Plasma Cell Dyscrasias

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 Indications for Laboratory Testing)
• 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 workup (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 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)
        • Connective tissue 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 more sensitive than urine IFE for M protein detection and characterization (initial diagnosis) 
      • 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 (usually in plasma) due to the clonal secretion of a single FLC by malignant plasma cells
      • The FLC ratio is indicated for the diagnosis 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
  • Cytogenetics – may be necessary to differentiate WM from IgM MM
    • IgH switch region rearrangements – t(14q32) predominant in MM
    • t(11;14) – high frequency in AL and IgM MM
  • FISH – more sensitive than cytogenetics for abnormalities 
• Expected laboratory findings for specific plasma cell dyscrasias

  Expected Laboratory Findings for Specific Plasma Cell Dyscrasias (International Myeloma Working Group Criteria)
  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 Symptomatic Serum 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) Beta-2 macroglobulin – level reflects tumor mass and is considered a standard measure of tumor burden Asymptomatic Above criteria (except no presence of end-organ damage) Plasma cell leukemia Absolute plasma cell count >2x109/L with plasma cells composing >20% of total leukocytes in peripheral blood WM Serum IgM M protein (regardless of the size of the M protein) Bone marrow lymphoplasmacytic 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 Immunoglobulin deposition diseases Primary 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 Light and heavy chain deposition diseases 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
  Dispenzieri, 2009

Histology

• Bone marrow biopsy
  • Immunophenotyping by flow cytometry – may be useful for initial diagnosis and monitoring response to therapy by identification of clonal plasma cell populations
    • Flow cytometry is not accurate in enumeration of plasma cell numbers
      • Minimum of 100 neoplastic cells necessary for accuracy
    • Flow may help differentiate MGUS from MM
      • In MGUS, >5% of plasma cells are normal; in MM, <5% are normal
    • Analysis of CD38, 56, 19, 45, and 138 allows for MM diagnosis in ~90% of patients
      • Addition of CD27, 117, and 20 identifies the remainder
      • MM – typically express CD138 (syndecan-1), CD38 (usually dim)
      • Other myeloma markers may include CD56, CD28, CD20, and CD117
      • Myelomas rarely express CD19 (lymphomas typically are CD19, 45, 38+, and CD56-)
    • WM – typically CD25+, CD21+, CD79–, FMC7+, BCL2+,  BCL6–, CD138+
    • PCL – CD38+, CD138+, CD20+; reduced expression of CD117, CD9, CD56
  • Immunohistochemistry staining – kappa or lambda staining should be sufficient for diagnosis unless lymphoma is suspected
    • CD38 or CD138 may help to highlight plasma cells
    • CD56 reaction confirms malignant nature of the infiltrate
    • Ki-67 identifies neoplastic plasma cells; indicates high-grade tumor when present
    • WM – typically sigM+, CD19+, CD20+, CD22+
      • CD5, CD10, or CD23 expressed in ~20% of cases but does not exclude diagnosis of WM

Imaging Studies

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

Prognosis

• New proposed molecular cytogenetic classification by IMWG (2009)
• Further testing for prognostication – FISH, cytogenetics, beta-2 microglobulin
  • Microglobulins
    • Three stages as defined by international staging system with >3.5 g/L being poor prognosis
  • Albumin
    • Decreased level 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 17p13 deletion associated with worse prognosis in MM
    • Presence of t(11;14), t(6;14), or hyperploidy associated with better prognosis
  • Plasma cell labeling index (PCLI) studies
    • PCLI ≥3% associated with poor prognosis
  • Flow cytometry
    • CD117+ – associated with longer progression, free survival
    • CD28+ – associated with higher risk cytogenetics and more organ involvement

Differential Diagnosis

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

Screening

Monitoring

Clinical Background

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

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 Sex – M>F Ethnicity – African Americans have double the risk of Caucasians; Asians have lowest risk Definition Premalignant disorder – risk of MGUS progressing to multiple myeloma (MM) or other related disorder increases 1% per 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; ongoing trials to evaluate if any treatment prevents progression to MM Follow patient to detect transformation to malignancy

  Multiple myeloma (MM)

  Epidemiology Incidence – 3-9/100,000 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 – twofold 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 Clinical Presentation May be asymptomatic (up to 1/3 of patients) Constitutional – weight loss, fatigue, anorexia, somnolence, 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, pathologic fracture, cord compression, anemia (Hgb <10 g/dL), hypercalcemia (serum calcium >11.5 mg/dL), renal failure (creatinine >1.95 mg/dL), symptomatic hyperviscosity, or amyloidosis Treatment Oral chemotherapy and bone marrow transplant

  Waldenström macroglobulinemia (WM)

  Epidemiology Incidence – 5/1,000,000 Age – average onset is 65 years Definition Malignant proliferation of lymphoid and plasma cells Clinical Presentation Many patients are asymptomatic; disease discovered through routine blood tests Most common presenting symptoms Hyperviscosity – headaches, blurred vision, epistaxis, 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 Bone fractures, severe osteoporosis Treatment No cure; disease progress may be slowed with oral chemotherapy and plasmapheresis for hyperviscosity

  Monoclonal light-chain amyloidosis (AL)

  Epidemiology Incidence – 5-13/100,000 Definition Malignant disorder of plasma cells 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 Incidence – rare Definition Malignant disorder 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

• Plasma cell leukemia (PCL)

  Epidemiology Age – median is 55 years Sex – M>F (minimal) Definition Absolute plasma cell count >2x109/L with plasma cells composing >20% of total leukocytes in peripheral blood Clinical Presentation Frequent bone involvement Renal failure common High incidence of extramedullary involvement Treatment Very poor prognosis Chemotherapy not highly successful Inability to induce remission often precludes bone marrow transplant

  POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes) syndrome

  Epidemiology Incidence – rare Age – 40s-50s Definition Paraneoplastic disorder associated with underlying plasma cell dyscrasias Clinical Presentation Major feature of disease is chronic, progressive polyneuropathy with prominent motor disability Hyperpigmentation common High risk of deep vein thromboses (both venous and arterial) Often coexists with Castleman disease Endocrine – hypogonadism most common, followed by thyroid and glucose abnormalities

  Immunoglobulin heavy-chain disease (includes α chain, γ chain, and μ chain disease)

  Epidemiology Incidence α chain disease – most common heavy-chain disease; seen especially in the Mediterranean γ chain disease – most common in the elderly μ chain disease – least common heavy-chain disease Clinical Presentation α chain disease Massive infiltration of lamina propria of intestine and abdominal lymph nodes by lymphocytes, plasma cells, and histiocytes, causing villous atrophy and malabsorption γ chain disease Resembles malignant lymphoma more than multiple myeloma Lymphadenopathy, anemia, fever, and often splenomegaly or hepatomegaly μ chain disease Splenomegaly and hepatomegaly; lymphadenopathy is rare

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: Quantitative Capillary Electrophoresis	SPEP can be used to monitor treatment response when plasma cell dyscrasia is known

Diagnostic Algorithm

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

  Plasma Cell Dyscrasias Testing Algorithm