Serum Free Light Chain Test Research Articles

Serum-free light chain test utilisation at a South African academic laboratory and comparison with serum protein electrophoresis results.

Serum protein electrophoresis (SPE), urine protein electrophoresis and immunofixation electrophoresis were traditionally utilised for the diagnosis of monoclonal gammopathies. The quantitative serum-free light chain (SFLC) assay is reportedly more sensitive and has been introduced to recent clinical guidelines. This study aimed to investigate SFLC test utilisation and describe SPE findings in patients with abnormal SFLC ratios. A retrospective audit of SFLC analyses was conducted in Cape Town, South Africa, from May 2018 to April 2020. Agreement between abnormal SFLC ratios and SPE results was determined in a sub-group of patients screened for monoclonal gammopathies. Serum-free light chains were analysed using Freelite® Kappa and Lambda assays. Of the 1425 patients included in the audit, 741 (52%) had abnormal SFLC ratios; 636 (45%) had increased and 105 (7%) had decreased SFLC ratios. In a sub-group analysis of 117 new patients with an abnormal SFLC ratio, 57 had a monoclonal protein (M-protein) on SPE (49%), and 60 (51%) did not. Four out of 60 patients without M-protein had a plasma cell dyscrasia, while renal impairment or inflammatory response accounted for the rest. Of the 57 patients with a M-protein and abnormal SFLC ratio, 41 (72%) had a plasma cell dyscrasia, seven (12%) had lymphomas and nine patients (16%) were unclassifiable. Serum-free light chains should be requested when there is a high index of clinical suspicion. Neither SFLC nor SPE should be performed in isolation when screening patients for monoclonal gammopathy, to ensure that no patient is missed. The study adds to the evidence on SFLC test utilisation. Serum protein electrophoresis alone may miss cases of light chain myeloma, while SFLC performed in isolation may produce false positive results in the setting of inflammatory disorders or renal impairment, leading to unnecessary further investigation.

Significance of the pee-value: relevance of 24-hour urine studies for patients with myeloma

International Myeloma Working Group (IMWG) response criteria require refrigerated 24-hour urine specimens for most patients. However, given that serum free light chain testing has been shown to outperform 24-hour urine immunofixation as a prognostic marker, the importance of maintaining urine testing options or requirements within each level of IMWG response criteria has not been investigated. We analyzed responses to induction therapy for all transplant-eligible patients with multiple myeloma at our institution over a 3-year period using traditional versus ‘urine-free’ IMWG response criteria (where references to urine were removed from the descriptions for every depth of response). Of 281 evaluable patients, responses changed for only 4% of patients (95% confidence interval 2–7%) using urine-free criteria. Our results call into question the continued requirement for 24-hour urine measurements as part of IMWG response assessments for all patients. Research into the prognostic performance of urine-free IMWG criteria is ongoing.

Pitfalls in Assessing Measurable Residual Disease in Plasma Cell Myeloma: a Comparison between Common Laboratory Tests.

Measurable residual disease (MRD) in plasma cell myeloma is one of the most important determinants for patients' outcome. Several laboratory tests exist to assess for the presence of MRD with variable accuracy. The aim of this study is to examine the sensitivity of immunofixation electrophoresis (IFE), serum free light chain (FLC), bone marrow immunohistochemistry (IHC), and multicolor flow cytometry (FC) and to address potential caveats of each test. Forty patients of plasma cell myeloma who were diagnosed with a positive MRD were retrospectively included in this study. The results of IFE and serum FLC at the time of bone marrow biopsy were collected. In all cases, malignant plasma cells constituted less than 5% of bone marrow cells. MRD was detected by FC in 38 cases (95%) and by IHC in 28 cases (70%). In 2 cases, residual malignant plasma cells appeared in the subcortical area which is difficult to aspirate, and thus they were detected by IHC but not by FC. Among the entire cohort, 38 patients (95%) had positive IFE at the time of bone marrow biopsy, while serum FLC abnormality was detected in 19 patients (48%) only. Both FC and IFE exhibited high sensitivity in detecting MRD in plasma cell myeloma with comparable results. IFE remains less invasive and less expensive than FC. Despite the lower sensitivity of bone marrow IHC staining, its diagnostic role is essential and can be superior to FC in a subset of cases, for which its routine examination is recommended. Serum FLC test provided the least sensitivity among all tests.

The Current Role of the Heavy/Light Chain Assay in the Diagnosis, Prognosis and Monitoring of Multiple Myeloma: An Evidence-Based Approach.

Despite tremendous progress being made in recent years, multiple myeloma (MM) remains a challenging disease. The laboratory plays a critical role in the overall management of patients. The diagnosis, prognosis, clinical monitoring and evaluation of the response are key moments in the clinical care process. Conventional laboratory methods have been and continue to be the basis of laboratory testing in monoclonal gammopathies, along with the serum free light chain test. However, more accurate methods are needed to achieve new and more stringent clinical goals. The heavy/light chain assay is a relatively new test which can overcome some of the limitations of the conventional methods for the evaluation of intact immunoglobulin MM patients. Here, we report an update of the evidence accumulated in recent years on this method regarding its use in MM.

Cardiac amyloidosis mimicking acute coronary syndrome: a case report and literature review.

BackgroundCardiac amyloidosis, a progressive cardiac disease, results from the accumulation of undegraded proteinaceous substrates in the extracellular matrix of the heart. It may present as acute coronary syndrome (ACS); therefore, a clear distinction remains challenging in clinical practice. We describe a case of cardiac amyloidosis mimicking ACS.Case summaryA 72-year-old man experienced chest discomfort for 2 days. He gradually developed dyspnoea during the preceding month. Electrocardiogram (ECG) showed sinus rhythm with right bundle branch block and low voltage. Echocardiography revealed concentric left ventricular thickening, biatrial dilation, and preserved ejection fraction with predominantly left ventricular basal hypokinesis. Serial testing of the cardiac biomarkers showed persistently increased high-sensitive cardiac troponin T levels and normal serum creatine kinase myocardial band levels. He was diagnosed with ACS with haemodynamic stability. However, coronary angiography demonstrated non-obstructive coronary arteries. Furthermore, significant macroglossia and periorbital purpura were noticed. Laboratory investigations revealed elevated serum immunoglobulin free light chain (FLC) kappa and lambda levels with an increased FLC ratio. Histological analysis of the biopsied abdominal skin confirmed amyloidosis.DiscussionCardiac amyloidosis often presents as restrictive cardiomyopathy. The usual symptoms include dyspnoea and peripheral oedema. Chest pain may manifest rarely, leading to misdiagnosis as coronary artery disease. Some findings suggestive of cardiac amyloidosis include clinical signs such as amyloid deposits, dyspnoea, low ECG voltage, and basal-predominant hypokinesis with relative apical sparing in echocardiography. Serum FLC test and abdominal skin biopsy can confirm the diagnosis of amyloidosis when a myocardial biopsy is not feasible.

The Real-World Frequency of 24-Hour Urine Protein Electrophoresis (UPEP), Serum Free Light Chain (SFLC), and Serum Protein Electrophoresis (SPEP) Testing in Patients with Multiple Myeloma (MM)

IntroductionUp to 20% of MM patients present with light-chain-only multiple myeloma (LCMM), which is not detectable using serum protein electrophoresis testing. 24-hour urinalysis may be the guideline-endorsed method for monitoring LCMM, but impracticalities can limit its use. We sought to assess how patients with MM and LCMM were followed for progression in the community setting by specimen type using real-world data, analyzing the frequency of testing for patients with MM (based on SPEP) or LCMM (based on UPEP or SFLC).MethodsThis retrospective cohort study used information from the Flatiron Health database, which is derived from electronic health record data; Institutional Review Board approval with a waiver of informed consent was obtained. The cohort included 4591 patients followed for MM and LCMM from 01/01/2011 to 06/30/2018 at community oncology clinics across the United States. The cohort was limited to patients with a confirmed diagnosis of MM on or after 01/01/2011, who received at least one line of therapy and did not receive a stem cell transplant. Patients whose start of MM treatment (captured through chart review) was > 30 days before the start of structured activity in the database were excluded as this may indicate missing therapy data. The specimen type was the test used to follow patients for progression throughout their disease course. Tests were eligible to define the specimen type if they occurred ≤ 90 days before or any time after an initial MM diagnosis. If a patient had multiple test types within this timeframe, the specimen type was determined using a hierarchy (at least one detectable SPEP [≥ 1 g/dL] > at least one detectable 24-hour UPEP [≥ 200 mg] > SFLC [any numeric value]), consistent with International Myeloma Working Group (IMWG) criteria. A LCMM diagnosis was assumed when a detectable M spike (≥1 g/dL) via SPEP could not be found 90 days before or any time after the initial MM diagnosis date, but a detectable lab value was found within that timeframe via 24-hour UPEP (≥ 200mg) or a SFLC (any numeric value).ResultsAmong all patients in the cohort with MM (N=4591), 27.7% (N=1272) received a UPEP test, 58.1% (N=2666) received a SFLC test, and 79.2% (N=3635) received a SPEP test at baseline, defined as occurring within 90 days on either side of the MM diagnosis date. Patients with a UPEP specimen type had less frequent testing than patients with a SPEP or SFLC specimen type. For patients with a UPEP specimen type (N=229), the median of the median time between two tests was 95 days, compared to 42 days for patients with a SFLC specimen type (N=1274) and 35 days for patients with a SPEP specimen type (N=2536). 32.7% (N=1503) of the cohort had LCMM; of those patients, 84.8% were followed by SFLC while only 15.2% were followed by UPEP.Conclusions24-hour urine tests for UPEP are not used often in routine clinical practice despite IMWG guidelines: the guidelines may not reflect a realistic standard of care in the real-world setting. While performing UPEP in addition to SFLC regularly may be the ideal practice for monitoring LCMM, impracticalities such as issues with collection technique and proper storage of urine samples may be hindering its regular use in the real world. The SFLC test may present a more realistic alternative for evaluation of disease status in patients with LCMM, and its ease of use could facilitate more frequent serial testing. This in turn could improve the measurement of progression at more regular intervals, potentially reducing patient exposure to therapies that are no longer effective. To our knowledge, this is the first study to investigate the differences in utilization of UPEP, SFLC, and SPEP testing conducted to follow MM and LCMM progression in the real world. [Display omitted] DisclosuresFoster:Flatiron Health: Employment. Lipitz:Flatiron Health: Employment. Torres:Flatiron Health: Employment. Carson:Roche: Consultancy; Flatiron Health: Employment; Washington University in St. Louis: Employment.

Clinical Characteristics and Outcome of Patients with Wild-Type Transthyretin and AL Cardiac Amyloidosis Confirmed By Mass Spectrometry

INTRODUCTIONCardiac involvement is common in both wild-type transthyretin (wATTR) and AL amyloidosis and these entities can have overlapping clinical features (Banypersad et al, JAHA 2012). Accurate diagnosis is vital given differences in spectrum of disease, management, and prognosis. We examined the presenting clinical features and survival outcome of patients diagnosed with cardiac wATTR and AL amyloidosis confirmed by mass spectrometry.MATERIALS & METHODS: Patients diagnosed between January 2014 and September 2017 with biopsy proven wATTR or AL amyloidosis and cardiac involvement by consensus criteria (Gertz et al, Amyloid 2010) were included. Mass spectrometry testing was performed at the Mayo Clinic Laboratories to confirm amyloid subtype in all cases. Patient records were retrospectively reviewed to identify clinical characteristics as well as details regarding treatment and survival. RESULTSForty-three patients were identified (wATTR n=27, AL n=16) with site of biopsy: 41 cardiac (95%); 1 gastric (2%); 1 skin (2%). Two (13%) patients with AL amyloid had coexisting multiple myeloma. Thirty-five (81%) patients were male, with a strong male predominance in wATTR patients (100% vs 50% for AL patients, p=<0.01). Median age at diagnosis was 73 years (range 45-86), with a trend towards older age in wATTR patients (median 75 vs 62 years for AL patients, p=0.09). No difference was seen in presenting NYHA class or levels of troponin and ntProBNP between amyloid subtypes. BNP trended towards higher values in AL patients (median 514 vs 249 ng/L for wATTR, p=0.09). wATTR amyloid patients had lower median presenting left ventricular ejection fraction (43 vs 53%, p=0.05). Two (7%) patients with wATTR amyloid had an M-protein on SPEP compared to 7 (44%) with AL amyloid. Only 2 patients with AL amyloid had M-protein greater than 5 g/L while both wATTR patients had less than 5 g/L. In those with serum free light chain testing available (wATTR n=24, AL n=16), median lambda light chain level was higher in AL patients (176.0 vs 16.9 mg/L for wtATTR, p=<0.01). No difference was seen in kappa light chains (16.5 vs 23.8 mg/L for wATTR, p=0.60), though the only patient with kappa AL amyloid had kappa light chains significantly elevated at 1640 mg/L. The kappa/lambda ratio was abnormal in 15% of wATTR patients (all kappa predominant) compared to 100% in AL amyloid patients (94% lambda predominant) (p=<0.01). The median difference between involved and uninvolved light chain (dFLC) was 22 mg/L for wtATTR patients compared to 249 mg/L for AL patients. In patients with bone marrow biopsy results available (AL n=15, wATTR n=7), bone marrow plasma cell percentage was higher in patients with AL amyloid (median 7% vs 2%, p=0.01). No monoclonal plasma cells were seen on bone marrow in wATTR patients by immunophenotype. Treatment for patients with AL amyloid wasbortezomib, cyclophosphamide, and dexamethasone (VCD) in 11 (69%); VCD followed by melphalan 200 mg/m2 autologous transplantation in 1 (6%); melphalan/dexamethasone in 1 (6%); no treatment in 2 (13%); unknown in 1 (6%). In evaluable patients, hematologic response rate was 54% (complete response n=4, very good partial response n=2, partial response n=1, no response n=6). With a median follow-up of 1.8 years for surviving patients, 1 year overall survival (OS) was 76% for the entire cohort. Patients with AL amyloidosis had significantly poorer 1 year OS (41% vs 92% for wATTR patients, p=<0.01). Patients with NYHA class 3-4 had significantly worse 1 year OS (54% vs 96% for those 1-2, p=<0.01), and this held true for both AL and wATTR patients. In AL patients, revised Mayo stage (Kumar et al, JCO 2012) of III-IV predicted for poor 1 year OS (19% vs 75% for stages I-II, p=0.03), as did not achieving complete response to primary treatment (1 year OS 33% vs 67% for CR patients, p=0.06).DISCUSSION & CONCLUSIONS: Male sex, older age, and lower LVEF were more common in patients with wATTR compared to AL amyloidosis. Higher levels of BNP, larger dFLC with lambda predilection, and higher bone marrow plasma cell percentage were more common in AL amyloid patients. Overall survival was significantly worse for patients with AL amyloidosis, particularly those with high NHYA class, advanced revised Mayo stage, and suboptimal response to primary therapy. These results highlight the importance of accurate amyloid sub-typing in patients with suspected cardiac amyloidosis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Non-Secretory Myeloma: Ready for a new Definition?

Non-secretory myeloma is a rare myeloma subtype whose diagnosis, until a few years ago, was established by demonstration of monoclonal plasma cells ≥10% in the bone marrow and by negative results on serum and urine electrophoresis and immunofixation studies. However, this type of myeloma could be misdiagnosed if the workup does not include an accurate study of serum free light chain test since some of the patients diagnosed as non-secretory could be light chain only with small amounts monoclonal proteinuria. Due to this limit in classification, all the information available today, generally coming from retrospective studies including patients studied completely and incompletely, could be misleading. A new definition is, thus, needed to distinguish between the true non-secretory, with a possible better prognosis, and the other forms of oligo-secretory myeloma with a prognosis more similar to the secretory form of myeloma. With all the data of the literature, the availability of laboratory and radiological tools, times are mature to depict a new definition of nonsecretory myeloma that deserves a peculiar work up and different response evaluation and, may be, a different therapeutic approach.

Multiple myeloma can be accurately diagnosed in acute kidney injury patients using a rapid serum free light chain test

BackgroundAcute kidney injury (AKI) is common in patients with multiple myeloma (MM). Whether serum free light chain (sFLC) measurements can distinguish between myeloma and other causes of AKI requires confirmation to guide early treatment. A rapid and portable sFLC test (Seralite®) is newly available and could reduce delays in obtaining sFLC results and accelerate diagnosis in patients with unexplained AKI. This study evaluated the accuracy of Seralite® to identify MM as the cause of AKI.MethodsFLCs were retrospectively analysed in patients with AKI stage 3 as per KDIGO criteria (i.e. serum creatinine ≥354 μmol/L or those on dialysis treatment) (n = 99); 45/99 patients had a confirmed MM diagnosis.ResultsThe Seralite® κ:λ FLC ratio accurately diagnosed all MM patients in the presence of AKI: a range of 0.14–2.02 returned 100% sensitivity and specificity for identifying all non-myeloma related AKI patients. The sFLC difference (dFLC) also demonstrated high sensitivity (91%) and specificity (100%): an optimal cut-off of 399 mg/L distinguished between myeloma and non-myeloma AKI patients. We propose a pathway of patient screening and stratification in unexplained AKI for use of Seralite® in clinical practice, with a κ:λ ratio range of 0.14–2.02 and dFLC 400 mg/L as decision points.ConclusionsSeralite® accurately differentiates between AKI due to MM and AKI due to other causes in patients considered at risk of myeloma. This rapid test can sensitively screen for MM in patients with AKI and help inform early treatment intervention.

Multiple Myeloma Can Be Accurately Diagnosed in Acute Kidney Injury Patients Using a Rapid Serum Free Light Chain Test

BACKGROUND: Acute kidney injury (AKI) is common in patients with multiple myeloma (MM). Whether serum free light chain (sFLC) measurements can distinguish between myeloma and other causes of AKI requires confirmation to guide early treatment. A rapid and portable sFLC test (Seralite®) is newly available and could reduce delays in obtaining sFLC results and accelerate diagnosis in patients with unexplained AKI. This study evaluated the accuracy of Seralite® to identify MM as the cause of AKI. METHOD: sFLCs were retrospectively analysed in patients with AKI stage 3 as per KDIGO criteria (i.e. serum creatinine ≥354 μmol/L or those on dialysis treatment) (n = 99); 45/99 patients had a confirmed MM diagnosis. RESULTS: The Seralite® κ:λ FLC ratio accurately diagnosed all MM patients in the presence of AKI: a range of 0.14-2.02 returned 100% sensitivity and specificity for identifying all non-myeloma related AKI patients. The sFLC difference (dFLC) also demonstrated high sensitivity (91%) and specificity (100%): an optimal cut-off of 399 mg/L distinguished between myeloma and non-myeloma AKI patients. We propose a pathway of patient screening and stratification in unexplained AKI for use of Seralite® in clinical practice, with a κ:λ ratio range of 0.14-2.02 and dFLC 400 mg/L as decision points. CONCLUSIONS: Seralite® accurately differentiates between AKI due to MM and AKI due to other causes in patients considered at risk of myeloma. This rapid test can sensitively screen for MM in patients with AKI and help inform early treatment intervention.

Serum free light chain assays not total light chain assays are the standard of care to assess Monoclonal Gammopathies.

The diagnosis of Multiple Myeloma is a challenge to the physician due to the non-specific symptoms (anemia, bone pain and recurrent infections) that are commonplace in the elderly population. However, early diagnosis is associated with less severe disease, including fewer patients presenting with acute renal injury, pathological fractures and severe anemia. Since 2006, the serum free light chain test Freelite® has been included alongside standard laboratory tests (serum and urine protein electrophoresis, and serum and urine immunofixation) as an aid in the identification of monoclonal proteins, which are a cornerstone for the diagnosis of Multiple Myeloma. The serum free light chain assay recognizes the light chain component of the immunoglobulin in its free form with high sensitivity. Other assays that measure light chains in the free and intact immunoglobulin forms are sensitive, but unfortunately, due to the nomenclature used, these assays (total light chains) are sometimes used in place of the free light chain assay. This paper reviews the available literature comparing the two assays and tries to clarify hypothetical limitations of the total assay to detect Multiple Myeloma. Furthermore, we elaborate on our study comparing the two assays used in 11 Light Chain Multiple Myeloma patients at presentation and 103 patients taken through the course of their disease. The aim of this article is to provide a clear discrimination between the two assays and to provide information to physicians and laboratory technicians so that they can utilize the International Myeloma Working Group guidelines.

64-Year-Old Woman With Diarrhea and Increased Abdominal Girth

64-year-old woman presented to our institution for evaluation of diarrhea and increasing abdominal girth. She had a 1-month history of postprandial diarrhea unrelated to the type of foods she consumed. Her stool was watery, with no evidence of gastrointestinal bleeding. Concurrently, she also noted increasing abdominal girth requiring new pants with a larger waist size. She had no abdominal pain, nausea/vomiting, flushing, light-headedness, or constitutional symptoms. Her medical history was notable for a previous stroke with a mild residual right hand tremor. She was a lifetime nonsmoker, had no history of illicit drug use, and drank alcohol rarely. She had no history of recent travel, infectious exposures, new medications, or herbal supplement intake. Her blood pressure was 136/83 mm Hg, and herheart rate was 98beats/min.Heroxygensaturation was 95% while she breathed room air, and her respiratory rate was 18 breaths/min. Her temperature was 36.9C. Her mental status was normal. Her abdomen was soft, nontender, and mildly distended with hyperactive bowel sounds. Shifting dullness with a fluid wave was present. 1. Which one of the following is the most appropriate diagnostic approach to evaluate the patient’s abdominal symptoms? a. Paracentesis b. Colonoscopy c. Clostridium difficile toxicology screen or polymerase chain reaction d. Serology testing for transglutaminase antibody e. Abdominal radiography

Retrospective audit of the freeliteTM serum free light chain (SFLC) assay: testing patterns, concordance with serum and urine electrophoresis/immunofixation and correlation with the N latex FLC assay

Aims A retrospective audit of the Freelite™ SFLC assay was conducted to compare concordance with electrophoresis (EPG)/immunofixation (IFX) and correlation with the N latex FLC assay. Methods 244 samples collected over 3.5 months were studied by nephelometry using the Freelite™ and N Latex FLC assays. Results were compared with serum (S) and/or urine (UEPG)/IFX. The precision and linearity of the N latex FLC assay were examined. Results 94% of samples with kappa restriction, and 100% with lambda restriction had detectable paraprotein by SEPG/IFX or UEPG/IFX. The correlation between the two assays was good for kappa (R 2 = 0.935) but not lambda (R 2 = 0.775) especially when lambda was above the ULN (R 2 = 0.406). Agreement in the categorical diagnosis of restricted SFLC was good (Cohen's kappa = 0.701). In discordant samples the Freelite™ assay displayed higher agreement with IFX (53% vs 47%). The N latex FLC assay displayed good precision and linearity. Discussion SFLC testing is popular despite traditional methods detecting paraproteins in most cases. Correlation between the Freelite™ and N latex FLC assays is better for kappa than lambda FLC. The two assays are not equivalent and the Freelite™ assay displays better agreement with IFX. Care should be taken by interpreting physicians and laboratories considering switching assays.

Serum Free Light Chain Assays in the Early Detection of Cast Nephropathy in Patients Presenting with Unexplained Acute Kidney Injury (AKI): Results from a Pharmacoeconomic Evaluation

International Kidney and Monoclonal research Group (IKMG) recommendations for screening for acute kidney injury (AKI) secondary to multiple myeloma (MM) include the assessment of patients with the serum free light chain test (sFLC). Here we compare the economic impact of following this recommendation compared to standard serum and urine electrophoretic techniques.An economic model was constructed using published UK data and centre specific clinician advice. The model compared the following scenarios: (i) serum protein electrophoresis (SPEP) + sFLC (IKMG recommendation), (ii) SPEP alone, (iii) SPEP + urine electrophoresis (SPEP + UPE), with a positive test in scenarios (i)—(iii) proceeding to immunofixation electrophoresis (IFE); (iv) all electrophoretic methods run in parallel (SPEP + UPE + sIFE + uIFE). The key economic drivers in the model were length of in-patient stay and dialysis costs. The incremental costs per QALY gained were modelled over a 365d time horizon.The economic model utilized a decision tree structure to the time of diagnosis and a Markov model including the health states: dialysis dependence, renal function recovery, other cause of AKI and death. The model structure and assumptions were validated through clinician consultation.Survival in the diagnostic pathway was estimated using hazard ratios applied to survival of MM based on the stage of AKI, obtained from a retrospective observational study (Han, et al., 2013). Survival within the Markov model post-diagnosis was based on UK data stratified for cast nephropathy patients who had or had not recovered renal function. Post-diagnosis, a probability of renal recovery based on the duration of AKI prior to diagnosis was applied.Utility values in the decision tree structure were estimated using the Modification of Diet in Renal Disease equation. The Markov model employed previously published utility values in MM with a decrement applied for dialysis dependence.Costs for medical resource use, medical management, dialysis, adverse events associated with dialysis and terminal care were derived from the 2012-2013 NHS Reference Cost and British National Formulary.Key user defined values for the comparison included a presenting patient distribution of 10% stage 2 AKI, 45% stage 3 AKI (dialysis independent) and 45% stage 3 AKI (dialysis dependent), 1% incidence of cast nephropathy as a cause of AKI, and a 20% incidence of renal biopsy following a positive diagnostic result.User amendable fields ensure the model is amenable to refinement as new data on assay performance and patient pathways become available.The incremental costs and QALYs for each comparator are shown in Table 1. The model predicts the pathway with SPEP + sFLC to be dominant; SPEP + sFLC accrues the most QALYs and the least costs. The savings in the diagnostic decision tree (£7, £31, -£5, respectively) are driven by reduced dialysis and in-patient bed stay costs. In the treatment pathway savings (£34, £37, £41, respectively) are driven by reduced dialysis costs. Probabilistic sensitivity analysis showed the model results to be robust - the probability of SPEP + sFLC being cost-effective at a £20,000 per QALY willingness to pay threshold was 98.6%, 93.8%, 92.6%, respectively.Table 1 -Base Case Cost-Effectiveness ResultsModel ResultsSPEP + sFLCSPEPDifferenceTotal Cost (GBP)£427£467-£40Total QALYs0.62450.62350.00099ICER=Incremental Cost/ Incremental QALYDominantModel ResultsSPEP + sFLCSPEPDifferenceTotal Cost (GBP)£427£495-£68Total QALYs0.62450.62310.00133ICER=Incremental Cost/ Incremental QALYDominantModel ResultsSPEP + sFLCSPEPDifferenceTotal Cost (GBP)£427£463-£36Total QALYs0.62450.62390.00055ICER=Incremental Cost/ Incremental QALYDominantThis model supports the recommended international guidelines for screening for AKI secondary to MM. Inclusion of the sFLC assay improves the probability of renal recovery and survival by reducing time to diagnosis and treatment.Cost savings and QALY gains are found in both the diagnostic stage and treatment stage of the patient pathway. The SPEP + sFLC pathway is therefore cost-effective at a willingness to pay threshold of £20,000 per QALY with a high probability of cost-effectiveness against all comparator pathways from probabilistic sensitivity analysis.The model template may be used in future health economic models to assess the contribution of new assays into diagnostic algorithms. DisclosuresNo relevant conflicts of interest to declare.

Seralite© Rapid Point-Of-Care Detection Of Free Light Chain Escape, Non-Secretory Relapse and Light Chain Only Relapse In Multiple Myeloma

Free light chain (FLC) testing in serum is a more sensitive method of monitoring FLC secretion from myeloma cells than FLC testing in urine because FLC do not appear in urine until their secretion exceeds the renal tubule threshold for FLC reabsorption. Serum protein electrophoresis (SPE) and immunofixation electrophoresis (IFE) are insensitive methods of detecting FLC in serum. In 2002 quantitative detection of serum FLC by turbidimetric and nephelometric assays using polyclonal sheep anti-sera specific for FLC (Freelite®) became available; this has become the internationally recommended method of measuring FLC levels in serum. Two thirds of non-secretory (NS) patients who are IFE negative in serum and urine have abnormal FLC levels in serum and might be better classified as oligosecretory light chain only (LCO) patients. Serum FLC testing is particularly useful in diagnosis and monitoring of these and conventional LCO patients in whom FLC are detectable in urine when their disease is very active. In 5% IgG and 10% IgA M-protein myeloma patients, relapse is characterised by an increase in abnormal serum FLC without a corresponding increase in whole M-protein, termed ‘free light chain escape' and their relapse is detected earliest by serum FLC testing.Despite the clinical advantages of serum FLC testing, existing quantitative serum FLC assays are restricted to centralised laboratories. The time between venesection and availability of FLC results, for most clinicians, varies from days to weeks. This delays diagnosis and delays changes in clinical management when assessing response or monitoring for relapse. We have developed a second generation of serum FLC tests that utilise monoclonal rather than polyclonal anti-FLC antibodies. One result of this new generation of assays has been the development of a new rapid serum FLC test (Seralite®, Serascience Ltd, Oxford UK) that provides point of care measurement of serum FLC levels in just ten minutes.We assessed FLC levels at diagnosis, remission and relapse in 31 patients diagnosed with intact immunoglobulin myeloma who relapsed with abnormal serum FLC but without an increase in M-protein level (termed ‘light chain escape'). In all evaluable samples, Seralite® detected an abnormal serum FLC level at diagnosis, followed by a normalisation of the serum FLC ratio during remission, and a subsequent abnormal FLC level at relapse. Seralite® FLC results correlated diagnostically with the existing laboratory serum FLC assay for all samples.Additionally, we analysed FLC levels at diagnosis, remission and relapse in 166 myeloma patients characterised as having no intact immunoglobulin M-protein by serum IFE at diagnosis. 16% had a negative urine IFE and were identified only by the presence of an abnormal FLC ratio in their serum (NS or oligosecretory LCO). The remaining 84% had FLC detected in urine by IFE at diagnosis (conventional LCO). All diagnosis samples had an imbalanced FLC ratio detected by Seralite®. With a median follow-up of over 5 years, 83% of these patients relapsed with abnormal serum FLC levels. Half of the conventional LCO patients were IFE negative in the urine at relapse. Seralite® FLC results correlated diagnostically with the existing laboratory FLC assay for all samples.In summary, Seralite® detected abnormal serum FLC levels in all myeloma patients relapsing with light chain escape, and patients relapsing with non-secretory (oligosecretory LCO) and conventional LCO myeloma. There were no false negatives and no false positives supporting the use of Seralite® for the monitoring of these distinct myeloma patient groups. Disclosures:Campbell:Serascience Ltd: Equity Ownership. Stride:Serascience Ltd: Employment. Goodall:Serascience Ltd: Equity Ownership. Drayson:Serascience Ltd: Equity Ownership.

Clinical Significance of Serum Free Light Chain Test in the First Onset of Multiple Myeloma

Abstract 4999 Objective:Clinical significance of serum free light chain (sFLC) test in the diagnosis, efficacy evaluation, prognosis judgment of first onset of multiple myeloma (MM). Method:Medical records of 39 cases of first-onset MM were gathered in our hospital from 1/2010 to 2/2012, including 25 male and 14 female patients with the median age being 63 years old. sFLC-kappa and sFLC-lambda were determined by immune turbidimetric assay, sFLC-kappa/lambda were calculated and the results were compared with that of immunofixation electrophoresis (IFE) as well as serum protein electrophoresis (SPE) for sensitivity assessment. All patients were treated with chemotherapy followed by sFLC detection and efficacy assessment. Patients with a sFLC results higher than median were marked as high-sFLC, the rest were marked as low-sFLC, and survival analysis were made comparing the two groups. Results:Of the 39 first-onset MM patients, 38 were detected as sFLC- kappa/lambda positive, that’s a sensitivity of 97. 4%, higher than IFE (79. 5%), SPE (53. 8%), and uPE (38. 5%). As condition improves after treatment, sFLC gradually decline and sFLC- kappa/lambda level falls back to normal. Evaluation of efficacy by sFLC results has an accuracy of 77. 27%, significantly higher than that of corresponding M protein test£. P=0. 009£©. Follow-up survival analysis showed that the OS time and TTP time of low-sFLC group are significantly higher than those of high-sFLC group (P=0. 037, 0. 009 respectively). Conclusion:sFLC detection is a highly sensitive quantitative method, can help the diagnosis of MM, gives a quicker assessment of treatment efficacy, and can predict disease recurrence. When it's the first onset, sFLC level can also roughly forecast the prognosis. Disclosures:No relevant conflicts of interest to declare.

Abnormalities of serum-free light chain in patients with primary antibody deficiency in the absence of B lymphocyte clonality

AimsA review of practice to determine whether serum-free light chain (SFLC) assays are helpful in detecting underlying clonal B-cell disorders or amyloidosis in patients with primary antibody deficiency (PAD) and...

Free Kappa and Lambda Light Chains in Plasma Cell Dyscrasias

Automated serum kappa (κ) and lambda (λ) free light chain (FLC) immunoassay may be used as a rapid screening tool for multiple myeloma and other light chain diseases as it is more sensitive and robust than serum protein electrophoresis (SPE) and urine immunofixation electrophoresis (IFE). Serum FLC enables earlier diagnosis and evaluation of tumour response to therapy. Serum FLC testing has been incorporated into an international guideline for all newly diagnosed plasma cell cancers for diagnosis, prognosis, monitoring and assessing treatment.

Value of Serum Free Light Chain Testing for the Diagnosis and Monitoring of Monoclonal Gammopathies in Hematology

The automated quantification of serum free κ and λ light chain concentrations provides a highly sensitive tool for the diagnosis and monitoring of monoclonal gammopathies. An abnormal κ:λ ratio supports the presence of clonal plasma cell expansion and requires further investigation. More than 94% of myeloma, light chain myeloma, and AL amyloidosis and, likewise, a majority of patients with light chain deposition disease are detectable with this technology. Importantly, these assays identify M-proteins in most patients with oligosecretory disease and permit their recruitment into clinical trials from which they have been previously excluded. Combining serum free light chain testing with traditional electrophoresis provides > 99% accuracy in the first-line diagnosis of monoclonal gammopathies and eliminates the need for urine testing in most instances. One third of patients with monoclonal gammopathy of undetermined significance have an abnormal free light chain ratio, and these patients harbor a greater risk of progression to plasma cell dyscrasia. For monitoring response to therapy, the international uniform response criteria define a normal free light chain ratio as an essential element of the "stringent complete response" category. Because the half-life of free light chains is < 6 hours, free light chain measurements at short sampling intervals allow real-time measurement of treatment-induced tumor kill, and provide prompt indications of chemosensitivity, dose adequacy, need for alternative approaches, and even prognosis, as demonstrated in AL amyloidosis if the involved free light chain concentration normalizes. Clinical applications of these assays will likely increase as their utility is more widely explored.