX-1097 was originally developed by scientists at Immune System Therapeutics Ltd. In 2015, Haemalogix Ltd acquired the rights to MDX-1097 and are taking it through clinical testing.

<span class="mw-page-title-main">Isatuximab</span> Monoclonal antibody

Isatuximab, sold under the brand name Sarclisa, is a monoclonal antibody (mAb) medication for the treatment of multiple myeloma.

<span class="mw-page-title-main">Ixazomib</span> Chemical compound

Ixazomib is a drug for the treatment of multiple myeloma, a type of white blood cell cancer, in combination with other drugs. It is taken by mouth in the form of capsules.

<span class="mw-page-title-main">Osteolytic lesion</span> Softened section of a bone

An osteolytic lesion is a softened section of a patient's bone formed as a symptom of specific diseases, including breast cancer and multiple myeloma. This softened area appears as a hole on X-ray scans due to decreased bone density, although many other diseases are associated with this symptom. Osteolytic lesions can cause pain, increased risk of bone fracture, and spinal cord compression. These lesions can be treated using biophosphonates or radiation, though new solutions are being tested in clinical trials.

<span class="mw-page-title-main">Selinexor</span> Anti-cancer drug

Selinexor sold under the brand name Xpovio among others, is a selective inhibitor of nuclear export used as an anti-cancer medication. It works by blocking the action of exportin 1 and thus blocking the transport of several proteins involved in cancer-cell growth from the cell nucleus to the cytoplasm, which ultimately arrests the cell cycle and leads to apoptosis. It is the first drug with this mechanism of action.

<span class="mw-page-title-main">Serum B-cell maturation antigen</span> Cleaved form of B-cell maturation antigen

Serum B-cell maturation antigen (sBCMA) is the cleaved form of B-cell maturation antigen (BCMA), found at low levels in the serum of normal patients and generally elevated in patients with multiple myeloma (MM). Changes in sBCMA levels have been found to correlate with a MM patient’s clinical status in response to treatment.

Monoclonal gammopathy of renal significance (MGRS) are a group of kidney disorders that present with kidney damage due to nephrotoxic monoclonal immunoglobulins secreted by clonal plasma cells or B cells. By definition, people with MGRS do not meet criteria for multiple myeloma or other hematologic malignancies. The term MGRS was introduced in 2012 by the International Kidney and Monoclonal Gammopathy Research Group (IKMG). MGRS is associated with monoclonal gammopathy of undetermined significance (MGUS). People with MGUS have a monoclonal gammopathy but does not meet the criteria for the clonal burden nor the presence of end organ damage seen in hematologic malignancies. In a population based study based on the NHANES III health survey; 6% of patients with MGUS were subsequently classified as having MGRS. The prevalence and incidence of MGRS in the general population or in specific populations is not known but it is more prevalent in those over the age of 50 as there is a monoclonal protein (M-protein) present in 3% of those 50 and years older and 5% of those 70 years and older, placing those 50 and older at increased risk of MGRS.

References

  1. ↑ "Myeloma Canada | What is Multiple Myeloma?". www.myelomacanada.ca. Archived from the original on 13 May 2020. Retrieved 17 April 2020.
  2. 1 2 3 4 Rajkumar SV (2018). "Multiple Myeloma". In Hensley ML, Milowsky MI, Rajkumar SV, Schuetze SM (eds.). ASCO-SEP : Medical Oncology Self-Evaluation Program (7th ed.). Alexandria, VA: American Society of Clinical Oncology. ISBN   978-0-9983747-4-1. OCLC   1080368315.
  3. 1 2 3 4 5 6 7 8 "Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment (PDQ®)–Health Professional Version". NCI. 29 July 2016. Archived from the original on 4 July 2016. Retrieved 8 August 2016.
  4. 1 2 3 World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 5.13. ISBN   978-92-832-0429-9.
  5. 1 2 World Cancer Report 2014. World Health Organization. 2014. pp. Chapter 2.3 and 2.6. ISBN   978-92-832-0429-9.
  6. 1 2 3 4 5 6 7 8 Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC (July 2009). "Multiple myeloma". Lancet. 374 (9686): 324–339. doi:10.1016/S0140-6736(09)60221-X. PMID   19541364. S2CID   12906881.
  7. 1 2 3 "SEER Stat Fact Sheets: Myeloma". NCI Surveillance, Epidemiology, and End Results Program. Archived from the original on 27 July 2016. Retrieved 8 August 2016.
  8. 1 2 Vos T, et al. (October 2016). "Global, regional, and national incidence, prevalence, and years lived with disability for 310 diseases and injuries, 1990-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1545–1602. doi:10.1016/S0140-6736(16)31678-6. PMC   5055577 . PMID   27733282.
  9. 1 2 Wang H, et al. (October 2016). "Global, regional, and national life expectancy, all-cause mortality, and cause-specific mortality for 249 causes of death, 1980-2015: a systematic analysis for the Global Burden of Disease Study 2015". Lancet. 388 (10053): 1459–1544. doi:10.1016/s0140-6736(16)31012-1. PMC   5388903 . PMID   27733281.
  10. 1 2 3 4 5 "Plasma Cell Neoplasms (Including Multiple Myeloma)—Patient Version". NCI. 1 January 1980. Archived from the original on 27 July 2016. Retrieved 8 August 2016.
  11. ↑ "Plasma Cell Neoplasms (Including Multiple Myeloma) Treatment". National Cancer Institute. 1 January 1980. Archived from the original on 9 January 2021. Retrieved 28 November 2017.
  12. ↑ Ferri FF (2013). Ferri's Clinical Advisor 2014 E-Book: 5 Books in 1. Elsevier Health Sciences. p. 726. ISBN   978-0-323-08431-4. Archived from the original on 18 August 2023. Retrieved 23 August 2020.
  13. 1 2 3 Georgakopoulou R, Fiste O, Sergentanis TN, Andrikopoulou A, Zagouri F, Gavriatopoulou M, et al. (September 2021). "Occupational Exposure and Multiple Myeloma Risk: An Updated Review of Meta-Analyses". Journal of Clinical Medicine. 10 (18): 4179. doi: 10.3390/jcm10184179 . PMC   8469366 . PMID   34575290.
  14. 1 2 3 4 5 6 7 De Roos AJ, Spinelli J, Brown EB, Atanackovic D, Baris D, Bernstein L, et al. (November 2018). "Pooled study of occupational exposure to aromatic hydrocarbon solvents and risk of multiple myeloma". Occupational and Environmental Medicine. 75 (11): 798–806. doi:10.1136/oemed-2018-105154. PMC   9386620 . PMID   30121582.
  15. ↑ van de Donk NW, Mutis T, Poddighe PJ, Lokhorst HM, Zweegman S (May 2016). "Diagnosis, risk stratification and management of monoclonal gammopathy of undetermined significance and smoldering multiple myeloma". International Journal of Laboratory Hematology. 38 (Suppl 1): 110–122. doi: 10.1111/ijlh.12504 . PMID   27161311.
  16. ↑ Martino M, Canale FA, Alati C, Vincelli ID, Moscato T, Porto G, Loteta B, Naso V, Mazza M, Nicolini F, Ghelli Luserna di Rorà A, Simonetti G, Ronconi S, Ceccolini M, Musuraca G (27 May 2021). "CART-Cell Therapy: Recent Advances and New Evidence in Multiple Myeloma". Cancers. 13 (11): 2639. doi: 10.3390/cancers13112639 . ISSN   2072-6694. PMC   8197914 . PMID   34072068.
  17. ↑ "Multiple Myeloma: Statistics". ASCO Cancer.net. March 2023. Archived from the original on 11 June 2023. Retrieved 10 June 2023.
  18. 1 2 "Cancer Stat Facts: Myeloma". National Cancer Institute. Archived from the original on 7 May 2020. Retrieved 10 June 2023.
  19. ↑ "Survival Rates for Multiple Myeloma". American Cancer Society. Archived from the original on 11 June 2023. Retrieved 10 June 2023.
  20. ↑ Diepenbrock NH (2011). Quick Reference to Critical Care. Lippincott Williams & Wilkins. p. 292. ISBN   978-1-60831-464-5. Archived from the original on 21 August 2016.
  21. 1 2 3 International Myeloma Working Group (June 2003). "Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group". British Journal of Haematology. 121 (5): 749–757. doi: 10.1046/j.1365-2141.2003.04355.x . PMID   12780789. S2CID   3195084.
  22. 1 2 "International Myeloma Working Group (IMWG) criteria for the diagnosis of multiple myeloma". International Myeloma Foundation. 26 October 2014. Archived from the original on 7 December 2022. Retrieved 11 June 2023.
  23. ↑ Longo D (2012). Harrison's Principles of Internal Medicine 18th Edition. Mc Graw Hill Medical. p. 938. ISBN   978-0-07-174889-6.
  24. ↑ "Hypercalcemia". The Lecturio Medical Concept Library. Archived from the original on 25 July 2021. Retrieved 11 August 2021.
  25. ↑ Bruns I, Cadeddu RP, Brueckmann I, Fröbel J, Geyh S, Büst S, et al. (September 2012). "Multiple myeloma-related deregulation of bone marrow-derived CD34(+) hematopoietic stem and progenitor cells". Blood. 120 (13): 2620–2630. doi:10.1182/blood-2011-04-347484. PMC   3460684 . PMID   22517906.
  26. ↑ Bladé J, Fernández-Llama P, Bosch F, Montolíu J, Lens XM, Montoto S, et al. (September 1998). "Renal failure in multiple myeloma: presenting features and predictors of outcome in 94 patients from a single institution". Archives of Internal Medicine. 158 (17): 1889–1893. doi: 10.1001/archinte.158.17.1889 . PMID   9759684.
  27. ↑ Knudsen LM, Hippe E, Hjorth M, Holmberg E, Westin J (October 1994). "Renal function in newly diagnosed multiple myeloma--a demographic study of 1353 patients. The Nordic Myeloma Study Group". European Journal of Haematology. 53 (4): 207–212. doi:10.1111/j.1600-0609.1994.tb00190.x. PMID   7957804. S2CID   2861880.
  28. 1 2 Nasr SH, Said SM, Valeri AM, Sethi S, Fidler ME, Cornell LD, et al. (March 2013). "The diagnosis and characteristics of renal heavy-chain and heavy/light-chain amyloidosis and their comparison with renal light-chain amyloidosis". Kidney International. 83 (3): 463–470. doi: 10.1038/ki.2012.414 . PMID   23302715.
  29. ↑ Castillo JJ (December 2016). "Plasma Cell Disorders". Primary Care. 43 (4): 677–691. doi:10.1016/j.pop.2016.07.002. PMID   27866585.
  30. 1 2 Blimark C (January 2015). "Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients". Haematologica. 100 (1): 107–113. doi:10.3324/haematol.2014.107714. PMC   4281323 . PMID   25344526.
  31. ↑ Chapel HM, Lee M (July 1994). "The use of intravenous immune globulin in multiple myeloma". Clinical and Experimental Immunology. 97 (Suppl 1): 21–24. PMC   1550368 . PMID   8033429.
  32. 1 2 "Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0" (PDF). U.S. Dept. of Health and Human Services. 27 November 2017. Archived (PDF) from the original on 19 May 2023. Retrieved 12 June 2023.
  33. 1 2 Lancman G (15 November 2022). "Infections and Severe Hypogammaglobulinemia in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies". Archived from the original on 11 June 2023. Retrieved 11 June 2023.
  34. 1 2 "Diagnosis of multiple myeloma". Canadian Cancer Society. Archived from the original on 11 June 2023. Retrieved 11 June 2023.
  35. ↑ Hargreaves RM, Lea JR, Griffiths H, Faux JA, Holt JM, Reid C, et al. (March 1995). "Immunological factors and risk of infection in plateau phase myeloma". Journal of Clinical Pathology. 48 (3): 260–266. doi:10.1136/jcp.48.3.260. PMC   502468 . PMID   7730490.
  36. ↑ Glick M (January 2015). Glick M (ed.). Burket's oral medicine. PMPH USA. ISBN   978-1-60795-188-9. OCLC   888026338.
  37. ↑ Shah A, Ali A, Latoo S, Ahmad I (June 2010). "Multiple Myeloma presenting as Gingival mass". Journal of Maxillofacial and Oral Surgery. 9 (2): 209–212. doi:10.1007/s12663-010-0050-7. PMC   3244103 . PMID   22190790.
  38. ↑ Landgren O, Kyle RA, Pfeiffer RM, Katzmann JA, Caporaso NE, Hayes RB, et al. (May 2009). "Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study". Blood. 113 (22): 5412–5417. doi:10.1182/blood-2008-12-194241. PMC   2689042 . PMID   19179464.
  39. 1 2 3 Dutta AK, Hewett DR, Fink JL, Grady JP, Zannettino AC (July 2017). "Cutting edge genomics reveal new insights into tumour development, disease progression and therapeutic impacts in multiple myeloma". British Journal of Haematology. 178 (2): 196–208. doi: 10.1111/bjh.14649 . PMID   28466550.
  40. 1 2 Willrich MA, Murray DL, Kyle RA (January 2018). "Laboratory testing for monoclonal gammopathies: Focus on monoclonal gammopathy of undetermined significance and smoldering multiple myeloma". Clinical Biochemistry. 51: 38–47. doi:10.1016/j.clinbiochem.2017.05.001. PMID   28479151.
  41. ↑ Roberts DL, Dive C, Renehan AG (2010). "Biological mechanisms linking obesity and cancer risk: new perspectives". Annual Review of Medicine. 61: 301–316. doi:10.1146/annurev.med.080708.082713. PMID   19824817.
  42. 1 2 Koura DT, Langston AA (August 2013). "Inherited predisposition to multiple myeloma". Therapeutic Advances in Hematology. 4 (4): 291–297. doi:10.1177/2040620713485375. PMC   3734900 . PMID   23926460.
  43. ↑ Schinasi LH, Brown EE, Camp NJ, Wang SS, Hofmann JN, Chiu BC, et al. (October 2016). "Multiple myeloma and family history of lymphohaematopoietic cancers: Results from the International Multiple Myeloma Consortium". British Journal of Haematology. 175 (1): 87–101. doi:10.1111/bjh.14199. PMC   5035512 . PMID   27330041.
  44. ↑ Sergentanis TN, Zagouri F, Tsilimidos G, Tsagianni A, Tseliou M, Dimopoulos MA, Psaltopoulou T (October 2015). "Risk Factors for Multiple Myeloma: A Systematic Review of Meta-Analyses". Clinical Lymphoma, Myeloma & Leukemia. 15 (10): 563–577.e3. doi:10.1016/j.clml.2015.06.003. PMID   26294217.
  45. ↑ Sekiguchi Y, Shimada A, Ichikawa K, Wakabayashi M, Sugimoto K, Ikeda K, et al. (2015). "Epstein-Barr virus-positive multiple myeloma developing after immunosuppressant therapy for rheumatoid arthritis: a case report and review of literature". International Journal of Clinical and Experimental Pathology. 8 (2): 2090–2102. PMC   4396324 . PMID   25973110.
  46. 1 2 Rezk SA, Zhao X, Weiss LM (September 2018). "Epstein-Barr virus (EBV)-associated lymphoid proliferations, a 2018 update". Human Pathology. 79: 18–41. doi:10.1016/j.humpath.2018.05.020. PMID   29885408. S2CID   47010934.
  47. 1 2 Yan J, Wang J, Zhang W, Chen M, Chen J, Liu W (April 2017). "Solitary plasmacytoma associated with Epstein-Barr virus: a clinicopathologic, cytogenetic study and literature review". Annals of Diagnostic Pathology. 27: 1–6. doi:10.1016/j.anndiagpath.2016.09.002. PMID   28325354.
  48. ↑ Dojcinov SD, Fend F, Quintanilla-Martinez L (March 2018). "EBV-Positive Lymphoproliferations of B- T- and NK-Cell Derivation in Non-Immunocompromised Hosts". Pathogens. 7 (1): 28. doi: 10.3390/pathogens7010028 . PMC   5874754 . PMID   29518976.
  49. ↑ Muthusamy N, Caligiuri MA (2021). "Chapter 73: The Structure of Lymphocytes and Plasma Cells". Williams Hematology (10th ed.). McGraw-Hill Education.
  50. ↑ Federico Caligaris-Cappio, Manlio Ferrarini (1997). Human B Cell Populations. Chemical Immunology. Vol. 67. Switzerland: S. Karger AG. p. 105. ISBN   978-3-8055-6460-1. Archived from the original on 27 May 2016.
  51. 1 2 Kyle RA, Rajkumar SV (October 2004). "Multiple myeloma". The New England Journal of Medicine. 351 (18): 1860–1873. doi:10.1056/NEJMra041875. PMC   2265446 . PMID   15509819.
  52. ↑ Spielmann M, Lupiáñez DG, Mundlos S (July 2018). "Structural variation in the 3D genome". Nature Reviews. Genetics. 19 (7): 453–467. doi:10.1038/s41576-018-0007-0. hdl: 21.11116/0000-0003-610A-5 . PMID   29692413. S2CID   22325904.
  53. ↑ Tricot G (January 2000). "New insights into role of microenvironment in multiple myeloma". Lancet. 355 (9200): 248–250. doi:10.1016/S0140-6736(00)00019-2. PMID   10675068. S2CID   41876106.
  54. ↑ Kalushkova A, Nylund P, Párraga AA, Lennartsson A, Jernberg-Wiklund H (8 October 2021). "One Omics Approach Does Not Rule Them All: The Metabolome and the Epigenome Join Forces in Haematological Malignancies". Epigenomes. 5 (4): 22. doi: 10.3390/epigenomes5040022 . ISSN   2075-4655. PMC   8715477 . PMID   34968247.
  55. ↑ Yang T, Liu X, Kumar SK, Jin F, Dai Y (January 2022). "Decoding DNA methylation in epigenetics of multiple myeloma". Blood Reviews. 51: 100872. doi:10.1016/j.blre.2021.100872. PMID   34384602.
  56. ↑ Agirre X, Castellano G, Pascual M, Heath S, Kulis M, Segura V, et al. (April 2015). "Whole-epigenome analysis in multiple myeloma reveals DNA hypermethylation of B cell-specific enhancers". Genome Research. 25 (4): 478–487. doi:10.1101/gr.180240.114. PMC   4381520 . PMID   25644835.
  57. ↑ Kalushkova A, Fryknäs M, Lemaire M, Fristedt C, Agarwal P, Eriksson M, et al. (July 2010). "Polycomb target genes are silenced in multiple myeloma". PLOS ONE. 5 (7): e11483. Bibcode:2010PLoSO...511483K. doi: 10.1371/journal.pone.0011483 . PMC   2901331 . PMID   20634887.
  58. ↑ Agarwal P, Alzrigat M, Párraga AA, Enroth S, Singh U, Ungerstedt J, et al. (February 2016). "Genome-wide profiling of histone H3 lysine 27 and lysine 4 trimethylation in multiple myeloma reveals the importance of Polycomb gene targeting and highlights EZH2 as a potential therapeutic target". Oncotarget. 7 (6): 6809–6823. doi:10.18632/oncotarget.6843. PMC   4872750 . PMID   26755663.
  59. ↑ Croonquist PA, Van Ness B (September 2005). "The polycomb group protein enhancer of zeste homolog 2 (EZH 2) is an oncogene that influences myeloma cell growth and the mutant ras phenotype". Oncogene. 24 (41): 6269–6280. doi: 10.1038/sj.onc.1208771 . PMID   16007202. S2CID   24588617.
  60. ↑ Prideaux SM, Conway O'Brien E, Chevassut TJ (2014). "The Genetic Architecture of Multiple Myeloma". Advances in Hematology. 2014: 1–16. doi: 10.1155/2014/864058 . ISSN   1687-9104. PMC   3996928 . PMID   24803933.
  61. ↑ Weaver CJ, Tariman JD (August 2017). "Multiple Myeloma Genomics: A Systematic Review". Seminars in Oncology Nursing. 33 (3): 237–253. doi:10.1016/j.soncn.2017.05.001. PMID   28729121. S2CID   20956622. Archived from the original on 18 July 2020. Retrieved 13 July 2019.
  62. ↑ Brigle K, Rogers B (August 2017). "Pathobiology and Diagnosis of Multiple Myeloma". Seminars in Oncology Nursing. 33 (3): 225–236. doi:10.1016/j.soncn.2017.05.012. PMID   28688533.
  63. ↑ Rajkumar SV (August 2022). "Multiple Myeloma: 2022 update on Diagnosis, Risk-stratification and Management". American Journal of Hematology. 97 (8): 1086–1107. doi:10.1002/ajh.26590. PMC   9387011 . PMID   35560063.
    Rajkumar SV (September 2024). "Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management". Am J Hematol. 99 (9): 1802–24. doi:10.1002/ajh.27422. PMC   3629949 . PMID   38943315.
  64. 1 2 Fernández de Larrea C, Kyle RA, Durie BG, Ludwig H, Usmani S, Vesole DH, et al. (April 2013). "Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group". Leukemia. 27 (4): 780–791. doi:10.1038/leu.2012.336. PMC   4112539 . PMID   23288300.
  65. ↑ Simeon V, Todoerti K, La Rocca F, Caivano A, Trino S, Lionetti M, et al. (July 2015). "Molecular Classification and Pharmacogenetics of Primary Plasma Cell Leukemia: An Initial Approach toward Precision Medicine". International Journal of Molecular Sciences. 16 (8): 17514–17534. doi: 10.3390/ijms160817514 . PMC   4581206 . PMID   26263974.
  66. ↑ Lyubimova NV, Timofeev YS, Abaev VM, Votyakova OM, Kushlinskii NE (May 2018). "Immunochemical Diagnosis of Multiple Myeloma". Bulletin of Experimental Biology and Medicine. 165 (1): 84–87. doi:10.1007/s10517-018-4105-y. ISSN   1573-8221. PMID   29797132.
  67. ↑ Lonial S, Kaufman JL (September 2013). "Non-secretory myeloma: a clinician's guide". Oncology. 27 (9): 924–8, 930. PMID   24282993. Archived from the original on 12 January 2018.
  68. ↑ Mitchell, Richard Sheppard, Kumar, Vinay, Abbas, Abul K., Fausto, Nelson (2007). "Multiple myeloma". Robbins Basic Pathology (8th ed.). Philadelphia: Saunders. p. 455. ISBN   978-1-4160-2973-1.
  69. ↑ Rajkumar SV (1 January 2005). "MGUS and smoldering multiple myeloma: update on pathogenesis, natural history, and management". Hematology. American Society of Hematology. Education Program. 2005 (1): 340–345. doi: 10.1182/asheducation-2005.1.340 . PMID   16304401.
  70. 1 2 3 4 Rajkumar SV, Dimopoulos MA, Palumbo A, Blade J, Merlini G, Mateos MV, et al. (November 2014). "International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma". The Lancet. Oncology. 15 (12): e538–e548. doi:10.1016/s1470-2045(14)70442-5. hdl: 2268/174646 . PMID   25439696. S2CID   36384542.
  71. ↑ "Robbins & Cotran Pathologic Basis of Disease – 9781455726134 | US Elsevier Health Bookshop". www.us.elsevierhealth.com. Archived from the original on 27 April 2021. Retrieved 26 October 2016.
  72. ↑ Klatt EC (8 September 2011). Robbins and Cotran Atlas of Pathology. Elsevier Health Sciences. ISBN   978-1-4557-2683-7. Archived from the original on 10 September 2017.
  73. ↑ Frigyesi I, Adolfsson J, Ali M, Christophersen MK, Johnsson E, Turesson I, et al. (February 2014). "Robust isolation of malignant plasma cells in multiple myeloma". Blood. 123 (9): 1336–1340. doi: 10.1182/blood-2013-09-529800 . PMID   24385542.
  74. ↑ "Mayo Stratification for Myeloma And Risk-adapted Therapy". nebula.wsimg.com. Archived from the original on 28 August 2021. Retrieved 29 September 2017.
  75. ↑ Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, et al. (June 2016). "Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group". Blood. 127 (24): 2955–2962. doi:10.1182/blood-2016-01-631200. PMC   4920674 . PMID   27002115.
  76. ↑ Angtuaco EJ, Fassas AB, Walker R, Sethi R, Barlogie B (April 2004). "Multiple myeloma: clinical review and diagnostic imaging". Radiology. 231 (1): 11–23. doi:10.1148/radiol.2311020452. PMID   14990813.
  77. ↑ Nishida Y, Kimura S, Mizobe H, Yamamichi J, Kojima K, Kawaguchi A, et al. (October 2017). "Automatic digital quantification of bone marrow myeloma volume in appendicular skeletons - clinical implications and prognostic significance". Scientific Reports. 7 (1): 12885. Bibcode:2017NatSR...712885N. doi:10.1038/s41598-017-13255-w. PMC   5635114 . PMID   29018236.
  78. ↑ Kyle RA, Rajkumar SV (January 2009). "Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma". Leukemia. 23 (1): 3–9. doi:10.1038/leu.2008.291. PMC   2627786 . PMID   18971951.
  79. 1 2 3 "International Myeloma Working Group (IMWG) Criteria for the Diagnosis of Multiple Myeloma". International Myeloma Working Group. 29 October 2015. Archived from the original on 7 November 2017. Retrieved 5 August 2018.
  80. 1 2 Greipp PR, San Miguel J, Durie BG, Crowley JJ, Barlogie B, Bladé J, et al. (May 2005). "International staging system for multiple myeloma". Journal of Clinical Oncology. 23 (15): 3412–3420. doi: 10.1200/JCO.2005.04.242 . PMID   15809451.
  81. 1 2 3 Costa LJ, Usmani SZ (December 2020). "Defining and Managing High-Risk Multiple Myeloma: Current Concepts". Journal of the National Comprehensive Cancer Network. 18 (12): 1730–1737. doi: 10.6004/jnccn.2020.7673 . PMID   33285523.
  82. ↑ Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosinol L, et al. (September 2015). "Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group". Journal of Clinical Oncology. 33 (26): 2863–2869. doi:10.1200/JCO.2015.61.2267. PMC   4846284 . PMID   26240224.
  83. ↑ Liedtke M, Fonseca R (2019). "Chapter 25: Plasma cell disorders". In Cuker A, Altman J, Gerds A, Wun T (eds.). American Society of Hematology Self-Assessment Program (Seventh ed.). American Society of Hematology. pp. 722–69. ISBN   978-0-9789212-4-8.
  84. ↑ Lauby-Secretan B, Scoccianti C, Loomis D, Grosse Y, Bianchini F, Straif K (August 2016). "Body Fatness and Cancer--Viewpoint of the IARC Working Group". The New England Journal of Medicine. 375 (8): 794–798. doi:10.1056/NEJMsr1606602. PMC   6754861 . PMID   27557308.
  85. 1 2 Rajkumar SV (8 December 2012). "Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma?". Hematology. American Society of Hematology. Education Program. 2012: 354–361. doi: 10.1182/asheducation.V2012.1.354.3798330 . PMID   23233604. Archived from the original on 11 June 2023. Retrieved 10 June 2023.
  86. ↑ Rubinstein SM (28 January 2020). "Standardizing Chemotherapy Regimen Nomenclature: A Proposal and Evaluation of the HemOnc and National Cancer Institute Thesaurus Regimen Content". JCO Clinical Cancer Informatics. 4 (4): 60–70. doi:10.1200/CCI.19.00122. PMC   7000232 . PMID   31990580.
  87. ↑ "Drug Therapy for Multiple Myeloma". American Cancer Society. Archived from the original on 11 June 2023. Retrieved 10 June 2023.
  88. ↑ "What Is DARZALEX®?". 9 April 2021. Archived from the original on 11 June 2023. Retrieved 10 June 2023.
  89. ↑ "Watchful waiting for multiple myeloma". Canadian Cancer Society. Archived from the original on 11 June 2023. Retrieved 10 June 2023.
  90. ↑ "Triplet and Quadruplet Regimens in Smoldering Multiple Myeloma". 10 March 2023. Archived from the original on 11 June 2023. Retrieved 10 June 2023.
  91. ↑ "Aggressive Smoldering Curative Approach Evaluating Novel Therapies and Transplant (ASCENT)". Archived from the original on 3 June 2023. Retrieved 3 June 2023.
  92. 1 2 "Immuno-PRISM (PRecision Intervention Smoldering Myeloma)". Archived from the original on 3 June 2023. Retrieved 3 June 2023.
  93. ↑ "Getting a Stem Cell or Bone Marrow Transplant". American Cancer Society. Archived from the original on 10 June 2023. Retrieved 10 June 2023.
  94. ↑ Kamboj M (1 June 2020). "Vaccination of the Stem Cell Transplant (SCT) recipient and the Hematologic Malignancy patient". Infectious Disease Clinics of North America. 33 (2): 593–609. doi:10.1016/j.idc.2019.02.007. PMC   6814287 . PMID   31005140.
  95. 1 2 Pan D (20 January 2022). "Where We Stand With Precision Therapeutics in Myeloma: Prosperity, Promises, and Pipedreams". Frontiers in Oncology. 11: 819127. doi: 10.3389/fonc.2021.819127 . PMC   8811139 . PMID   35127532.
  96. ↑ Kumar S (2020). "Updated results from BELLINI, a phase III study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma". Journal of Clinical Oncology. 38 (15_suppl): 8509. doi:10.1200/JCO.2020.38.15_suppl.8509. S2CID   219779811. Archived from the original on 18 August 2023. Retrieved 3 June 2023.
  97. ↑ "FDA Approves BCMA-Targeted CAR T-Cell Therapy for Multiple Myeloma". National Cancer Institute. 14 April 2021. Archived from the original on 11 June 2023. Retrieved 10 June 2023.
  98. ↑ "Carvykti Approval Marks Second CAR T-Cell Therapy for Multiple Myeloma". National Cancer Institute. 30 March 2022. Archived from the original on 10 June 2023. Retrieved 10 June 2023.
  99. ↑ "FDA approves teclistamab-cqyv for relapsed or refractory multiple myeloma". U.S. Food and Drug Administration. 25 October 2022. Archived from the original on 27 October 2022. Retrieved 10 June 2023.
  100. ↑ Chari A (15 December 2022). "Talquetamab, a T-Cell–Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma". New England Journal of Medicine. 387 (24): 2232–2244. doi: 10.1056/NEJMoa2204591 . PMID   36507686. S2CID   254560960.
  101. ↑ "Clinical Trials". Archived from the original on 18 December 2020. Retrieved 3 June 2023.
  102. ↑ "American Society of Hematology". Archived from the original on 3 June 2023. Retrieved 3 June 2023.
  103. ↑ "American Society of Clinical Oncology". Archived from the original on 23 August 2020. Retrieved 3 June 2023.
  104. ↑ "European Hematology Association". Archived from the original on 3 June 2023. Retrieved 3 June 2023.
  105. ↑ Korde N, Kristinsson SY, Landgren O (May 2011). "Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM): novel biological insights and development of early treatment strategies". Blood. 117 (21): 5573–5581. doi:10.1182/blood-2011-01-270140. PMC   3316455 . PMID   21441462.
  106. ↑ Kyle RA, Rajkumar SV (March 2008). "Multiple myeloma". Blood. 111 (6): 2962–2972. doi:10.1182/blood-2007-10-078022. PMC   2265446 . PMID   18332230.
  107. ↑ Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, et al. (20 September 2016). "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation. 10 (1): 2937. doi:10.1002/cncr.30334. PMC   7052475 . PMID   32166015. S2CID   78285186.
  108. ↑ "Stem Cell Transplant for Multiple Myeloma". www.cancer.org. Archived from the original on 13 October 2019. Retrieved 13 October 2019.
  109. ↑ San Miguel JF, Schlag R, Khuageva NK, Dimopoulos MA, Shpilberg O, Kropff M, et al. (August 2008). "Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma". The New England Journal of Medicine. 359 (9): 906–917. doi:10.1056/NEJMoa0801479. hdl: 10261/59573 . PMID   18753647.
  110. ↑ Curran MP, McKeage K (May 2009). "Bortezomib: a review of its use in patients with multiple myeloma". Drugs. 69 (7): 859–888. doi:10.2165/00003495-200969070-00006. PMID   19441872.
  111. ↑ Durie BG (August 2008). "Treatment of myeloma--are we making progress?". The New England Journal of Medicine. 359 (9): 964–966. doi:10.1056/NEJMe0805176. PMID   18753654.
  112. 1 2 Piechotta V, Jakob T, Langer P, Monsef I, Scheid C, Estcourt LJ, et al. (Cochrane Haematology Group) (November 2019). "Multiple drug combinations of bortezomib, lenalidomide, and thalidomide for first-line treatment in adults with transplant-ineligible multiple myeloma: a network meta-analysis". The Cochrane Database of Systematic Reviews. 2019 (11). doi:10.1002/14651858.CD013487. PMC   6876545 . PMID   31765002.
  113. ↑ Abraham J (February 2009). "Advances in multiple myeloma treatment: lenalidomide and bortezomib". Community Oncology. 6 (2): 53–55. doi:10.1016/S1548-5315(11)70208-X.
  114. ↑ Sonneveld P, Dimopoulos MA, Boccadoro M, Quach H, Ho PJ, Beksac M, Hulin C, Antonioli E, Leleu X, Mangiacavalli S, Perrot A, Cavo M, Belotti A, Broijl A, Gay F (12 December 2023). "Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma". New England Journal of Medicine. 390 (4): 301–313. doi:10.1056/NEJMoa2312054. ISSN   0028-4793. PMID   38084760. S2CID   266217426.
  115. ↑ Johnson WJ, Kyle RA, Pineda AA, O'Brien PC, Holley KE (April 1990). "Treatment of renal failure associated with multiple myeloma. Plasmapheresis, hemodialysis, and chemotherapy". Archives of Internal Medicine. 150 (4): 863–869. doi:10.1001/archinte.1990.00390160111022. PMID   2183734.
  116. ↑ Paul M, Walker F, Bear RA (November 1982). "Plasmapheresis therapy in a patient with multiple myeloma". Canadian Medical Association Journal. 127 (10): 956. PMC   1862296 . PMID   7139441.
  117. ↑ McCarthy PL, Holstein SA, Petrucci MT, Richardson PG, Hulin C, Tosi P, et al. (October 2017). "Lenalidomide Maintenance After Autologous Stem-Cell Transplantation in Newly Diagnosed Multiple Myeloma: A Meta-Analysis". Journal of Clinical Oncology. 35 (29): 3279–3289. doi:10.1200/JCO.2017.72.6679. PMC   5652871 . PMID   28742454.
  118. ↑ Sonneveld P, Schmidt-Wolf IG, van der Holt B, El Jarari L, Bertsch U, Salwender H, et al. (August 2012). "Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial". Journal of Clinical Oncology. 30 (24): 2946–2955. doi:10.1200/JCO.2011.39.6820. hdl: 1765/73197 . PMID   22802322. Archived from the original on 18 August 2023. Retrieved 23 December 2022.
  119. ↑ Rajkumar SV (June 2019). "Multiple myeloma: Every year a new standard?". Hematological Oncology. 37 (Suppl 1): 62–65. doi:10.1002/hon.2586. PMC   6570407 . PMID   31187526.
  120. ↑ "FDA granted accelerated approval to belantamab mafodotin-blmf for multiple myeloma". U.S. Food and Drug Administration (FDA). 5 August 2020. Archived from the original on 6 August 2020. Retrieved 6 August 2020.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  121. ↑ "FDA Approves GSK's BLENREP (belantamab mafodotin-blmf) for the Treatment of Patients with Relapsed or Refractory Multiple Myeloma" (Press release). GlaxoSmithKline. 6 August 2020. Retrieved 6 August 2020– via Business Wire.
  122. ↑ "Kyprolis (carfilzomib) for Injection, for Intravenous Use. Full Prescribing Information" (PDF). Thousand Oaks, CA: Onyx Pharmaceuticals. Archived from the original (PDF) on 23 October 2016. Retrieved 20 August 2016.
  123. ↑ "Darzalex (daratumumab) Injection, for Intravenous Use. Full Prescribing Information" (PDF). Horsham, PA: Janssen Biotech. Archived from the original (PDF) on 18 August 2016. Retrieved 18 August 2016.
  124. ↑ "Empliciti (elotuzumab) for Injection, for Intravenous Use. Full Prescribing Information" (PDF). Princeton, NJ: Bristol-Myers Squibb Company. Archived from the original (PDF) on 8 December 2015. Retrieved 18 August 2016.
  125. ↑ "FDA approves isatuximab-irfc for multiple myeloma". U.S. Food and Drug Administration (FDA). 2 March 2020. Archived from the original on 5 March 2020. Retrieved 2 March 2020.
  126. ↑ Martin TG, Corzo K, Chiron M, Velde HV, Abbadessa G, Campana F, et al. (November 2019). "Therapeutic Opportunities with Pharmacological Inhibition of CD38 with Isatuximab". Cells. 8 (12): 1522. doi: 10.3390/cells8121522 . PMC   6953105 . PMID   31779273.
  127. ↑ "Ninlaro (ixazomib) Capsules, for Oral Use. Full Prescribing Information" (PDF). Millennium Pharmaceuticals, Inc. Archived from the original (PDF) on 19 August 2016. Retrieved 18 August 2016.
  128. ↑ "Farydak (panobinostat) Capsules, for Oral Use. Full Prescribing Information" (PDF). East Hanover, New Jersey: Novartis Pharmaceuticals Corporation. Archived from the original (PDF) on 22 October 2016. Retrieved 18 August 2016.
  129. ↑ "Xpovio (selinexor) Tablets, for Oral Use. Full Prescribing Information" (PDF). Newton, MA: Karyopharm Therapeutics. Archived from the original (PDF) on 3 August 2019. Retrieved 3 August 2019.
  130. 1 2 "FDA Approves First Cell-Based Gene Therapy for Adult Patients with Multiple Myeloma" (Press release). US Food and Drug Administration; FDA. 27 March 2021.
  131. ↑ "FDA grants accelerated approval to talquetamab-tgvs for relapsed or refractory multiple myeloma". U.S. Food and Drug Administration (FDA). 9 August 2023. Archived from the original on 11 August 2023. Retrieved 10 August 2023.
  132. ↑ "U.S. FDA Approves Talvey (talquetamab-tgvs), a First-in-Class Bispecific Therapy for the Treatment of Patients with Heavily Pretreated Multiple Myeloma" (Press release). Janssen. 10 August 2023. Retrieved 17 August 2023– via PR Newswire.
  133. ↑ "FDA grants accelerated approval to elranatamab-bcmm for multiple myeloma". U.S. Food and Drug Administration (FDA) (Press release). 14 August 2023. Retrieved 14 August 2023.
  134. ↑ "Pfizer's Elrexfio Receives U.S. FDA Accelerated Approval for Relapsed or Refractory Multiple Myeloma" (Press release). Pfizer. 14 August 2023. Retrieved 17 August 2023– via Business Wire.
  135. 1 2 3 Fisher SA, Cutler A, Doree C, Brunskill SJ, Stanworth SJ, Navarrete C, Girdlestone J, et al. (Cochrane Haematological Malignancies Group) (January 2019). "Mesenchymal stromal cells as treatment or prophylaxis for acute or chronic graft-versus-host disease in haematopoietic stem cell transplant (HSCT) recipients with a haematological condition". The Cochrane Database of Systematic Reviews. 1 (1): CD009768. doi:10.1002/14651858.CD009768.pub2. PMC   6353308 . PMID   30697701.
  136. ↑ "Mozobil- plerixafor injection, solution". DailyMed. 26 June 2023. Retrieved 13 September 2023.
  137. ↑ "BioLineRx Announces FDA Approval of Aphexda (motixafortide) in Combination with Filgrastim (G-CSF) to Mobilize Hematopoietic Stem Cells for Collection and Subsequent Autologous Transplantation in Patients with Multiple Myeloma" (Press release). BioLineRx Ltd. 11 September 2023. Retrieved 13 September 2023– via PR Newswire.
  138. 1 2 "FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma". U.S. Food and Drug Administration (FDA). 7 March 2022. Archived from the original on 17 March 2022. Retrieved 16 March 2022.PD-icon.svg This article incorporates text from this source, which is in the public domain .
  139. ↑ Estcourt L, Stanworth S, Doree C, Hopewell S, Murphy MF, Tinmouth A, Heddle N, et al. (Cochrane Haematological Malignancies Group) (May 2012). "Prophylactic platelet transfusion for prevention of bleeding in patients with haematological disorders after chemotherapy and stem cell transplantation". The Cochrane Database of Systematic Reviews (5): CD004269. doi:10.1002/14651858.CD004269.pub3. PMID   22592695.
  140. ↑ Estcourt LJ, Stanworth SJ, Doree C, Hopewell S, Trivella M, Murphy MF, et al. (Cochrane Haematological Malignancies Group) (November 2015). "Comparison of different platelet count thresholds to guide administration of prophylactic platelet transfusion for preventing bleeding in people with haematological disorders after myelosuppressive chemotherapy or stem cell transplantation". The Cochrane Database of Systematic Reviews. 2015 (11): CD010983. doi:10.1002/14651858.CD010983.pub2. PMC   4717525 . PMID   26576687.
  141. 1 2 3 Knips L, Bergenthal N, Streckmann F, Monsef I, Elter T, Skoetz N, et al. (Cochrane Haematological Malignancies Group) (January 2019). "Aerobic physical exercise for adult patients with haematological malignancies". The Cochrane Database of Systematic Reviews. 1 (1): CD009075. doi:10.1002/14651858.CD009075.pub3. PMC   6354325 . PMID   30702150.
  142. ↑ The American Society of Clinical Oncology has made this recommendation based on various cancers. See American Society of Clinical Oncology, "Five Things Physicians and Patients Should Question" (PDF), Choosing Wisely: an initiative of the ABIM Foundation , American Society of Clinical Oncology, archived from the original (PDF) on 31 July 2012, retrieved 14 August 2012
  143. ↑ Snowden JA, Ahmedzai S, Ashcroft J, et al. (2010). "Guidelines for Supportive Care in Myeloma" (PDF). British Committee for Standards in Haematology. Archived from the original (PDF) on 23 September 2015. Retrieved 21 August 2014.
  144. ↑ Higginson IJ, Evans CJ (2010). "What is the evidence that palliative care teams improve outcomes for cancer patients and their families?". Cancer Journal. 16 (5): 423–435. doi: 10.1097/PPO.0b013e3181f684e5 . PMID   20890138. S2CID   39881122.
  145. ↑ Lorenz KA, Lynn J, Dy SM, Shugarman LR, Wilkinson A, Mularski RA, et al. (January 2008). "Evidence for improving palliative care at the end of life: a systematic review". Annals of Internal Medicine. 148 (2): 147–159. doi: 10.7326/0003-4819-148-2-200801150-00010 . PMID   18195339.
  146. ↑ Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, et al. (2 May 2018). "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation. 10 (1): 383–399. doi:10.12968/denu.2018.45.5.383. PMC   7052475 . PMID   32166015.
  147. 1 2 "Myeloma—Cancer Stat Facts". SEER. Archived from the original on 7 May 2020. Retrieved 17 April 2020.
  148. ↑ Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, et al. (May 2003). "High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma". The New England Journal of Medicine. 348 (19): 1875–1883. doi: 10.1056/NEJMoa022340 . PMID   12736280. S2CID   41048909.
  149. ↑ Avet-Loiseau H, Li C, Magrangeas F, Gouraud W, Charbonnel C, Harousseau JL, et al. (September 2009). "Prognostic significance of copy-number alterations in multiple myeloma". Journal of Clinical Oncology. 27 (27): 4585–4590. doi:10.1200/JCO.2008.20.6136. PMC   2754906 . PMID   19687334.
  150. ↑ Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, et al. (2021). "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation. 10 (1): 361–370. doi:10.1177/2045894020908782. PMC   7052475 . PMID   32166015.
  151. ↑ "WHO Disease and injury country estimates". World Health Organization. 2009. Archived from the original on 11 November 2009. Retrieved 11 November 2009.
  152. ↑ GBD 2013 Mortality and Causes of Death Collaborators (January 2015). "Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the Global Burden of Disease Study 2013". Lancet. 385 (9963): 117–171. doi:10.1016/s0140-6736(14)61682-2. PMC   4340604 . PMID   25530442.{{cite journal}}: |author1= has generic name (help)CS1 maint: numeric names: authors list (link)
  153. ↑ "Myeloma statistics". Cancer Research UK. Archived from the original on 28 October 2014. Retrieved 28 October 2014.
  154. ↑ Collins CD (November 2005). "Problems monitoring response in multiple myeloma". Cancer Imaging. 5 Spec No A (Spec No A): S119–S126. doi:10.1102/1470-7330.2005.0033. PMC   1665317 . PMID   16361127.
  155. ↑ Brown LM, Linet MS, Greenberg RS, Silverman DT, Hayes RB, Swanson GM, et al. (June 1999). "Multiple myeloma and family history of cancer among blacks and whites in the U.S". Cancer. 85 (11). Wiley: 2385–2390. doi: 10.1002/(sici)1097-0142(19990601)85:11<2385::aid-cncr13>3.0.co;2-a . PMID   10357409. S2CID   41616510.
  156. ↑ Saygin D, Tabib T, Bittar HE, Valenzi E, Sembrat J, Chan SY, et al. (6 December 2014). "Transcriptional profiling of lung cell populations in idiopathic pulmonary arterial hypertension". Pulmonary Circulation. 10 (1). American Society of Hematology: 1292. doi:10.1182/blood.v124.21.1292.1292. PMC   7052475 . PMID   32166015.
  157. ↑ Ettinger SJ, Feldman EC (1 June 2000). Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Vol. 1. W.B. Saunders. pp. 516–9. ISBN   978-0-7216-7257-1.
  158. ↑ MacAllister C, Qualls C, Tyler R, Root CR (August 1987). "Multiple myeloma in a horse". Journal of the American Veterinary Medical Association. 191 (3): 337–339. PMID   3654300.
  159. 1 2 3 Matus RE, Leifer CE, MacEwen EG, Hurvitz AI (June 1986). "Prognostic factors for multiple myeloma in the dog". Journal of the American Veterinary Medical Association. 188 (11): 1288–1292. PMID   3721983.
  160. ↑ MacEwen EG, Hurvitz AI (February 1977). "Diagnosis and management of monoclonal gammopathies". The Veterinary Clinics of North America. 7 (1): 119–132. doi:10.1016/S0091-0279(77)50010-X. PMID   403649.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.