Plasma Cell Disorders Flashcards Preview

Heme/Onc > Plasma Cell Disorders > Flashcards

Flashcards in Plasma Cell Disorders Deck (12):

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


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


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)


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


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


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


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


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


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


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


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


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