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11-SEPTEMBER-2008 12:20:15 - Multiple myeloma Multiple myeloma Classification and external resources ICD-10 C90.0 ICD-9 203.0 ICD-O: M9732/3 OMIM 254500 DiseasesDB 8628 MedlinePlus 000583 eMedicine med/1521 MeSH D009101 Multiple myeloma also known as MM, myeloma, plasma cell myeloma, or as Kahler's disease after Otto Kahler is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies. Myeloma is regarded as incurable, but remissions may be induced with steroids, chemotherapy, thalidomide and stem cell transplants. Myeloma is part of the broad group of diseases called hematological malignancies. Contents 1 Signs and symptoms 1.1 Bone pain 1.2 Infection 1.3 Renal failure 1.4 Anemia 1.5 Neurological symptoms 2 Diagnosis 2.1 Investigations 2.2 Workup 2.3 Diagnostic criteria 2.4 Staging 3 Pathophysiology 4 Treatment 4.1 Initial therapy 4.2 Relapse 5 Prognosis 6 Epidemiology 7 See also 8 References 9 External links 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.1 Myeloma has many possible symptoms, and all symptoms may be due to other causes. They are presented here in decreasing order of incidence. 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 proliferation of tumor cells and release of IL-6, also known as osteoclast activating factor OAF, which stimulates osteoclasts to break down bone. These bone lesions are lytic in nature and are best seen in plain radiographs, which may show punched-out resorptive lesions. The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms. 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.2 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.3 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. 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. 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. Diagnosis Investigations 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: κ- or λ-light chains or any of the five types of heavy chains α-, γ-, δ-, ε- or μ-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. Workup 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 X-ray 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. 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.1 Cytogenetics may also be performed in myeloma for prognostic purposes. Other useful laboratory tests include quantitative measurement of IgA, IgG, IgM immunoglobulins to look for immune paresis, and β2-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 Diagnostic criteria In 2003, the International Myeloma Working Group1 agreed on diagnostic criteria for symptomatic myeloma, asymptomatic myeloma and MGUS monoclonal gammopathy of undetermined significance: Symptomatic myeloma: Clonal plasma cells 10% on bone marrow biopsy or in any quantity in a biopsy from other tissues plasmacytoma A monoclonal protein paraprotein in either serum or urine Evidence of end-organ damage related organ or tissue impairment, ROTI: 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 Frequent severe infections 2 a year Amyloidosis of other organs Hyperviscosity syndrome Asymptomatic myeloma: Serum paraprotein 30 g/L AND/OR Clonal plasma cells 10% on bone marrow biopsy AND NO myeloma-related organ or tissue impairment Monoclonal gammopathy of undetermined significance MGUS: Serum paraprotein 30 g/L AND Clonal plasma cells 10% on bone marrow biopsy AND 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. Staging International Staging System The International Staging System ISS for myeloma was published by the International Myeloma Working Group in 2005:4 Stage I: β2-microglobulin β2M 3.5 mg/L, albumin = 3.5 g/dL Stage II: β2M 3.5 and albumin 3.5; or β2M = 3.5 and 5.5 Stage III: β2M = 5.5 Durie-Salmon staging system First published in 1975, the Durie-Salmon staging system 5 is still in use, but has largely been superseded by the simpler ISS: stage 1: all of Hb 10g/dL normal calcium Skeletal survey: normal or single plasmacytoma or osteoporosis Serum paraprotein level 5 g/dL if IgG, 3 g/dL if IgA Urinary light chain excretion 4 g/24h stage 2: fulfilling the criteria of neither 1 nor 3 stage 3: one or more of Hb 8.5g/dL high calcium 12mg/dL Skeletal survey: 3 or more lytic bone lesions Serum paraprotein 7g/dL if IgG, 5 g/dL if IgA Urinary light chain excretion 12g/24h Stages 1, 2 and 3 of the Durie-Salmon staging system can be divided into A or B depending on serum creatinine: A: serum creatinine 2mg/dL 177 umol/L B: serum creatinine 2mg/dL 177 umol/L Pathophysiology Multiple myeloma develops in post-germinal center B lymphocytes. 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 20q116 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 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. 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. 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. 7 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. 6 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 population8 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.9 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,6 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. 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.4 Cytogenetic analysis of myeloma cells may be of prognostic value, with deletion of chromosome 13, non-hyperdiploidy and the balanced translocations t4;14 and t14;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 poor-risk disease. Epidemiology There are approximately 45,000 people in the United States living with multiple myeloma, and the American Cancer Society estimates that approximately 14,600 new cases of myeloma are diagnosed each year in the United States. It follows from here that the average survival at diagnosis is about three years. Multiple myeloma is the second most prevalent blood cancer 10% after non-Hodgkin's lymphoma. It represents approximately 1% of all cancers and 2% of all cancer deaths. Although the peak age of onset of multiple myeloma is 65 to 70 years of age, recent statistics indicate both increasing incidence and earlier age of onset. Multiple myeloma affects slightly more men than women. African Americans and Native Pacific Islanders have the highest reported incidence of this disease in the United States and Asians the lowest. Results of a recent study found the incidence of myeloma to be 9.5 cases per 100,000 African Americans and 4.1 cases per 100,000 Caucasian Americans. Among African Americans, myeloma is one of the top 10 leading causes of cancer death. See also Waldenström macroglobulinemia Plasma cell leukemia Multiple Myeloma Research Consortium Multiple Myeloma Research Foundation MM Support Network Monoclonal antibodies References ^ a b c International Myeloma Working Group 2003. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br. J. Haematol. 121 5: 749-57. doi:10.1046/j.1365-2141.2003.04355.x. PMID 12780789. ^ Chapel HM, Lee M 1994. The use of intravenous immune globulin in multiple myeloma. Clin. Exp. Immunol. 97 Suppl 1: 21-4. PMID 8033429. Full text at PMC: 1550368 ^ Hargreaves RM, Lea JR, Griffiths H, et al 1995. Immunological factors and risk of infection in plateau phase myeloma PDF. J. Clin. Pathol. 48 3: 260-6. doi:10.1136/jcp.48.3.260. PMID 7730490. Full text at PMC: 502468 ^ a b Greipp PR, San Miguel J, Durie BG, et al 2005. International staging system for multiple myeloma. J. Clin. Oncol. 23 15: 3412-20. doi:10.1200/JCO.2005.04.242. PMID 15809451. ^ Durie BG, Salmon SE 1975. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 36 3: 842-54. doi:10.1002/1097-014219750936:3842::AID-CNCR28203603033.0.CO;2-U. PMID 1182674. ^ a b c Kyle RA, Rajkumar SV 2004. Multiple myeloma. N. Engl. J. Med. 351 18: 1860-73. doi:10.1056/NEJMra041875. PMID 15509819. ^ Kyle, R.A., Rajkumar, S.V. 2008. Multiple myeloma. Blood. 111: 2962-2972. ^ San Miguel, J.F. et al 2008. Bortezomib plus Melphalan and Prednisone for Initial Treatment of Multiple Myeloma. New England Journal of Medicine 359: 906-917. ^ Durie, B.G.M. 2008. Treatment of Myeloma - Are We Making Progress?. New England Journal of Medicine 359: 964-966. External links Myeloma UK International Myeloma Foundation Online Myeloma ISS scoring tool Multiple Myeloma Research Foundation MM Support Network Myeloma Euronet - European Network of Myeloma Patient Groups The Leukemia Lymphoma Society's Myeloma Page Overview at Mayo Clinic Risk Adapted Approach to Myeloma Therapy v d e Pathology: hematology, myeloid hematologic disease primarily D50-D77, 280-289 RBCs/ hemoglobinopathy + Polycythemia - Macrocytosis - Anemia Nutritional Iron deficiency anemia Plummer-Vinson syndrome, Megaloblastic anemia Pernicious anemia Hemolytic Herary enzyme: G6PD Deficiency - Pyruvate kinase deficiency - Triosephosphate isomerase deficiency hemoglobin: Thalassemia - Sickle-cell disease/trait membrane: Herary spherocytosis - Herary elliptocytosis - Herary stomatocytosis Acquired Autoimmune Warm, Cold, HUS, MAHA, PNH, PCH, Myelophthisic Aplastic Acquired PRCA, Diamond-Blackfan anemia, Fanconi anemia, Sideroblastic anemia Blood tests Normocytic - Microcytic - Macrocytic - Normochromic - Hypochromic Other Methemoglobinemia Coagulation/platelets/ coagulopathy/ bleeding diathesis + Hypercoagulability primary: Antithrombin III deficiency - Protein C deficiency/Activated protein C resistance/Protein S deficiency/Factor V Leiden - Hyperprothrombinemia acquired: DIC Congenital afibrinogenemia, Purpura fulminans - autoimmune Antiphospholipid Other Essential thrombocytosis - clotting factor: Hemophilia A/VIII, B/IX, C/XI Von Willebrand disease Hypoprothrombinemia/II - XIII platelet function: Bernard-Soulier syndrome - Glanzmann's thrombasthenia - Gray platelet syndrome - May Hegglin anomaly - Pelger-Huet anomaly Purpura: Henoch-Schönlein, ITP Evans syndrome, TTP Thrombocytopenia Heparin-induced thrombocytopenia Monocytes/ macrophages + Histiocytosis WHO-I Langerhans cell histiocytosis WHO-II/non-Langerhans-cell Juvenile xanthogranuloma, Hemophagocytic lymphohistiocytosis WHO-III/malignant Acute monocytic leukemia, Malignant histiocytosis, Erdheim-Chester disease Other Chronic granulomatous disease -cytosis: Monocytosis - -penia: Monocytopenia Granulocytes + -cytosis: granulocytosis Neutrophilia, Eosinophilia, Basophilia - -penia: Granulocytopenia/agranulocytosis Neutropenia/Kostmann syndrome, Eosinopenia, Basopenia See also hematological malignancy and immune disorders v d e Hematological malignancy/leukemia histology ICD-O 9590-9989, C81-C96, 200-208 Lymphoid/ Lymphoproliferative Lymphomas/ Lymphoid leukemias 9590-9739, 9800-9839 B cell lymphoma, leukemia most CD19, CD20 TdT+ ALL Precursor B acute lymphoblastic leukemia/lymphoma CD5+ SLL/CLL - mantle zone Mantle cell CD22+ Prolymphocytic - Hairy cell leukemia CD79a+ marginal zone Splenic marginal zone, MALT, Nodal marginal zone germinal center Follicular, Burkitt's, Diffuse large Other B Primary effusion - Lymphomatoid granulomatosis Plasma cells Plasmacytoma - Multiple myeloma - Waldenström macroglobulinemia - Heavy chain disease - MGUS - Primary amyloidosis -- Plasma cell leukemia T cell/NK cell lymphoma, leukemia most CD3, CD4, CD8 TdT+ ALL Precursor T acute lymphoblastic leukemia/lymphoma TdT- Cutaneous - Mycosis fungoides/Sézary's disease, Angioimmunoblastic - Anaplastic large cell - Hepatosplenic - Lymphomatoid papulosis Adult - Large granular lymphocyte - Prolymphocytic - Acute lymphoblastic Aggressive NK-cell leukemia Other Hodgkin's lymphoma usually B cell - Post-transplant lymphoproliferative disorder - Acute biphenotypic leukaemia Myeloid Myeloid leukemias 9840-9939 AML: Acute myeloblastic leukemia M0, M1, M2 - APL/M3 - monocyte M4, AMoL/M5, Myeloid dendritic cell leukemia - Erythroleukemia/M6 - AMKL/M7 - megakaryoblast - granulocyte Acute basophilic, Acute eosinophilic - Acute panmyelosis with myelofibrosis CML: CMoL, Philadelphia chromosome - Myeloid sarcoma Myelodysplastic- myeloproliferative 9945-9946 Juvenile myelomonocytic leukemia - Chronic myelomonocytic leukemia Myeloproliferative 9950-9964 Polycythemia vera - Essential thrombocytosis - Myelofibrosis - granulocyte CNL, Chronic eosinophilic leukemia/Hypereosinophilic syndrome Myelodysplastic 9980-9989 Sideroblastic anemia - Paroxysmal nocturnal hemoglobinuria Mast cell tumor 9740-9749 Mast cell leukemia - Mast cell sarcoma - Systemic mastocytosis Malignant histiocytosis 9750-9759 Langerhans cell histiocytosis See also hematology and immune disorders Retrieved from http://en..org/wiki/Multiple_myeloma Categories: Hematology | Types of cancerHidden categories: All articles with statements | Articles with statements since February 2007 Views Article Discussion this page History Personal tools Log in / create account Navigation Main page Contents Featured content Current events Random article Search Go Search Interaction Community portal Recent changes Contact Donate to Help Toolbox What links here Related changes Upload file Special pages Printable version Permanent link Cite this page Languages العربية বাংলা Deutsch Español Français Italiano עברית Nederlands 日本語 Polski Português РуÑ?Ñ?кий Svenska This page was last modified on 1 September 2008, at 10:08
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