Monoclonal Light Chains Assays: TLC assay vs FLC assay
Introduction
Understanding the Difference: Total Light Chain (TLC) assays and Free Light Chain (FLC) assays
When dealing with plasma cell disorders such as monoclonal gammopathies, understanding the difference between Total Light Chain (TLC) and Free Light Chain (FLC) assays is crucial.
While TLC assays measure both bound and unbound free light chains, FLC assays specifically target the free light chains. The difference in targeting has significant implications on sensitivity, accuracy, and utility in diagnosing and monitoring monoclonal gammopathies.
Total light chain assays are not recommended by guidelines in the diagnosis of Multiple Myeloma
2009: Serum FLCs adopted as diagnostic panel by International Myeloma Working Group (IMWG) guidelines- Freelite® brand.
2021: CAP strongly recommended that "clinical providers should NOT use total light chains for the quantification of M proteins in patients with suspected myeloma."
2024: Spanish External Quality Assurance (EQA) scheme provided the following information to labs: "the measurement of total light chains has been replaced by free light chains, as they have greater sensitivity for the diagnosis of monoclonal disease."
Why Choose Free Light Chain Assays?
Total light chain assays should not be considered interchangeable with FLC assays, as evidenced by the weak correlation between their results (r=0.12; p=0.008)1. Imbalances in the κ/λ light chain ratio can indicate the overproduction of a specific plasma cell clone. Serum FLC assays provide a more sensitive and specific measure of light chain clonality. Unlike TLC assays that require significant overproduction of clonal light chains to detect changes, FLC assays can detect even small alterations in the κ/λ light chain ratio. This enhanced sensitivity is crucial in diagnosing and monitoring monoclonal gammopathies.
Total light chain assays should not be considered interchangeable with FLC assays, as evidenced by the weak correlation between their results (r=0.12; p=0.008)1. Imbalances in the κ/λ light chain ratio can indicate the overproduction of a specific plasma cell clone. Serum FLC assays provide a more sensitive and specific measure of light chain clonality. Unlike TLC assays that require significant overproduction of clonal light chains to detect changes, FLC assays can detect even small alterations in the κ/λ light chain ratio. This enhanced sensitivity is crucial in diagnosing and monitoring monoclonal gammopathies.
FLC assays are supported by Research and Guidelines
FLC assays are widely supported by over 20 years of scientific publications and are included in both international2-4 and national5 diagnostic and monitoring guidelines. These guidelines specifically recommend the use of serum free light chain assays for diagnosing and monitoring Multiple Myeloma, while discouraging the use of total light chain assays.
Studies have shown that FLC assays provide superior detection power compared to TLC assays when diagnosing and monitoring Multiple Myeloma.
- In newly diagnosed Multiple Myeloma (MM) patient cohorts, sFLC testing showed a higher detection rate (96.8%)6 compared to total light chain assays (45%)7
- In MM patients with κ Light Chain isotype (κLC), a higher percentage of abnormal results were seen using the sFLC ratio (86.4%) compared to the total light chain ratio (54.5%). Similar findings were observed in patients with a λLC isotype (88.9% vs 55.5%)8
- In Light Chain only MM patients, sFLC assay accurately identified clonality in 100% of presentation samples and detected persistent disease in 77.7% of samples during the disease course, while total light chain assay had lower sensitivity (18.2% and 24.3%, respectively)9
- In patients with non-secretory MM, total light chain assay inaccurately reported as negative 8/9 samples. Abnormal κ/λ sFLC ratio was observed in 6 out of 9 patients10
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In summary
1. International guidelines recommend the use of serum free light chain assays (and not total light chain assays) for diagnosing and monitoring Multiple Myeloma.
2. Free light chain assays are more sensitive in detecting alterations in the κ/λ light chain ratio, and therefore in detecting plasma cell clonality in monoclonal gammopathies.
3. Total light chain assays have limitations and show lower sensitivity compared to free light chain assays.
Below are some examples of how laboratories guide clinician test requesting:
- Contact the Requesting Clinician. Reach out to the clinician who submitted the request to discuss the context and clarify the purpose of the request. Often, this conversation helps identify the need for a switch from TLC to sFLC testing
- Add a comment to TLC results. To avoid confusion and ensure accurate interpretation of results, consider adding a comment in the TLC results report. Clearly state that the performed assay is Total Light Chain, not Free Light Chain, and that for investigations related to monoclonal gammopathies, it is crucial to request the FLC test instead of TLC
- Advocate for sFLC Assays. Share the benefits of utilizing sFLC assays with the requesting clinician. Explain how sFLC assays provide reliable and guideline compliant testing for patient diagnosis and monitoring of monoclonal gammopathies
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References
- Stein R, Mehta J, Vickrey E, Resseguie W, Singhal S. Correlation of Serum Free Light Chain Levels with Other Parameters in Myeloma. Blood 2006;108 11:5019a as doi: 10.1182/blood.V108.11.5019.5019.
- Rajkumar SV, Dimopolous MA, Palumbo A, Blade J, Merlini G, Mateos MV, Kumar S, et al. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol 2014 2014;15:e538-e48.
- Kumar S, Paiva B, Anderson KC, Durie B, Landgren O, Moreau P, Munshi N, et al. International Myeloma Working Group consensus criteria for response and minimal residual disease assessment in multiple myeloma. Lancet Oncol 2016 Aug;17 8:e328-46 as doi: 10.1016/S1470-2045(16)30206-6.
- Keren DF, Bocsi G, Billman BL, Etzell J, Faix JD, Kumar S, Lipe B, 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 [eng]. Arch Pathol Lab Med 2021 Aug 4;146 5:575-90. Epub 2021/08/05 as doi: 10.5858/arpa.2020-0794-CP.
- NICE. Myeloma: diagnosis and management. NICE Guidelines 2016 2016.
- Katzmann JA, Kyle RA, Benson J, Larson DR, Snyder MR, Lust JA, Rajkumar SV, Dispenzieri A. Screening panels for detection of monoclonal gammopathies. Clin Chem 2009 2009;55 8:1517-22 as doi: clinchem.2009.126664 [pii] 10.1373/clinchem.2009.126664.
- Zamora-Ortiz G, Velazquez-Sanchez-de-Cima S, Hernandez-Reyes J, Martagon-Herrera NA, Ruiz-Arguelles A, Ruiz-Delgado GJ, Ruiz-Arguelles GJ. Poor performance of the total kappa/lambda light chain quantification in the diagnosis and follow-up of patients with multiple myeloma. Rev Invest Clin 2014 7/2014;66 4:314-8.
- Korpysz M, Morawska M, Burska A, Donica H. Comparison of the free and total light chain assays in serum and urine samples with immunofixation electrophoresis for detecting monoclonal proteins in patients with monoclonal gammopathy. Current Issues in Pharmacy and Medical Sciences 2015 2015;27 3:165-70.
- Tietsche de Moraes Hungria V, Allen S, Kampanis P, Soares EM. Serum free light chain assays not total light chain assays are the standard of care to assess Monoclonal Gammopathies. Rev Bras Hematol Hemoter 2016 Jan-Feb;38 1:37-43 as doi: 10.1016/j.bjhh.2015.11.003.
- Chen HF, Hou J, Yuan ZG, Wang DX, Fu WJ, Chen YB. [Detection of serum free light chain and its clinical significance in nonsecretory multiple myeloma]. Zhonghua Xue Ye Xue Za Zhi 2008 2008;29 2:113-6.