Clinical presentation and outcomes in light chain amyloidosis patients with non-evaluable serum free light chains

Leukemia ◽  
2017 ◽  
Vol 32 (3) ◽  
pp. 729-735 ◽  
Author(s):  
S Sidana ◽  
N Tandon ◽  
A Dispenzieri ◽  
M A Gertz ◽  
F K Buadi ◽  
...  
Keyword(s):  
Light Chain ◽  
Clinical Presentation ◽  
Light Chains ◽  
Free Light Chains ◽  
Serum Free ◽  
Light Chain Amyloidosis ◽  
Serum Free Light Chains

Quantification by Ultrafiltration and Immunofixation Electrophoresis Testing for Monoclonal Serum Free Light Chains

2020 ◽  
Vol 51 (6) ◽  
pp. 592-600 ◽  
Author(s):  
Gurmukh Singh ◽  
Roni Bollag
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Limit Of Detection ◽  
Light Chains ◽  
Total Serum ◽  
Reliable Estimate ◽  
Free Light Chains ◽  
Serum Free ◽  
Immunofixation Electrophoresis ◽  
Serum Free Light Chains

Abstract Objective Measurement of monoclonal immunoglobulins is a reliable estimate of the plasma cell tumor mass. About 15% of plasma cell myelomas secrete light chains only. The concentration of serum free light chains is insufficient evidence of the monoclonal light chain burden. A sensitive quantitative estimate of serum free monoclonal light chains could be useful for monitoring patients with light chain myeloma. We describe such an assay that does not require mass-spectrometry equipment or expertise. Methods Serum specimens from patients with known light chain myelomas and controls were subjected to ultrafiltration through a membrane with pore size of 50 kDa. The filtrate was concentrated and tested by immunofixation electrophoresis. The relative area under the monoclonal peak, compared to that of the total involved light chain composition, was estimated by densitometric scanning of immunofixation gels. The proportion of the area occupied by the monoclonal peak in representative densitometric scans was used to arrive at the total serum concentration of the monoclonal serum free light chains. Results Using an ultracentrifugation and concentration process, monoclonal serum free light chains were detectable, along with polyclonal light chains, in all 10 patients with active light chain myelomas. Monoclonal light chains were identified in serum specimens that did not reveal monoclonal light chains by conventional immunofixation electrophoresis. The limit of detection by this method was 1.0 mg/L of monoclonal serum free light chains. Conclusion The method described here is simple enough to be implemented in academic medical center clinical laboratories and does not require special reagents, equipment, or expertise. Even though urine examination is the preferred method for the diagnosis of light chain plasma cell myelomas, measurement of the concentration of serum free light chains provides a convenient, albeit inadequate, way to monitor the course of disease. The method described here allows effective electrophoretic differentiation of monoclonal serum free light chain from polyclonal serum free light chains and provides a quantitation of the monoclonal serum free light chains in monitoring light chain monoclonal gammopathies.

In Patients With Chronic Lymphocytic Leukemia (CLL) Ibrutinib Effectively Reduces Clonal IgM Paraproteins and Serum Free Light Chains While Increasing Normal IgM, IgA Serum Levels, Suggesting a Nascent Recovery Of Humoral Immunity

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4182-4182 ◽  
Author(s):  
Georg Aue ◽  
Mohammed Farooqui ◽  
Jade Jones ◽  
Janet Valdez ◽  
Sabrina E. Martyr ◽  
...  
Keyword(s):  
B Cell ◽  
Light Chain ◽  
Serum Levels ◽  
Light Chains ◽  
Free Light Chains ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Upper Limit ◽  
Serum Free Light Chains ◽  
Pre Treatment

Abstract Introduction The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib induces objective clinical responses in the majority of CLL patients (Byrd et al., NEJM 2013). Ibrutinib covalently binds to BTK and with once daily dosing (420 mg, PO) results in > 90% inhibition of kinase activity. Germline inactivating mutations in BTK lead to an immunodeficiency syndrome first described by the pediatrician Dr. Bruton in boys suffering from recurrent bacterial infections. These kids, diagnosed with what is now known as Bruton’s agammaglobulinemia, have a severe defect in B cell maturation resulting in the virtual absence of immunoglobulins. Hypogammaglobulinemia is a common complication of CLL and likely is a significant contributor to the increased rate of infections that are a leading cause of death in CLL. Thus, to what degree ibrutinib affects normal B cell function and immunoglobulin levels may in part determine the safety profile of continuous treatment with this agent. Patients and Methods Here we present data from a phase II trial (NCT01500733) of ibrutinib 420 mg daily on 28 day cycles for relapsed/refractory (RR) and treatment naïve (TN) CLL/SLL patients (pts). Serum immune globulins (IgG, IgM, IgA), serum free light chains, and immunofixation electrophoresis were obtained at baseline, and every 6 months thereafter. For statistical analysis of pre-treatment to on-treatment measurements the paired Student t-test was used. Results Here we report on 25 patients (10 TN, 15 RR) who completed >12 months on ibrutinib and never received immunoglobulin replacement therapy. By 6 and 12 months, there was a non-statistically significant trend toward decreased IgG levels (ref. range 642-1730) from a pre-treatment median of 601 to 587 mg/dL (at 6 months) and 495 mg/dL (at 12 months; P = 0.14). In contrast, median serum IgA (ref. range 91-499) rose from 42 (baseline) to 58 (at 6 mo) to 61 mg/dL by 12 months (P< 0.005). Three patients had a clonal IgM on electrophoresis, which decreased with treatment. In the remaining 22 patients IgM (ref. range 34-342) rose from 16 (baseline) to 25 (6 months) to 23 mg/dL by 12 months (P<0.01). TN patients had higher IgA and IgM levels at baseline and achieved the higher absolute increase by 12 months. However, the relative rate of increase from baseline was similar for both groups, suggesting that ibrutinib enables a recovery of IgA and IgM levels equally in both TN and RR patients. In 20 patients serum free light chain measurements were available, with an abnormal pre-treatment kappa/lambda ratio in 17. In 11 patients the CLL cells were kappa clonal by flow cytometry and in 9 they were lambda clonal. Eight of 11 pts with a kappa CLL clone had kappa serum free light chain (KSFLC, ref. range 0.57 – 2.22 mg/dL) levels > upper limit of normal (median 5.7 mg/dl). At 6 and 12 months there was a 76% and 72% reduction of the KSFLC (P< 0.01), and in 7 pts the level normalized by 6 months. In contrast, prior to therapy the lambda serum free light chains (LSFLC, ref. range 0.66-2.32 mg/dL) were low (median 0.62 mg/dL) in these patients and increased by 68% (P<0.005) to normal levels by 6 months in all of them. Conversely, 8 of 9 patients with lambda clonal CLL by flow cytometry had LSFLC > upper limit of normal (median 8.4 mg/dL), which decreased on ibrutinib by > 80% (P< 0.03) and normalized in 88% of pts by 12 months. The KSFLC in most of these patients was in the low normal range and only increased by 19% from baseline by 12 months. Thus, ibrutinib effectively reduces the clonal light chain, a correlate of tumor control, while the non-clonal light chains, presumably in part reflecting normal B-cells, are low pre-treatment and increase during treatment. Conclusion Consistent with other reports we see little change in IgG levels in the first 12 months. Importantly, ibrutinib leads to a significant increase in both IgA and IgM serum levels, suggesting a beginning recovery of humoral immunity. The reduction of clonal light chains, a tumor marker, correlates with clinical response. In contrast, the increasing levels of the non-clonal light chain may herald a recovery of the normal B-cell (and possibly plasma cell compartment) raising the possibility that ibrutinib may selectively target CLL cells while allowing the re-growth of normal B-cells. We are currently investigating this further. Supported by the Intramural Research Program of NHLBI. We thank our patients for participating and acknowledge Pharmacyclics for providing study drug. Disclosures: Off Label Use: Ibrutinib not FDA approved for CLL.

scholarly journals Treatment of Light Chain Deposition Disease Using Bortezomib-Based Regimen Followed by Thalidomide-Based Regimen in a Saudi Male

2016 ◽  
Vol 2016 ◽  
pp. 1-4 ◽  
Author(s):  
Bappa Adamu ◽  
Mushabab Al-Ghamdi ◽  
Mustafa Ahmad ◽  
Khaled O. Alsaad
Keyword(s):  
Light Chain ◽  
Light Chains ◽  
Cell Transplant ◽  
Free Light Chains ◽  
Light Chain Deposition Disease ◽  
Serum Free ◽  
Deposition Disease ◽  
Serum Free Light Chains ◽  
Light Chain Deposition ◽  
Saudi Male

Light chain deposition disease (LCDD) is a rare illness with, as yet, no clear evidence-based guidelines for its treatment. To the best of our knowledge, LCDD has not been previously reported from Saudi Arabia. We present in this report, a 38-year-old Saudi male who presented with clinical features suggestive of hypertensive nephropathy but kidney biopsy later revealed the diagnosis of LCDD. His serum creatinine at presentation was 297 μmol/L which came down to 194 μmol/L on treatment with Bortezomib, Cyclophosphamide and Dexamethasone. His 24-hour protein excretion at presentation was 6 g/L which also came down to less than 1 g/day. He was later placed on Cyclophosphamide, Thalidomide, and Dexamethasone regimen because of persistent high titres of serum free light chains. He went into remission with undetectable serum free light chains and remained so for three years at the time of writing this report. We conclude that LCDD, though rare, does occur in Saudi population. The treatment of LCDD is challenging but the use of Bortezomib, a proteosome inhibitor, is promising. However, suboptimal response may require further treatment with other therapeutic options such as chemotherapy with alkylating agents or high-dose Melphalan with autologous stem cell transplant.

scholarly journals Serum Free Light Chains: An Alternative to the Urine Bence Jones Proteins Screening Test for Monoclonal Gammopathies

2006 ◽  
Vol 52 (9) ◽  
pp. 1743-1748 ◽  
Author(s):  
Peter G Hill ◽  
Julia M Forsyth ◽  
Baldeep Rai ◽  
Stewart Mayne
Keyword(s):  
Light Chain ◽  
False Positive ◽  
False Positive Rate ◽  
Light Chains ◽  
Free Light Chains ◽  
Serum Free ◽  
Monoclonal Gammopathies ◽  
Positive Serum ◽  
Positive Rate ◽  
Serum Free Light Chains

Abstract Background: Retrospective analyses have established the role of quantitative serum free light chains (FLCs) in the diagnosis of monoclonal light chain disorders. The aims of this study were to assess (a) whether the addition of serum FLCs to serum protein electrophoresis (SPEP) identified additional patients with monoclonal gammopathies; (b) whether serum FLC measurements could replace urinalysis for Bence Jones protein (BJP); and (c) the cost/quality implications of routinely measuring serum FLCs. Methods: Serum FLCs were added to consecutive requests for SPEP from August to November 2004 and measured by automated immunoassay. Results: Seventy-one of 923 patients had abnormal serum FLC ratios. Seven patients with monoclonal gammopathies and 1 patient with malignant lymphoma (but no monoclonal band) were detected among 43 patients with negative SPEP but positive serum FLC ratios. Thirty-five patients with negative SPEP had false-positive serum FLC ratios. The false-positive rate for a ratio &gt;1.65 was higher than previously described and associated with polyclonal increases in immunoglobulins and renal impairment. Serum FLC ratios were normal in 2 of 13 patients with low-level persistent urine BJP. However, no significant pathology would have been missed by replacing BJP with serum FLCs. Revenue and manpower savings offset 60% of the costs of serum FLCs. Conclusions: Additional diagnostic information is gained by adding serum FLCs to SPEP as first-line tests for investigating possible B-cell disorders. The quality of the diagnostic service is enhanced by more confident exclusion of light chain disorders and improved interpretive assessment of SPEP and immunofixation electrophoresis.

Serum and Urine Protein Electrophoresis and Serum-Free Light Chain Assays in the Diagnosis and Monitoring of Monoclonal Gammopathies

2020 ◽  
Vol 5 (6) ◽  
pp. 1358-1371
Author(s):  
Gurmukh Singh
Keyword(s):  
Light Chain ◽  
Protein Electrophoresis ◽  
Free Light Chain ◽  
Light Chains ◽  
Free Light Chains ◽  
Urine Protein ◽  
Serum Free ◽  
Monoclonal Gammopathies ◽  
Serum Free Light Chain ◽  
Serum Free Light Chains

Abstract Background Laboratory methods for diagnosis and monitoring of monoclonal gammopathies have evolved to include serum and urine protein electrophoresis, immunofixation electrophoresis, capillary zone electrophoresis, and immunosubtraction, serum-free light chain assay, mass spectrometry, and newly described QUIET. Content This review presents a critical appraisal of the test methods and reporting practices for the findings generated by the tests for monoclonal gammopathies. Recommendations for desirable practices to optimize test selection and provide value-added reports are presented. The shortcomings of the serum-free light chain assay are highlighted, and new assays for measuring monoclonal serum free light chains are addressed. Summary The various assays for screening, diagnosis, and monitoring of monoclonal gammopathies should be used in an algorithmic approach to avoid unnecessary testing. Reporting of the test results should be tailored to the clinical context of each individual patient to add value. Caution is urged in the interpretation of results of serum-free light chain assay, kappa/lambda ratio, and myeloma defining conditions. The distortions in serum-free light chain assay and development of oligoclonal bands in patients‘ status post hematopoietic stem cell transplants is emphasized and the need to note the location of original monoclonal Ig is stressed. The need for developing criteria that consider the differences in the biology of kappa and lambda light chain associated lesions is stressed. A new method of measuring monoclonal serum-free light chains is introduced. Reference is also made to a newly defined entity of light chain predominant intact immunoglobulin monoclonal gammopathy. The utility of urine testing in the diagnosis and monitoring of light chain only lesions is emphasized.

scholarly journals Serum free light chains, not urine specimens, should be used to evaluate response in light-chain multiple myeloma

Blood ◽  
2016 ◽  
Vol 128 (25) ◽  
pp. 2941-2948 ◽  
Author(s):  
Thomas Dejoie ◽  
Jill Corre ◽  
Helene Caillon ◽  
Cyrille Hulin ◽  
Aurore Perrot ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Light Chain ◽  
Sensitive Indicator ◽  
Light Chains ◽  
Free Light Chains ◽  
Prognostic Information ◽  
Serum Free ◽  
Key Points ◽  
Serum Free Light Chains ◽  
Urine Specimens

Key PointsSerum FLC analysis is a more sensitive indicator of disease than urinalysis. Improved sensitivity of serum over urine measurements during monitoring translates into valuable prognostic information.

scholarly journals Serum Free Light Chain Concentration (>1000mg/dl) at Diagnosis and at Relapse Predicts for Very Poor Prognosis in Multiple Myeloma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5698-5698
Author(s):  
Abhishek Chilkulwar ◽  
Prerna Mewawalla ◽  
Anna Miller ◽  
Gina Berteotti ◽  
Entezam Sahovic ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Disease Progression ◽  
Light Chain ◽  
Free Light Chain ◽  
Light Chains ◽  
Free Light Chains ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Serum Free Light Chains

Abstract Background: There have been significant improvements in the outcomes for patients with multiple myeloma over the past 10 years. The course of the disease remains highly variable. While some patients experience 10-15 year survivals, others succumb to highly refractory disease within a few months. Many studies have focused on the description of prognostic factors capable of predicting this heterogeneity in survival. Baseline Serum free light chain concentration is a major prognostic indicator for plasma cell neoplasms and normalization of free light chain ratio with treatment has been reported as an indicator for favorable prognosis. High Baseline free light chain concentration at presentation indicates aggressive disease. Furthermore High serum free light chain ratio correlates with elevated serum creatinine, elevated LDH and extensive marrow infiltration. Objectives: To determine if serum free light chain concentration > 1000mg/dl at the time of diagnosis and at disease progression was an independent prognostic marker for multiple myeloma. Methods: The results of all the serum free light chain analyses of patients evaluated at western Pennsylvania hospital between 2007 -2015 were reviewed and patients with serum free light chain concentration >1000mg/dl at the time of initial diagnosis and disease progression were identified Retrospective chart review was done to study the survival in these patients. Results: Total of 15 patients in whom serum free light chain concentration was greater than 1000 mg/dl at diagnosis were identified. Median age at diagnosis was 60.81 years (45.2-77.3). The median survival in this population is 1.85 years (range 0.06-8.85 years), with 5 deaths. Of these 15, 9 patients received an autologous PBSCT as a part of their initial therapy. Six of them are alive with a median overall survival of 2.44 years and mean survival of 3.89 years (range 0.87-8.89). In the remaining 6 patients that did not undergo an auto PBSCT 3 of them are alive with median overall survival of 1.21 years and a mean survival 1.20 years (range 06-2.76 years). There is an overall trend toward very poor prognosis in this specific group of patients irrespective of the age, sex, stage at time of diagnosis, the immunoglobulin subtype and the free light chain subtype (kappa vs lambda). We also conducted a retrospective review of patients in whom serum free light chains concentration was greater than 1000mg/dl at disease progression. Twenty patients were identified all of whom are deceased with a median overall survival from the time of progression with serum free light chains greater than 1000 mg /dl was dismal at 0.27 years and mean survival was 0.53 years (range 0.04-2.52 years) Conclusion: Patients with multiple myeloma who presented with a serum free light chain concentration greater than 1000 mg/dl at diagnosis have very poor prognosis. These specific subgroups of patients should be identified and treated aggressively at the time of diagnosis to prevent complications from multiple myeloma and improve their overall survival. In our small cohort of patients those who underwent auto PBSCT as a part of their initial therapy tend to have better outcomes in terms of overall survival compared to patients who received therapy without auto PBSCT consolidation. Patients with serum free light chains greater than 1000 mg/dl at disease progression will need to be treated aggressively with perhaps a salvage auto PBSCT to improve their overall outcome. A larger study to evaluate elevated serum free light chains (greater than 1000 mg/dl) as a prognostic indicator at diagnosis and progression should be done to further validate these findings Table 1 Table 1. Disclosures No relevant conflicts of interest to declare.

Serum Free Light Chain Levels in Asymptomatic Myeloma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4880-4880 ◽  
Author(s):  
Bradley M. Augustson ◽  
Steven D. Reid ◽  
Graham P. Mead ◽  
Mark T. Drayson ◽  
J. Anthony Child ◽  
...  
Keyword(s):  
Median Time ◽  
Light Chain ◽  
Normal Serum ◽  
Free Light Chain ◽  
Light Chains ◽  
Time To Progression ◽  
Free Light Chains ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Serum Free Light Chains

Abstract Introduction: Patients with asymptomatic myeloma fulfil two of the diagnostic criteria for myeloma having more than 10% bone marrow plasma cells and an M protein of greater than 30g/l, but they are asymptomatic with no evidence of end organ or tissue damage. The median time to disease progression is 12–32 months. These patients do not require treatment but do require monitoring for progression to symptomatic myeloma. Predicting progression of asymptomatic myeloma would be of clinical benefit to optimise monitoring and initiate treatment prior to substantial end organ damage. However monoclonal spike, plasma cell labelling index, bone marrow plasmacytosis, immunoparesis and the presence of Bence Jones protein have limited value in predicting progression. Abnormal levels of serum free light chains are present in 95% of all multiple myeloma patients and have clinical benefit in diagnosis and monitoring of disease. In monoclonal gammopathy of undetermined significance (MGUS) 60% of patients have abnormal serum free light chain ratios and are an independent risk factor for progression to myeloma. The aim of this study was to examine the serum of asymptomatic patients for serum free light chains at diagnosis and to determine if they are predictive of disease progression. Methods: Archived presentation sera were studied from forty three asymptomatic myeloma patients who had been registered into United Kingdom Medical Research Council trials (1980 – 2002). Archived presentation sera were assayed for serum free light chains using the serum free light chain assay on an Olympus AU400 analyzer. Times to progression for those with abnormal versus normal serum free light chain ratios were compared. Times to progression were examined by Kaplan-Meier survival curves and log-rank sum statistical analysis. Results: Abnormal serum free light ratios were present in 36/43 (84%) of asymptomatic myeloma patients at the time of diagnosis and the remaining 7 patients had normal ratios. The median follow-up time for all 43 patients was 2807 days. Six patients with a normal kappa/lambda ratio had a median time to progression of 1323 days. In contrast, 26 patients with abnormal serum free kappa/lambda ratios had a median time to progression of 713 days. Ten patients who had an abnormal kappa/lambda ratio had not progressed at the time of follow-up. Although the median time to progression of patients with normal serum free light chain ratios was greater than those with abnormal ratios, this did not reach statistical significance (p<0.13). Conclusions: In summary, 84% of asymptomatic myeloma patients have an abnormal kappa/lambda ratio at diagnosis, in comparison with 95% of multiple myeloma and 60 % of (MGUS) patients. Furthermore, our data suggest that those with normal serum free light chain ratio may progress more slowly than those with abnormal ratios. Due to the small number of patients in this study, this did not reach statistical significance. In the spectrum of malignancy from MGUS to asymptomatic and symptomatic myeloma serum free light chain levels have an increasing frequency of abnormality and are associated with increased risk of progression to symptomatic myeloma.

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