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Anthony Roberts
Anthony Roberts

Abnormal Serum Light Chain Ratio

The serum free light chain test measures the quantity of unbound immunoglobulin kappa and lambda light chain molecules in the serum. The ratio of the serum free kappa to serum free lambda is useful for detecting and following a monoclonal free light chain process. [back to top]

Abnormal Serum Light Chain Ratio

If the serum free kappa and lambda are in the reference interval and the ratio of serum free kappa/serum free lambda is in the reference interval, the test does not support the presence of a monoclonal gammopathy.

When only one of the serum free light chains is increased and the ratio of serum free kappa/serum free lambda is outside of the reference interval, it is evidence supporting the presence of a monoclonal gammopathy.

When both serum free light chains are elevated and the ratio of serum free kappa/serum free lambda is either within the reference interval or only slightly increased, this may indicate the presence of renal disease or chronic inflammation. [back to top]

No. Whereas an abnormal result can support the diagnosis of a monoclonal gammopathy, demonstration of a monoclonal spike in the serum or urine by protein electrophoresis and immunofixation provide more definitive proof of the presence of a monoclonal process. [back to top]

Patients with renal disease and/or chronic inflammation may have an increase in one or both of the serum free light chains and there may be a modest increase in the ratio of serum free kappa/serum free lambda.

If there is a marked increase in one of the serum free light chains, this may yield a falsely low value due to a phenomenon called the high-dose hook effect, also known as antigen excess effect. [back to top]

We searched a computerized database and reviewed medical records of all patients seen at Mayo Clinic within 30 days of recognition of an IgG or IgA monoclonal protein of 3 g/dL or more or a bone marrow containing 10% or more plasma cells between 1970 through 1995, which allowed for a minimum potential follow-up of 10 years. Patients found to have end organ damage at diagnosis as a result of the plasma cell proliferative disorder (including symptomatic MM or light chain amyloidosis) were excluded. Patients who received chemotherapy at diagnosis were also excluded. A total of 276 patients fulfilled clinical criteria for a diagnosis of SMM and had a bone marrow available for central review during this 26-year period. Of these patients who have recently been reported,10 273 had serum available within 30 days of diagnosis for evaluation by the FLC assay.

The FLC assay (Freelite; the Binding Site, Birmingham, United Kingdom) was performed on a Dade-Behring Nephelometer (Dade-Behring, Marburg, Germany).15,16 The assay consists of 2 separate measurements, 1 to detect free κ (normal range, 0.33-1.94 mg/dL) and the other to detect free λ (normal range, 0.57-2.63 mg/dL) light chains.16 In addition to measuring the absolute levels of FLC, the test also allows an assessment of clonality based on the ratio of κ/λ light chain levels (normal reference range, 0.26-1.65).16 Patients with a κ/λ FLC ratio lower than 0.26 are typically defined as having a monoclonal λ FLC, and those with ratios greater than 1.65 are defined as having a monoclonal κ FLC.

The prognostic effect of abnormal κ to λ FLC ratio on progression of SMM was studied. To estimate the continuous risk effect of the FLC ratio, a smoothing spline17 was used in univariate and multivariate Cox proportional hazards models.18 The risk of progression depending on the extent to which the FLC ratio was abnormal was also estimated after adjusting for the prognostic system for SMM that we have recently described (high-risk: BMPCs greater than or equal to 10% and serum M protein greater than or equal to 3 g/dL; intermediate-risk: BMPCs greater than or equal to 10% but serum M protein less than 3 g/dL; and low-risk: and serum M protein greater than or equal to 3 g/dL but BMPCs less than 10%).10

The primary study endpoint was progression to symptomatic MM or light chain amyloidosis requiring therapy. The endpoint with respect to progression was calculated in terms of both the cumulative probability and the cumulative incidence of progression. The cumulative probability was calculated with a Kaplan-Meier estimate19 in which patients who died were censored; curves were compared by the log-rank test.20 The cumulative incidence curve, which explicitly accounted for death as a competing risk, was computed by the method of Gooley et al21 The effects of potential risk factors on progression rates were examined in a Cox proportional-hazards model.18

The characteristics of the 273 patients are shown in Table 1. Their median age at diagnosis was 64 years (range, 26-90 years), and only 13% were younger than 50 years. Of these, 169 (62%) were men. The light-chain type was κ in 68% and λ in 32%. A total of 3% were biclonal. The serum M protein at diagnosis of SMM ranged from 0.5 g/dL to 5.4 g/dL (median, 2.9 g/dL). An abnormal FLC ratio (κ to λ ratio 1.65) was detected in 245 (90%) patients. The median level of the involved immunoglobulin FLC was 7.4 mg/dL (range, 0.1-1, 110 mg/dL), and the median ratio of involved to uninvolved was 11.2 (range, 0.3-11 186).

As shown in Table 2 and Figure 1, an increasingly abnormal FLC ratio was associated with a higher risk for progression to active MM. Patients with a normal (0.26 to 1.65) or near normal (0.25 to 4) ratio had a rate of progression of 5% per year, while patients with increasingly abnormal ratios had a progressive increase in the risk of progression. Patients with markedly abnormal ratios either less than 0.0312 (1 to 32) or more than 32 had a rate of progression of 8.1% per year. This increase persisted after adjusting for the competing risk of death (Table 2).

Effect of increasingly abnormal FLC ratio on the relative risk of progression of SMM to MM or related disorder. As the serum kappa/lambda FLC ratio becomes increasingly abnormal, the risk of progression increases. The middle curve in represents relative risk; upper and lower curves represent 95% confidence intervals. Vertical bars represent the normal range for kappa to lambda ratio. (A) Unadjusted. (B) Adjusted for BMPC count and M protein.

The best cut-point for progression was a FLC ratio less than 0.125 (can be alternatively expressed as a ratio less than 1:8) or greater than 8. A total of 164 patients (60% of the cohort) had this degree of abnormality, and their hazard ratio for progression to active multiple myeloma was 2.3 (95% CI, 1.6-3.2) compared with patients with FLC ratios of 0.125 to 8 (Figure 2).

Risk of progression to myeloma or related disorder in 273 patients with SMM. Risk of progression of SMM to active myeloma using serum κ to λ FLC ratio of less than 0.125 (

Risk stratification based on bone marrow plasmacytosis, serum M protein, and serum immunoglobulin FLC ratio. Patients are assigned 1 point for meeting each of the following criteria: BMPCs greater than or equal to 10%; serum M protein greater than or equal to 3 g/dL; and serum immunoglobulin FLC ratio either less than 0.125 or more than 8. The median times to progression for 1, 2, or 3 risk factors are 10, 5.1, and 1.9 years, respectively.

Serum free light Chain (sFLC) ratios have been correlated with survival outcomes in Hodgkin and non-Hodgkin lymphoma subtypes. This study was undertaken to investigate the prognostic impact of abnormal sFLC ratios in mantle cell lymphoma (MCL). two patient cohorts were analysed for sFLC parameters: a preliminary retrospective cohort and a uniformly treated cohort of 20 relapsed/refractory MCL patients, enrolled in a phase II clinical trial of single agent lenalidomide treatment. 52% of patients had an abnormality of one or more sFLC parameter (71% of the first cohort and 40% of the second cohort). In cohort two, a high baseline SFLC ratio correlated with poorer overall survival (OS) compared to a low/normal ratio (median OS: 14 months vs. 19 months respectively; P = 0001). For patients presenting with an elevated sFLC ratio at trial entry a rise of >35% in the sFLC ratio correlated with disease progression and a sFLC ratio of >2 normal at trial entry correlated with aggressive disease. These data are the first to show a clear clinical correlation between sFLC ratios and survival outcomes in a uniformly treated cohort of MCL patients. We suggest that these markers may be useful in managing patients with MCL in the future.

Critical to the diagnosis of myeloma is testing serum for the presence of an M-protein (paraprotein) plus serum and/or urine testing for monoclonal free light chains (FLC). Absence of an M-protein and abnormal serum FLC ratio is only found in the rare non-secretory myeloma, and therefore with close to 100% sensitivity for diagnosis of myeloma, encouraging widespread use of these simple blood tests may reduce delays in myeloma diagnosis.6 However, ordering these tests is tempered because they also reveal the 100 times more common condition monoclonal gammopathy of undetermined significance (MGUS).7 In clinical practice the majority of M-proteins and abnormal serum FLC ratios derive from MGUS plasma cell clones or are small abnormalities in the ratio caused by conditions unrelated to neoplastic plasma cells, including kidney disease, inflammation and infection. Myeloma arises in an age range in which these conditions are common and there is a need to define serum FLC ratio reference ranges better in these groups of patients.108 MGUS is not usually clinically significant and not the cause of the patients presenting illness but requires differentiation from myeloma and this can be difficult.11 Particularly in primary care and other specialties there may be unnecessary rapid referrals to hematologists, inappropriate testing (imaging or bone marrow biopsies), and associated anxiety in patients. This is a significant problem in the UK where patients are frequently referred unnecessarily as urgent suspected cases of cancer and contributes to gross inefficiency within healthcare systems that are struggling with capacity. There is a lack of guidance for non-hematologists in interpretation of abnormal test results in this setting. It would be useful to have evidence-based guidelines on laboratory reporting of M-protein levels and serum FLC ratios that would enable primary care and other specialty doctors to decide which patients to refer urgently to hematology for suspected myeloma. 041b061a72


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