scholarly journals Increased Serum Free Light Chains Precede the Presentation of Immunoglobulin Light Chain Amyloidosis

2014 ◽  
Vol 32 (25) ◽  
pp. 2699-2704 ◽  
Author(s):  
Brendan M. Weiss ◽  
Joseph Hebreo ◽  
Daniel V. Cordaro ◽  
Mark J. Roschewski ◽  
Thomas P. Baker ◽  
...  
Keyword(s):  
Light Chain ◽  
Early Death ◽  
Immunoglobulin M ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Serum Free ◽  
Light Chain Amyloidosis ◽  
Serum Free Light Chain ◽  
Immunoglobulin Light Chain Amyloidosis

PurposePatients with immunoglobulin light chain amyloidosis (AL amyloidosis) generally present with advanced organ dysfunction and have a high risk of early death. We sought to characterize monoclonal immunoglobulin (M-Ig) light chains before clinical presentation of AL amyloidosis.Patients and MethodsWe obtained prediagnostic sera from 20 cases with AL amyloidosis and 20 healthy controls matched for age, sex, race, and age of serum sample from the Department of Defense Serum Repository. Serum protein electrophoresis with immunofixation and serum free light chain (FLC) analysis were performed on all samples.ResultsAn M-Ig was detected in 100% of cases and 0% of controls (P < .001). The M-Ig was present in 100%, 80%, and 42% of cases at less than 4 years, 4 to 11 years, and more than 11 years before diagnosis, respectively. The median FLC differential (FLC-diff) was higher in cases compared with controls at all time periods, less than 4 years (174.8 v 0.3 mg/L; P < .001), 4 to 11 years (65.1 v 2.2 mg/L; P < .001), and more than 11 years (4.5 v 0.4 mg/L; P = .03) before diagnosis. The FLC-diff was greater than 23 mg/L in 85% of cases and 0% of controls (P < .001). The FLC-diff level increased more than 10% per year in 84% of cases compared with 16% of controls (P < .001).ConclusionIncrease of FLCs, including within the accepted normal range, precedes the development of AL amyloidosis for many years.

Nonchemotherapy Treatment of Immunoglobulin Light Chain Amyloidosis

2020 ◽  
Vol 143 (4) ◽  
pp. 373-380
Author(s):  
Layla Van Doren ◽  
Suzanne Lentzsch
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Cell Clone ◽  
Standard Of Care ◽  
Organ Damage ◽  
Current Therapy ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Light Chain Amyloidosis ◽  
Immunoglobulin Light Chain Amyloidosis

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a rare, life-threatening disease characterized by the deposition of misfolded proteins in vital organs such as the heart, the lungs, the kidneys, the peripheral nervous system, and the gastrointestinal tract. This causes a direct toxic effect, eventually leading to organ failure. The underlying B-cell lymphoproliferative disorder is almost always a clonal plasma cell disorder, most often a small plasma cell clone of <10%. Current therapy is directed toward elimination of the plasma cell clone with the goal of preventing further organ damage and reversal of the existing organ damage. Autologous stem cell transplantation has been shown to be a very effective treatment in patients with AL amyloidosis, although it cannot be widely applied as patients are often frail at presentation, making them ineligible for transplantation. Treatment with cyclophosphamide, bortezomib, and dexamethasone has emerged as the standard of care for the treatment of AL amyloidosis. Novel anti-plasma cell therapies, such as second generation proteasome inhibitors, immunomodulators, monoclonal antibodies targeting a surface protein on the plasma cell (daratumumab, elotuzumab), and the small molecular inhibitor venetoclax, have continued to emerge and are being evaluated in combination with the standard of care. However, there is still a need for therapies that directly target the amyloid fibrils and reverse organ damage. In this review, we will discuss current and emerging nonchemotherapy treatments of AL amyloidosis, including antifibril directed therapies under current investigation.

scholarly journals Identification of Amyloidogenic Light Chains Requires the Combination of Serum-Free Light Chain Assay with Immunofixation of Serum and Urine

2009 ◽  
Vol 55 (3) ◽  
pp. 499-504 ◽  
Author(s):  
Giovanni Palladini ◽  
Paola Russo ◽  
Tiziana Bosoni ◽  
Laura Verga ◽  
Gabriele Sarais ◽  
...  
Keyword(s):  
Light Chain ◽  
Gel Electrophoresis ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Agarose Gel ◽  
Agarose Gel Electrophoresis ◽  
Serum Free ◽  
Serum Free Light Chain ◽  
Amyloid Deposits ◽  
Serum And Urine

Abstract Background: The diagnosis of systemic immunoglobulin light-chain (AL) amyloidosis requires demonstration of amyloid deposits in a tissue biopsy and amyloidogenic monoclonal light chains. The optimal strategy to identify the amyloidogenic clone has not been established. We prospectively assessed the diagnostic sensitivity of the serum free light chain (FLC) κ/λ ratio, a commercial serum and urine agarose gel electrophoresis immunofixation (IFE), and the high-resolution agarose gel electrophoresis immunofixation (HR-IFE) developed at our referral center in patients with AL amyloidosis, in whom the amyloidogenic light chain was unequivocally identified in the amyloid deposits. Methods: The amyloidogenic light chain was identified in 121 consecutive patients with AL amyloidosis by immunoelectron microscopy analysis of abdominal fat aspirates and/or organ biopsies. We characterized the monoclonal light chain by using IFE and HR-IFE in serum and urine and the FLC κ/λ ratio in serum. We then compared the diagnostic sensitivities of the 3 assays. Results: The HR-IFE of serum and urine identified the amyloidogenic light chain in all 115 patients with a monoclonal gammopathy. Six patients with a biclonal gammopathy were omitted from the statistical analysis. The diagnostic sensitivity of commercial serum and urine IFE was greater than that of the FLC κ/λ ratio (96% vs 76%). The combination of serum IFE and the FLC assay detected the amyloidogenic light chain in 96% of patients. The combination of IFE of both serum and urine with the FLC κ/λ ratio had a 100% sensitivity. Conclusions: The identification of amyloidogenic light chains cannot rely on a single test and requires the combination of a commercially available FLC assay with immunofixation of both serum and urine.

scholarly journals Systemic Light Chain Amyloidosis (Congo Red Inconclusive) with Underlyng Clonal Expansion Not Meeting the Criteria of Light Chain Monoclonal Gammopathy of Renal Significance or Light Chain Myeloma:A Case Report

2020 ◽  
Vol 07 (04) ◽  
pp. 15-19
Author(s):  
Sanjay Kumar ◽  
Keyword(s):  
Light Chain ◽  
Congo Red ◽  
Monoclonal Gammopathy ◽  
Plasma Cells ◽  
Clonal Expansion ◽  
Chronic Diarrhoea ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Light Chain Amyloidosis ◽  
Immunoglobulin Light Chain Amyloidosis

Fifty-eight-year-old male admitted for evaluation of nephrotic syndrome and chronic diarrhoea was detected to have Immunoglobulin light chain amyloidosis (AL Amyloidosis) which was congo red inconclusive from renal biopsy. Bone marrow biopsy showed monoclonal plasma cells of 40% and light chain assay showed predominance of immunoglobulin lambda light chain. The diagnosis was neither fitting into the current diagnostic criteria for light chain Monoclonal Gammopathy of Renal Significance (MGRS) nor light chain myeloma. Literature is scarce regarding patients with AL amyloidosis having underlying clonal expansion not meeting the criteria of light chain myeloma or light chain MGRS.

scholarly journals Light Chain Stabilization: A Therapeutic Approach to Ameliorate AL Amyloidosis

Hemato ◽  
2021 ◽  
Vol 2 (4) ◽  
pp. 645-659
Author(s):  
Gareth J. Morgan ◽  
Joel N. Buxbaum ◽  
Jeffery W. Kelly
Keyword(s):  
Light Chain ◽  
Plasma Cells ◽  
Light Chains ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Organ Function ◽  
Conserved Residues ◽  
Light Chain Amyloidosis ◽  
Emerging Therapies ◽  
Chain Conformations

Non-native immunoglobulin light chain conformations, including aggregates, appear to cause light chain amyloidosis pathology. Despite significant progress in pharmacological eradication of the neoplastic plasma cells that secrete these light chains, in many patients impaired organ function remains. The impairment is apparently due to a subset of resistant plasma cells that continue to secrete misfolding-prone light chains. These light chains are susceptible to the proteolytic cleavage that may enable light chain aggregation. We propose that small molecules that preferentially bind to the natively folded state of full-length light chains could act as pharmacological kinetic stabilizers, protecting light chains against unfolding, proteolysis and aggregation. Although the sequence of the pathological light chain is unique to each patient, fortunately light chains have highly conserved residues that form binding sites for small molecule kinetic stabilizers. We envision that such stabilizers could complement existing and emerging therapies to benefit light chain amyloidosis patients.

scholarly journals Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2021

2021 ◽  
Vol 11 (5) ◽  
Author(s):  
M. Hasib Sidiqi ◽  
Morie A. Gertz
Keyword(s):  
At Risk ◽  
Light Chain ◽  
Treatment Algorithm ◽  
Al Amyloidosis ◽  
Preserved Ejection Fraction ◽  
Immunoglobulin Light Chain ◽  
Light Chain Amyloidosis ◽  
Unexplained Weight Loss ◽  
Immunoglobulin Light Chain Amyloidosis ◽  
Nephrotic Range Proteinuria

AbstractImmunoglobulin light chain amyloidosis (AL) commonly presents with nephrotic range proteinuria, heart failure with preserved ejection fraction, nondiabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea, and should be considered in patients presenting with these symptoms. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Herein we provide a review of established and investigational treatments for patients with AL amyloidosis and provide algorithms for workup and management of these patients.

The Utility of High Sensitivity Cardiac Troponin Among Patients with Immunoglobulin Light Chain Amyloidosis

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2887-2887 ◽  
Author(s):  
Angela Dispenzieri ◽  
Morie A Gertz ◽  
Amy K Saenger ◽  
Martha Grogan ◽  
Shaji Kumar ◽  
...  
Keyword(s):  
Light Chain ◽  
Cardiac Involvement ◽  
High Sensitivity ◽  
Staging System ◽  
Cardiac Response ◽  
Al Amyloidosis ◽  
Immunoglobulin Light Chain ◽  
Light Chain Amyloidosis ◽  
Staging Systems ◽  
Immunoglobulin Light Chain Amyloidosis

Abstract Abstract 2887 Introduction: Cardiac involvement is the major cause of death in patients with immunoglobulin light chain amyloidosis (AL). Detection of cardiac involvement and risk stratification has been facilitated by cardiac biomarkers like troponin T (cTnT) and N-terminal brain natriuretic peptide (NT-proBNP). A novel high sensitivity cTnT (hs-cTnT) assay has been developed, and we evaluated its diagnostic use with three questions in mind: 1) How do the cTnT and hs-cTnT perform in the AL amyloid staging system? 2) Does higher sensitivity add significant additional value in terms of prognosticating outcomes for patients with AL amyloidosis? 3) Can the current AL amyloidosis staging system be further improved upon? Methods: Stored serum samples (-20°C) from 224 pts with AL were analyzed for concentrations of hsTnT, TnT, and NT-proBNP on the E170 Modular analyzer (Roche Diagnostics, Penzberg, Germany). 99th percentile reference limits were <0.014 and <0.010 mcg/L for hsTnT and TnT, respectively. Results: Median values for hsTnT, TnT, and NT-proBNP were 38 ng/L (range 0–075.4), 0.017 mcg/L (<0.0–0.904), and 1230 ng/L (0–32, 226), respectively. The correlation coefficient between hsTnT and TnT was 0.972. Those classified by echocardiographic parameters as having (n=143) or not having (n=81) cardiac involvement had TnT concentrations of 0.04 and 0.01 mcg/L and hsTnT levels of 52.2 and 15.6 ng/L, respectively. The direct numeric result from the hs-cTnT result CANNOT merely be substituted for a cTnT result in the Mayo AL staging system since 14% of patients would be misclassified. The performance of the receiver operation curve derived hs-cTnT cut-point of 54 ng/L is a slight improvement over the direct substitution of 35 ng/L if replacement of one assay for another is required. An alternate staging option using hs-cTnT alone—using the two thresholds14 ng/L and 54 ng/L (figure)—performs as well as either the original Mayo AL staging system or a derivative system incorporating hs-cTnT with respective relative risks of death (95%CI) of 3.6 (2.3, 5.7), 3.8 (2.5, 5.9), and 3.3 (2.2, .50). On multivariate analysis, our newly described alternate 3 level, hs-cTnT alone staging system is independent of other factors including period of diagnosis, type of therapy, and NT-proBNP value, the last of which dropped out of the model. Alternate models using NT-proBNP and cTnT were explored, but none performed better than the original staging system or the new hs-cTnT system. Conclusion: The direct numeric result from the hs-cTnT result cannot merely be substituted for a cTnT result in the Mayo amyloid staging system. Consideration could be made for AL staging systems using hs-cTnT alone and relegating the NT-proBNP for measuring cardiac response. Disclosures: Jaffe: Roche: Consultancy.

scholarly journals Genetic pathogenesis of immunoglobulin light chain amyloidosis: basic characteristics and clinical applications

2021 ◽  
Vol 10 (1) ◽  
Author(s):  
Linchun Xu ◽  
Yongzhong Su
Keyword(s):  
Plasma Cell ◽  
Light Chain ◽  
Amyloid Fibril ◽  
Treatment Modalities ◽  
Driver Gene ◽  
Immunoglobulin Light Chain ◽  
Disease Evolution ◽  
Genetic Aberrations ◽  
Light Chain Amyloidosis ◽  
Immunoglobulin Light Chain Amyloidosis

AbstractImmunoglobulin light chain amyloidosis (AL) is an indolent plasma cell disorder characterized by free immunoglobulin light chain (FLC) misfolding and amyloid fibril deposition. The cytogenetic pattern of AL shows profound similarity with that of other plasma cell disorders but harbors distinct features. AL can be classified into two primary subtypes: non-hyperdiploidy and hyperdiploidy. Non-hyperdiploidy usually involves immunoglobulin heavy chain translocations, and t(11;14) is the hallmark of this disease. T(11;14) is associated with low plasma cell count but high FLC level and displays distinct response outcomes to different treatment modalities. Hyperdiploidy is associated with plasmacytosis and subclone formation, and it generally confers a neutral or inferior prognostic outcome. Other chromosome abnormalities and driver gene mutations are considered as secondary cytogenetic aberrations that occur during disease evolution. These genetic aberrations contribute to the proliferation of plasma cells, which secrete excess FLC for amyloid deposition. Other genetic factors, such as specific usage of immunoglobulin light chain germline genes and light chain somatic mutations, also play an essential role in amyloid fibril deposition in AL. This paper will propose a framework of AL classification based on genetic aberrations and discuss the amyloid formation of AL from a genetic aspect.

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