Plasma Cell Dyscrasias

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

Indications for Testing

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

Laboratory Testing

  • Major differential diagnosis is between monoclonal gammopathy of undetermined significance (MGUS), multiple myeloma (MM), and monoclonal light-chain amyloidosis (AL)
  • 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
        • Thrombocytopenia – uncommon
        • Thrombocytosis – rare; consider polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome evaluation
      • Leukocytosis – rare; except in plasma cell leukemia (PCL)
        • Plasma cells ≥20% on smear confirms PCL
    • Electrolytes, blood urea nitrogen (BUN), calcium, lactate dehydrogenase (LD), protein, albumin
      • For evaluation of end-organ damage in determination of MGUS versus MM
    • Viscosity measurement (serum, whole blood)
      • Order if hyperviscosity symptoms present (eg, blurred vision, retinal hemorrhage, stroke)
        • Increased viscosity suggests Waldenström macroglobulinemia (WM)
    • Evaluate for other causes of chronic infections – HIV, immunoglobulin deficiencies, autoimmune disorders, malignancy, chronic inflammatory disease (eg, liver disease)
  • MM specifications
    • Serum protein electrophoresis (SPEP) with urine protein electrophoresis (UPEP), immunofixation electrophoresis (IFE), and serum free light chain (kappa [κ], lambda [λ]) analysis followed by bone marrow biopsy if suspicious for plasma cell dyscrasias
      • SPEP with UPEP
        • Urine test requires 24-hr collection
        • Quantifies M protein
        • SPEP can be normal in patients with oligosecretory or nonsecretory myeloma
          • Oligosecretory – proteins reduced to levels that make detection difficult by standard tests
          • Nonsecretory – no identification of serum or urine proteins or free light chains
      • IFE (serum, urine)
        • Serum IFE is more sensitive than urine IFE for M protein detection and characterization for initial diagnosis
        • Particularly useful in early identification of minor M proteins or free light chain (FLC) M-components initially identified by abnormal banding patterns on SPEP
        • In plasma cell dyscrasia, a proteinuria pattern may show a discrete band in the alpha (α)-2, beta (β), or gamma (γ) region
          • Produced by M-components or Bence Jones protein
      • Free κ and λ light chains testing (urine, serum)
        • Abnormal κ-to-λ FLC ratio (usually in plasma) due to the clonal secretion of a single FLC by malignant plasma cells in plasma cell dyscrasias
        • FLC ratio is indicated for the diagnosis of patients with oligosecretory or nonsecretory MM and AL
        • Bence Jones protein measurements may be necessary

Histology

  • Morphology
    • >10% clonal plasma cells confirms MM
      • CD138 stains should be used to determine percentage of plasma cells
  • 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
    • Molecular testing may help to confirm WM/lymphoplasmacytic lymphoma (LPL)
      • MYD88 L265P gene mutation found in >90% of patients with WM
        • Not detected in MM MGUS or MM
        • May be detected other lymphoproliferative disorders such as marginal zone lymphomas
        • MYD88 L256P is marker of risk for disease progression to WM in patients with WM MGUS
      • CXCR4 gene
        • Mutations are similar to those found in warts, hypogammaglobulinemia, immunodeficiency, myelokathexis (WHIM) syndrome
        • CXCR4 gene mutations and WHIM syndrome – associated with decreased response to tyrosine kinase inhibitors
  • FISH
    • More sensitive than cytogenetic testing
    • IGH/CCND1 t(11;14)
    • CKS1B (1q21)
    • IGH (14q32)
    • TP53 (17p13.1)
    • 11q13/15q22/9q34 for ploidy analysis
    • If IGH gene rearrangement is detected that does not involve the CCND1 gene, additional probes are added
      • IGH/FGFR3 t(4;14)
      • IGH/MAF t(14;16)
  • 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 cytometry may help differentiate MGUS from MM
      • In MGUS – >5% of plasma cells are normal
      • In MM – <5% are normal
    • MM
      • CD19, CD38, CD45, CD56, and CD138 – positive in ~90% of MM patients
        • Addition of CD20, CD27, and CD117 identifies the remainder
      • Typically express CD138 (syndecan-1), CD38 (usually dim)
      • Other myeloma markers may include CD20, CD28, CD56, and CD117
      • Myelomas rarely express CD19 (lymphomas typically are CD19, CD38+, CD45, and CD56-)
    • WM
      • Typically CD19, CD20, and CD22 – positive
      • CD5, CD10, and CD23 – may be positive (but not usually)
    • Plasma cell leukemia (PCL) – CD20+, CD38+, CD138+; reduced expression of CD9, CD56, CD117
  • Immunohistochemistry staining – κ or λ 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
  • AL is a tissue diagnosis
    • Biopsy of an affected site using special stains
      • Required to recognize AL – 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

Imaging Studies

  • Skeletal survey x-ray with specific views of affected sites – lytic lesions found in MM and WM
  • Magnetic resonance imaging (MRI)/positron emission tomography (PET)/computed tomography (CT) – if skeletal survey negative and lesions suspected

Prognosis

  • Multiple myeloma
    • Proposed molecular cytogenetic classification from International Myeloma Working Group (IMWG, 2009)
    • Non-molecular testing for prognostication
      • Microglobulin
        • 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, smoldering multiple myeloma (SMM), and SP
    • Molecular testing
      • Cytogenetics
      • FISH
      • 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
  • Waldenström macroglobulinemia
    • Three genomic groups – MYD88WTCXCR4WT; MYD88L265CXCR4WT; MDY88L265PCXCR4WHIM
      • MYD88L265PCXCR4WHIM and MYD88WTCXCR4WT – higher bone marrow disease burden; higher IgM levels; more likely to have symptomatic disease
      • MYD88WTCXCR4WT lowest bone marrow disease burden
      • MYD88L265PCXCRWT intermediate disease burden
    • Response to tyrosine kinase inhibitors (TKIs) (eg, ibrutinib) may be determined by CXCR4 status (Treon, 2015)
      • CXCR4WTMYD88L265P has highest response rates
  • AL amyloidosis
    • Dependent on burden of amyloid in tissue and size of the plasma cell clone

Differential Diagnosis

 

  • No recommendation for universal screening
  • Consider screening in the following situations
    • Age-inappropriate bone fractures with no known risk factors
      • Premenopausal females
      • Males <65 years
    • Unexplained proteinuria
    • Elevated total serum protein
    • Unexplained peripheral neuropathy
  • Monoclonal gammopathy of undetermined significance (MGUS) – quantification of serum and urine monoclonal protein (using serum protein electrophoresis [SPEP]),  urine protein electrophoresis [UPEP], and immunofixation electrophoresis [IFE]) at 6 months after initial diagnosis (Kyle, 2010)
    • Monitor every 2-3 years when stable, or if symptoms indicate low-risk MGUS
    • Monitor every 6 months if symptoms indicate intermediate- or high-risk MGUS
  • Smoldering multiple myeloma (SMM) (Kyle, 2010) – quantification of serum and urine monoclonal protein 2-3 months after initial diagnosis
    • If stable, test every 4-6 months for a year, then every 6-12 months (Kyle, 2010)
  • Free light chain (FLC) – monitor response to therapy in patients with no measurable disease with serum and protein electrophoresis
    • Measurable disease = serum M protein ≥1g/100 ml or urine M protein ≥200 mg/24-hour (requires initial FLC ≥100 mg/L with clonal ratio to be used)
    • Nonsecretory MM – marrow assessment and imaging are only reliable means of monitoring (Lonial, 2013)

Imaging Studies

  • Repeat skeletal survey if disease progresses
  • Magnetic resonance imaging (MRI) if skeletal survey is negative and disease has progressed
  • Positron emission tomography (PET)/MIBI imaging not recommended

Plasma cell dyscrasias are a diverse group of diseases characterized by clonal protein accumulation.

Risk Factors

  • Ionizing radiation
  • Farm and petrochemical industrial exposure

Specific Plasma Cell Dyscrasias

Rare 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

Limitations

IFE can be normal in patients with nonsecretory MM

Follow Up

If M protein detected, as well as calcium and beta-2 microglobulin concentration, order Kappa and Lambda Free Light Chains (Bence Jones Protein), Qualitative, Urine; skeletal survey; and a bone marrow biopsy to rule out plasma cell dyscrasia

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

Limitations

SPEP can be normal in patients with oligosecretory or nonsecretory MM

Follow Up

Order Kappa and Lambda Free Light Chains (Bence Jones Protein), Qualitative, Urine; skeletal survey; and a bone marrow biopsy to rule out plasma cell dyscrasia if M protein detected

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 and Lambda Free Light Chains (Bence Jones Protein), Quantitative, Urine 0050618
Method: Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

Follow Up

Sequential levels for monitoring disease progress

Kappa and Lambda Free Light Chains (Bence Jones Protein), Qualitative, Urine 0050161
Method: Qualitative Immunofixation Electrophoresis/Quantitative Nephelometry

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

Limitations

Low levels of FLC are found in serum of normal individuals due to the overproduction and secretion of FLC by plasma cells

Follow Up

Order sequential levels for monitoring disease progress and response to therapy

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

Limitations

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

Kappa Free Light Chains (Bence Jones Protein), Quantitative, Urine 0050689
Method: Quantitative Nephelometry/Qualitative Immunofixation Electrophoresis

Follow Up

Sequential levels for monitoring disease progress

Lambda Free Light Chains (Bence Jones Protein), Quantitative, Urine 0050682
Method: Quantitative Nephelometry/Qualitative Immunofixation Electrophoresis

Follow Up

Sequential levels for monitoring disease progress

Immunofixation Electrophoresis, Qualitative, Gel 2012572
Method: Qualitative Immunofixation Electrophoresis

Limitations

Immunofixation electrophoresis gel includes a qualitative interpretation of an IFE only

Information should be correlated with the results of serum protein electrophoresis, quantitative immunoglobulins, and other clinical and laboratory information

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

Chromosome Analysis, Bone Marrow 2002292
Method: Giemsa Band

Limitations

Normal metaphase results are suggestive of a stroma-dependant early myeloma, whereas abnormal metaphase results are suggestive of a stroma-independent later-stage myeloma with an associated poorer prognosis.

Recommend test be performed in conjunction with MM FISH panel for increased sensitivity, especially in early stage stroma-dependant myeloma

Follow Up

Repeat testing as clinically indicated to monitor disease progression

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

Limitations

Only detects aberrations specific to probes utilized

Follow Up

Repeat testing as clinically indicated to monitor disease progression

Chromosome FISH, Multiple Myeloma Panel Process and Hold 2006270
Method: Cell culture/Fluorescence in situ Hybridization

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

Limitations

Some hematopoietic neoplasms do not show phenotypic abnormalities and therefore may not be detected by flow cytometry

Poor cell viability may adversely affect antigens and impede the ability to properly identify neoplastic cells

Flow results cannot be used alone to diagnose malignancy

Should be interpreted in conjunction with morphology, clinical information, and other necessary ancillary tests for a definitive diagnosis

Viscosity, Serum 0020056
Method: Quantitative Viscometry

Limitations

Patients with rheumatoid arthritis, lupus erythematosus, or hyperfibrinogenemia may occasionally have increased serum viscosity in serum samples

Follow Up

Repeat testing as clinically indicated to monitor disease progression

Viscosity, Whole Blood 0020054
Method: Quantitative Viscometry

Limitations

Patients with rheumatoid arthritis, lupus erythematosus, or hyperfibrinogenemia may occasionally have increased blood viscosity in serum samples

Follow Up

Repeat testing as clinically indicated to monitor disease progression

Kappa/Lambda Light Chain Panel by in situ Hybridization, Paraffin 2002888
Method: In situ Hybridization

Chromosome FISH, Interphase 2002298
Method: Fluorescence in situ Hybridization

Kappa Light Chains by Immunohistochemistry 2003981
Method: Immunohistochemistry

Follow Up

Useful in initial diagnosis and therapy follow up

Lambda Light Chains by Immunohistochemistry 2003984
Method: Immunohistochemistry

CD138 (Syndecan-1) by Immunohistochemistry 2003812
Method: Immunohistochemistry

CD56 (NCAM) by Immunohistochemistry 2003589
Method: Immunohistochemistry

Ki-67 with Interpretation by Immunohistochemistry 2007182
Method: Immunohistochemistry

CD20, L26 by Immunohistochemistry 2003532
Method: Immunohistochemistry

CD19 by Immunohistochemistry 2005114
Method: Immunohistochemistry

CD23 by Immunohistochemistry 2003541
Method: Immunohistochemistry

Related Tests

Guidelines

Berenson JR, Anderson KC, Audell RA, Boccia RV, Coleman M, Dimopoulos MA, Drake MT, Fonseca R, Harousseau J, Joshua D, Lonial S, Niesvizky R, Palumbo A, Roodman D, San-Miguel JF, Singhal S, Weber DM, Zangari M, Wirtschafter E, Yellin O, Kyle RA. Monoclonal gammopathy of undetermined significance: a consensus statement. Br J Haematol. 2010; 150(1): 28-38. PubMed

Bird J, Owen R, D'Sa S, et al. Guidelines for the Diagnosis and Management of Multiple Myeloma 2014. British Committee for Standards in Haematology (BCSH), British Society for Haematology. London, UK [Accessed: Apr 2014]

Chng WJ, Dispenzieri A, Chim C, Fonseca R, Goldschmidt H, Lentzsch S, Munshi N, Palumbo A, Miguel JS, Sonneveld P, Cavo M, Usmani S, Durie BG M, Avet-Loiseau H, International Myeloma Working Group. IMWG consensus on risk stratification in multiple myeloma. Leukemia. 2014; 28(2): 269-77. PubMed

Dimopoulos M, Kyle R, Fermand J, Rajkumar V, San Miguel J, Chanan-Khan A, Ludwig H, Joshua D, Mehta J, Gertz M, Avet-Loiseau H, Beksaç M, Anderson KC, Moreau P, Singhal S, Goldschmidt H, Boccadoro M, Kumar S, Giralt S, Munshi NC, Jagannath S, International Myeloma Workshop Consensus Panel 3. Consensus recommendations for standard investigative workup: report of the International Myeloma Workshop Consensus Panel 3. Blood. 2011; 117(18): 4701-5. PubMed

Dimopoulos M, Terpos E, Comenzo RL, Tosi P, Beksac M, Sezer O, Siegel D, Lokhorst H, Kumar S, Rajkumar SV, Niesvizky R, Moulopoulos LA, Durie BG M, IMWG. International myeloma working group consensus statement and guidelines regarding the current role of imaging techniques in the diagnosis and monitoring of multiple Myeloma. Leukemia. 2009; 23(9): 1545-56. PubMed

Dispenzieri A, Buadi F, Kumar SK, Reeder CB, Sher T, Lacy MQ, Kyle RA, Mikhael JR, Roy V, Leung N, Grogan M, Kapoor P, Lust JA, Dingli D, Go RS, Hwa YLisa, Hayman SR, Fonseca R, Ailawadhi S, Bergsagel L, Chanan-Khan A, Rajkumar V, Russell SJ, Stewart K, Zeldenrust SR, Gertz MA. Treatment of Immunoglobulin Light Chain Amyloidosis: Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Statement. Mayo Clin Proc. 2015; 90(8): 1054-81. PubMed

Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, Palumbo A, Jagannath S, Bladé J, Lonial S, Dimopoulos M, Comenzo R, Einsele H, Barlogie B, Anderson K, Gertz M, Harousseau JL, Attal M, Tosi P, Sonneveld P, Boccadoro M, Morgan G, Richardson P, Sezer O, Mateos MV, Cavo M, Joshua D, Turesson I, Chen W, Shimizu K, Powles R, Rajkumar SV, Durie BG M, International Myeloma Working Group. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009; 23(2): 215-24. PubMed

Durie BG M, Harousseau J, Miguel JS, Bladé J, Barlogie B, Anderson K, Gertz M, Dimopoulos M, Westin J, Sonneveld P, Ludwig H, Gahrton G, Beksac M, Crowley J, Belch A, Boccadaro M, Cavo M, Turesson I, Joshua D, Vesole D, Kyle R, Alexanian R, Tricot G, Attal M, Merlini G, Powles R, Richardson P, Shimizu K, Tosi P, Morgan G, Rajkumar SV, International Myeloma Working Group. International uniform response criteria for multiple myeloma. Leukemia. 2006; 20(9): 1467-73. PubMed

FernándezdeLarrea C, Kyle RA, Durie BG M, Ludwig H, Usmani S, Vesole DH, Hajek R, San Miguel JF, Sezer O, Sonneveld P, Kumar SK, Mahindra A, Comenzo R, Palumbo A, Mazumber A, Anderson KC, Richardson PG, Badros AZ, Caers J, Cavo M, LeLeu X, Dimopoulos MA, Chim CS, Schots R, Noeul A, Fantl D, Mellqvist U, Landgren O, Chanan-Khan A, Moreau P, Fonseca R, Merlini G, Lahuerta JJ, Bladé J, Orlowski RZ, Shah JJ, International Myeloma Working Group. Plasma cell leukemia: consensus statement on diagnostic requirements, response criteria and treatment recommendations by the International Myeloma Working Group. Leukemia. 2013; 27(4): 780-91. PubMed

Fonseca R, Bergsagel PL, Drach J, Shaughnessy J, Gutierrez N, Stewart AK, Morgan G, Van Ness B, Chesi M, Minvielle S, Neri A, Barlogie B, Kuehl WM, Liebisch P, Davies F, Chen-Kiang S, Durie BG M, Carrasco R, Sezer O, Reiman T, Pilarski L, Avet-Loiseau H, International Myeloma Working Group. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23(12): 2210-21. PubMed

Gertz MA. Waldenström macroglobulinemia: 2013 update on diagnosis, risk stratification, and management. Am J Hematol. 2013; 88(8): 703-11. PubMed

Kyle RA, Durie BG M, Rajkumar SV, Landgren O, Bladé J, Merlini G, Kröger N, Einsele H, Vesole DH, Dimopoulos M, San Miguel J, Avet-Loiseau H, Hajek R, Chen WM, Anderson KC, Ludwig H, Sonneveld P, Pavlovsky S, Palumbo A, Richardson PG, Barlogie B, Greipp P, Vescio R, Turesson I, Westin J, Boccadoro M, International Myeloma Working Group. Monoclonal gammopathy of undetermined significance (MGUS) and smoldering (asymptomatic) multiple myeloma: IMWG consensus perspectives risk factors for progression and guidelines for monitoring and management. Leukemia. 2010; 24(6): 1121-7. PubMed

Mikhael JR, Dingli D, Roy V, Reeder CB, Buadi FK, Hayman SR, Dispenzieri A, Fonseca R, Sher T, Kyle RA, Lin Y, Russell SJ, Kumar S, Bergsagel L, Zeldenrust SR, Leung N, Drake MT, Kapoor P, Ansell SM, Witzig TE, Lust JA, Dalton RJ, Gertz MA, Stewart K, Stewart K, Rajkumar V, Chanan-Khan A, Lacy MQ, Mayo Clinic. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines 2013. Mayo Clin Proc. 2013; 88(4): 360-76. PubMed

Moreau P, San Miguel J, Ludwig H, Schouten H, Mohty M, Dimopoulos M, Dreyling M, ESMO Guidelines Working Group. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 Suppl 6: vi133-7. PubMed

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: Jun 2015]

NCCN Clinical Practice Guidelines in Oncology, Systemic Light Chain Amyloidosis. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

NCCN Clinical Practice Guidelines in Oncology, Waldenstrom Macroglobinemia/Lymphoplasmacytic Lymphoma. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

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: October 2009. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

Protocol for the Examination of Specimens From Patients With Non-Hodgkin Lymphoma/Lymphoid Neoplasms. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: June 2010. College of American Pathologists (CAP). Northfield, IL [Accessed: Jun 2015]

Rajkumar V, Dimopoulos MA, Palumbo A, Bladé J, Merlini G, Mateos M, Kumar S, Hillengass J, Kastritis E, Richardson P, Landgren O, Paiva B, Dispenzieri A, Weiss B, LeLeu X, Zweegman S, Lonial S, Rosiñol L, Zamagni E, Jagannath S, Sezer O, Kristinsson SY, Caers J, Usmani SZ, Lahuerta JJosé, Johnsen HErik, Beksaç M, Cavo M, Goldschmidt H, Terpos E, Kyle RA, Anderson KC, Durie BG M, San Miguel JF. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol. 2014; 15(12): e538-48. PubMed

General References

Albarracin F, Fonseca R. Plasma cell leukemia. Blood Rev. 2011; 25(3): 107-12. PubMed

Bianchi G, Anderson KC, Harris NLee, Sohani AR. The heavy chain diseases: clinical and pathologic features. Oncology (Williston Park). 2014; 28(1): 45-53. PubMed

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

Hunter ZR, Xu L, Yang G, Zhou Y, Liu X, Cao Y, Manning RJ, Tripsas C, Patterson CJ, Sheehy P, Treon SP. The genomic landscape of Waldenstrom macroglobulinemia is characterized by highly recurring MYD88 and WHIM-like CXCR4 mutations, and small somatic deletions associated with B-cell lymphomagenesis. Blood. 2014; 123(11): 1637-46. PubMed

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

Landgren O, Tageja N. MYD88 and beyond: novel opportunities for diagnosis, prognosis and treatment in Waldenström's Macroglobulinemia. Leukemia. 2014; 28(9): 1799-803. PubMed

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

Lonial S, Kaufman JL. Non-secretory myeloma: a clinician's guide. Oncology (Williston Park). 2013; 27(9): 924-8, 930. PubMed

Rajkumar V, Kumar S. Multiple Myeloma: Diagnosis and Treatment. Mayo Clin Proc. 2016; 91(1): 101-19. PubMed

Rajkumar V. Multiple myeloma: 2014 Update on diagnosis, risk-stratification, and management. Am J Hematol. 2014; 89(10): 999-1009. PubMed

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

Treon SP, Tripsas CK, Meid K, Warren D, Varma G, Green R, Argyropoulos KV, Yang G, Cao Y, Xu L, Patterson CJ, Rodig S, Zehnder JL, Aster JC, Harris NLee, Kanan S, Ghobrial I, Castillo JJ, Laubach JP, Hunter ZR, Salman Z, Li J, Cheng M, Clow F, Graef T, Palomba L, Advani RH. Ibrutinib in previously treated Waldenström's macroglobulinemia. N Engl J Med. 2015; 372(15): 1430-40. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Chen Z, Issa B, Huang S, Aston E, Xu J, Yu M, Brothman AR, Glenn M. A practical approach to the detection of prognostically significant genomic aberrations in multiple myeloma. J Mol Diagn. 2005; 7(5): 560-5. PubMed

Heikal NM, Shetty S. Spindle cell variant of multiple myeloma: immunophenotype and cytogenetics abnormalities. Ann Hematol. 2012; 91(5): 803-4. PubMed

Jaskowski TD, Litwin CM, Hill HR. Detection of kappa and lambda light chain monoclonal proteins in human serum: automated immunoassay versus immunofixation electrophoresis. Clin Vaccine Immunol. 2006; 13(2): 277-80. PubMed

Kelley TW, Baz R, Hussein M, Karafa M, Cook JR. Clinical significance of cyclin D1, fibroblast growth factor receptor 3, and p53 immunohistochemistry in plasma cell myeloma treated with a thalidomide-based regimen. Hum Pathol. 2009; 40(3): 405-12. PubMed

Pandey S, Post SR, Alapat DV, Smock KJ, Post GR. Prolonged prothrombin time correlates with serum monoclonal protein concentration in patients with plasma cell dyscrasia. Int J Lab Hematol. 2013; 35(4): 421-7. PubMed

Salama ME, Lange H, Tripp SR, Kohan J, Landis ND, Krueger JS, Potts SJ. AngioMap is a novel image analysis algorithm for assessment of plasma cell distribution within bone marrow vascular niche. Appl Immunohistochem Mol Morphol. 2014; 22(7): 550-4. PubMed

Shetty S, Siady M, Mallempati KC, Wilson A, Poarch J, Chandler B, Gray J, Salama ME. Utility of a column-free cell sorting system for separation of plasma cells in multiple myeloma FISH testing in clinical laboratories. Int J Hematol. 2012; 95(3): 274-81. PubMed

Smock KJ, Perkins SL, Bahler DW. Quantitation of plasma cells in bone marrow aspirates by flow cytometric analysis compared with morphologic assessment. Arch Pathol Lab Med. 2007; 131(6): 951-5. PubMed

Zhou W, Yang Y, Xia J, Wang H, Salama ME, Xiong W, Xu H, Shetty S, Chen T, Zeng Z, Shi L, Zangari M, Miles R, Bearss D, Tricot G, Zhan F. NEK2 induces drug resistance mainly through activation of efflux drug pumps and is associated with poor prognosis in myeloma and other cancers. Cancer Cell. 2013; 23(1): 48-62. PubMed

Medical Reviewers

Last Update: April 2016