Plasma Cell Disorders Flashcards Preview

Heme/Onc > Plasma Cell Disorders > Flashcards

Flashcards in Plasma Cell Disorders Deck (12):
1

What is the definition of plasma cell disorders? What is the spectrum of disease?

  • Definition:
    • Plasma cell disorders or monoclonal gammopathies result from the expansion of a single clone of immunoglobulin secreting B cells
    • Polyclonal gammopathies consist of one or more different heavy chains with both kappa and lambda immunoglobulin (Ig) light chains
  • Spectrum of diseases:
    • Monoclonal gammopathies are associated with a variety of plasma cell disorders
    • These include plasma cell myeloma, (multiple myeloma), plasmacytomas, and primary amyloidosis
    • Monoclonal gammopathies can also occur without an identifiable underlying disease and are termed monoclonal gammopathy of undetermined significance (MGUS)
    • Monoclonal gammopathies can also be associated with lymphomas but they will not be discussed in this lecture

2

What are the initial steps of the initial diagnostic protein studies for plasma cell disorders?

  • Serum and urine protein electrophoresis (SPEP, UPEP) should be done when a plasma cell proliferative problem is suspected to determine how much and what types of protein are present
  • Immunofixation gel electrophoresis is more sensitive and is used to determine the specific subtypes of proteins detected by SPEP/UPEP
  • Symptoms that indicate testing for abnormal serum/urine proteins include:
    • weakness
    • fatigue
    • back pain
    • recurrent infections
    • laboratory evidence of anemia with increased protein gap
    • increased ESR
    • increased calcium
    • renal insufficiency
    • radiographic findings of lytic bone lesions
    • osteoporosis

3

What is multiple myeloma? What is the cause and epidemiology?

  • Definition:
    • Multiple myeloma represents a malignant proliferation of plasma cells derived from a single clone
    • The tumor, its products, and the host response to it result in a number of organ dysfunctions and symptoms, including:
      • bone pain or fracture
      • renal failure
      • susceptibility to infection
      • anemia
      • hypercalcemia
      • occasionally clotting abnormalities
      • neurologic symptoms
      • manifestations of hyperviscosity
  • Cause:
    • Unknown but frequency is increased with exposure to:
      • radiation
      • petroleum products
      • in wood and leather workers
      • in farmers. 
  • Epidemiology:
    • Comprise 15% of hematologic malignancies (1% all malignancies)
    • Median age at diagnosis is 70, more prevalent in African Americans vs Caucasian, and in M:F ( 4:3)

4

What are the clinical findings of multiple myeloma?

  • ​Anemia:
    • erythropoietin production from renal insufficiency, hemolysis, production of inhibitor factors
    • RBC production due to: marrow plasma cell infiltration
  • Bone pain:
    • Lytic bone lesions, pathologic fractures, diffuse bone loss and osteoporosis
    • Osteolytic bone lesions are the result of excessive bone resorption due to increased osteoclast formation and activity and suppressed bone mineralization by osteoblasts
    • This is caused by plasma cell-derived osteoclast-activating factors and cytokines (RANKL, MIP1α, IL3, IL6 etc.)
  • Hypercalcemia (corrected serum calcium level > 11.5mg/dL):
    • Secondary to progressive bone destruction
    • Patient may present with nausea, fatigue, confusion, polyuria or constipation
    • Considered oncological emergency and requires prompt treatment.
  • Renal insufficiency:
    • ~20% patients present with renal insufficiency and another 20% develop this complication in later phase of the disease
    • Myeloma cast nephropathy (myeloma kidney) is the most common cause
    • Other causes include amyloidosis and light chain deposition disease
    • Myeloma kidney
      • waxy laminated casts of precipitated monoclonal light chains in distal and collecting tubes
      • this causes dilation and atrophy of tubules lead to decreased functioning
      • light chain deposition in glomeruli produce renal insufficiency or nephrotic syndrome
      • hypercalcemia or hyperuricemia
      • amyloid deposits in kidney
  • Infection:
    • Myeloma patients have increased susceptibility to bacterial infections, especially with encapsulated organisms
    • This is due to impairment of host defense mechanisms, such as hypogammaglobulinemia (reduced production of normal functional immunoglobulins), granulocytopenia and decreased cell-mediated immunity
  • Neurologic involvement
    • Radiculopathy 2° to nerve compression by vertebral lesion or collapsed bone
    • Hyperviscosity most common with IgM, IgG3, and IgA
    • Spinal cord compression 10% of patients with MM
    • Peripheral neuropathy associated with amyloidosis
    • Rarely meningeal involvement

5

What is the pathology and laboratory findings of multiple myeloma?

  • Pathology:
    • Characterized by clonal proliferation of plasma cells that replaces normal bone marrow and produce monoclonal immunoglobulins
  • Laboratory findings:
    • Peripheral blood: normocytic, normochromic anemia with increased rouleaux formation
      • Plasma cells may be present
    • Bone marrow: plasmacytosis
      • Strongly positive for CD38, CD138 and cytoplasmic immunoglobulin (cIg)
      • Detect monoclonality by staining with antibodies to κ and l Ig light chains
    • Monoclonal proteins in the serum and/or urine: the type of monoclonal protein produced are IgG (60%), IgA (20%), IgD (2%), IgE (<0.1%) or light chain κ or l only (18%)
      • Biclonal occurs in <1%, and non-secretory (no Ig secreted in plasma) myeloma in <5%.
    • Reciprocal immunoglobulin changes: the affected immunoglobulin class is produced in excess, while the other immunoglobulin classes are usually depressed

6

What are the steps of diagnostic evaluation of multiple myeloma?

  • SPEP and UPEP
    • Detects protein and differentiates monoclonal vs. polyclonal gammopathy
    • Identical immunoglobulin molecules will have same size and electrical charge and will migrate to same spot and be detected as a monoclonal peak, M spike
    • 24 hour urine collection will quantitate amount of protein excreted
      • 20% of multiple myeloma secrete only Ig light chain which is excreted in urine; therefore no monoclonal protein is in the serum
  • Immunofixation electrophoresis
    • Identifies which types of  heavy and light chains are overproduced
  • Serum free light analysis
  • CBC,  Chemistry profile (Ca, Cr, Albumin, total protein, LDH quantitative immunoglobulins, b2 microglobulin)
  • Bone marrow aspirate and biopsy
  • Radiographic skeletal survey

7

What are the key diagnostic criteria for multiple myeloma?

  • Presence of an M-protein (no concentration specified) in serum and/or urine
  • Presence of clonal bone marrow plasma cells (>10%)
  • Presence of related organ or tissue impairment
    • increased plasma Calcium level
    • Renal insufficiency
    • Anemia
    • lytic Bone lesions
      • felt to be related to the underlying plasma cell proliferative disorder
      • lytic bone lesions are typically detected by a radiographic skeletal survey

8

What are the general treatment options for multiple myeloma?

  • Induction chemotherapy: chemotherapy, corticosteroids, novel agents (Thalidomide, Lenalidomide, Bortezomib) or combinations
  • High-dose chemotherapy (melphalan) followed by autologous stem cell transplant (for some patients)
  • Maintenance therapy (steroid, thalidomide, lenalidomide, bortezomib)
  • Melphalan-based combination chemotherapy for non-transplant candidates
  • Supportive therapy
  • Bisphosphonates: pamidronate or zolendronate.
  • Radiation – for local treatment of plasmacytoma or symptomatic relief

9

What is plasmacytoma?

  • A plasmacytomas is a single localized lesion in the bone (solitary plasmacytomas) or extramedullary tissue (extraosseous plasmacytomas) due to clonal plasma cell proliferation
  • The bone marrow not consistent with MM but a small M protein may be present
    • There is no related end organ damage
    • Up to 2/3 of patients with solitary plasmacytomas and a minority with extraosseous plasmacytomas evolve to MM or additional plasmacytomas

10

What is POEMS syndrome? (not tested)

  • POEMS syndrome is characterized by:
    • Polyneuropathy
    • Organomegaly
    • Endocrinopathy
    • Multiple Myeloma
    • Skin changes
  • It is a rare subtype of MM characterized by sclerotic myeloma bone lesions, and patients often have lymphadenopathy and splenomegaly
    • Polyneuropathy is sensorimotor
    • Endocrine abnormalities include:
      • type 2 diabetes mellitus
      • amenorrhea in women
      • impotence and gynecomastia in men
    • Treatment is similar to conventional MM

11

What is monoclonal gammopathy of undertermined significance (MGUS)? What are the diagnostic criteria?

  • MGUS is much more common than MM occurring in 1% of population older than 50yrs and 10% of those >75yrs old
  • About 1% per year of MGUS cases progress to MM or lymphoid neoplasm
  • The diagnostic criteria are:
    • No myeloma related organ or tissue impairment
    • No evidence of a B cell lymphoma is present
    • Clonal plasma cells in bone marrow <10%, and M protein <3mg/dl

12

What is primary amyloidosis (AL)? What are some associated conditions?

  • Pathogenesis:
    • Plasma cell neoplasm that secretes an abnormal immunoglobulin which forms a β pleated sheet and deposits in various tissues
    • Amyloid binds Congo red dye with characteristic apple green birefringence
  • Associated conditions:
    • Can occur as manifestation of myeloma or as an independent process that has monoclonal light chains without marrow evidence of myeloma or lymphoma (Primary amyloidosis)
  • Several types of proteins can form amyloid deposits and amyloidosis is classified according to the type of protein. eg:
    • Primary or immunoglobulin-light chain (AL), Plasma cell associated disease process
    • Secondary (AA) Amyloidosis - inflammation associated
    • Familial (AF)
    • Β-2 microglobulin amyloidosis ( renal failure)
  • Characterized by low level serum M component that is better detected by immunofixation than protein electrophoresis
    • Bone marrow has low numbers of plasma cells (~5%)
    • Bleeding complication due to adsorption of clotting factor X to amyloid occurs
    • Disease is rapidly progressive and fatal if untreated