Plasma Cell Dyscrasias

Diagnostic Algorithm

  Immunodeficiency Evaluation for Chronic Infections in Adults and Older Children Testing Algorithm

  Plasma Cell Dyscrasias Testing Algorithm

Clinical Background

Plasma cell dyscrasias (immunosecretory disorders) are a diverse group of diseases characterized by accumulation of IgG clones.

Risk Factors

• Ionizing radiation
• Farm and petrochemical industrial exposure

Specific Plasma Cell Dyscrasias

Monoclonal Gammopathy of Unknown Significance (MGUS)

• Incidence
  • Most common plasma cell dyscrasia – 1-2/100 in patients >50 years
    • 50 years – 3% of individuals
    • ≥70 years – 5% of individuals
    • ≥85years – 7.5% of individuals
  • Premalignant disorder – risk of MGUS progressing to multiple myeloma (MM) or other related disorder increases 1% each year over lifetime
• Clinical presentation
  • Asymptomatic in most patients
  • ~20% of MM develops from MGUS
    • Elevated monoclonal (M) protein level, non-IgM MGUS and abnormal free light chain (FLC) ratio increase risk of MM to 58% over 20 years
• Treatment
  • None required
  • Follow patient to detect transformation to malignancy

Multiple Myeloma (MM)

• Epidemiology
  • Incidence – 5-7/100,000 in U.S.
  • Age – median onset is 66-70 years; <5% of individuals <40 years (younger patients often have more aggressive disease)
  • Sex – M>F, 1.4:1
  • Ethnicity – two-fold increased incidence in African Americans (most common lymphoid malignancy in these patients)
• Categories
  • Light-chain MM
    • Up to 20% of patients with MM lack heavy-chain expression in the M protein
  • Nonsecretory MM
    • 3% have no detectable M protein in serum or urine
  • Plasma cell leukemia
    • Absolute plasma cell count >2x10⁹/L with plasma cells comprising >20% of total leukocytes in peripheral blood
• Clinical presentation
  • May be asymptomatic (up to 1/3 of patients)
  • Constitutional – weight loss, fatigue, anorexia, somnolencem malaise
  • Musculoskeletal – bone pain, back pain, pathologic fractures (25-35% of presenting patients)
  • Neurological  – neuropathy (carpal tunnel most common), paresthesias
  • Metabolic – nausea and polydipsia are signs and symptoms of hypercalcemia
  • Recurrent infections – encapsulated organisms most common, especially pneumonia
  • Hematologic – weakness from anemia
  • Complications – pain, hypercalcemia, renal disease, infection
  • End organ damage – lytic bone lesions, anemia, hypercalcemia or renal failure
• Treatment
  • Oral chemotherapy and bone marrow transplant

Waldenström Macroglobulinemia (WM)

• Epidemiology
  • Malignant proliferation of lymphoid and plasma cells
  • Incidence – 7-10/100,000
• Clinical presentation
  • Most common presenting symptoms
    • Hyperviscosity – headaches, blurred vision, lepistaysis, retinal hemorrhage
    • Anemia
    • Constitutional symptoms – weakness, fatigue, night sweats, weight loss
    • Raynaud phenomenon – acrocyanosis, ulcers, purpura (secondary to cryoglobulinemia)
    • Lymphadenopathy
    • Hepatosplenomegaly, macroglossia (due to amyloid deposition)
    • Peripheral neuropathies, foot drop (secondary to autoantibodies – myelin-associated glycoprotein [MAG], GM1)
  Treatment
  • Oral chemotherapy and plasmapheresis for hyperviscosity

Monoclonal Light-Chain Amyloidosis (AL) 

• Epidemiology
  • Malignant disorder of plasma cells
  • Incidence – 5-13/100,000
• Clinical presentation
  • Varies – may be asymptomatic; determined by dominant organ involved
  • Nephrotic syndrome, restrictive cardiomyopathy and peripheral neuropathy are common presenting syndromes
• Treatment
  • Oral chemotherapy and bone marrow transplant

Solitary Plasmacytoma (SP)

• Epidemiology
  • Malignant disorder
  • Incidence – rare
• Clinical presentation
  • Absence of end organ damage attributable to a plasma cell proliferative disorder
  • Most common in medullary sites but can occur in extramedullary sites
    • 80% localized in the upper respiratory tract (nasal cavity, sinuses and nasopharynx)
  • Risk of progression to MM
• Treatment
  • Therapy includes radiation of the involved site

Rare Plasma Cell Dyscrasias 

• POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome
• Immunoglobulin heavy-chain disease

Diagnosis

Indications for Testing

• Bone pain, recurrent infections, anemia, lytic lesions on plain films

Laboratory Testing 

• Major differential diagnosis is between MGUS, MM and AL; use of the following tests aids the clinician in determining disease (also refer to Lab Tests)
• Initial testing 
  • CBC with differential
    • Anemia not uncommon – typically normochromic normocytic
    • Thrombocytopenia uncommon (10-15%)
    • Leukocytosis rare
  •  If anemia is out of proportion to disease, consider hemolytic work-up (reticulocyte counts, haptoglobin, cold agglutinins, direct and indirect Coombs)
  • Serum viscosity measurement
    • Order if hyperviscosity symptoms present
    • Serum or whole blood specimen
  • Electrolytes, BUN, calcium, lactate dehydrogenase [LD], protein, albumin
    • LD, calcium, creatinine may be elevated – suggests end organ damage
• Additional testing 
  • SPEP or IFE next, followed by bone marrow biopsy if suspicious of plasma cell dyscrasias
    • SPEP
      • Quantifies M protein
      • If serum M-component >3 g/L – perform bone marrow biopsy
      • SPEP can be normal in patients with oligo-secretory (~10-15%) or non-secretory myeloma (~1%)
      • Abnormal patterns of protein fraction values are observed in various conditions
        • Inflammatory and infectious disorders (polyclonal gamma increase)
        • Rheumatic disease (polyclonal gamma increase)
        • Protein-losing disorders
        • Chronic liver disease (polyclonal gamma increase)
        • Chronic renal disease (polyclonal gamma decrease)
        • Genetic and metabolic disorders
    • IFE
      • Serum IFE is a more sensitive method for M protein detection and characterization 
      • Particularly useful in early identification of minor M proteins or FLC M-components initially identified by abnormal banding patterns seen on SPEP
  • May need to follow with Bence Jones protein (urine) and free kappa and lambda light chains (urine,serum) based on above results
    • In plasma cell dyscrasia, a proteinuria pattern may show a discrete band in the alpha-2, beta, or gamma region
      • Produced by M-components or Bence Jones protein
    • Patients with plasma cell dyscrasias have an abnormal kappa to lambda FLC ratio due to the clonal secretion of a single FLC by malignant plasma cells
      • The FLC ratio is indicated for the diagnosis and monitoring of patients with oligo-secretory or non-secretory MM and AL
      • If all the above results do not fulfill criteria for MGUS, MM, or WM, then AL should be suspected
        • Tissue biopsy required
• Immunohistochemistry –  CD138 usually positive in plasma cells; neoplastic plasma cells will usually show kappa or lambda light chain restriction
  •  CD20 is usually negative but CD79a may be positive
  • Monoclonality may also be detected using kappa and lambda in situ hybridization
• Cytogenetics – may be necessary to differentiate WM from IgM myeloma
  • IgH switch region rearrangements (14q32 translocations predominate in MM)
• Flow cytometry – may be useful for initial diagnosis and monitoring response to therapy by identification of clonal plasma cell populations, although flow cytometry is not accurate in enumeration of plasma cell numbers
  • Myelomas typically express CD138 (syndecan-1), CD38 and monotypic cytoplasmic immunoglobulin light chains
    • Other myeloma markers may include – CD56, CD28 and CD117
    • Myelomas rarely express CD19
• Expected laboratory findings for specific plasma cell dyscrasias (International Myeloma Working Group [IMWG] Criteria [Dispenzieri, 2009])
  • MGUS
    • Serum M protein levels ≤3 g/dL and bone marrow plasma cells ≤10%
    • Absence of end organ damage – lytic bone lesions, anemia, hypercalcemia or renal failure
  • MM
    • Serum and or urinary M protein levels ≥3 g/dL
    • Bone marrow plasma cells ≥10%
    • Similar to normal heavy chain distribution in serum; approximately 50-75% of monoclonal gammopathies are IgG, 20% are IgA and <1% are IgD; IgE gammopathies rare
    • Presence of end organ damage (defined as hypercalcemia, renal failure, anemia or bone lesions)
      • If no end organ damage noted, disease referred to as smoldering MM (SMM)
  • WM
    • Serum IgM M protein (regardless of the size of the M protein)
    • Bone marrow lymphoplasmatic infiltration ≥10%
    • Presence of end organ damage (defined as anemia, hyperviscosity, lymphadenopathy or hepatosplenomegaly)
      • If no end organ damage noted, disease referred to as indolent or asymptomatic WM
  • SP
    • Biopsy of proven lesion with evidence of clonal plasma cells
    • Normal bone marrow
    • Normal skeletal survey (except for lesion site)
    • Absence of end organ damage
  • AL
    • Presence of amyloid-related organ system involvement
      • Evidence of a monoclonal plasma cell proliferative disorder by serum or urine M protein or by clonal plasma cells in the bone marrow
      • Evidence that amyloid is light chain related (established by immunohistochemistry, direct sequencing)
    • Deposit of a fibrillar proteinaceous material (detected by Congo red staining) in various tissues such as liver, kidney, heart, peripheral nerves, tongue and subcutaneous tissue
    • Presence of end organ damage
  • POEMS syndrome
    • Presence of monoclonal plasma cell disorder
    • Peripheral neuropathy and at least one of the following
      • Osteosclerotic bone lesions
      • Castleman disease
      • Organomegaly
      • Endocrinopathy (excluding diabetes mellitus and thyroid disease)
      • Edema
      • Typical skin changes
      • Papilledema

Imaging Studies

• Skeletal survey x-ray of affected sites – lytic lesions are frequent in MM and WM
• MRI/PET/CT – if skeletal survey negative and lesions suspected

Prognosis

• Further testing for prognostication – FISH, Cytogenetics, beta-2 microglobulin
  • Microglobulins
    • Elevated (>2.5 mg/L) – associated with worse prognosis in MM
  • Albumin
    • Decreased levels associated with poor prognosis in MM
  • FLC
    • Elevated level associated with poor prognosis in MM, MGUS, SMM and SP
  • Cytogenetics
    • Presence of hypoploidy and del 13 associated with worse prognosis in MM
  • FISH
    • Presence of t(4;14), t(14;16) or 17p deletion associated with worse prognosis
  • Plasma cell labeling index (PCLI) studies
    • PCLI ≥3% associated with poor prognosis

Differential Diagnosis

• Connective tissue diseases
• Metastatic bone disease
• Paget disease
• Infectious disorders
• Rheumatic disease
• Protein-losing disorders
• Chronic liver disease
• Chronic renal disease
• Genetic and metabolic disorders
• Non-Hodgkin lymphoma
• Vitamin D deficiency
• Hypoparathyroidism
• Polymyalgia rheumatica

Monitoring

Indications for Laboratory Testing

• Tests generally appear in the order most useful for common clinical situations
• Click on number for test-specific information in the ARUP Laboratory Test Directory

Click the plus sign to expand the table of additional tests.

Test Name and Number	Comments
Protein Electrophoresis, Serum 0050640 Method: Capillary Electrophoresis	SPEP can be used to monitor treatment response when plasma cell dyscrasia is known