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Lecture 24
Myeloma & Other Monoclonal Gammopathies
| Question | Answer |
|---|---|
| What portion of the antibody is the antigen recognition site? | Fab region (2 per molecule) |
| What is the first antibody produced in the initial repsonse to antigen? | IgM |
| What are the components of the pentameric Plasma IgM molecule? | (1) 5 IgM monomers (2) J chain |
| What antibodies are found in external secretions? | IgA and IgE |
| What are the components of Secretory IgA? | (1) 2 monomeric IgA molecules (2) Secretory peice (3) J chain |
| What are Bence-Jones proteins? | These are immunoglobulin subunits composed of either monomers or dimers of light chains. These are produced in excess of heavy chains in upt o 30% of patients with multiple myeloma. |
| How are Bence-Jones proteins detected? | Bence-Jones proteins are secreted in the urine and can only be detected in most cases by urinary protein electrophoresis. |
| What What is the mean age of diagnosis of Multiple Myeloma? | ~62 years of age. Multiple myeloma is rare before the age of 50 years and very rare before the age of 40 years. |
| (T or F) Incidence of multiple myeloma in African-Americans is twice that of Caucasians. | True. |
| What are the clinical features of Multiple Myeloma? | 1)Cytopenias:Anemia/thrombocytopenia/neutropenia 2)Lytic bone lesions with secondary hypercalcemia 3)Hyperviscosity syndrome 4)Renal dysfunction 5)Polyneuropathy 6)Increased propensity to infection 7) elevated plasma cell levels |
| A light chain nephropathy that is a consequence of light chain precipitation in the renal tubule that results in destruction of the nephron. This process is potentially reversible with treatment. | Renal case nephropathy (myeloma kidney) |
| A light chain nephropathy that is characterized by the deposition of light chain on the basement membrane in the subendothelial region of the glomeruli and on the interstitial side of hte basement membrane of renal tubules. The process is not reversible. | Light chain deposition disease |
| A light chain neprhropathy resulting from amyloid formation from a portion of light chain molecules and deposition inthe subendothelial area of glomeruli, in the wall of blood vessels, and in the interstitium of hte kidney and other organs. | Amyloidosis |
| What is the treatment for light chain deposition disease? | (1) Plasmapheresis (2) Initiation of chemotherapy |
| What is the most common causes of radiculopathy and spinal cord compression in multiple myeloma? | (1) Vertebral collapse (2) Compression by tumor |
| What are the clinical manifestations of hyperviscosity syndrome? | (1) Hematologic-mainly hemorrhagic (2)Neuro-Headache, dizziness, abtundation, stupor, and coma (3)CHF (4)Renal dysfunction (5)Ocular-blurred vision, loss of vision (6)Other-Weakness, anorexia |
| Treatment for symptomatic hyperviscosity syndrome? | Plasmapheresis |
| What is the most common organism responsible for infection at diagnosis of multiple myeloma? | Gram positive encapsulated bacteria (eg Streptococcus) |
| What is the most common organism responsible for infection after the initiation of therapy in multiple myeloma? | Gram negative bacteria |
| What are the factors responsible for the immunodeficiency state in multiple myeloma? | (1)Suppressed B cell function (2) Impaired neutrophil migration, adherence, and phagocytosis (3) Granulocytopenia (4) Chemotherapy/Radiotherapy (5) Renal Failure (6) Immobilization due to bone pain |
| What are the diagnostic criteria for multiple myeloma? | (1) Plasmacytosis>10% on bone marrow aspirate (2) 1 or both of the following:a)serum "M" protein >3 g/dL and/or Bence-Jones proteinuria or b)discrete osteolytic lesions |
| What are the diagnostic criteria for Monoclonal gammopathy of undetermined signifiance (MGUS)? | (1)Plasmacytosis<10% on bone marrow aspirate (2) Serum "M" protein <3 g/dL (3) No or minimal Bence-Jones proteinuria (4) No osteolytic leisons, anemia, or other organ dysfunction due to myelomatous process |
| What are the diagnostic criteria for smoldering multiple myeloma? | (1)Plasmacytosis >10% on bone marrow aspirate (2) Serum "M" protein >3g/dL and/or Bence-Jones proteinuria (3) No osteolytic lesions, anemia, or other organ dysfunction due to myelomatous process |
| What variables is the New International Staging System for multiple myelomas based on? | (1) Serum beta-2-microglobulin (2) Albumin levels |
| What is the criteria for Stage I based on the New International Staging System for multiple myeloma? | (1) Serum beta-2-microglobulin <3.5 mg/L (2) serum albumin >3.5g/dL |
| What is the criteria for Stage II based on the New International Staging System for multiple myeloma? | (1) Serum beta-2-microglobulin <3.5 mg/L but serum albumin <3.5g/dL or (2) Serum beta-2-microglobulin between 3.5-5.5 irrespective of the serum albumin |
| What is the criteria for Stage III based on the New International Staging System for multiple myeloma? | Serum beta-2-microglobulin >5.5 mg/L |
| (T or F) Rapid response to chemotherapy in multiple myeloma is a good prognostic factor. | False. A rapid response to chemotherapy is a poor prognostic factor. |
| (T or F) CALLA positivity is a poor prgnostic factor for multiple myeloma. | True. |
| Treatment for multiple myeloma | (1)Alkylating agents (2)High dose dexamethasone (3)Antiangiogenic agents (4)Proteasome inhibitors (5)Autologous peripheral stem cell transplantation (6)Radiotherapy (7)Chemotherapy combinations |
| A malignant disorder of B-cells which secrete a monoclonal IgM. | Waldenstrom's Macroglobulinemia |
| What are the clinical features of Waldenstrom's Macroglobulinemia? | (1)Mucosal bleeding (2)Hepatomegaly (3)Lymphadenopathy (4)Mental changes (5)Alterations in visual acuity (6)Fundal abnormalities (7)Anemia (8)Serum Hyperviscosity |
| What is the first line of therapy for Waldenstrom's Macroglobulinemia? | Alkylating agents: Chlorambucil and melphalan |
| A malignant disorder characterized as isolated or multiple plasma cell tumors which may be intraosseous or extramedullary in location. | Plasmacytoma |
| Treatment for plasmacytoma | High dose localized radiotherapy with curative intent |
| What disease process can plasmacytomas progress to? | Multiple myeloma |
| What is a common long-term complicaton of akylating agent therapy in multiple myeloma patients? | Acute nonlymphocytic leukemia |
| What techniques are used to visualize amyloid protein? | (1)Apple-green birefingence under plarized light after staining with Congo red (2) Bridging, nonbranching fibrils seen on elctron microscopy |
| Describe the formation of amyloid in tissues | It is the result of misfolding of proteins in the extracellular environment. The misfolded proteins form beta-pleated sheets which stack/aggregate and become resistant to proteolysis. |
| Definition of Primary Amyloidosis. | The predominant finding at diagnosis is amyloid deposition in the absence of other manifestations of myeloma. Most patients have less than 10% of plasma cells in the bone marrow at diagnosis. |
| Definition of mulitple myeloma with amyloidosis. | Manifestations of myeloma are present along with amyloid deposition. |
| Treatment for Primary Amyloidosis | No specific form of therapy |
| What protein are amyloid fibrils derived from in secondary amyloidosis? | Normal serum AA protein, an acute phase reactant found in high cirulating levels associated with chronic inflammatory states (eg familial Mediterranean fever, rhuematoid arthritis, tuberculosis). |
| Treatment for secondary amyloidosis | Treatment is directed at the underlying chronic inflammatory disorders. |
| Eitology of most hereditary forms of amyloidosis | Hereditary forms are due to an amino acid substitution in a normal protein rendering that protein amyloidogenic. |
| Treatment for familial amyloidosis due to the amyloidogenic protein, transthyretin? | Liver transplant is effective in arresting disease progression. |
| Definition of Monoclonal Gammopathy of Undetermined Significance (MGUS) | The presence of monoclonal immunoglobulin or subunit inthe plasma and/or urine int he absence of other clinical or laboratory manifestations considered to be diagnositc of overt multiple myeloma, primary amyloidosis, lymphoproliferative disorders. |
| (T or F) Similar to multiple myeloma, MGUS is more frequent in African-Americans than Caucasians. | True. |
| Management for MGUS | Blood counts+serum protein electrophoresis every 4-6 mo then annually if stable for 2-3 yrs. If excess urine light chain are found, a 24hr urinary protein+urinary protein electrophoresis+renal studies are needed every visit. |
| A clonal lymphoplasmacytic disorder characterized by secretion of mutated clonal heavy chain without a light chain localized to the small intestine. Symptoms include chronic diarrhea and malabsorption. Campylobacter jejuni may be a causative agent. | Immunoproliferative Small Intestinal Diseae (IPSID) (Alpha-Heavy-Chain-Disease) |
| What is stage A of Immunoproliferative Small Intestinal Diseae (IPSID) (Alpha-Heavy-Chain-Disease)? | Mature lymphoplasmacytic infiltrate in lamina propria |
| What is stage B of Immunoproliferative Small Intestinal Diseae (IPSID) (Alpha-Heavy-Chain-Disease)? | Appearance of atypical plasma cells and immunoblasts |
| What is stage C of Immunoproliferative Small Intestinal Diseae (IPSID) (Alpha-Heavy-Chain-Disease)? | Immunoblastic lymphoma |
| Geographic distribution of Immunoproliferative Small Intestinal Diseae (IPSID) (Alpha-Heavy-Chain-Disease) | Mediterranean area and Middle East |
| Treatment for Immunoproliferative Small Intestinal Diseae (IPSID) (Alpha-Heavy-Chain-Disease) | Antibiotic therapy (tetracycline, metronidazole, and ampicillin) results in complete remission, including immunologic remission in 40% of patients with Stage A disease. May take up to 6 months to achieve. |
| A clonal (gamma-heavy chains) lymphoplasmacytic proliferation in LNs, bone marrow, and spleen. Associated with autoimmune disorders in >25%. Symptoms include constitutional symptoms and palatal edema. | Gamma Heavy-Chain Disease. |
| A clonal lymphoplasmacytic disorder which evolves in the course of another lymphoplasmacytic process. It is characterized by young vacuolated plasma cells in bone arrow. Large amounts of kappa light chains are found in urine. | Mu-Heavy-Chain Disease |
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UVAPATH4
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