Abstract
The disease causing agent in systemic AL amyloidosis is a monoclonal immunoglobulin free light chain, or fragments thereof, circulating in the blood. It is not surprising, therefore, that measurement of serum free light chains plays a central role in the management of this disorder. In this paper, we review the utility of the serum free light chain assay in the investigation, prognostication and monitoring of AL amyloidosis. Data on the two currently available commercial assays is compared and some practical applications of the assay’s use are presented. While there are limitations, it is clear that the availability of the free light chain assay in the laboratory is a major advance and plays an essential role in the management of patients with AL amyloidosis.
Acknowledgments
GM is partly supported by grants from the “Associazione Italiana per la Ricerca sul Cancro” Special Program Molecular Clinical Oncology 5 per mille n. 9965 and from the Cariplo Foundation (n 2013–0964).
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Research funding: PM has received free FLC assay kits for research projects from The Binding Site and from Siemens.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interests: The funding organization(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.
References
1. Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol 2011;29:1924–33.10.1200/JCO.2010.32.2271Suche in Google Scholar PubMed PubMed Central
2. Weiss BM, Hebreo J, Cordaro DV, Roschewski MJ, Baker TP, Abbott KC, et al. Increased serum free light chains precede the presentation of immunoglobulin light chain amyloidosis. J Clin Oncol 2014;32:2699–704.10.1200/JCO.2013.50.0892Suche in Google Scholar PubMed PubMed Central
3. Nasr SH, Said SM, Valeri AM, Sethi S, Fidler ME, Cornell LD, et al. The diagnosis and characteristics of renal heavy-chain and heavy/light-chain amyloidosis and their comparison with renal light-chain amyloidosis. Kidney Int 2013;83:463–70.10.1038/ki.2012.414Suche in Google Scholar PubMed
4. Dispenzieri A, Kyle R, Merlini G, Miguel JS, Ludwig H, Hajek R, et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia 2009;23:215–24.10.1038/leu.2008.307Suche in Google Scholar PubMed
5. Gillmore JD, Wechalekar A, Bird J, Cavenagh J, Hawkins S, Kazmi M, et al. Guidelines on the diagnosis and investigation of AL amyloidosis. Br J Haematol 2015;168:207–18.10.1111/bjh.13156Suche in Google Scholar PubMed
6. Weber N, Mollee P, Augustson B, Brown R, Catley L, Gibson J, et al. Management of systemic AL amyloidosis: Recommendations of the Myeloma Foundation of Australia Medical and Scientific Advisory Group. Intern Med J 2015;45:371–82.10.1111/imj.12566Suche in Google Scholar PubMed
7. Katzmann JA, Kyle RA, Benson J, Larson DR, Snyder MR, Lust JA, et al. Screening panels for detection of monoclonal gammopathies. Clin Chem 2009;55:1517–22.10.1373/clinchem.2009.126664Suche in Google Scholar PubMed PubMed Central
8. Palladini G, Russo P, Bosoni T, Verga L, Sarais G, Lavatelli F, et al. Identification of amyloidogenic light chains requires the combination of serum-free light chain assay with immunofixation of serum and urine. Clin Chem 2009;55:499–504.10.1373/clinchem.2008.117143Suche in Google Scholar PubMed
9. Bochtler T, Hegenbart U, Heiss C, Benner A, Cremer F, Volkmann M, et al. Evaluation of the serum-free light chain test in untreated patients with AL amyloidosis. Haematologica 2008;93:459–62.10.3324/haematol.11687Suche in Google Scholar PubMed
10. Morris KL, Tate JR, Gill D, Kennedy G, Wellwood J, Marlton P, et al. Diagnostic and prognostic utility of the serum free light chain assay in patients with AL amyloidosis. Intern Med J 2007;37:456–63.10.1111/j.1445-5994.2007.01368.xSuche in Google Scholar PubMed
11. Akar H, Seldin DC, Magnani B, O’Hara C, Berk JL, Schoonmaker C, et al. Quantitative serum free light chain assay in the diagnostic evaluation of AL amyloidosis. Amyloid 2005;12:210–5.10.1080/13506120500352339Suche in Google Scholar PubMed
12. Mollee P, Tate J, Pretorius CJ. Evaluation of the N latex free light chain assay in the diagnosis and monitoring of AL amyloidosis. Clin Chem Lab Med 2013;51:2303–10.10.1515/cclm-2013-0361Suche in Google Scholar PubMed
13. Palladini G, Bosoni T, Milani P, Pirolini L, Foli A, Li Bergolis F, et al. Use of the novel monoclonal assay for the measurement of circulating free light chain in the diagnosis, prognostication of survival and assessment of response to therapy in AL amyloidosis. Paper presented at Annual Meeting of the Americal Society of Hematology December 10, 2012 Atlanta GA 2012.10.1182/blood.V120.21.3913.3913Suche in Google Scholar
14. Merlini G, Wechalekar AD, Palladini G. Systemic light chain amyloidosis: an update for treating physicians. Blood 2013;121:5124–30.10.1182/blood-2013-01-453001Suche in Google Scholar PubMed
15. Kumar S, Dispenzieri A, Katzmann JA, Larson DR, Colby CL, Lacy MQ, et al. Serum immunoglobulin free light-chain measurement in primary amyloidosis: prognostic value and correlations with clinical features. Blood 2010;116:5126–9.10.1182/blood-2010-06-290668Suche in Google Scholar PubMed PubMed Central
16. Dispenzieri A, Lacy MQ, Katzmann JA, Rajkumar SV, Abraham RS, Hayman SR, et al. Absolute values of immunoglobulin free light chains are prognostic in patients with primary systemic amyloidosis undergoing peripheral blood stem cell transplantation. Blood 2006;107:3378–83.10.1182/blood-2005-07-2922Suche in Google Scholar PubMed PubMed Central
17. Bryce AH, Ketterling RP, Gertz MA, Lacy M, Knudson RA, Zeldenrust S, et al. Translocation t(11;14) and survival of patients with light chain (AL) amyloidosis. Haematologica 2009;94:380–6.10.3324/haematol.13369Suche in Google Scholar PubMed PubMed Central
18. Kumar S, Zhang L, Dispenzieri A, Van Wier S, Katzmann JA, Snyder M, et al. Relationship between elevated immunoglobulin free light chain and the presence of IgH translocations in multiple myeloma. Leukemia 2010;24:1498–505.10.1038/leu.2010.128Suche in Google Scholar PubMed PubMed Central
19. Lachmann HJ, Gallimore R, Gillmore JD, Carr-Smith HD, Bradwell AR, Pepys MB, et al. Outcome in systemic AL amyloidosis in relation to changes in concentration of circulating free immunoglobulin light chains following chemotherapy. Br J Haematol 2003;122:78–84.10.1046/j.1365-2141.2003.04433.xSuche in Google Scholar PubMed
20. Palladini G, Dispenzieri A, Gertz MA, Kumar S, Wechalekar A, Hawkins PN, et al. New criteria for response to treatment in immunoglobulin light chain amyloidosis based on free light chain measurement and cardiac biomarkers: impact on survival outcomes. J Clin Oncol 2012;30:4541–9.10.1200/JCO.2011.37.7614Suche in Google Scholar PubMed
21. Yoshida T, Matsuda M, Katoh N, Tazawa K, Shimojima Y, Gono T, et al. Long-term follow-up of plasma cells in bone marrow and serum free light chains in primary systemic AL amyloidosis. Internal Med 2008;47:1783–90.10.2169/internalmedicine.47.0966Suche in Google Scholar PubMed
22. Kourelis TV, Kumar SK, Gertz MA, Lacy MQ, Buadi FK, Hayman SR, et al. Coexistent multiple myeloma or increased bone marrow plasma cells define equally high-risk populations in patients with immunoglobulin light chain amyloidosis. J Clin Oncol 2013;31:4319–24.10.1200/JCO.2013.50.8499Suche in Google Scholar PubMed PubMed Central
23. Gertz MA, Kyle RA, Greipp PR. The plasma cell labeling index: a valuable tool in primary systemic amyloidosis. Blood 1989;74:1108–11.10.1182/blood.V74.3.1108.1108Suche in Google Scholar
24. Pardanani A, Witzig TE, Schroeder G, McElroy EA, Fonseca R, Dispenzieri A, et al. Circulating peripheral blood plasma cells as a prognostic indicator in patients with primary systemic amyloidosis. Blood 2003;101:827–30.10.1182/blood-2002-06-1698Suche in Google Scholar PubMed
25. Dispenzieri A, Gertz MA, Kyle RA, Lacy MQ, Burritt MF, Therneau TM, et al. Serum cardiac troponins and N-terminal pro-brain natriuretic peptide: a staging system for primary systemic amyloidosis. J Clin Oncol 2004;22:3751–7.10.1201/9781420037494-24Suche in Google Scholar
26. Kumar S, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Colby C, et al. Revised prognostic staging system for light chain amyloidosis incorporating cardiac biomarkers and serum free light chain measurements. J Clin Oncol 2012;30:989–95.10.1200/JCO.2011.38.5724Suche in Google Scholar PubMed PubMed Central
27. Palladini G, Lavatelli F, Russo P, Perlini S, Perfetti V, Bosoni T, et al. Circulating amyloidogenic free light chains and serum N-terminal natriuretic peptide type B decrease simultaneously in association with improvement of survival in al. Blood 2006;107:3854–8.10.1182/blood-2005-11-4385Suche in Google Scholar PubMed
28. Perlini S, Musca F, Salinaro F, Fracchioni I, Palladini G, Obici L, et al. Functional correlates of N-terminal natriuretic peptide type B (NT-proBNP) response to therapy in cardiac light chain (AL) amyloidosis. Amyloid 2011;18 (Suppl 1):96–7.10.3109/13506129.2011.574354035Suche in Google Scholar PubMed
29. van G, II, van Rijswijk MH, Bijzet J, Vellenga E, Hazenberg BP. Histological regression of amyloid in AL amyloidosis is exclusively seen after normalization of serum free light chain. Haematologica 2009;94:1094–100.10.3324/haematol.2008.004119Suche in Google Scholar PubMed PubMed Central
30. Kumar SK, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, Zeldenrust SR, et al. Changes in serum-free light chain rather than intact monoclonal immunoglobulin levels predicts outcome following therapy in primary amyloidosis. Am J Hematol 2011;86:251–5.10.1002/ajh.21948Suche in Google Scholar PubMed PubMed Central
31. Comenzo RL, Reece D, Palladini G, Seldin D, Sanchorawala V, Landau H, et al. Consensus guidelines for the conduct and reporting of clinical trials in systemic light-chain amyloidosis. Leukemia 2012;26:2317–25.10.1038/leu.2012.100Suche in Google Scholar PubMed
32. Wechalekar AD, Lachmann HJ, Goodman HJ, Bradwell A, Hawkins PN, Gillmore JD. AL amyloidosis associated with IgM paraproteinemia: clinical profile and treatment outcome. Blood 2008;112:4009–16.10.1182/blood-2008-02-138156Suche in Google Scholar PubMed
33. Palladini G, Russo P, Bosoni T, Sarais G, Lavatelli F, Foli A, et al. Al amyloidosis associated with IgM monoclonal protein: a distinct clinical entity. Clin Lymphoma Myeloma 2009; 9:80–3.10.3816/CLM.2009.n.021Suche in Google Scholar PubMed
34. Gertz MA, Buadi FK, Hayman SR. IgM amyloidosis: clinical features in therapeutic outcomes. Clin Lymphoma Myeloma Leuk 2011;11:146–8.10.3816/CLML.2011.n.034Suche in Google Scholar PubMed
35. Wechalekar AD, Gillmore JD, Foard D, Rannigan L, Lane T, Pinney JH, et al. Evaluation of an early switch to second line chemotherapy in AL amyloidosis among patients who fail to achieve a very good partial response to frontline treatment. Presented at the XIIIth International Symposium on Amyloidosis Groningen, The Netherlands, 2012.Suche in Google Scholar
36. Tate J, Bazeley S, Sykes S, Mollee P. Quantitative serum free light chain assay–analytical issues. Clin Biochem Rev 2009;30:131–40.Suche in Google Scholar
37. Tate JR, Mollee P, Dimeski G, Carter AC, Gill D. Analytical performance of serum free light-chain assay during monitoring of patients with monoclonal light-chain diseases. Clin Chim Acta 2007;376:30–6.10.1016/j.cca.2006.07.011Suche in Google Scholar PubMed
38. Pretorius CJ, Klingberg S, Tate J, Wilgen U, Ungerer JP. Evaluation of the N latex FLC free light chain assay on the Siemens BN analyser: precision, agreement, linearity and variation between reagent lots. Ann Clin Biochem 2012;49:450–5.10.1258/acb.2012.011264Suche in Google Scholar PubMed
39. te Velthuis H, Knop I, Stam P, van den Broek M, Bos HK, Hol S, et al. N latex FLC – new monoclonal high-performance assays for the determination of free light chain kappa and lambda. Clin Chem Lab Med 2011;49:1323–32.10.1515/CCLM.2011.624Suche in Google Scholar PubMed
40. Mills JR, Barnidge DR, Murray DL. Detecting monoclonal immunoglobulins in human serum using mass spectrometry. Methods 2015;81:56–65.10.1016/j.ymeth.2015.04.020Suche in Google Scholar PubMed
41. VanDuijn MM, Jacobs JF, Wevers RA, Engelke UF, Joosten I, Luider TM. Quantitative measurement of immunoglobulins and free light chains using mass spectrometry. Anal Chem 2015;87:8268–74.10.1021/acs.analchem.5b01263Suche in Google Scholar PubMed
©2016 by De Gruyter
Artikel in diesem Heft
- Frontmatter
- Editorial
- Protein electrophoresis and serum free light chains in the diagnosis and monitoring of plasma cell disorders: laboratory testing and current controversies
- Laboratory Testing as Recommended by the Guidelines and the International Myeloma Working Group
- Laboratory testing requirements for diagnosis and follow-up of multiple myeloma and related plasma cell dyscrasias
- Free light chain testing for the diagnosis, monitoring and prognostication of AL amyloidosis
- Laboratory testing in monoclonal gammopathy of renal significance (MGRS)
- The impact of renal function on the clinical performance of FLC measurement in AL amyloidosis
- Serum and Urine Protein Electrophoresis and Immunofixation Testing
- Challenges of measuring monoclonal proteins in serum
- Screening immunofixation should replace protein electrophoresis as the initial investigation of monoclonal gammopathy: Point
- Should routine laboratories stop doing screening serum protein electrophoresis and replace it with screening immune-fixation electrophoresis? No quick fixes: Counterpoint
- Moving towards harmonized reporting of serum and urine protein electrophoresis
- Multiple qualitative and quantitative methods for free light chain analysis are necessary as first line tests for AL amyloidosis
- Use of isoelectric focusing to discriminate transient oligoclonal bands from monoclonal protein in treated myeloma
- New patterns of relapse in multiple myeloma: a case of “light chain escape” in which FLC predicted relapse earlier than urine and serum immunofixation
- Serum Free Light Chain Methods and Controversies
- Analytical issues of serum free light chain assays and the relative performance of polyclonal and monoclonal based reagents
- Measurement of free light chains with assays based on monoclonal antibodies
- Measurement of free light chains – pros and cons of current methods
- Is accuracy of serum free light chain measurement achievable?
- Performance goals for immunoglobulins and serum free light chain measurements in plasma cell dyscrasias can be based on biological variation
- A patient with AL amyloidosis with negative free light chain results
- Strengths and weaknesses of methods for identifying monoclonal free light chains of Ig: examples from two cases with renal disease
- Comparison of Freelite™ and N Latex serum free light chain assays in subjects with end stage kidney disease on haemodialysis
- New Laboratory Assays and Challenges
- Quantification of β-region IgA monoclonal proteins – should we include immunochemical Hevylite® measurements? Point
- Quantification of β region IgA paraproteins – should we include immunochemical “heavy/light chain” measurements? Counterpoint
- Free light chains and heavy/light chains in monitoring POEMS patients
- Monitoring free light chains in serum using mass spectrometry
- Monoclonal antibody therapeutics as potential interferences on protein electrophoresis and immunofixation
- Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference
- Interference of daratumumab in monitoring multiple myeloma patients using serum immunofixation electrophoresis can be abrogated using the daratumumab IFE reflex assay (DIRA)
- Letter to the Editor
- Discrepancy between FLC assays: only a problem of quantification?
Artikel in diesem Heft
- Frontmatter
- Editorial
- Protein electrophoresis and serum free light chains in the diagnosis and monitoring of plasma cell disorders: laboratory testing and current controversies
- Laboratory Testing as Recommended by the Guidelines and the International Myeloma Working Group
- Laboratory testing requirements for diagnosis and follow-up of multiple myeloma and related plasma cell dyscrasias
- Free light chain testing for the diagnosis, monitoring and prognostication of AL amyloidosis
- Laboratory testing in monoclonal gammopathy of renal significance (MGRS)
- The impact of renal function on the clinical performance of FLC measurement in AL amyloidosis
- Serum and Urine Protein Electrophoresis and Immunofixation Testing
- Challenges of measuring monoclonal proteins in serum
- Screening immunofixation should replace protein electrophoresis as the initial investigation of monoclonal gammopathy: Point
- Should routine laboratories stop doing screening serum protein electrophoresis and replace it with screening immune-fixation electrophoresis? No quick fixes: Counterpoint
- Moving towards harmonized reporting of serum and urine protein electrophoresis
- Multiple qualitative and quantitative methods for free light chain analysis are necessary as first line tests for AL amyloidosis
- Use of isoelectric focusing to discriminate transient oligoclonal bands from monoclonal protein in treated myeloma
- New patterns of relapse in multiple myeloma: a case of “light chain escape” in which FLC predicted relapse earlier than urine and serum immunofixation
- Serum Free Light Chain Methods and Controversies
- Analytical issues of serum free light chain assays and the relative performance of polyclonal and monoclonal based reagents
- Measurement of free light chains with assays based on monoclonal antibodies
- Measurement of free light chains – pros and cons of current methods
- Is accuracy of serum free light chain measurement achievable?
- Performance goals for immunoglobulins and serum free light chain measurements in plasma cell dyscrasias can be based on biological variation
- A patient with AL amyloidosis with negative free light chain results
- Strengths and weaknesses of methods for identifying monoclonal free light chains of Ig: examples from two cases with renal disease
- Comparison of Freelite™ and N Latex serum free light chain assays in subjects with end stage kidney disease on haemodialysis
- New Laboratory Assays and Challenges
- Quantification of β-region IgA monoclonal proteins – should we include immunochemical Hevylite® measurements? Point
- Quantification of β region IgA paraproteins – should we include immunochemical “heavy/light chain” measurements? Counterpoint
- Free light chains and heavy/light chains in monitoring POEMS patients
- Monitoring free light chains in serum using mass spectrometry
- Monoclonal antibody therapeutics as potential interferences on protein electrophoresis and immunofixation
- Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference
- Interference of daratumumab in monitoring multiple myeloma patients using serum immunofixation electrophoresis can be abrogated using the daratumumab IFE reflex assay (DIRA)
- Letter to the Editor
- Discrepancy between FLC assays: only a problem of quantification?