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Serum Free Light Chain Measurement[edit]

Measurement of immunoglobulin free light chains in serum has recently become possible as an alternative to the analysis of Bence Jones proteins in urine. These tests are used as an aid in the diagnosis and monitoring of multiple myeloma and related disorders. There are two types of immunoglobulin light chain produced in humans, designated by the Greek letters kappa (κ) and lambda (λ). Comparing the ratio of kappa / lambda free light chains in the serum of an individual with that measured in a number of subjects known to be disease-free, indicates whether the individual might have a plasma cell tumour such as multiple myeloma or AL amyloidosis [1] [2].

Serum free light chain assays have been utilised in a number of published studies which have indicated superiority over the urine tests, particularly for patients producing low levels of monoclonal free light chains, as seen in nonsecretory multiple myeloma [3][4][5] and AL amyloidosis [6][7][8][9]. This is primarily because of the re-absorption of free light chains in the kidneys, creating a “threshold” of light chain production which must be exceeded before measurable quantities overflow into the urine [10][11][12]. While there are a number of publications indicating that serum free light chain analysis is preferable to urine analysis at diagnosis [13][14][15] [16] there is currently no consensus on whether urine tests for monitoring should be replaced [17] [18][19] [20].

A series of studies, principally from the Mayo Clinic, have indicated that patients with an abnormal free kappa / free lambda ratio have an increased risk of progression to active myeloma from precursor conditions including Monoclonal Gammopathy of Undetermined Significance (MGUS) [21][22] Smoldering Myeloma [23] and solitary plasmacytoma of the bone [24]. Abnormal free light chain production has also been reported to be prognostic of a worse outcome in multiple myeloma [25] [26][27] and chronic lymphocytic leukaemia [28].

Guidelines[edit]

The International Myeloma Working Group have recently published guidelines making recommendations of when serum free light chain analysis should be used in the management of multiple myeloma [29]:

Diagnosis[edit]

The serum free light chain assay in combination with serum protein electrophoresis and serum immunofixation electrophoresis is sufficient to screen for pathological monoclonal plasmaproliferative disorders other than AL amyloidosis which requires all the serum tests as well as 24h immunofixation electrophoresis .

Prognosis[edit]

The serum free light chain assay should be measured at diagnosis for all patients with MGUS, smoldering or active multiple myeloma. Solitary plasmacytoma and AL amyloidosis.

Monitoring[edit]

Serial FLC ascertainment should be routinely performed in patients with AL amyloidosis and multiple myeloma patients with oligosecretory disease. It should also be done in all patients who have achieved a complete response to determine whether they have attained a stringent complete response.

Other guidelines for the use of serum free light chain measurement in the management of AL amyloidosis [30] plasmacytoma [31] and the comparison of treatment responses in clinical trials [32] have also been published.

Technical/clinical reviews of serum free light chain assays have recently been written by Pratt and Jagannath [33][34]

Patient Information[edit]

Information about serum free light chain assays from a patient perspective, is available from the Myeloma Foundation and Myeloma UK

References[edit]

  1. ^ Bradwell AR, Carr-Smith HD, Mead GP, Tang LX, Showell PJ, Drayson MT, Drew R. Highly sensitive automated immunoassay for immunoglobulin free light chains in serum and urine. Clin Chem 2001; 47: 673-680
  2. ^ Katzmann JA, Clark RJ, Abraham RS, Bryant S, Lymp JF, Bradwell AR, Kyle RA. Serum Reference Intervals and Diagnostic Ranges for Free k and Free l Immunoglobulin Light Chains: Relative Sensitivity for Detection of Monoclonal Light Chains. Clin Chem 2002; 48: 1437-1444
  3. ^ Drayson MT, Tang LX, Drew R, Mead GP, Carr-Smith HD, Bradwell AR. Serum free light-chain measurements for identifying and monitoring patients with nonsecretory multiple myeloma. Blood 2001; 97 (9): 2900-2902
  4. ^ Shaw GR. Nonsecretory Plasma Cell Myeloma - Becoming Even More Rare With Serum Free Light-Chain Assay: A Brief Review. Arch Pathol Lab Med. 2006; 130: 1212-1215
  5. ^ 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
  6. ^ Lachmann HJ, Gallimore R, Gillmore JD, Carr-Smith HD, Bradwell AR, Pepys MB, Hawkins PN. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br J Haematol 2003; 122: 78-84
  7. ^ 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
  8. ^ Abraham RS, Katzmann JA, Clark RC, Bradwell AR, Kyle RA, Gertz MA. Quantitative analysis of serum free light chains. A new marker for the diagnostic evaluation of primary systemic amyloidosis. Am J Clin Pathol 2003; 119: 274-278.
  9. ^ Akar H, Seldin DC, Magnani B, O’Hara C, Berk JL, Schoonmaker C, Cabral H, Dember LM, Sanchorwala V, Connors LH, Falk RH, Skinner M. Quantitative serum free light chain assay in the diagnostic evaluation of AL amyloidosis. Amyloid 2005; 12 (4): 210-215.
  10. ^ Nowrousian MR, Brandhorst D, Sammet C, Kellert M, Daniels R, Schuett P, Poser M, Mueller S, Ebeling P, Welt A, Bradwell AR, Buttkereit U, Opalka B, Flasshove M, Moritz T, Seeber S. Serum Free Light Chain Analysis and Urine Immunofixation Electrophoresis in Patients with Multiple Myeloma. Clin Cancer Res 2005; 11 (24): 8706-8714
  11. ^ Bradwell AR, Carr-Smith HD, Mead GP, Harvey TC, Drayson MT. Serum test for assessment of patients with Bence Jones myeloma. Lancet 2003; 361: 489-491
  12. ^ Alyanakian M-A, Abbas A, Delarue R, Arnulf B, Aucouturier P. Free Immunoglobulin Light-chain Serum Levels in the Follow-up of Patients With Monoclonal Gammopathies: Correlation With 24-hr Urinary Light-chain Excretion. Am J of Haem 2004; 75: 246-248
  13. ^ Hill PG, Forsyth JM, Rai B, Mayne S. Serum Free Light Chains: An Alternative to the Urine Bence Jones Proteins Screening Test for Monoclonal Gammopathies. Clin Chem 2006; 52 (9): 1743-1748
  14. ^ Bakshi NA, Guilbranson R, Garstka D, Bradwell AR, Keren DF. Serum Free Light Chain (FLC) Measurement Can Aid Capillary Zone Electrophoresis (CZE) In Detecting Subtle FLC M-Proteins. Am J Clin Path 2005;124: 214-218.
  15. ^ Abadie JM, Bankson DD. Assessment of Serum Free Light Chain Assays for Plasma Cell Disorder Screening in a Veterans Affairs Population. Ann Clin Lab Sci 2006; 36 (2): 157-162.
  16. ^ Katzmann JA, Dispenzieri A, Kyle RA, Snyder MR, Plevak MF, Larson DR, Abraham RS, Lust JA, Melton III LJ, Rajkumar SV. Elimination of the Need for Urine Studies in the Screening Algorithm for Monoclonal Gammopathies by Using Serum Immunofixation and Free Light Chain Assays. Mayo Clin Proc. 2006; 81 (12): 1575-1578
  17. ^ Abraham RS, Clark RJ, Bryant SC, Lymp JF, Larson T, Kyle RA, Katzmann JA. Correlation of serum immunoglobulin free light chain quantitation with urine Bence Jones protein in Light Chain Myeloma. Clin Chem 2002; 48: 655-657.
  18. ^ Dispenzieri A, Zhang L, Katzmann J, Snyder M, Blood E, DeGoey R, Henderson K, Kyle R, Oken M, Bradwell A, Greipp P. Appraisal of Immunoglobulin Free Light Chain as a Marker of Response. Blood 2008; 111 (10): 4908-4915
  19. ^ Alyanakian M-A, Abbas A, Delarue R, Arnulf B, Aucouturier P. Free Immunoglobulin Light-chain Serum Levels in the Follow-up of Patients With Monoclonal Gammopathies: Correlation With 24-hr Urinary Light-chain Excretion. Am J of Haem 2004; 75: 246-248.
  20. ^ Nowrousian MR, Brandhorst D, Sammet C, Kellert M, Daniels R, Schuett P, Poser M, Mueller S, Ebeling P, Welt A, Bradwell AR, Buttkereit U, Opalka B, Flasshove M, Moritz T, Seeber S. Serum Free Light Chain Analysis and Urine Immunofixation Electrophoresis in Patients with Multiple Myeloma. Clin Cancer Res 2005; 11 (24): 8706-8714
  21. ^ Rajkumar SV, Kyle RA, Therneau TM, Melton LJ III, Bradwell AR Clark RJ, Larson DR, Plevak MF, Dispenzieri A, Katzmann JA. Serum free light chain ratio is an independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood 2005: 106: 812-817
  22. ^ Rajkumar SV, Lacy MQ, Kyle RA. Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma. Blood Rev 2007; 21 (5): 255-265
  23. ^ Dispenzieri A, Kyle RA, Katzmann JA, Therneau TM, Larson DR, Bensen J, Clark RJ, Melton III LJ, Gertz MA, Kumar SK, Fonseca R, Jelinek DF, Rajkumar SV. Immunoglobulin Free Light Chain Ratio Is an Independent Risk Factor for Progression of Smoldering (Asymptomatic) Muliple Myeloma. Blood 2008; 111: (2) 785-789
  24. ^ Dingli D, Kyle RA, Rajkumar SV, Nowakowski GS, Larson DR, Bida JP, Gertz MA, Therneau TM, Melton LJ, 3rd, Dispenzieri A, Katzmann JA. Immunoglobulin free light chains and solitary plasmacytoma of bone. Blood 2006; 108 (6): 1979-1983
  25. ^ Kyrtsonis M-C, Vassilakopoulos TP, Kafasi N, Sachanas S, Tzenou T, Papadgiannis A, Galanis Z, Kalpadakis C, Dimou M, Kyriakou E, Angelpoulou MK, Dimopoulou MN, Siakantaris MP, Dimitriadou EM, Kokoris SI, Panayiotidis P, Pangalis GA. Prognostic value of serum free light chain ratio at diagnosis in multiple myeloma. Br J Haematol 2007; 137: 240-243
  26. ^ Snozek CLH, Katzmann JA, Kyle RA, Dispenzieri A, Larson DR, Therneau TM, Melton LJ III, Kumar S, Greipp PR, Clark RJ, Rajkumar SV. Prognostic value of the serum free light chain ratio in newly diagnosed myeloma: proposed incorporation into the international staging system. Leukemia 2007; 22; 1933-1937
  27. ^ van Rhee F. Bolejack V, Hollmig K, Pineda-Roman M, Anaissie E, Epstein J, Shaughnessy Jr JD, Zangari M, Tricot G, Mohiuddin A, Alsayed Y, Woods G, Crowley J, Barlogie B. High serum free-light chain levels and their rapid reduction in response to therapy define an aggressive multiple myeloma subtype with poor prognosis. Blood 2007; 110 (3): 827-832
  28. ^ Pratt G, Harding S, Holder R, Fegan C, Pepper C, Oscier D, Gardiner A, Bradwell AR, Mead G. Abnormal serum free light chain ratios are associated with poor survival and may reflect biological subgroups in patients with chronic lymphocytic leukaemia. Br J Haem 2009; 144: 217-222
  29. ^ Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, et al. International Myeloma Working Group guidelines for serum free light chain analysis in multiple myeloma and related disorders. Leukemia 2008; 23: 215-224
  30. ^ Gertz MA, Comenzo R, Falk RH, Fermand JP, Hazenberg BP, Hawkins PN, Merlini G, Moreau P, Ronco P, Sanchorawala V, Sezer O, Solomon Al, Grateau G. Definition of Organ Involvement and Treatment Response in Immunoglobulin Light Chain Amyloidosis (AL): A Consensus Opinion From the 10th International Symposium on Amyloid and Amyloidosis. Am J Hematology 2005; 79: 319-328
  31. ^ Hughes M, Soutar R, Lucraft H, Owen R, Bird J. “Guidelines on the diagnosis and management of solitary plasmacytoma of bone, extramedullary plasmacytoma and multiple solitary plasmacytomas: 2009 update” UKMF Guidelines Working Group, Published online
  32. ^ Durie BGM, 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
  33. ^ Pratt G. The evolving use of serum free light chain assays in haematology. Br J Haem; 2008; 141; 413-422
  34. ^ Jagannath S. Value of serum free light chain testing for the diagnosis and monitoring of monoclonal gammopathies in hematology. Clinical Lymphoma and Myeloma 2007; 7 (8): 518-523
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