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Multiple Myeloma

Multiple Myeloma. Dr. Edward Warren Chair, Geriatrics Carolinas Campus May 2012. Goals. Define multiple myeloma . Discuss the clinical manifestations of multiple myeloma. Discuss variants of multiple myeloma. Order laboratory testing effectively to diagnose and evaluate multiple myeloma .

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Multiple Myeloma

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  1. Multiple Myeloma Dr. Edward Warren Chair, Geriatrics Carolinas Campus May 2012

  2. Goals • Define multiple myeloma. • Discuss the clinical manifestations of multiple myeloma. • Discuss variants of multiple myeloma. • Order laboratory testing effectively to diagnose and evaluate multiple myeloma. • Stage multiple myeloma. • Discuss treatment options for multiple myeloma.

  3. Historical Landmarks • In 1850, MacIntyre published the first complete clinical and pathologic narration of "a case of mollities and fragilitasossium accompanied with urine strongly charged with animal matter. • The term "multiple myeloma" was first used to describe the presence of multiple tumors originating in the bone.

  4. Epidemiology • Multiple myeloma is the most common primary cancer of bones in adults. • The annual incidence in the United States is 3 - 4 per 100,000 population. • Multiple myeloma represents 1% of all cancers diagnosed in the United States and 10% of all hematologic malignancies. • The median age at diagnosis of multiple myeloma is 62 years. • Only 2% - 3% of cases are reported in patients younger than 30 years.

  5. Epidemiology • Blacks in the United States are twice as likely to suffer from multiple myeloma as whites. • In fact, multiple myeloma is the most common hematologic malignancy in the U.S. black population. • Multiple myeloma is rare among persons of Asian descent, with an incidence of only 1 - 2 cases per 100,000 population.

  6. Multiple myeloma • Multiple myeloma is a malignant proliferation of plasma cells that involves more than 10% of the bone marrow. • It is a prototype primary malignancy of the bone associated with malignant plasma cells that secrete monoclonal immunoglobulins into the serum, the urine or both.

  7. Pathophysiology • A precursor cell arises in patients with multiple myeloma when one or more exogenous stimuli induce cytogenetic changes in the B-cell lineage at the lymph node. • On average, 50 percent of patients with multiple myeloma have an abnormal karyotype. • Commonly detected abnormalities involve single or combinations of • hyperdiploidy of chromosomes 3, 5, 7, 9, 11, 15 and 19 • hypodiploidy of chromosomes 8, 13, 14 • sex chromosome X.13

  8. Pathophysiology • Normally, plasma cells make up less than 1% of cells in the bone marrow. • Myeloma plasma cells, however, have specific adhesion molecules on their surface allowing them to target bone marrow. • After they enter the bone marrow, these adhesion molecules allow them to attach to structural cells called stromal cells. • Once myeloma cells attach to bone marrow stromal cells, several interactions cause myeloma cells to grow.

  9. Pathophysiology • Cytokines are produced by both myeloma cells and stromal cells. • interleukin 6 (IL-6) • receptor for activation of NF_KB (RANK) ligand • tumor necrosis factor (TNF) • They stimulate the growth of myeloma cells • They inhibit natural cell death (called apoptosis), leading to proliferation of myeloma cells and ultimately resulting in bone destruction.

  10. Pathophysiology • IL-6 is one of several osteoclast-activating factors produced as a result of the multiple myeloma / stromal cell interaction. • Increased osteoclastic activity plus inhibited osteoblastic activity results in osteoporosis, painful lytic lesions and hypercalcemia. • As tumors grow, they invade the hard outer part of the bone, the solid tissue. • In most cases, the myeloma cells spread into the cavities of all the large bones of the body, forming multiple small lesions. • This is why the disease is known as "multiple" myeloma.

  11. Pathophysiology • The multiple myeloma cell clone produces an excess of monoclonal (M proteins) and free light chain proteins. • The M proteins may be recognized as IgA, IgD, IgG, IgE or IgM, depending on their heavy chain class. • This excess of M proteins is responsible for the hyperviscosity syndrome, which interferes with fibrin aggregation and platelet function. • The light chain proteins may be designated as kappa or lambda. They may precipitate and deposit, producing organ damage.

  12. Immunoglobulin Anatomy

  13. Pathophysiology • Myeloma cells also produce growth factors that promote angiogenesis. This provides the oxygen and nutrients necessary for tumor growth. • The myeloma cells increase in number and begin to infiltrate the bone marrow, eventually comprising more than 10% of the cells present. • Mature myeloma cells may fail to activate the immune system and may produce substances that decrease the body's normal immune response to a foreign body. Thus, the cells can grow unchecked.

  14. Histology Bone marrow aspirates in patients with suspected myeloma show an increased number of abnormal plasma cells with a morphologic appearance outside the range of a reactive process. In many instances, the neoplastic cells appear as mature plasma cells, but all ranges of immaturity may be encountered including undifferentiated cells resembling lymphoid precursors

  15. Morphology Plasma cell morphology is usually abnormal with increased cell size, prominent nucleoli, vacuolated cytoplasm and multi-nucleated cells.

  16. Clinical Manifestations • The clinical presentation of multiple myeloma seems to be changing, probably as a result of diagnostic services that detect the disease in earlier stages. • Thirty percent of new cases are diagnosed incidentally during evaluation for seemingly unrelated problems. • A pathologic fracture is the presenting feature in 30 percent of cases. • Two thirds of patients complain of bone pain, frequently located in the back, long bones, skull and pelvis. • It commonly presents with lower back pain.

  17. Clinical Manifestations Generalized malaise Recalcitrant Infections Fever Bleeding Symptoms of high Ca++ • Nausea • Fatigue • Thirst Symptoms of hyperviscosity Headaches Bruising Ischemic neurologic symptoms Other neurologic symptoms Peripheral neuropathy from • Hyperviscosity • Spinal cord compression • Amyloid deposition. Meningitis

  18. Red Flags for MM in Back Pain • +Age over 50 years • Pain that is worse in supine position • Pain that is worse at night or awakens patient from sleep • Pain with a band-like distribution around the body • Progressive neurologic deficit in lower extremities • Pain that is not relieved with conventional methods (i.e., rest, NSAIDS, acetaminophen) • Associated constitutional symptoms (fever, weight loss, dehydration)

  19. Laboratory Tests of Blood and Urine • The blood and/or urine can be examined for an abnormal immunoglobulin -- serum protein electrophoresis and urine protein electrophoresis. • monoclonal immunoglobulin, M protein, M spike, and paraprotein. • high levels beta-2-microglobulin • Bone Marrow Biopsy • Imaging Studies • bone destruction can be detected with x-rays. • MRI scan, may locate bone destruction caused by the tumor before it is seen by x-ray examination. • Computed tomography (CT):

  20. Diagnosis Patients with multiple myeloma show a "spike" in the α,β, or γregions of the serum protein electrophoresis: an M (myeloma) spike.

  21. Diagnosis • The diagnosis of multiplemyeloma requires a significant M spike (3.5 g/dL of IgG or 2.0 g/dL of IgA) • Plasmacytosis greater than 30% in the marrow, or plasmacytoma on tissue biopsy • The presence of lytic bone lesions or low residual immunoglobulins provides supportive evidence • Cytogenetic analysis of the bone marrow may contribute significant prognostic information. i.e. abnormalities of chromosome 13

  22. Diagnosis • Major criteria: • A biopsy result shows a plasma cell tumor. • Over 30% of cells in the bone marrow sample are plasma cells. • The monoclonal immunoglobulin in the blood or urine exceeds a certain amount. • Minor criteria: • Between 10% and 30% of cells in the bone marrow sample are plasma cells. • A monoclonal immunoglobulin is found but not enough is present to fulfill a major criterion. • Holes in bones due to tumor growth are found on imaging studies. • The amount of normal antibody (not produced by the cancer cells) in the blood is abnormally low. • The diagnosis of multiple myeloma requires that a patient with appropriate symptoms have at least 1 major criterion or at least 3 minor criteria from the list above.

  23. Skeletal Survey • Perform a complete skeletal survey at diagnosis, including the skull (a very common site of bone lesions in myeloma), the long bones (look for impending fractures), and the spine. • Diffuse osteopenia may suggest myeloma involvement before discrete lytic lesions are apparent. • Impending pathologic fracturesmay be treatable preemptively. • Bone scans do not show myeloma because cytokines secreted by myeloma cells suppress osteoblast activity, and no increased uptake is observed.

  24. MRI & PET • MRI scans of the vertebrae are often positive when plain radiographs are not. • Evaluate symptomatic patients with MRI to obtain a clearer view of the spinal column and to assess its integrity. • PET scans detect early marrow involvement to assess • the extent of active disease at the time of initial diagnosis • effectiveness of treatment

  25. Lytic Lesions in a Skull

  26. Variants of Multiple Myeloma • MGUS: monoclonal gammopathy of unknown significance • M Protein < 3 mg/dl • < 10% plasma cells in bone marrow • no lytic lesions, hypercalcemia, renal compromise, urinary M protein, nor anemia • SMM: smoldering multiple myeloma • M Protein > 3 mg/dl • > 10% plasma cells in bone marrow • no lytic lesions, hypercalcemia, renal compromise, nor anemia • PCL: plasma cell leukemia • 20% plasma cells in peripheral blood • small levels of M protein • few bone lesions in a relatively young person

  27. Variants of Multiple Myeloma (cont.) • SP: solitary plasmacytoma • a single bone tumor • no other bone lesions • no urine nor serum abnormalities • WM: Waldenstrom’smacroglobulinemia • IgM M Protein > 3 mg/dl • hypercellularbone marrow with extensive lymphoplasma cell infiltration • hyperviscosity • HCD: heavy chain disease • M Protein with an incomplete heavy chain, lacking a light chain • LCD: light chain disease • light chains only – see below

  28. Plasmacytoma. • Multiple myeloma is a type of cancer formed by malignant plasma cells. • When plasma cells grow out of control, they can produce a tumor. These tumors generally develop in the bone marrow. • If there is only one tumor, it is called a plasmacytoma. • Usually, the myeloma tumors are spread throughout the bone marrow and then they are referred to as multiple myeloma.

  29. Solitary Plasmacytomas • This is also part of the spectrum of myeloma. • Patient present with a single lytic bone lesion, but the routine bone marrow is normal or shows only a very low level of abnormal plasma cells. • In some patients MRI may show additional asymptomatic bone lesions. • About 50% of patients progress to overt myeloma in 10 years. The prognosis is therefore much better than for typical myeloma. • Solitary plasmacytomas at other sites are very rarely associated with myeloma.

  30. Monoclonal Gammopathy of Unknown Significance (MGUS) • The distinction between myeloma and MGUS is based on: • Low and stable levels of paraprotein (IgG < 35g/l or IgA < 20g/l or urinary free light chain < 500mg/24hrs) • Absence of lytic bone lesions • Absence of renal impairment, anemia or hypercalcemia. • Low levels of marrow plasma cells < 5% • Mixture of normal and neoplastic marrow plasma cells as identified by flow cytometry. • Low levels of paraprotein are often detected in asymptomatic patients. Only a small proportion of patients progress to myeloma.

  31. MGUS • The cumulative probability of progression from MGUS to multiple myeloma or related cancers is about 1% per year, even after years of stability. • Annual serum protein electrophoresis, hemoglobin, creatinine, and calcium testing is a reasonable approach. • Patients with higher concentrations of monoclonal protein or new symptoms should be monitored more closely. • Elderly patients with MGUS are more likely to die of unrelated causes, such as cardiovascular disease, stroke or a non-plasma-cell cancer.

  32. Waldenstrom'sMacroglobulinemia • This is a proliferation of neoplastic B cells, which produce an M protein of the IgM class. • Incidence of approximately one-tenth that of myeloma. • The serum protein electrophoresis demonstrates a protein peak of gamma mobility (IgM), and frequently a monoclonal light chain is present in the urine. • The bone marrow demonstrates extensive infiltration with so-called plasmacytoid lymphocytes.

  33. Waldenstrom'sMacroglobulinemia Clinically, the symptoms are frequently from the very high viscosity caused by the increased level of IgM in the plasma. • visual changes • neurologic symptoms • congestive heart failure • recurrent infections • bone pain and lytic lesions are rare in macroglobulinemia. • hepatosplenomegaly and lymphadenopathy are common. • retinal hemorrhage and vascular segmentation (sausage links) are characteristic • chronic demyelinating polyneuropathy occurs in 10% of the patients

  34. Waldenstrom'sMacroglobulinemia • The prognosis for patients with Waldenstrom'smacroglobulinemia can be quite variable. • About one-third of patients will die of unrelated causes and one-third will die of infectious complications. • The remainder will die of complications of their illness: • conversion to a higher-grade lymphoma • conversion to AML • renal failure • other complications

  35. Light Chain Disease

  36. Light Chain Disease • Normal immunoglobulin is made up of two heavy chains and two light chains that are attached to each other. The normalimmunoglobulin is too large to pass through the kidney, so it is present in the blood, but not the urine. • The M protein in myeloma, like the normal immunoglobulin, is also made up of two heavy chains and two light chains attached to each other. However, in many cases of myeloma, the coordination of making and attaching light chains and heavy chains in the malignant plasma cells is lost and light chains (also called Bence Jones protein) leave the cell unattached. This fragment of immunoglobulin, the light chain, enters the blood, but is excreted rapidly in the urine.

  37. Light Chain Disease (Bence Jones Myeloma) • Light Chain Disease (LCD) is a variant of multiple myeloma in which the malignant population of marrow cells produces free monoclonal light chains but no associated heavy chain or complete immunoglobulin. • The monoclonal light chains are small enough to be freely filtered by the kidneys and become Bence-Jones protein. LCD comprises about 18% of multiple myeloma patients.

  38. Light Chain Disease • More malignant course as compared to classic myeloma. • Extremely rapid doubling time. • Tendency for more osteolytic lesions. • Increased hypercalcemia. • Higher incidence of renal failure (including azotemia at presentation) as compared to other patients with multiple myeloma. • Higher incidence of amyloidosis and plasma cell leukemia in the terminal stages of the disease. Renal failure is the principle cause of death in these patients.

  39. Light Chain Disease Pathogenesis Structural gene loss involving the deletion of the J-H segment of the heavy chain locus (situated on Chromosome 14) is the most probable cause leading to isolated production of light chains in the disease.

  40. Light Chain Disease Renal Damage • Light chains can cause a rapid decline of renal function and early clinical deterioration. The freely filtered light chains harm every segment of the nephron. • In the glomerulus, they can cause a non-fibrillaryglomerulopathywith deposition of light chains as well as a fibrillaryglomerulopathywith amyloidosis. • In the proximal tubules, reabsorption leads to formation of toxic metabolites and an acquired Fanconi syndrome. • The distal tubules suffer what has been termed "cast nephropathy" as a result of epithelial damage due to cast formation in the lumina. Proteinaceous casts are prominent in the distal convoluted tubules and collecting ducts. Some of the casts are surrounded by multi-nucleated giant cells derived from fusion of infiltrating macrophages.

  41. Renal Biopsy, low power • Low-power view of an H&E stained kidney biopsy with multiple convoluted tubules and ducts filled with proteinaceous accumulations. • This is a characteristic finding in myeloma nephrosis.

  42. Labs in Light Chain Disease • The laboratory features of LCD show distinction from classical myeloma. • The serum total protein is normal to low. • Hypogammaglobulinemia is common. • All patients have Bence-Jones proteins in the urine. • There is often no serum M (monoclonal) component on electrophoresis since most light chains are quickly filtered by the kidneys. Urine electrophoresis is important test in such cases. • Using Immuno Fixation Electrophoresis, the ratio of kappa to lambda chains in the disease population is about 2:1. This distinction is important because lambda LCD has a three times worse prognosis than kappa LCD.

  43. Staging • The staging system for myeloma is complex, but it is well correlated with outcome. • Stage II involves criteria that fit neither stage I nor stage III. • Durie-Salmon Subclassifications • A: creatinine < 2.0 • B: creatinine ≥ 2.0

  44. Stage I Stage I involves all of the following: • Hemoglobin >10 g/dL • Calcium ≤ 12 mg/dL • Radiograph showing normal bones or solitary plasmacytoma • Low M protein values (i.e. IgG < 5 g/dL, IgA < 3 g/dL, urine Bence Jones < 4 g/24 h)

  45. Stage III Stage III involves any one of the following: • Hemoglobin level less than 8.5 g/dL • Calcium level greater than 12 mg/dL • Radiograph showing advanced lytic bone disease • High M protein value (ie, IgG> 7 g/dL, IgA > 5 g/dL, urine Bence Jones > 12 g/24 h)

  46. Staging • Stage I is associated with median survival of longer than 60 months • stage II is 41 months • stage III is 23 months. • Stage B disease has a significantly worse outcome (2-12 mo in 4 separate series).

  47. Treatment Most physicians refer multiple myeloma patients to an oncologist to arrange therapy based on current protocols and up to date research. What follows is an overview of options that have been used in the past.

  48. Treatment Stem Cell Transplantation • Autologous transplants • the patient's own peripheral blood stem cells. • fairly safe • low risk of serious complications • difficult to kill all the myeloma cells with high dose chemotherapy • most patients who undergo this procedure will eventually have their myeloma return.

  49. Treatment Allogeneic transplants • use stem cells from • donors (usually close relatives) • unrelated donors whose tissue type is closely matched to the patient). • carry a higher risk of serious complications, even death • may produce more long-lasting remissions because the transplanted (donor) immune system cells may actually help to destroy the myeloma cells. • not used often in myeloma patients • must be relatively young and healthy (most myeloma patients are elderly) • donor’s tissue type must be compatible with the patient's.

  50. NonmyeloablativeTransplant. Some allogeneic transplants • use low doses of certain kinds of chemotherapy drugs to allow the transplanted stem cells to "take" without all the toxicity of high doses. • This type of transplant allows the treatment to be done on older patients. • Although the myeloma hasn’t been destroyed by the low-dose chemotherapy, the transplanted stem cells are expected to react against the myeloma cells and destroy them.

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