Plasma Cell Disorders

Question 1

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

Answer 1

• 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

Question 2

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

Answer 2

• 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

Question 3

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

Answer 3

• 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)

Question 4

What are the clinical findings of multiple myeloma?

Answer 4

• ​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

Question 5

What is the pathology and laboratory findings of multiple myeloma?

Answer 5

• 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

Question 6

What are the steps of diagnostic evaluation of multiple myeloma?

Answer 6

• 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

Question 7

What are the key diagnostic criteria for multiple myeloma?

Answer 7

• 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

Question 8

What are the general treatment options for multiple myeloma?

Answer 8

• 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

Question 9

What is plasmacytoma?

Answer 9

• 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

Question 10

What is POEMS syndrome? (not tested)

Answer 10

• 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

Question 11

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

Answer 11

• 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

Question 12

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

Answer 12

• 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