Comparison of two free light chain assays: performance of the involved free light chain ratio and implications for diagnosis of multiple myeloma.
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ABSTRACT:
SUBMITTER: Willrich MAV
PROVIDER: S-EPMC9440004 | biostudies-literature | 2022 Sep
REPOSITORIES: biostudies-literature
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Comparison of two free light chain assays: performance of the involved free light chain ratio and implications for diagnosis of multiple myeloma.
Willrich Maria Alice V MAV Murray David L DL Rajkumar S Vincent SV Bryant Sandra C SC Larson Dirk D Pazdernik Vanessa V Snyder Melissa R MR Kyle Robert A RA Dispenzieri Angela A
Blood cancer journal 20220902 9
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Project description:The measurement of serum-free light chains (FLC) is standard of care in the diagnosis and management of multiple myeloma (MM). The revised international myeloma working group (IMWG) implemented the involved FLC/noninvolved FLC (iFLC/niFLC) ratio as a biomarker for MM requiring treatment. Recently, a new definition of high-risk smoldering MM (SMM) including iFLC/niFLC ratio was published. These recommendations were solely based on a single assay method (Freelite assay). Today, two additional assays, N Latex FLC and ELISA-based Sebia FLC, are available. Here, we report on a single-center-study comparing results of all three different assays for FLC correlation and its potential implications for diagnostic and clinical use. In total, 187 samples from 47 MM patients were examined, and determination of FLC was performed. Comparison analyses showed similar FLC results for Sebia FLC and N Latex FLC assay with markedly lower absolute values for κ/λ ratio compared with Freelite. Values of λ FLC exhibited high variability. The ratio of iFLC/niFLC showed significant discrepancies among these assays. Our data demonstrate that the three available assays may result in markedly discrepant results, and should not be used interchangeably to monitor patients. Furthermore, modifications of the assay-specific diagnostic (iFLC/niFLC) thresholds for SMM and MM are recommended.
| S-EPMC6949235 | biostudies-literature
Project description:Background and aimsThe serum free light chain assay (sFLC) is well established for aiding in the diagnosis, prognosis, and monitoring of plasma cell proliferative disorders. There are currently two commercially available sFLC immunoassays, Freelite, based on polyclonal antibody technology, and N Latex FLC, based on monoclonal antibodies. This study aimed to compare the analytical and clinical performance of these two assays in a Chinese population.MethodsThis study included 74 consecutive patients who were newly diagnosed with monoclonal gammopathies (MGs) including multiple myeloma (MM), AL amyloidosis, and light chain deposition disease (LCDD) between January 2014 and May 2015 at the First Affiliated Hospital of Zhejiang University. Alongside serum and urine electrophoresis analysis, the serum samples were retrospectively tested with both sFLC assays according to the manufacturers' instructions.ResultsThe two sFLC assays showed a moderate correlation for κFLC (Passing-Bablok slope = 0.645, coefficient of determination (R 2) = 0.83, and Spearman coefficient = 0.904). However, for λFLC, a poor correlation was found (Passing-Bablok slope = 0.690, R 2 = 0.39, and Spearman coefficient = 0.852). The concordance rate of κFLC, λFLC, and κ/λ FLC ratio were 83.78%, 75.68%, and 86.49%, respectively. The clinical sensitivity of the κ/λ ratios were 83.8% for the Freelite assay and 75.7% for the N Latex FLC assay.ConclusionAlthough the concordance and the clinical sensitivity of the two assays appeared comparable, a number of discrepancies were observed. There is a low correlation between the two assays in clinical practice, suggesting that the assays are not equivalent and, thus, current IMWG guidelines, based on Freelite, cannot be cross-applied to N Latex FLC.
| S-EPMC6482328 | biostudies-literature
Project description:IntroductionQuantification of serum-free light chains (FLCs) is important in the diagnosis and monitoring of paraprotein-related diseases. There are currently 2 FLC assays available: the Freelite assay (Binding Site) and the N Latex assay (Siemens). There is emerging evidence that these assays give different results, but it is not established how kidney dysfunction affects these assays differently.MethodsIn this study, we measured and compared serum FLCs in patients with mild-to-moderate chronic kidney disease (CKD) using both assays.ResultsAlthough κ FLCs are higher by Freelite, λ FLCs are higher by N Latex. Both κ and λ FLCs correlate inversely with estimated glomerular filtration rate (eGFR) in the 2 assays, but this effect is more pronounced in λ-free light-chain measurement by N Latex. Consequently, although the κ/λ ratio by Freelite is inversely correlated by eGFR, the κ/λ ratio by N Latex is positively correlated with eGFR.ConclusionOur results clearly demonstrate that the 2 available FLC assays cannot be used interchangeably in patients with CKD.
| S-EPMC7210599 | biostudies-literature
Project description:We investigated the prognostic impact of time-dependent serum free light chain ratio (FLCr) normalization in 590 patients with secretory multiple myeloma (MM) during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. Serum free light chains (sFLC) were assessed by the Freelite test at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow up within two years after the start of maintenance. The proportion of patients with a normal or normalized FLCr increased from 3.6% at baseline to 23.2% after induction and 64.7% after consolidation. The achievement of FLCr normalization at any one time before the start of maintenance was associated with significantly prolonged progression-free survival (PFS) (p < 0.01, hazard ratio (HR) = 0.61, 95% confidence interval (95% CI) = 0.47-0.79) and overall survival (OS) (p = 0.02, HR = 0.67, 95% CI = 0.48-0.93) in multivariable time-dependent Cox regression analyses. Furthermore, reaching immune reconstitution, defined as the normalization of uninvolved immunoglobulins, before maintenance was associated with superior PFS (p = 0.04, HR = 0.77, 95% CI = 0.60-0.99) and OS (p = 0.01, HR = 0.59, 95% CI = 0.41-0.86). We conclude that FLCr normalization during therapy is an important favorable prognostic factor in MM. Therefore, we recommend serial measurements of sFLC during therapy until achieving FLCr normalization, even in patients with secretory MM.
| S-EPMC8507729 | biostudies-literature
Project description:BackgroundDetection of free light chains (fLC) in animals relies on protein electrophoresis or the Bence-Jones protein test on urine.ObjectiveTo describe the detection of both serum fLC (sfLC) and urine fLC (ufLC) in 8 dogs and 2 cats using a commercially available human immunofixation (IF) kit.AnimalsArchived serum or urine samples from 27 dogs and 2 cats submitted to the Colorado State University Veterinary Diagnostic Laboratory for routine diagnostics.MethodsRetrospective study evaluating the presence of fLC in dogs and cats using agarose gel electrophoresis and routine and fLC IF performed on serum and urine. The performance of the fLC IF reagents was evaluated using samples characterized by routine IF, tandem mass spectrometry, and a combination of fLC IF and western blotting. Free light chains were documented by paired electrophoresis and fLC IF.ResultsThe fLC only myeloma case developed end-stage renal failure 5 months post initial diagnosis. All electrophoresis-defined urinary Bence-Jones proteins were labeled by the anti-free λ light chain (anti-fλ) reagent; none were labeled by the anti-free κ light chain (anti-fκ); 2 of these were identified as fκ by mass spectrometry. An electrophoretically identical protein restriction that was labeled by the anti-fλ reagent was present in the paired serum from 5/8 of cases, documenting sfLC.Conclusions and clinical importanceCommercially available human IF reagents identified sfLC and ufLC in both dogs and cats. Free light chains may be nephrotoxic in dogs.
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Project description:Response criteria for multiple myeloma are based upon changes in monoclonal protein levels quantified using serum and/or urine protein electrophoresis. The latter lacks sensitivity at low monoclonal protein levels and since 2001, the serum free light chain test has been available and its clinical utility proven, yet guidelines have not recommended it as a replacement for urine assessment. Herein we evaluated responses using serum free light chain measurements and serum and urine electrophoresis after 2 and 4 cycles of therapy and after stem cell transplantation in 25 light chain and 157 intact immunoglobulin myeloma patients enrolled in the IFM 2007-02 MM trial. All 25 light chain patients had measurable disease by serum free light chain and urine methods at presentation. By contrast 98 out of 157 intact immunoglobulin patients had measurable disease by serum free light chain compared to 55 out of 157 by urine electrophoresis. In all patients there was substantial agreement between predicate (serum/urine protein electrophoresis) and test (serum protein electrophoresis and serum free light chain) methods for response assessment (Weighted Kappa=0.83). Urine immunofixation became negative in 47% light chain and 43% intact immunoglobulin patients after 2 cycles of therapy. At this time the serum free light chain ratio normalised in only 11% and 27% patients, respectively. In summary we found good agreement between methods for response assessment, but the serum free light chain test provided greater sensitivity than urine electrophoresis for monitoring. To our knowledge this is the first report comparing both methods for response assignment based on the International Myeloma Working Group guidelines. (Clinical Trials Register.eu identifier: 2007-005204-40).
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Project description:Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant clonal plasma cell disorder, with a 1% yearly risk of progression to multiple myeloma (MM). Evolution of M-spike and serum free light chain (sFLC) during follow-up could identify patients at high risk of progression. In this region-wide study, including 4756 individuals, 987 patients with MGUS were identified, and baseline factors as well as evolving involved FLC (iFLC) were evaluated as potential markers for risk of progression from MGUS to MM. Furthermore, evolving iFLC and M-spike were assessed quarterly for a median of 5 years. At baseline, patients that progressed had significantly higher iFLC compared to non-progressors. The risk factors of M-spike >1.5 g/dL, age >65 years and iFLC >100 mg/L were all independently associated with increased risk of MGUS to MM progression. For patients that had any two or three risk factors, the 5-year cumulative probability of progression was significantly higher (31%) compared to no risk factors (2%). Evolving iFLC >100 mg/L during follow-up was consistently associated with increased risk of progression. Based on our observations, we propose to include iFLC as a monitoring tool for all MGUS patients. Furthermore, we recommend a quarterly monitoring in all high-risk patients. Finally, we suggest that the risk of MGUS progression should be stratified with age, M-spike, and iFLC at baseline.
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Project description:Guidelines for monitoring multiple myeloma (MM) patients expressing light chains only (light-chain MM [LCMM]) rely on measurements of monoclonal protein in urine. Alternatively, serum free light chain (sFLC) measurements have better sensitivity over urine methods, however, demonstration that improved sensitivity provides any clinical benefit is lacking. Here, we compared performance of serum and urine measurements in 113 (72κ, 41λ) newly diagnosed LCMM patients enrolled in the Intergroupe Francophone du Myélome (IFM) 2009 trial. All diagnostic samples (100%) had an abnormal κ:λ sFLC ratio, and involved (monoclonal) FLC (iFLC) expressed at levels deemed measurable for monitoring (≥100 mg/L). By contrast, only 64% patients had measurable levels of monoclonal protein (≥200 mg per 24 hours) in urine protein electrophoresis (UPEP). After 1 and 3 treatment cycles, iFLC remained elevated in 71% and 46% of patients, respectively, whereas UPEP reported a positive result in 37% and 18%; all of the patients with positive UPEP at cycle 3 also had elevated iFLC levels. Importantly, elevated iFLC or an abnormal κ:λ sFLC ratio after 3 treatment cycles associated with poorer progression-free survival (P = .006 and P < .0001, respectively), whereas positive UPEP or urine immunofixation electrophoresis (uIFE) did not. In addition, patients with an abnormal κ:λ sFLC ratio had poorer overall survival (P = .022). Finally, early normalization of κ:λ sFLC ratio but not negative uIFE predicted achieving negative minimal residual disease, as determined by flow cytometry, after consolidation therapy (100% positive predictive value). We conclude that improved sensitivity and prognostic value of serum over urine measurements provide a strong basis for recommending the former for monitoring LCMM patients.
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