Understanding light chains and the importance of sFLC testing in multiple myeloma
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Understanding light chains and the importance of sFLC testing in multiple myeloma

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Introduction
What is the importance of free light chains (FLC) in multiple myeloma?
The importance of sFLC testing in multiple myeloma diagnosis

Light chains are an important component of multiple myeloma pathophysiology. When analyzed through tests such as serum free light chain (sFLC) assays, their presence, quantity, and ratio can help inform diagnostic and treatment decisions.

Understanding light chains and their role in myeloma first requires a basic understanding of antibody structure. 

The structure of an antibody

Antibodies are a type of immunoglobulin secreted by B-cells. They bind to antigens to neutralize or eliminate them and therefore play a major role in the immune system. Antibodies fall into one of five classes that differ based on function and structure of the heavy protein chains they contain: immunoglobulin (Ig) A, D, E, G, or M.1 Each immunoglobulin is then further differentiated by its light chain type (kappa or lambda).

The Y-shaped structure of an antibody consists of two identical heavy protein chains and two identical light protein chains. The heavy chains are connected to each other along the stem of the Y and diverge at the top, each heavy chain having a light chain attached to it.  The upper region (forming the arms of the Y) contains the antigen binding sites, while the stem of the Y interacts with other components of the immune system.1

Heavy chains antibody structure

What is a light chain? 

Light chains are small proteins produced by plasma cells. They may be found in a free form (as either monomers or dimers) or bound to heavy chains to make up an intact antibody. Two types of light chains exist: lambda and kappa, of which only one type occurs in a given antibody.1

Antibody production in multiple myeloma

When there is abnormal proliferation of clonal B cells, there is excess production of the antibodies they secrete. This typically causes a monoclonal “spike” (M spike) in immunoglobulin levels observed by protein electrophoresis.2 The sFLC ratio may also be distorted with clonal B cell proliferation, as the clonal cells can produce either kappa or lambda unbound light chains that circulate in the blood, called free light chains (FLC).1 The sFLC ratio is presented in terms of quantity of kappa over lambda (κ/λ). Depending on which light chain is produced in excess, the ratio either falls below or above the reference range for normal sFLC ratios. 

What is the importance of free light chains (FLC) in multiple myeloma?

Multiple myeloma is a hematologic malignancy caused by the clonal expansion of plasma cells in the bone marrow. The proliferation of clonal cells results in disproportionate increased production of that cell type’s protein and excessive secretion of monoclonal (M) proteins that can include intact immunoglobulins and/or free light chains.2 In most cases of myeloma, patients have increased levels of both intact immunoglobulins and free light chains circulating in the blood.3,4

Excess immunoglobulins in circulation may result in hyperviscosity syndrome, which can cause bleeding problems as well as ocular, neurological, cardiovascular and other symptoms.5 These proteins can also accumulate in the kidneys, causing renal disease and organ failure. This is particularly the case in light-chain only myeloma, wherein high levels of free light chains collect in the proximal tubules of the kidneys and exceed the reabsorption capacity.6 Over time, light chain deposition can lead to a number of kidney disorders. This includes cast nephropathy, in which the monoclonal protein binds to Tamm-Horsfall protein (also known as uromodulin) and forms casts in the distal tubules.6 Renal manifestations are more common in patients with light-chain only myeloma than in patients with other types of multiple myeloma.6

Light chain-only myeloma or light-chain multiple myeloma is a form of myeloma where the underlying tumor only secretes light chains, not intact immunoglobulins. In this form of multiple myeloma, the FLC quantities and ratios are abnormal. This form of myeloma affects up to 1 in 5 patients.3

Learn about other signs and symptoms of multiple myeloma, and when to suspect it in your patients

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The importance of sFLC testing in multiple myeloma diagnosis

Most patients with multiple myeloma have intact M protein in the blood, but 15-20% of patients have light chain-only myeloma and up to 3% of patients secrete little or no monoclonal proteins at all (intact or free).3,4 (Many patients with intact immunoglobulin multiple myeloma also secrete FLC.) These variations in in what monoclonal protein myeloma patients produce make guideline-based, comprehensive serum testing for abnormal monoclonal protein and monoclonal excess FLC essential.

Numerous myeloma association guidelines recommend the following tests for aiding in the initial detection, myeloma diagnosis and/or monitoring:7-14

  • Serum protein electrophoresis (SPEP)
  • Serum immunofixation electrophoresis (sIFE)
  • Serum free light chain (sFLC) assay
  • Serum quantitative immunoglobulins*

24-hour urine testing (urine protein electrophoresis/immunofixation) can also detect the presence of FLCs, but serum testing is more sensitive, reliable, and easier for patients.15

Together, SPEP, sFLC, and sIFE can identify >99% of myeloma cases.16 Using SPEP alone may miss as many as 1 in 8 patients with myeloma.16

Serum free light chain testing makes up a key component of the updated diagnostic criteria for multiple myeloma.7 Historically, only CRAB criteria (hypercalcemia, renal insufficiency, anemia, and lytic bone lesions) alongside bone marrow testing were used to diagnose myeloma. However, when CRAB criteria are present, organ damage has already occurred. Earlier diagnosis and treatment can improve survival and quality of life for myeloma patients.17,18 SLiM criteria were adopted by the International Myeloma Working Group as an additional category for a myeloma-defining event, to improve early myeloma identification and enable earlier treatment of patients at risk of imminent end-organ damage before end organ damage occurs:7

  • S: At least 60% clonal plasma cells on bone marrow examination
  • Li: A ratio of 100 or more of the involved-to-uninvolved free light chains in serum free light chain (sFLC) testing, provided the absolute level of the involved light chain is 100 mg/L or greater
  • M: At least one focal lesion 5 mm or larger in size on MRI

sFLC is an essential test to help identify myeloma patients early, and to aid in the diagnosis of patients with light chain-only myeloma.3,7 Urgent referral to a hematologist/oncologist is appropriate for patients with significantly abnormal M protein concentrations or sFLC ratios.19 Furthermore, patients with any free light chain ratio imbalance may require consultation with a specialist who can inform about appropriate next steps, such as further testing or long-term monitoring.19

Multiple myeloma is not the only disorder where there is an excess intact monoclonal immunoglobulins or free light chains in the blood. These may also occur in premalignant plasma cell disorders, such as MGUS, and other plasma cell dyscrasias.3,7,20 It’s also important to note that immunosuppression or autoimmunity, renal impairment, and infection can cause mild abnormalities in sFLC results.21
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Learn how to interpret multiple myeloma test results

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*Where there is suspicion of or confirmation of an IgG, IgA or IgM paraprotein, guidelines indicate the use of SPE/UPE and/or sIFE/uIFE. Serum IgG, IgA or IgM concentrations can be useful to assess, after the monoclonal protein has been identified.

References
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  2. Mikhael J et al. Multiple Myeloma for the Primary Care Provider: A Practical Review to Promote Earlier Diagnosis Among Diverse Populations. Am J Med. 2023;136(1):33-41.
  3. Kumar SK et al. Multiple myeloma. Nat Rev Dis Primers. 2017;3:17046. 
  4. Vermeersch P, et al. Use of interval-specific likelihood ratios improves clinical interpretation of serum FLC results for the diagnosis of malignant plasma cell disorders. Clin Chim Acta. 2009 Dec;410(1-2):54-8.
  5. Mehta J, Singhal S. Hyperviscosity syndrome in plasma cell dyscrasias. Seminars in thrombosis and hemostasis. 2003;29(5):467-472.
  6. Rafae A et al. An overview of light chain multiple myeloma: clinical characteristics and rarities, management strategies, and disease monitoring. Cureus. 2018;10(8).
  7. Rajkumar SV et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014;15(12):e538-e548.
  8. Mikhael J et al. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline. J Clin Oncol 2019; 37:1228-1263.
  9. Bergstrom DJ et al.; Myeloma Canada Research Network Consensus Guideline Consortium. Consensus Guidelines on the Diagnosis of Multiple Myeloma and Related Disorders: Recommendations of the Myeloma Canada Research Network Consensus Guideline Consortium. Clin Lymphoma Myeloma Leuk. 2020 Jul;20(7):e352-e367.
  10. Keren DF et al. Laboratory detection and initial diagnosis of monoclonal gammopathies: Guideline from the College of American Pathologists in collaboration with the American Association for Clinical Chemistry and the American Society for Clinical Pathology. Arch Pathol Lab Med. 2022;146(5):575–590.
  11. Dimopoulos et al. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Annals Onc. 2021;32:309-322.
  12. Caers J et al. European Myeloma Network recommendations on tools for the diagnosis and monitoring of multiple myeloma: what to use and when. Haematologica. 2018;103(11):1772-1784.
  13. NCCN Clinical Practice Guidelines in Oncology® for Multiple Myeloma V.1.2025. National Comprehensive Cancer Network. Accessed 20 March 2025 at https://www.nccn.org/professionals/physician_gls/pdf/myeloma.pdf.
  14. NICE. Myeloma: Diagnosis and Management (NG35). National Institute for Health and Care Excellence. Updated October 2018. ISBN: 978-1-4731-1659-7. Accessed 20 March 2025 at https://www.nice.org.uk/guidance/ng35/resources/myeloma-diagnosis-and-management-pdf-1837394042821.
  15. Dejoie T et al. Comparison of serum free light chain and urine electrophoresis for the detection of the light chain component of monoclonal immunoglobulins in light chain and intact immunoglobulin multiple myeloma. Haematologica. 2016;101(3):356-62.
  16. Katzmann JA et al. Screening panels for detection of monoclonal gammopathies. Clin Chem. 2009;55(8):1517-22.
  17. Kariyawasan CC et al. Multiple myeloma: causes and consequences of delay in diagnosis. QJM. 2007;100(10):635-640.
  18. Seesaghur A et al. Clinical features and diagnosis of multiple myeloma: a population-based cohort study in primary care. BMJ Open 2021;11:e052759.
  19. Drayson M et al. For Myeloma UK working group for laboratory best practice. Laboratory practice is central to earlier myeloma diagnosis: Utilizing a primary care diagnostic tool and laboratory guidelines integrated into haematology services. Br J Haematol. 2024;204(2):476-486.
  20. Rajkumar SV et al. Smoldering multiple myeloma current treatment algorithms. Blood Cancer J. 2022;12(9):129.
  21. Dispenzieri A et al. International Myeloma Working Group guidelines for serum-free light chain analysis in multiple myeloma and related disorders. Leukemia. 2009;23(2):215-224.
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