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 – 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, 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 – 5/100,000,000 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 64 years Sex – M>F (minimal) 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 cell 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 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 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
• 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 
• 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 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) Beta-2 macroglobulin – level reflects tumor mass and is considered a standard measure of tumor burden 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
  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, although flow cytometry is not accurate in enumeration of plasma cell numbers
    • MM – 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
    • 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
    • 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 17p13 deletion associated with worse prognosis
    • 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

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

• 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 protein (serum)
  • Unexplained peripheral neuropathy

• MGUS – monitor at 6 months (IMWG, 2010)
  • When stable or if symptoms indicate low-risk MGUS, monitor every 2-3 years  
  • Continue monitoring every 6 months if symptoms indicate intermediate or high-risk MGUS
  • Smoldering MM (IMWG 2010) – test 2-3 months after initial diagnosis; if stable, test every 4-6 months for a year, then every 6-12 months
  • FLC – monitor response to therapy in patients with no measurable disease on 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)
    • Low-risk disease = serum M protein <1.5 gm/dL, IgG subtype, normal FLC ratio (0.26-1.65)
    • Low-intermediate risk disease = any one factor abnormal
    • High-intermediate risk disease = any two factors abnormal
    • High-risk disease = all three factors abnormal
  • SPEP and IFE – monitor response to therapy
• IMWG Response Criteria for MM
  • Complete response (CR)
    • Negative immunofixation (serum, urine)
    • Disappearance of soft tissue plasmacytomas
    • <5% plasma cells in bone marrow
      • In patients for whom the only measurable disease is by FLC levels, CR is defined as a normal FLC ratio (0.26-1.65) in addition to the previous criteria
  • Stringent CR (sCR)
    • CR criteria above
    • Normal FLC ratio
    • Absence of clonal cells in bone marrow (by immunohistochemistry or immunofluorescence)
  • Very good partial response (VGPR) – one of the following criteria
    • Serum and urine M-component detectable by immunofixation but not electrophoresis
    • ≥90% reduction in serum M-component plus urine M-component <100 mg/24-hour
      • In patients for whom the only measurable disease is by FLC levels, VGPR is defined as a >90% decrease in difference between involved and uninvolved FLC levels
  • Partial response (PR)
    • ≥50% reduction of serum M protein and reduction in 24-hour urinary M protein by ≥90% or to <200 mg/24-hour
      • If serum and urine M protein are unmeasurable, ≥50% decrease in the difference between involved and uninvolved FLC levels is required
      • If serum and urine M protein are unmeasurable and serum free light assay is also unmeasurable, ≥50% reduction in bone marrow plasma cells is required, provided baseline percentage was ≥30%
      • Additionally (if present at baseline), a ≥50% reduction in size of soft tissue plasmacytomas is also required
  • Progressive disease (PD)
    • 25% increase from lowest response value in one or more of the following
      • Serum M-component (absolute increase must be ≥0.5g/100 ml)
        • Increases of ≥1g/100ml are sufficient to define relapse if starting level is ≥5g/100 ml
      • Urine M-component (absolute increase must be ≥200 mg/24-hour)  
      • In patients without measurable M protein (serum and urine), the difference between involved and uninvolved FLC levels (absolute increase must be >100 mg/l)
      • Bone marrow plasma cell percentage (absolute percentage must be ≥10%)
      • Definite increase in size or definite development of new bone lesions or soft tissue plasmacytomas
      • Development of hypercalcemia (corrected serum calcium >11.5mg/100ml) attributable solely to the disease
  • Stable disease (SD)
    • Does not meet criteria for CR, VGPR, PR or progressive disease
  • Response categories CR, sCR, VGPR and PR require two consecutive assessments made at any time before the start of any new therapy
    • CR, PR, and SD categories also require no known evidence of progressive or new bone lesions (if radiographic studies performed)
      • Radiographic studies are not required to satisfy response requirements
      • Bone marrow assessments do not need confirmation

Imaging studies

• Repeat skeletal survey if disease progresses
• MRI if skeletal survey is negative and disease has progressed
• PET/MIBI imaging not recommended

Tests generally appear in the order most useful for common clinical situations

Guidelines

• Ansell SM, Kyle RA, Reeder CB, Fonseca R, Mikhael JR, Morice WG, Bergsagel PL, Buadi FK, Colgan JP, Dingli D, Dispenzieri A, Greipp PR, Habermann TM, Hayman SR, Inwards DJ, Johnston PB, Kumar SK, Lacy MQ, Lust JA, Markovic SN, Micallef IN, Nowakowski GS, Porrata LF, Roy V, Russell SJ, Short KE, Stewart AK, Thompson CA, Witzig TE, Zeldenrust SR, Dalton RJ, Rajkumar SV, Gertz MA. Diagnosis and management of Waldenstrom macroglobulinemia: Mayo stratification of macroglobulinemia and risk-adapted therapy (mSMART) guidelines. Mayo Clin Proc. 2010; 85 (9) :824-833.PubMed
• Berenson JR, Anderson KC, Audell RA, Boccia RV, Coleman M, Dimopoulos MA, Drake MT, Fonseca R, Harousseau JL, Joshua D, Lonial S, Niesvizky R, Palumbo A, Roodman GD, 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
• Blade J, Dimopoulos M, Rosinol L, Rajkumar SV, Kyle RA. Smoldering (asymptomatic) multiple myeloma: current diagnostic criteria, new predictors of outcome, and follow-up recommendations. J Clin Oncol. 2010; 28 (4) :690-697.PubMed
• College of American Pathologists (CAP). 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. [Accessed: 25 Jun 2010] 
• College of American Pathologists (CAP). 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: October 2009. [Accessed: 25 Jun 2010] 
• 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. 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) :1545-1556.PubMed
• Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, Palumbo A, Jagannath S, Blade 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. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009; 23 (2) :215-224.PubMed
• Durie BG, Harousseau JL, Miguel JS, Blade 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, 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 uniform response criteria for multiple myeloma. Leukemia. 2006; 20 (9) :1467-1473.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, Carrasco R, Sezer O, Reiman T, Pilarski L, vet-Loiseau H. International Myeloma Working Group molecular classification of multiple myeloma: spotlight review. Leukemia. 2009; 23 (12) :2210-2221.PubMed
• Graziani M, Merlini G, Petrini C. Guidelines for the analysis of Bence Jones protein. Clin Chem Lab Med. 2003; 41 (3) :338-346.PubMed
• Kumar SK, Mikhael JR, Buadi FK, Dingli D, Dispenzieri A, Fonseca R, Gertz MA, Greipp PR, Hayman SR, Kyle RA, Lacy MQ, Lust JA, Reeder CB, Roy V, Russell SJ, Short KE, Stewart AK, Witzig TE, Zeldenrust SR, Dalton RJ, Rajkumar SV, Bergsagel PL. Management of newly diagnosed symptomatic multiple myeloma: updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo Clin Proc. 2009; 84 (12) :1095-1110.PubMed
• Kyle RA, Durie BG, Rajkumar SV, Landgren O, Blade J, Merlini G, Kroger N, Einsele H, Vesole DH, Dimopoulos M, San Miguel J, vet-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. 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) :1121-1127.PubMed
• Kyle RA, Treon SP, Alexanian R, Barlogie B, Bjorkholm M, Dhodapkar M, Lister TA, Merlini G, Morel P, Stone M, Branagan AR, Leblond V. Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003; 30 (2) :116-120.PubMed
• NCCN Clinical Practice Guidelines in Oncology, Multiple Myeloma. National Comprehensive Cancer Network Multiple Myeloma Panel. Fort Washington: Pennsylvania [Accessed: 28 Apr 2011] 
• NCCN Clinical Practice Guidelines in Oncology, Waldenstrom Macroglobinemia. National Comprehensive Cancer Network. Fort Washington: Pennsylvania [Accessed: 28 Apr 2011] 

General

• Blade J, Rosinol L, Cibeira MT, de Larrea CF. Pathogenesis and progression of monoclonal gammopathy of undetermined significance. Leukemia. 2008; 22 (9) :1651-1657.PubMed
• Chee CE, Dispenzieri A, Gertz MA. Amyloidosis and POEMS syndrome. Expert Opin Pharmacother. 2010; 11 (9) :1501-1514.PubMed
• Davids MS, Murali MR, Kuter DJ. Serum free light chain analysis. Am J Hematol. 2010; 85 (10) :787-790.PubMed
• Gertz MA. Relevant prognostic features of multiple myeloma and the new International Staging System. Leuk Lymphoma. 2007; 48 (3) :458-468.PubMed
• Katzmann JA, Abraham RS, Dispenzieri A, Lust JA, Kyle RA. Diagnostic performance of quantitative kappa and lambda free light chain assays in clinical practice. Clin Chem. 2005; 51 (5) :878-881.PubMed
• Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009; 23 (1) :3-9.PubMed
• Kyle RA, Rajkumar SV. Multiple myeloma. Blood. 2008; 111 (6) :2962-2972.PubMed
• Lin P. Plasma cell myeloma. Hematol Oncol Clin North Am. 2009; 23 (4) :709-727.PubMed
• Nau KC, Lewis WD. Multiple myeloma: diagnosis and treatment. Am Fam Physician. 2008; 78 (7) :853-859.PubMed
• Paiva B, Almeida J, Perez-Andres M, Mateo G, Lopez A, Rasillo A, Vidriales MB, Lopez-Berges MC, Miguel JF, Orfao A. Utility of flow cytometry immunophenotyping in multiple myeloma and other clonal plasma cell-related disorders. Cytometry B Clin Cytom. 2010; 78 (4) :239-252.PubMed
• Raab MS, Podar K, Breitkreutz I, Richardson PG, Anderson KC. Multiple myeloma. Lancet. 2009; 374 (9686) :324-339.PubMed
• Rajkumar SV, Dispenzieri A, Kyle RA. Monoclonal gammopathy of undetermined significance, Waldenstrom macroglobulinemia, AL amyloidosis, and related plasma cell disorders: diagnosis and treatment. Mayo Clin Proc. 2006; 81 (5) :693-703.PubMed
• Shaheen SP, Talwalkar SS, Medeiros LJ. Multiple myeloma and immunosecretory disorders: an update. Adv Anat Pathol. 2008; 15 (4) :196-210.PubMed
• Sher T, Miller KC, Deeb G, Lee K, Chanan-Khan A. Plasma cell leukaemia and other aggressive plasma cell malignancies. Br J Haematol. 2010; 150 (4) :418-427.PubMed
• Treon SP. How I treat Waldenstrom macroglobulinemia. Blood. 2009; 114 (12) :2375-2385.PubMed
• Zhan F, Sawyer J, Tricot G. The role of cytogenetics in myeloma. Leukemia. 2006; 20 (9) :1484-1486.PubMed

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) :560-565.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) :277-280.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) :405-412.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) :951-955.PubMed

Chronic Lymphocytic Leukemia
Common Variable Immune Deficiency
Cryoglobulinemia
Immunoglobulin Disorders
Lymphoma Phenotyping
Lymphomas, B-Cell
Neuropathic Disease
Paraneoplastic Neurological Syndromes
Tumor Markers