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eMedicine Specialties > Hematology > Plasma Cell Disorders
Multiple Myeloma
Author: Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University Coauthor(s): Lilian M Thomas, MD, Fellow, Department of Hematology/Oncology, State University of New York Upstate Medical University Contributor Information and Disclosures Updated: Jun 28, 2010 Print This Email This
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Overview Differential Diagnoses & Workup Treatment & Medication Follow-up Multimedia
References Keywords Further Reading Introduction
Background
Multiple myeloma (see images below) is a debilitating malignancy that is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. First described in 1848, multiple myeloma is a disease characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein. An intriguing feature of multiple myeloma is that the antibodyforming cells (ie, plasma cells) are malignant and, therefore, may cause unusual manifestations.
Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
The presentation of multiple myeloma can range from asymptomatic to severely symptomatic with complications requiring emergent treatment. Systemic ailments include bleeding, infection and renal failure; local catastrophes include pathologic fractures and spinal cord compression. Although patients benefit from treatment (ie, longer life, less pain, fewer complications), currently no cure exists. Recent advances in therapy have helped to lessen the occurrence and severity of adverse effects of multiple myeloma. For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Myeloma.
Pathophysiology
Multiple myeloma can cause a wide variety of problems. The proliferation of plasma cells may interfere with the normal production of blood cells, resulting in leukopenia, anemia, and thrombocytopenia. The cells may cause soft-tissue masses (plasmacytomas) or lytic lesions in the skeleton. Feared complications of multiple myeloma are bone pain, hypercalcemia, renal failure, and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity, and patients have a high prevalence of infection, especially with encapsulated organisms such as Pneumococcus. The overproduction of these antibodies may lead to hyperviscosity, amyloidosis, and renal failure.
Frequency
United States
The age-adjusted annual incidence of multiple myeloma is 4.3 cases per 100,000 white men, 3 cases per 100,000 white women, 9.6 cases per 100,000 black men, and 6.7 cases per 100,000 black women.
Mortality/Morbidity
Multiple myeloma affects the kidneys in several ways. The most common mechanisms of renal injury are direct tubular injury, amyloidosis, or involvement by plasmacytoma.1,2 Physicians manage the acute clinical condition with plasmapheresis to rapidly lower circulating abnormal proteins. Data about this approach are limited, but a small randomized study showed a survival advantage with the use of apheresis.2 Conventional therapy may take weeks to months to show a benefit. Renal impairment resulting from multiple myeloma is associated with a very poor prognosis. A recent case series demonstrated that patients
with renal failure from myeloma may benefit from autologous stem cell transplants, and as many as one third may demonstrate improvement in their renal function with this approach.3 Spinal cord compression is one of the most severe adverse effects of multiple myeloma. Reports indicate that as many as 20% of patients develop spinal cord compression at some point during the course of their disease. Symptoms typically include back pain, weakness or paralysis in the legs, numbness, or dysesthesias in the lower extremities. However, depending on the level of involvement, patients may present with upper extremity symptoms. The mechanism of these symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. The dysfunction may be reversible, depending on the duration of the cord compression; however, once established, the dysfunction is only rarely fully reversed. A frequent complication of multiple myeloma is pathologic fractures. Bony involvement is typically lytic in nature. Physicians should orthopedically stabilize (ie, typically pin) and irradiate these lesions. Careful attention to a patient's bony symptoms, intermittent radiographic surveys, and the use of bisphosphonates may be useful to prevent fractures.4,5,6 Patients with multiple myeloma commonly develop hypercalcemia. The mechanisms include bony involvement and, possibly, humoral mechanisms. Treatment for myeloma-induced hypercalcemia is the same as that for other malignancy-associated hypercalcemia; however, the dismal outcome observed with hypercalcemia in solid tumors is not observed in multiple myeloma.
Race
Multiple myeloma accounts for 1.1% of the malignancies in white US residents and 2.1% of the malignancies in black residents.
Sex
The male-to-female ratio of multiple myeloma is 3:2.
Age
The median age of patients with multiple myeloma is 68 years for men and 70 years for women.
Clinical
History
Presenting symptoms of multiple myeloma include bone pain, pathologic fractures, weakness, anemia, infection (often pneumococcal), hypercalcemia, spinal cord compression, or renal failure. Increasingly, physicians are identifying asymptomatic patients through routine blood screening. Typically, a large gap between the total protein and the
albumin levels observed on an automated chemistry panel suggests a problem (ie, protein minus albumin equals globulin).
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Bone pain o This is the most common presenting symptom in multiple myeloma. Most case series report that 70% of patients have bone pain at presentation. o The lumbar spine is one of the most common sites of pain. Pathologic fractures and bone lesions o Pathologic fractures are very common in multiple myeloma; 93% of patients have more than one site of bony involvement. o A severe bony event is a common presenting issue. Spinal cord compression o This complication occurs in approximately 10-20% of patients with multiple myeloma at some time during the course of disease. o The symptoms that should alert physicians to consider spinal cord compression are back pain, weakness, numbness, or dysesthesias in the extremities. o It is common for spinal cord compressions in multiple myeloma to occur at multiple levels, so comprehensive evaluation of the spine is warranted. o Patients who are ambulatory at the start of therapy have the best likelihood of preserving function and avoiding paralysis. Bleeding o Occasionally, a patient may come to medical attention for bleeding resulting from thrombocytopenia. o Rarely, monoclonal protein may absorb clotting factors and lead to bleeding. Hypercalcemia o Confusion, somnolence, bone pain, constipation, nausea, and thirst are the presenting symptoms of hypercalcemia. o This complication may be present in as many as 30% of patients with multiple myeloma at presentation. In most solid malignancies, hypercalcemia carries an ominous prognosis, but in multiple myeloma, its occurrence does not adversely affect survival. Infection o Abnormal humoral immunity and leukopenia may lead to infection. o Pneumococcal organisms are commonly involved, but shingles (ie, herpes zoster) and Haemophilus infections are also more common among patients with multiple myeloma. Hyperviscosity o Epistaxis may be a presenting symptom of multiple myeloma with a high tumor volume. Occasionally, patients may have such a high volume of monoclonal protein that their blood viscosity increases, resulting in complications such as stroke, myocardial ischemia, or infarction. o Patients may report headaches and somnolence, and they may bruise easily and have hazy vision. Patients with multiple myeloma typically experience these symptoms when their serum viscosity is greater than 4 times that of normal serum. Neurologic symptoms
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Carpal tunnel syndrome is a common complication of myeloma. Meningitis (especially that resulting from pneumococcal or meningococcal infection) is more common in patients with multiple myeloma. o Some peripheral neuropathies have been attributed to multiple myeloma. Anemia o Anemia, which may be quite severe, is the most common cause of weakness in patients with multiple myeloma.
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Physical
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Pallor from anemia may be present. Ecchymoses or purpura from thrombocytopenia may be evident. Bony tenderness is not uncommon in multiple myeloma, resulting from focal lytic destructive bone lesions or pathologic fracture. Pain without tenderness is typical. Neurologic findings may include a sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal cord compression), weakness, or carpal tunnel syndrome. Extramedullary plasmacytomas, which consist of soft-tissue masses of plasma cells, are not uncommon. Plasmacytomas have been described in almost every site in the body. Although the aerodigestive tract is the most common location, reports also describe orbital, ear canal, cutaneous, gastric, rectal, prostatic, and retroperitoneal lesions. Amyloidosis may develop in some patients with multiple myeloma. The characteristic physical examination findings that suggest amyloidosis include the following: o The shoulder pad sign is defined by bilateral swelling of the shoulder joints secondary to amyloid deposition. Physicians describe the swelling as hard and rubbery. Amyloidosis may also be associated with carpal tunnel syndrome and subcutaneous nodules. o Macroglossia is a common finding in patients with amyloidosis (see image below).
Amyloidosis infiltrating the tongue in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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Skin lesions that have been described as waxy papules or nodules may occur on the torso, ears, or lips. o Postprotoscopic peripalpebral purpura strongly suggests amyloidosis. Patients may develop raccoonlike dark circles around their eyes following any procedure that parallels a prolonged Valsalva maneuver. The capillary fragility associated with amyloidosis may account for this observation. In the past, this correlation was observed when patients underwent rectal biopsies to make the diagnosis. The most widely accepted schema for the diagnosis of multiple myeloma uses particular combinations of laboratory, imaging, and procedure findings as diagnostic criteria. The findings are as follows: o I = Plasmacytoma on tissue biopsy o II = Bone marrow with greater than 30% plasma cells o III = Monoclonal globulin spike on serum protein electrophoresis, with an immunoglobulin (Ig) G peak of greater than 3.5 g/dL or an IgA peak of greater than 2 g/dL, or urine protein electrophoresis (in the presence of amyloidosis) result of greater than 1 g/24 h o a = Bone marrow with 10-30% plasma cells o b = Monoclonal globulin spike present but less than category III o c = Lytic bone lesions o d = Residual IgM level less than 50 mg/dL, IgA level less than 100 mg/dL, or IgG level less than 600 mg/dL The following combinations of findings are used to make the diagnosis of multiple myeloma: o I plus b, c, or d o II plus b, c, or d o III plus a, c, or d o a plus b plus c o a plus b plus d
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Causes
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Genetic causes o A study by the Mayo clinic found multiple myeloma in 8 siblings from a group of 440 patients; these 8 siblings had different heavy chains but the same light chains. o Ongoing research is investigating whether human leukocyte antigen (HLA)Cw5 or HLA-Cw2 may play a role in the pathogenesis of multiple myeloma. Environmental or occupational causes: Case-controlled studies have suggested a significant risk of developing multiple myeloma in individuals with significant exposures in the agriculture, food, and petrochemical industries. Long-term (>20 y) exposure to hair dyes has been tied to an excessive risk of developing multiple myeloma. MGUS: Approximately 19% of patients with MGUS develop multiple myeloma within 2-19 years. Radiation o Radiation has been linked to the development of multiple myeloma.
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In 109,000 survivors of the atomic bombing of Nagasaki during World War II, 29 died from multiple myeloma between 1950 and 1976; however, some more recent studies do not confirm that these survivors have an increased risk of developing multiple myeloma. A recent study of workers at the Oak Ridge Diffusion Plant in eastern Tennessee showed only a weak correlation of risk of multiple myeloma to uranium exposure.7
http://en.wikipedia.org/wiki/Multiple_myeloma
Multiple myeloma
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Multiple myeloma
Classification and external resources
Micrograph of a plasmacytoma, the histologic correlate of multiple myeloma. H&E stain. ICD - 10 ICD -9 C90.0 203.0 M9732/3
ICD-O: OMIM
254500 8628
DiseasesDB
MedlinePlus
000583
eMedicine
med/1521
MeSH
D009101
Multiple myeloma (from Gk.myelo-, bone marrow), also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease (after Otto Kahler) is a cancer of the white blood cells known as plasma cells.[1] A type of B cell, plasma cells are a crucial part of the immune system responsible for the production of antibodies in humans and other vertebrates. They are produced in the bone marrow and are transported through the lymphatic system. Due to the fundamental nature of the system affected, multiple myeloma manifests systemic symptoms that make it difficult to diagnose. Myeloma is generally thought to be incurable, but remissions may be induced with steroids, chemotherapy, thalidomide and stem cell transplants.[2] Despite the name myeloma, this form of cancer does not involve myeloid cells, as plasma cells are lymphoid, but is so named because it mainly involves the myelum (bone marrow). There were 15,271 cases diagnosed and 11,070 deaths in the United States in 2004, and an incidence of 4/100,000 worldwide.[3] Median survival is 50±55 months.[4] Chromosome diagnosis can separate patients into more or less favorable prognoses. Myeloma is part of the broad group of diseases called hematological malignancies.
Contents
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1 Signs and symptoms o 1.1 Bone pain o 1.2 Infection o 1.3 Renal failure o 1.4 Anemia o 1.5 Neurological symptoms 2 Diagnosis o 2.1 Investigations o 2.2 Workup o 2.3 Diagnostic criteria o 2.4 Staging 3 Pathophysiology 4 Treatment o 4.1 Initial therapy o 4.2 Relapse 5 Prognosis 6 Epidemiology 7 Gallery 8 See also 9 References 10 External links
[edit] Signs and symptoms
Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB: C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions.[5] Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.
[edit] Bone pain
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. Myeloma bone disease is due to the overexpression of Receptor Activator for Nuclear Factor B Ligand (RANKL) by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. The resultant bone lesions are lytic in nature and are best seen in plain radiographs, which may show "punched-out" resorptive lesions (including the "pepper pot" appearance of the skull on radiography). The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.
[edit] Infection
The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S. pneumoniae, S. aureus, and K. pneumoniae, while common pathogens causing pyelonephritis include E. coli and other gram-negative organisms. The greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy.[6] The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies. A selected group of patients may benefit from replacement immunoglobulin therapy to reduce the risk of infection.[7]
[edit] Renal failure
Renal failure may develop both acutely and chronically. It is commonly due to hypercalcemia (see above). It may also be due to tubular damage from excretion of light chains, also called Bence Jones proteins, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.
[edit] 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.
[edit] Neurological symptoms
Common problems are weakness, confusion and fatigue due to hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, there may be 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). It may give rise to paraplegia in late presenting cases.
[edit] Diagnosis
[edit] Investigations
Serum protein electrophoresis showing a paraprotein (peak in the gamma zone) in a patient with multiple myeloma. The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised immunoglobulin) may prompt further testing. A doctor will 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 (see below). Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins). 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: - or -light chains or any of the five types of heavy chains ( -, -, -, - or -heavy chains). Additional findings include: a raised calcium (when osteoclasts are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced renal function, which may be due to paraprotein deposition in the kidney.
[edit] Workup
A 59 year-old patient presented with a left facial droop and a known history of multiple myeloma. A CT of the brain was performed looking for a cerebral cause. The brain appeared normal. Close inspection revealed a lytic lesion in the left temporal bone (right side of image), and focused reconstructions of the petrous temporal bones confirmed a lytic lesion involving the mastoid segment of the facial nerve canal. Red arrows: lesion; green arrow: normal contralateral facial nerve canal. The lytic lesion was one of many in the skull and is consistent with a myeloma deposit.
The workup of suspected multiple myeloma includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull Xray as "punched-out lesions" (pepper pot skull). Magnetic resonance imaging (MRI) is more sensitive than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected. Occasionally a CT scan is performed to measure the size of soft tissue plasmacytomas. Bone scans are typically not of any additional value in the workup of myeloma patients (no new bone formation, lytic lesions not well visualized on bone scan). 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 which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically CD56, CD38, CD138 positive and CD19 and CD45 negative.[5] Cytogenetics may also be performed in myeloma for prognostic purposes, including a myeloma-specific FISH and Virtual Karyotype. Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (immunoglobulins) to look for immune paresis, and 2-microglobulin which provides prognostic information. On peripheral blood smear the rouleaux formation of red blood cells is commonly seen. 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 monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.[citation needed] 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. The prognosis of myeloma varies widely depending upon various risk factors. The Mayo Clinic has developed a risk-stratification model termed Mayo Stratification for Myeloma and Riskadapted Therapy (mSMART) which divides patients into high-risk and standard-risk categories. Patients with deletion of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or more) are considered to have high-risk myeloma.
[edit] Diagnostic criteria
In 2003, the International Myeloma Working Group[5] agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of undetermined significance), which was subsequently updated in 2009:[8]
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Symptomatic myeloma: 1. Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma) 2. A monoclonal protein (paraprotein) in either serum or urine(except in cases of true non-secretory myeloma) 3. Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, ROTI, commonly referred to by the acronym "CRAB"): HyperCalcemia (corrected calcium >2.75 mmol/L) Renal insufficiency attributable to myeloma Anemia (hemoglobin <10 g/dL) Bone lesions (lytic lesions or osteoporosis with compression fractures)
Note: Recurrent infections alone in a patient who has none of the CRAB features is not sufficient to make the diagnosis of myeloma. Patients 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 it is imperative that these abnormalities are felt to be directly attributable to the related plasma cell disorder and every attempt made to rule out other underlying causes of anemia, renal failure etc.
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Asymptomatic myeloma: 1. Serum paraprotein >30 g/L AND/OR 2. Clonal plasma cells >10% on bone marrow biopsy AND 3. NO myeloma-related organ or tissue impairment Monoclonal gammopathy of undetermined significance (MGUS): 1. Serum paraprotein <30 g/L AND 2. Clonal plasma cells <10% on bone marrow biopsy AND 3. NO myeloma-related organ or tissue impairment
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 POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes).
[edit] Staging
International Staging System The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2005:[9]
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Stage I: 2-microglobulin ( 2M) < 3.5 mg/L, albumin >= 3.5 g/dL Stage II: 2M < 3.5 and albumin < 3.5; or 2M >= 3.5 and < 5.5 Stage III: 2M >= 5.5
Note that the ISS should be used only in patients who meet diagnostic criteria for myeloma. Patients with MGUS and asymptomatic myeloma who have renal dysfunction from unrelated
causes such as diabetes or hypertension may have elevated 2M levels just from the renal dysfunction and cannot be considered as stage III myeloma. This is one of the main drawbacks of the ISS. It does not really quantify tumor burden or extent unlike staging systems used in other cancers. It is more of a prognostic index rather than a true staging system. For this reason, it is recommended that the ISS be used along with the Durie Salmon Staging System (see below) Durie-Salmon staging system First published in 1975, the Durie-Salmon staging system[10] is still in use:
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stage I: all of o Hb > 10g/dL o normal calcium o Skeletal survey: normal or single plasmacytoma or osteoporosis o Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA o Urinary light chain excretion < 4 g/24h stage II: fulfilling the criteria of neither I nor III stage III: one or more of o Hb < 8.5g/dL o high calcium > 12 mg/dL o Skeletal survey: Three or more lytic bone lesions o Serum paraprotein > 7g/dL if IgG, > 5 g/dL if IgA o Urinary light chain excretion > 12g/24h
Stages I, II, and III of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:
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A: serum creatinine < 2 mg/dL (< 177 umol/L) B: serum creatinine > 2 mg/dL (> 177 umol/L)
[edit] Pathophysiology B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surface. When they are activated to secrete antibodies, they are known as plasma cells. Multiple myeloma develops in B lymphocytes after they have left the part of the lymph node known as the germinal center. The normal cell line 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.[11] The immune system keeps the proliferation of B cells and the secretion of antibodies under tight control. When chromosomes and genes are damaged, often through rearrangement, this control is lost. Often, a promoter gene moves (or translocates) to a chromosome where it stimulates an antibody gene to overproduction. A chromosomal translocation between the immunoglobulin heavy chain gene (on the fourteenth chromosome, locus 14q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11[2]) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of
the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is 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) the thirteenth chromosome is also observed in about 50% of cases. Production of cytokines[12]) (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the attraction of new blood vessels) is increased. The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms. [edit] Treatment Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred. In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat anemia.
[edit] Initial therapy
Initial treatment of multiple myeloma depends on the patient¶s age and comorbidities. In recent years, high-dose chemotherapy with hematopoietic stem-cell transplantation has become the preferred treatment for patients under the age of 65. Prior to stem-cell transplantation, these patients receive an initial course of induction chemotherapy. The most common induction regimens used today are thalidomide±dexamethasone, bortezomib based regimens, and lenalidomide±dexamethasone.[13] Autologous stem cell transplantation, the transplantation of a patient¶s own stem cells after chemotherapy, is the most common type of stem cell transplantation for multiple myeloma. It is not curative, but does prolong overall survival. Allogeneic stem cell transplantation, the transplantation of a healthy person¶s stem cells into the affected patient, has the potential for a cure, but is only available to a small percentage of patients. [2] Furthermore, there is a 5-10% treatment-associated mortality rate. Patients over age 65 and patients with significant concurrent illness often cannot tolerate stem cell transplantation. For these patients, the standard of care has been chemotherapy with melphalan and prednisone. Recent studies among this population[14] suggest improved outcomes with new chemotherapy regimens. 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.[15]
[edit] Relapse
The natural history of myeloma is of relapse following treatment. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant. Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect,[2] and some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib (or Velcade) is a recent addition to the therapeutic arsenal, especially as second line therapy, since 2005. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is showing promise for treating myeloma. Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.
[edit] Prognosis
The International Staging System can help to predict survival, with a median survival of 62 months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease.[9] Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis. Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally "poorrisk" disease. SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel.[16] In MM, lack of a proliferative clone makes conventional cytogenetics informative in only ~30% of cases. 1. 2. 3. 4. Virtual karyotyping identified chromosomal abnormalities in 98% of MM cases del(12p13.31)is an independent adverse marker amp(5q31.1) is a favorable marker The prognostic impact of amp(5q31.1) over-rides that of hyperdiploidy and also identifies patients who greatly benefit from high-dose therapy.
Array-based karyotyping cannot detect balanced translocations, such as t(4;14) seen in ~15% of MM. Therefore, FISH for this translocation should also be performed if using SNP arrays to detect genome-wide copy number alterations of prognostic significance in MM.
According to the Multiple Myeloma Research Foundation, some myeloma patients live for more than 15 years after diagnosis.[citation needed]
eMedicine Specialties > Hematology > Plasma Cell Disorders
Multiple Myeloma
Author: Sara J Grethlein, MD, Associate Dean for Graduate Medical Education, Professor, Department of Internal Medicine, Division of Hematology and Oncology, State University of New York Upstate Medical University Coauthor(s): Lilian M Thomas, MD, Fellow, Department of Hematology/Oncology, State University of New York Upstate Medical University Contributor Information and Disclosures Updated: Jun 28, 2010 Print This Email This
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Overview Differential Diagnoses & Workup Treatment & Medication Follow-up Multimedia
References Keywords Further Reading Introduction
Background
Multiple myeloma (see images below) is a debilitating malignancy that is part of a spectrum of diseases ranging from monoclonal gammopathy of unknown significance (MGUS) to plasma cell leukemia. First described in 1848, multiple myeloma is a disease characterized by a proliferation of malignant plasma cells and a subsequent overabundance of monoclonal paraprotein. An intriguing feature of multiple myeloma is that the antibodyforming cells (ie, plasma cells) are malignant and, therefore, may cause unusual manifestations.
Bone marrow aspirate demonstrating plasma cells of multiple myeloma. Note the blue cytoplasm, eccentric nucleus, and perinuclear pale zone (or halo). All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
Bone marrow biopsy demonstrating sheets of malignant plasma cells in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
The presentation of multiple myeloma can range from asymptomatic to severely symptomatic with complications requiring emergent treatment. Systemic ailments include bleeding, infection and renal failure; local catastrophes include pathologic fractures and spinal cord compression. Although patients benefit from treatment (ie, longer life, less pain, fewer complications), currently no cure exists. Recent advances in therapy have helped to lessen the occurrence and severity of adverse effects of multiple myeloma. For excellent patient education resources, visit eMedicine's Blood and Lymphatic System Center. Also, see eMedicine's patient education article Myeloma.
Pathophysiology
Multiple myeloma can cause a wide variety of problems. The proliferation of plasma cells may interfere with the normal production of blood cells, resulting in leukopenia, anemia, and thrombocytopenia. The cells may cause soft-tissue masses (plasmacytomas) or lytic lesions in the skeleton. Feared complications of multiple myeloma are bone pain, hypercalcemia, renal failure, and spinal cord compression. The aberrant antibodies that are produced lead to impaired humoral immunity, and patients have a high prevalence of infection, especially with encapsulated organisms such as Pneumococcus. The overproduction of these antibodies may lead to hyperviscosity, amyloidosis, and renal failure.
Frequency
United States
The age-adjusted annual incidence of multiple myeloma is 4.3 cases per 100,000 white men, 3 cases per 100,000 white women, 9.6 cases per 100,000 black men, and 6.7 cases per 100,000 black women.
Mortality/Morbidity
Multiple myeloma affects the kidneys in several ways. The most common mechanisms of renal injury are direct tubular injury, amyloidosis, or involvement by plasmacytoma.1,2 Physicians manage the acute clinical condition with plasmapheresis to rapidly lower circulating abnormal proteins. Data about this approach are limited, but a small randomized study showed a survival advantage with the use of apheresis.2 Conventional therapy may take weeks to months to show a benefit. Renal impairment resulting from multiple myeloma is associated with a very poor prognosis. A recent case series demonstrated that patients
with renal failure from myeloma may benefit from autologous stem cell transplants, and as many as one third may demonstrate improvement in their renal function with this approach.3 Spinal cord compression is one of the most severe adverse effects of multiple myeloma. Reports indicate that as many as 20% of patients develop spinal cord compression at some point during the course of their disease. Symptoms typically include back pain, weakness or paralysis in the legs, numbness, or dysesthesias in the lower extremities. However, depending on the level of involvement, patients may present with upper extremity symptoms. The mechanism of these symptoms may be the development of an epidural mass with compression, a compression fracture of a vertebral body destroyed by multiple myeloma, or, rarely, an extradural mass. The dysfunction may be reversible, depending on the duration of the cord compression; however, once established, the dysfunction is only rarely fully reversed. A frequent complication of multiple myeloma is pathologic fractures. Bony involvement is typically lytic in nature. Physicians should orthopedically stabilize (ie, typically pin) and irradiate these lesions. Careful attention to a patient's bony symptoms, intermittent radiographic surveys, and the use of bisphosphonates may be useful to prevent fractures.4,5,6 Patients with multiple myeloma commonly develop hypercalcemia. The mechanisms include bony involvement and, possibly, humoral mechanisms. Treatment for myeloma-induced hypercalcemia is the same as that for other malignancy-associated hypercalcemia; however, the dismal outcome observed with hypercalcemia in solid tumors is not observed in multiple myeloma.
Race
Multiple myeloma accounts for 1.1% of the malignancies in white US residents and 2.1% of the malignancies in black residents.
Sex
The male-to-female ratio of multiple myeloma is 3:2.
Age
The median age of patients with multiple myeloma is 68 years for men and 70 years for women.
Clinical
History
Presenting symptoms of multiple myeloma include bone pain, pathologic fractures, weakness, anemia, infection (often pneumococcal), hypercalcemia, spinal cord compression, or renal failure. Increasingly, physicians are identifying asymptomatic patients through routine blood screening. Typically, a large gap between the total protein and the
albumin levels observed on an automated chemistry panel suggests a problem (ie, protein minus albumin equals globulin).
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Bone pain o This is the most common presenting symptom in multiple myeloma. Most case series report that 70% of patients have bone pain at presentation. o The lumbar spine is one of the most common sites of pain. Pathologic fractures and bone lesions o Pathologic fractures are very common in multiple myeloma; 93% of patients have more than one site of bony involvement. o A severe bony event is a common presenting issue. Spinal cord compression o This complication occurs in approximately 10-20% of patients with multiple myeloma at some time during the course of disease. o The symptoms that should alert physicians to consider spinal cord compression are back pain, weakness, numbness, or dysesthesias in the extremities. o It is common for spinal cord compressions in multiple myeloma to occur at multiple levels, so comprehensive evaluation of the spine is warranted. o Patients who are ambulatory at the start of therapy have the best likelihood of preserving function and avoiding paralysis. Bleeding o Occasionally, a patient may come to medical attention for bleeding resulting from thrombocytopenia. o Rarely, monoclonal protein may absorb clotting factors and lead to bleeding. Hypercalcemia o Confusion, somnolence, bone pain, constipation, nausea, and thirst are the presenting symptoms of hypercalcemia. o This complication may be present in as many as 30% of patients with multiple myeloma at presentation. In most solid malignancies, hypercalcemia carries an ominous prognosis, but in multiple myeloma, its occurrence does not adversely affect survival. Infection o Abnormal humoral immunity and leukopenia may lead to infection. o Pneumococcal organisms are commonly involved, but shingles (ie, herpes zoster) and Haemophilus infections are also more common among patients with multiple myeloma. Hyperviscosity o Epistaxis may be a presenting symptom of multiple myeloma with a high tumor volume. Occasionally, patients may have such a high volume of monoclonal protein that their blood viscosity increases, resulting in complications such as stroke, myocardial ischemia, or infarction. o Patients may report headaches and somnolence, and they may bruise easily and have hazy vision. Patients with multiple myeloma typically experience these symptoms when their serum viscosity is greater than 4 times that of normal serum. Neurologic symptoms
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Carpal tunnel syndrome is a common complication of myeloma. Meningitis (especially that resulting from pneumococcal or meningococcal infection) is more common in patients with multiple myeloma. o Some peripheral neuropathies have been attributed to multiple myeloma. Anemia o Anemia, which may be quite severe, is the most common cause of weakness in patients with multiple myeloma.
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Physical
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Pallor from anemia may be present. Ecchymoses or purpura from thrombocytopenia may be evident. Bony tenderness is not uncommon in multiple myeloma, resulting from focal lytic destructive bone lesions or pathologic fracture. Pain without tenderness is typical. Neurologic findings may include a sensory level change (ie, loss of sensation below a dermatome corresponding to a spinal cord compression), weakness, or carpal tunnel syndrome. Extramedullary plasmacytomas, which consist of soft-tissue masses of plasma cells, are not uncommon. Plasmacytomas have been described in almost every site in the body. Although the aerodigestive tract is the most common location, reports also describe orbital, ear canal, cutaneous, gastric, rectal, prostatic, and retroperitoneal lesions. Amyloidosis may develop in some patients with multiple myeloma. The characteristic physical examination findings that suggest amyloidosis include the following: o The shoulder pad sign is defined by bilateral swelling of the shoulder joints secondary to amyloid deposition. Physicians describe the swelling as hard and rubbery. Amyloidosis may also be associated with carpal tunnel syndrome and subcutaneous nodules. o Macroglossia is a common finding in patients with amyloidosis (see image below).
Amyloidosis infiltrating the tongue in multiple myeloma. All images and text are (c) 2002 by the American Society of Hematology. All rights reserved.
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Skin lesions that have been described as waxy papules or nodules may occur on the torso, ears, or lips. o Postprotoscopic peripalpebral purpura strongly suggests amyloidosis. Patients may develop raccoonlike dark circles around their eyes following any procedure that parallels a prolonged Valsalva maneuver. The capillary fragility associated with amyloidosis may account for this observation. In the past, this correlation was observed when patients underwent rectal biopsies to make the diagnosis. The most widely accepted schema for the diagnosis of multiple myeloma uses particular combinations of laboratory, imaging, and procedure findings as diagnostic criteria. The findings are as follows: o I = Plasmacytoma on tissue biopsy o II = Bone marrow with greater than 30% plasma cells o III = Monoclonal globulin spike on serum protein electrophoresis, with an immunoglobulin (Ig) G peak of greater than 3.5 g/dL or an IgA peak of greater than 2 g/dL, or urine protein electrophoresis (in the presence of amyloidosis) result of greater than 1 g/24 h o a = Bone marrow with 10-30% plasma cells o b = Monoclonal globulin spike present but less than category III o c = Lytic bone lesions o d = Residual IgM level less than 50 mg/dL, IgA level less than 100 mg/dL, or IgG level less than 600 mg/dL The following combinations of findings are used to make the diagnosis of multiple myeloma: o I plus b, c, or d o II plus b, c, or d o III plus a, c, or d o a plus b plus c o a plus b plus d
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Causes
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Genetic causes o A study by the Mayo clinic found multiple myeloma in 8 siblings from a group of 440 patients; these 8 siblings had different heavy chains but the same light chains. o Ongoing research is investigating whether human leukocyte antigen (HLA)Cw5 or HLA-Cw2 may play a role in the pathogenesis of multiple myeloma. Environmental or occupational causes: Case-controlled studies have suggested a significant risk of developing multiple myeloma in individuals with significant exposures in the agriculture, food, and petrochemical industries. Long-term (>20 y) exposure to hair dyes has been tied to an excessive risk of developing multiple myeloma. MGUS: Approximately 19% of patients with MGUS develop multiple myeloma within 2-19 years. Radiation o Radiation has been linked to the development of multiple myeloma.
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In 109,000 survivors of the atomic bombing of Nagasaki during World War II, 29 died from multiple myeloma between 1950 and 1976; however, some more recent studies do not confirm that these survivors have an increased risk of developing multiple myeloma. A recent study of workers at the Oak Ridge Diffusion Plant in eastern Tennessee showed only a weak correlation of risk of multiple myeloma to uranium exposure.7
http://en.wikipedia.org/wiki/Multiple_myeloma
Multiple myeloma
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Multiple myeloma
Classification and external resources
Micrograph of a plasmacytoma, the histologic correlate of multiple myeloma. H&E stain. ICD - 10 ICD -9 C90.0 203.0 M9732/3
ICD-O: OMIM
254500 8628
DiseasesDB
MedlinePlus
000583
eMedicine
med/1521
MeSH
D009101
Multiple myeloma (from Gk.myelo-, bone marrow), also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease (after Otto Kahler) is a cancer of the white blood cells known as plasma cells.[1] A type of B cell, plasma cells are a crucial part of the immune system responsible for the production of antibodies in humans and other vertebrates. They are produced in the bone marrow and are transported through the lymphatic system. Due to the fundamental nature of the system affected, multiple myeloma manifests systemic symptoms that make it difficult to diagnose. Myeloma is generally thought to be incurable, but remissions may be induced with steroids, chemotherapy, thalidomide and stem cell transplants.[2] Despite the name myeloma, this form of cancer does not involve myeloid cells, as plasma cells are lymphoid, but is so named because it mainly involves the myelum (bone marrow). There were 15,271 cases diagnosed and 11,070 deaths in the United States in 2004, and an incidence of 4/100,000 worldwide.[3] Median survival is 50±55 months.[4] Chromosome diagnosis can separate patients into more or less favorable prognoses. Myeloma is part of the broad group of diseases called hematological malignancies.
Contents
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1 Signs and symptoms o 1.1 Bone pain o 1.2 Infection o 1.3 Renal failure o 1.4 Anemia o 1.5 Neurological symptoms 2 Diagnosis o 2.1 Investigations o 2.2 Workup o 2.3 Diagnostic criteria o 2.4 Staging 3 Pathophysiology 4 Treatment o 4.1 Initial therapy o 4.2 Relapse 5 Prognosis 6 Epidemiology 7 Gallery 8 See also 9 References 10 External links
[edit] Signs and symptoms
Because many organs can be affected by myeloma, the symptoms and signs vary greatly. A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB: C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions.[5] Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence.
[edit] Bone pain
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. Myeloma bone disease is due to the overexpression of Receptor Activator for Nuclear Factor B Ligand (RANKL) by bone marrow stroma. RANKL activates osteoclasts, which resorb bone. The resultant bone lesions are lytic in nature and are best seen in plain radiographs, which may show "punched-out" resorptive lesions (including the "pepper pot" appearance of the skull on radiography). The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.
[edit] Infection
The most common infections are pneumonias and pyelonephritis. Common pneumonia pathogens include S. pneumoniae, S. aureus, and K. pneumoniae, while common pathogens causing pyelonephritis include E. coli and other gram-negative organisms. The greatest risk period for the occurrence of infection is in the initial few months after the start of chemotherapy.[6] The increased risk of infection is due to immune deficiency resulting from diffuse hypogammaglobulinemia, which is due to decreased production and increased destruction of normal antibodies. A selected group of patients may benefit from replacement immunoglobulin therapy to reduce the risk of infection.[7]
[edit] Renal failure
Renal failure may develop both acutely and chronically. It is commonly due to hypercalcemia (see above). It may also be due to tubular damage from excretion of light chains, also called Bence Jones proteins, which can manifest as the Fanconi syndrome (type II renal tubular acidosis). Other causes include glomerular deposition of amyloid, hyperuricemia, recurrent infections (pyelonephritis), and local infiltration of tumor cells.
[edit] 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.
[edit] Neurological symptoms
Common problems are weakness, confusion and fatigue due to hypercalcemia. Headache, visual changes and retinopathy may be the result of hyperviscosity of the blood depending on the properties of the paraprotein. Finally, there may be 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). It may give rise to paraplegia in late presenting cases.
[edit] Diagnosis
[edit] Investigations
Serum protein electrophoresis showing a paraprotein (peak in the gamma zone) in a patient with multiple myeloma. The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised immunoglobulin) may prompt further testing. A doctor will 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 (see below). Quantitative measurements of the paraprotein are necessary to establish a diagnosis and to monitor the disease. The paraprotein is an abnormal immunoglobulin produced by the tumor clone. Very rarely, the myeloma is nonsecretory (not producing immunoglobulins). 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: - or -light chains or any of the five types of heavy chains ( -, -, -, - or -heavy chains). Additional findings include: a raised calcium (when osteoclasts are breaking down bone, releasing calcium into the bloodstream), raised serum creatinine due to reduced renal function, which may be due to paraprotein deposition in the kidney.
[edit] Workup
A 59 year-old patient presented with a left facial droop and a known history of multiple myeloma. A CT of the brain was performed looking for a cerebral cause. The brain appeared normal. Close inspection revealed a lytic lesion in the left temporal bone (right side of image), and focused reconstructions of the petrous temporal bones confirmed a lytic lesion involving the mastoid segment of the facial nerve canal. Red arrows: lesion; green arrow: normal contralateral facial nerve canal. The lytic lesion was one of many in the skull and is consistent with a myeloma deposit.
The workup of suspected multiple myeloma includes a skeletal survey. This is a series of X-rays of the skull, axial skeleton and proximal long bones. Myeloma activity sometimes appear as "lytic lesions" (with local disappearance of normal bone due to resorption), and on the skull Xray as "punched-out lesions" (pepper pot skull). Magnetic resonance imaging (MRI) is more sensitive than simple X-ray in the detection of lytic lesions, and may supersede skeletal survey, especially when vertebral disease is suspected. Occasionally a CT scan is performed to measure the size of soft tissue plasmacytomas. Bone scans are typically not of any additional value in the workup of myeloma patients (no new bone formation, lytic lesions not well visualized on bone scan). 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 which express immunoglobulin in the cytoplasm but usually not on the surface; myeloma cells are typically CD56, CD38, CD138 positive and CD19 and CD45 negative.[5] Cytogenetics may also be performed in myeloma for prognostic purposes, including a myeloma-specific FISH and Virtual Karyotype. Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM (immunoglobulins) to look for immune paresis, and 2-microglobulin which provides prognostic information. On peripheral blood smear the rouleaux formation of red blood cells is commonly seen. 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 monoclonal gammopathy of undetermined significance (MGUS) to multiple myeloma.[citation needed] 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. The prognosis of myeloma varies widely depending upon various risk factors. The Mayo Clinic has developed a risk-stratification model termed Mayo Stratification for Myeloma and Riskadapted Therapy (mSMART) which divides patients into high-risk and standard-risk categories. Patients with deletion of chromosome 13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16) or 17p- by molecular genetic studies, or with a high plasma cell labeling index (3% or more) are considered to have high-risk myeloma.
[edit] Diagnostic criteria
In 2003, the International Myeloma Working Group[5] agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and MGUS (monoclonal gammopathy of undetermined significance), which was subsequently updated in 2009:[8]
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Symptomatic myeloma: 1. Clonal plasma cells >10% on bone marrow biopsy or (in any quantity) in a biopsy from other tissues (plasmacytoma) 2. A monoclonal protein (paraprotein) in either serum or urine(except in cases of true non-secretory myeloma) 3. Evidence of end-organ damage felt related to the plasma cell disorder (related organ or tissue impairment, ROTI, commonly referred to by the acronym "CRAB"): HyperCalcemia (corrected calcium >2.75 mmol/L) Renal insufficiency attributable to myeloma Anemia (hemoglobin <10 g/dL) Bone lesions (lytic lesions or osteoporosis with compression fractures)
Note: Recurrent infections alone in a patient who has none of the CRAB features is not sufficient to make the diagnosis of myeloma. Patients 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 it is imperative that these abnormalities are felt to be directly attributable to the related plasma cell disorder and every attempt made to rule out other underlying causes of anemia, renal failure etc.
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Asymptomatic myeloma: 1. Serum paraprotein >30 g/L AND/OR 2. Clonal plasma cells >10% on bone marrow biopsy AND 3. NO myeloma-related organ or tissue impairment Monoclonal gammopathy of undetermined significance (MGUS): 1. Serum paraprotein <30 g/L AND 2. Clonal plasma cells <10% on bone marrow biopsy AND 3. NO myeloma-related organ or tissue impairment
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 POEMS syndrome (peripheral neuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, skin changes).
[edit] Staging
International Staging System The International Staging System (ISS) for myeloma was published by the International Myeloma Working Group in 2005:[9]
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Stage I: 2-microglobulin ( 2M) < 3.5 mg/L, albumin >= 3.5 g/dL Stage II: 2M < 3.5 and albumin < 3.5; or 2M >= 3.5 and < 5.5 Stage III: 2M >= 5.5
Note that the ISS should be used only in patients who meet diagnostic criteria for myeloma. Patients with MGUS and asymptomatic myeloma who have renal dysfunction from unrelated
causes such as diabetes or hypertension may have elevated 2M levels just from the renal dysfunction and cannot be considered as stage III myeloma. This is one of the main drawbacks of the ISS. It does not really quantify tumor burden or extent unlike staging systems used in other cancers. It is more of a prognostic index rather than a true staging system. For this reason, it is recommended that the ISS be used along with the Durie Salmon Staging System (see below) Durie-Salmon staging system First published in 1975, the Durie-Salmon staging system[10] is still in use:
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stage I: all of o Hb > 10g/dL o normal calcium o Skeletal survey: normal or single plasmacytoma or osteoporosis o Serum paraprotein level < 5 g/dL if IgG, < 3 g/dL if IgA o Urinary light chain excretion < 4 g/24h stage II: fulfilling the criteria of neither I nor III stage III: one or more of o Hb < 8.5g/dL o high calcium > 12 mg/dL o Skeletal survey: Three or more lytic bone lesions o Serum paraprotein > 7g/dL if IgG, > 5 g/dL if IgA o Urinary light chain excretion > 12g/24h
Stages I, II, and III of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine:
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A: serum creatinine < 2 mg/dL (< 177 umol/L) B: serum creatinine > 2 mg/dL (> 177 umol/L)
[edit] Pathophysiology B lymphocytes start in the bone marrow and move to the lymph nodes. As they progress, they mature and display different proteins on their cell surface. When they are activated to secrete antibodies, they are known as plasma cells. Multiple myeloma develops in B lymphocytes after they have left the part of the lymph node known as the germinal center. The normal cell line 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.[11] The immune system keeps the proliferation of B cells and the secretion of antibodies under tight control. When chromosomes and genes are damaged, often through rearrangement, this control is lost. Often, a promoter gene moves (or translocates) to a chromosome where it stimulates an antibody gene to overproduction. A chromosomal translocation between the immunoglobulin heavy chain gene (on the fourteenth chromosome, locus 14q32) and an oncogene (often 11q13, 4p16.3, 6p21, 16q23 and 20q11[2]) is frequently observed in patients with multiple myeloma. This mutation results in dysregulation of
the oncogene which is thought to be an important initiating event in the pathogenesis of myeloma. The result is 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) the thirteenth chromosome is also observed in about 50% of cases. Production of cytokines[12]) (especially IL-6) by the plasma cells causes much of their localised damage, such as osteoporosis, and creates a microenvironment in which the malignant cells thrive. Angiogenesis (the attraction of new blood vessels) is increased. The produced antibodies are deposited in various organs, leading to renal failure, polyneuropathy and various other myeloma-associated symptoms. [edit] Treatment Treatment for multiple myeloma is focused on disease containment and suppression. If the disease is completely asymptomatic (i.e. there is a paraprotein and an abnormal bone marrow population but no end-organ damage), treatment may be deferred. In addition to direct treatment of the plasma cell proliferation, bisphosphonates (e.g. pamidronate or zoledronic acid) are routinely administered to prevent fractures and erythropoietin to treat anemia.
[edit] Initial therapy
Initial treatment of multiple myeloma depends on the patient¶s age and comorbidities. In recent years, high-dose chemotherapy with hematopoietic stem-cell transplantation has become the preferred treatment for patients under the age of 65. Prior to stem-cell transplantation, these patients receive an initial course of induction chemotherapy. The most common induction regimens used today are thalidomide±dexamethasone, bortezomib based regimens, and lenalidomide±dexamethasone.[13] Autologous stem cell transplantation, the transplantation of a patient¶s own stem cells after chemotherapy, is the most common type of stem cell transplantation for multiple myeloma. It is not curative, but does prolong overall survival. Allogeneic stem cell transplantation, the transplantation of a healthy person¶s stem cells into the affected patient, has the potential for a cure, but is only available to a small percentage of patients. [2] Furthermore, there is a 5-10% treatment-associated mortality rate. Patients over age 65 and patients with significant concurrent illness often cannot tolerate stem cell transplantation. For these patients, the standard of care has been chemotherapy with melphalan and prednisone. Recent studies among this population[14] suggest improved outcomes with new chemotherapy regimens. 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.[15]
[edit] Relapse
The natural history of myeloma is of relapse following treatment. Depending on the patient's condition, the prior treatment modalities used and the duration of remission, options for relapsed disease include re-treatment with the original agent, use of other agents (such as melphalan, cyclophosphamide, thalidomide or dexamethasone, alone or in combination), and a second autologous stem cell transplant. Later in the course of the disease, "treatment resistance" occurs. This may be a reversible effect,[2] and some new treatment modalities may re-sensitize the tumor to standard therapy. For patients with relapsed disease, bortezomib (or Velcade) is a recent addition to the therapeutic arsenal, especially as second line therapy, since 2005. Bortezomib is a proteasome inhibitor. Finally, lenalidomide (or Revlimid), a less toxic thalidomide analog, is showing promise for treating myeloma. Renal failure in multiple myeloma can be acute (reversible) or chronic (irreversible). Acute renal failure typically resolves when the calcium and paraprotein levels are brought under control. Treatment of chronic renal failure is dependent on the type of renal failure and may involve dialysis.
[edit] Prognosis
The International Staging System can help to predict survival, with a median survival of 62 months for stage 1 disease, 45 months for stage 2 disease, and 29 months for stage 3 disease.[9] Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t(4;14) and t(14;16) conferring a poorer prognosis. The 11q13 and 6p21 cytogenetic abnormalities are associated with a better prognosis. Prognostic markers such as these are always generated by retrospective analyses, and it is likely that new treatment developments will improve the outlook for those with traditionally "poorrisk" disease. SNP array karyotyping can detect copy number alterations of prognostic significance that may be missed by a targeted FISH panel.[16] In MM, lack of a proliferative clone makes conventional cytogenetics informative in only ~30% of cases. 1. 2. 3. 4. Virtual karyotyping identified chromosomal abnormalities in 98% of MM cases del(12p13.31)is an independent adverse marker amp(5q31.1) is a favorable marker The prognostic impact of amp(5q31.1) over-rides that of hyperdiploidy and also identifies patients who greatly benefit from high-dose therapy.
Array-based karyotyping cannot detect balanced translocations, such as t(4;14) seen in ~15% of MM. Therefore, FISH for this translocation should also be performed if using SNP arrays to detect genome-wide copy number alterations of prognostic significance in MM.
According to the Multiple Myeloma Research Foundation, some myeloma patients live for more than 15 years after diagnosis.[citation needed]
