Plasma Cell Dyscrasias

Plasma cell dyscrasias are characterized by clonal protein accumulation. Symptoms occur due to clonal expansion, but also secondarily due to abnormal protein effects (amyloid deposition, renal failure). There are several types of plasma cell neoplasms, including monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma.

  • Diagnosis
  • Algorithms
  • Screening
  • Monitoring
  • Background
  • Lab Tests
  • References
  • Related Topics

Indications for Testing

  • Unexplained anemia, elevated serum protein, bone pain with lytic lesions on plain films, recurrent infections, renal failure, hypercalcemia, fatigue, or other systemic symptoms indicating malignancy
  • Age-inappropriate bone fractures with no known risk factors
    • Premenopausal females
    • Males <65 years
  • Unexplained proteinuria
  • Unexplained peripheral neuropathy
  • Premalignant condition (eg, monoclonal gammopathy) detected incidentally in asymptomatic patient
  • Solitary plasmacytoma visualized on imaging or with local symptoms

Criteria for Diagnosis

Laboratory Testing

  • Initial diagnostic workup
    • CBC with differential
      • Anemia – not uncommon
        • Typically normochromic normocytic
        • If anemia is disproportionate to disease, consider hemolytic workup – reticulocyte count, haptoglobin, cold agglutinin, direct and indirect Coombs
      • Platelet disturbances
        • Thrombocytosis – rare; consider polyneuropathy, organomegaly, endocrinopathy, M protein, and evaluation of POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes)
      • Leukocytosis – rare except in plasma cell leukemia (PCL)
        • Plasma cells ≥20% on smear confirms PCL
    • Serum protein electrophoresis (SPEP)
      • Quantifies M protein
      • Can be normal in patients with oligosecretory or nonsecretory myeloma
        • Oligosecretory – M protein concentration below detection threshold of SPEP
        • Nonsecretory – no identification of M protein in serum or urine
    • Serum immunofixation electrophoresis (IFE)
      • More sensitive than SPEP for M protein detection and characterization
      • Particularly useful in early identification of minor M proteins or monoclonal components initially identified by abnormal banding patters on SPEP
    • Urinary protein electrophoresis (UPEP) with immunofixation (24 hour)
      • In plasma cell dyscrasia, a proteinuria pattern may show a discrete band in the α2, β, or γ region
      • Produced by monoclonal FLC components (Bence Jones protein)
    • Free kappa (κ) and lambda (λ) light-chains testing (serum)
      • Abnormal κ-to-λ FLC ratio due to clonal secretion of a single FLC by malignant plasma cells in plasma cell dyscrasias
      • FLC ratio is indicated for diagnosis of patients with oligosecretory or nonsecretory multiple myeloma (MM) and amyloid light-chain (AL) amyloidosis
    • Calcium (serum)
    • Creatinine (serum)
  • Extended workup for classification and staging
    • Bone marrow aspiration and biopsy
    • Lactate dehydrogenase (LDH)
    • Albumin (serum)
    • Beta-2 microglobulin (serum)
    • Viscosity measurement
      • Consider if signs of hyperviscosity present
        • Blurred vision, retinal hemorrhage, stroke
      • Increased viscosity suggests Waldenström macroglobulinemia (WM)
    • Complete metabolic profile


  • Bone marrow aspiration and biopsy required for diagnosis
    • Morphology
      • >10% clonal plasma cells confirms MM
      • CD138 stains should be used to determine percentage of plasma cells
    • Flow cytometry
    • Cytogenetics
  • Plasmacytoma – biopsy indicated
  • Amyloidosis suspected – tissue biopsy required
  • Chromosome analysis
  • Fluorescence in situ hybridization (FISH) on plasma cells
    • Performed on plasma cells purified by cell selection (CD138+ isolation) or in combination with cytoplasmic immunoglobulin staining (cIg-FISH)
    • Probes (Palumbo, International Myeloma Working Group [IMWG], 2015)
      • Recommended panel for prognostic assessment – include, at the minimum (National Comprehensive Cancer Network [NCCN], 2017)
        • 1q21 (CKS1B) gain/amplification
        • t(4;14)(p16;q32) (IGH-FGFR3/NSD2) – high risk
        • t(14;16)(q32;q23) (IGH-MAF) – high risk
        • 17p13 (TP53) deletion – high risk
      • Additional probes
        • Common trisomies (+3, +7, +9, +11, and/or 15)
        • 1p (1p32 or 1p21) deletion
        • t(6;14)(p21;q32) (IGH-CCND3)
        • 8q24 (MYC) rearrangement
        • t(11;14)(q13;q32) (IGH-CCND1)
        • 13q- or 13q (RB1/LAMP1) deletion
        • 14q32 (IGH) rearrangement
        • t(14;20)(q32;q12) (IGH-MAFB)
  • Immunophenotyping by flow cytometry
    • May be useful for initial diagnosis, classification, and monitoring response to therapy by identification of clonal plasma cell populations
    • Plasma cell
      • Normally express CD19, CD38 (bright), CD45 (dim to negative), and CD138
      • Clonal plasma cells are mostly CD19 negative
        • May express additional aberrant markers including CD20, CD56, and CD117
        • Cytoplasmic κ or λ light-chain restricted
      • Flow cytometry should not be used to enumerate plasma cells
    • Myelomas rarely express CD19 (lymphomas typically express CD19, CD38, CD45, and are negative for CD56)
  • Immunohistochemistry (IHC) staining
    • CD138 may help to highlight plasma cells
    • Use κ and λ staining for clonality
    • Amyloidosis may be present in plasma cell dyscrasias
      • Diagnosis of plasma cell proliferative disorder is necessary for this diagnosis
      • AL amyloidosis is a tissue diagnosis
      • Biopsy of an affected site using special stains
        • Required to recognize AL amyloidosis – Congo red, thioflavin T, sulfated Alcian blue
        • Gold standard – Congo red avidity with apple-green birefringence under polarized light
      • ​Amyloidosis subtyping is next step after amyloidosis is identified
        • Use direct sequencing, mass spectometry, immunostaining to identify subtype
        • Presence of serum or urine monoclonal protein does not ensure AL amyloidosis diagnosis
        • Other paraproteins can cause amyloidosis – confirmation of subtyping is necessary

Imaging Studies

  • Skeletal survey x-ray with specific views of affected sites
  • CT scan
  • Positron emission tomography (PET)/CT
  • Magnetic resonance imaging (MRI)


  • Risk for MM determined based on traditional criteria
    • Albumin, LDH, and beta-2 microglobulin in combination with cytogenetics

Differential Diagnosis

No recommendation for universal screening

  • Imaging and lab testing are used to evaluate disease response
  • Traditional definitions of multiple myeloma response included
    • Serum protein electrophoresis (SPEP) with immunofixation (IFE)
    • Urinary protein electrophoresis (UPEP) with IFE
    • Serum free light-chain analysis
    • Bone marrow plasma cell quantification
  • Several methods are being studied to detect minimal residual disease (MRD), but there is no current consensus on approach (Kumar, 2016)
    • Multiparametric flow cytometry (MFC)
    • Allele-specific oligonucleotide (ASO)-quantitative polymerase chain reaction (qPCR)  
    • Tandem mass spectometry
    • Next generation sequencing of VDJ sequences
      • International Myeloma Working Group (IMWG) also recommends use of next generation sequencing to evaluate MRD in bone marrow (Kumar, 2016)
  • National Comprehensive Cancer Network (NCCN) (2017) guidelines list specific criteria for categorizing disease as stable, progressive, or clinical relapse following treatment

Risk Factors

  • Ionizing radiation
  • Farm and industrial petrochemical  exposure

Specific Plasma Cell Dyscrasias

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.

Monoclonal Protein Detection Quantitation and Characterization, SPEP, IFE, IgA, IgG, IgM, Serum 0050615
Method: Qualitative Immunofixation Electrophoresis/Quantitative Capillary Electrophoresis/Quantitative Nephelometry

Protein Electrophoresis with Reflex to Immunofixation Electrophoresis Monoclonal Protein Detection, Quantitation & Characterization, IgA, IgG, & IgM, Serum 2002109
Method: Quantitative Capillary Electrophoresis/Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

Bence Jones Protein, Quantitation and Characterization, with Reflex to Kappa/Lambda Free Light Chains with Ratio, Urine 2002464
Method: Semi-Quantitative Electrophoresis/Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

Kappa/Lambda Quantitative Free Light Chains with Ratio, Serum 0055167
Method: Quantitative Nephelometry

MYD88 L265P Mutation Detection by PCR, Quantitative 2009318
Method: Real-time Polymerase Chain Reaction


Does not detect mutations in other regions of the MYD88 gene

Does not detect MYD88 codon 265 mutations other than L265P

Results of this test must be interpreted in the context of morphological and other relevant data

Test should not be used alone to diagnose malignancy

Immunofixation Electrophoresis, Immunoglobulin D and Immunoglobulin E, Serum 0050049
Method: Qualitative Immunofixation Electrophoresis

Beta-2 Microglobulin, Serum or Plasma 0080053
Method: Quantitative Immunoturbidimetry

Chromosome Analysis, Bone Marrow 2002292
Method: Giemsa Band

Multiple Myeloma Panel by FISH 2002294
Method: Fluorescence in situ Hybridization


Only detects aberrations specific to probes utilized

Kappa/Lambda Light Chain Panel by In Situ Hybridization, Stain Only 2013595
Method: In Situ Hybridization

Viscosity, Serum 0020056
Method: Quantitative Viscometry

Viscosity, Whole Blood 0020054
Method: Quantitative Viscometry

Leukemia/Lymphoma Phenotyping by Flow Cytometry 2008003
Method: Flow Cytometry


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Munshi NC, Anderson KC, Bergsagel L, Shaughnessy J, Palumbo A, Durie B, Fonseca R, Stewart K, Harousseau J, Dimopoulos M, Jagannath S, Hajek R, Sezer O, Kyle R, Sonneveld P, Cavo M, Rajkumar V, San Miguel J, Crowley J, Avet-Loiseau H, International Myeloma Workshop Consensus Panel 2. Consensus recommendations for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood. 2011; 117(18): 4696-700. PubMed

NCCN Clinical Practice Guidelines in Oncology, Multiple Myeloma. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: May 2017]

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Palumbo A, Avet-Loiseau H, Oliva S, Lokhorst HM, Goldschmidt H, Rosiñol L, Richardson P, Caltagirone S, Lahuerta JJ, Facon T, Bringhen S, Gay F, Attal M, Passera R, Spencer A, Offidani M, Kumar S, Musto P, Lonial S, Petrucci MT, Orlowski RZ, Zamagni E, Morgan G, Dimopoulos MA, Durie BG, Anderson KC, Sonneveld P, San Miguel J, Cavo M, Rajkumar V, Moreau P. Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group. J Clin Oncol. 2015; 33(26): 2863-9. PubMed

Protocol for the Examination of Specimens From Patients With Hematopoietic Neoplasms Involving the Bone Marrow. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Jun 2012. College of American Pathologists (CAP). Northfield, IL [Revised: Jun 2012; Accessed: May 2017]

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General References

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Bladé J, Dimopoulos M, Rosiñol L, Rajkumar V, Kyle RA. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol. 2010; 28(4): 690-7. PubMed

Chee CE, Dispenzieri A, Gertz MA. Amyloidosis and POEMS syndrome. Expert Opin Pharmacother. 2010; 11(9): 1501-14. PubMed

Davids MS, Murali MR, Kuter DJ. Serum free light chain analysis. Am J Hematol. 2010; 85(10): 787-90. PubMed

Dispenzieri A, Buadi FK. A review of POEMS syndrome. Oncology (Williston Park). 2013; 27(12): 1242-50. PubMed

Dispenzieri A. POEMS syndrome: 2014 update on diagnosis, risk-stratification, and management. Am J Hematol. 2014; 89(2): 214-23. PubMed

Dispenzieri A. POEMS syndrome: update on diagnosis, risk-stratification, and management. Am J Hematol. 2015; 90(10): 951-62. PubMed

FernándezdeLarrea C, Delforge M, Davies F, Bladé J. Response evaluation and monitoring of multiple myeloma. Expert Rev Hematol. 2014; 7(1): 33-42. PubMed

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Kraj M. Immunoglobulin heavy chain/light chain pairs (HLC, Hevylite™) assays for diagnosing and monitoring monoclonal gammopathies. Adv Clin Exp Med. 2014; 23(1): 127-33. PubMed

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Levinson SS. POEMS syndrome: importance of the clinical laboratory practitioner's role. Clin Chim Acta. 2012; 413(21-22): 1800-7. PubMed

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Treon SP, Cao Y, Xu L, Yang G, Liu X, Hunter ZR. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenstrom macroglobulinemia. Blood. 2014; 123(18): 2791-6. PubMed

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References from the ARUP Institute for Clinical and Experimental Pathology®

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Medical Reviewers

Content Reviewed: 
June 2017

Last Update: October 2017