Involved free light chains <10 mg/L with treatment predict better outcomes in systemic light-chain amyloidosis.
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ABSTRACT:
SUBMITTER: Godara A
PROVIDER: S-EPMC8436337 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Intervention into amyloid deposition with anti-amyloid agents like the polyphenol epigallocatechin-3-gallate (EGCG) is emerging as an experimental secondary treatment strategy in systemic light chain amyloidosis (AL). In both AL and multiple myeloma (MM), soluble immunoglobulin light chains (LC) are produced by clonal plasma cells, but only in AL do they form amyloid deposits in vivo We investigated the amyloid formation of patient-derived LC and their susceptibility to EGCG in vitro to probe commonalities and systematic differences in their assembly mechanisms. We isolated nine LC from the urine of AL and MM patients. We quantified their thermodynamic stabilities and monitored their aggregation under physiological conditions by thioflavin T fluorescence, light scattering, SDS stability, and atomic force microscopy. LC from all patients formed amyloid-like aggregates, albeit with individually different kinetics. LC existed as dimers, ?50% of which were linked by disulfide bridges. Our results suggest that cleavage into LC monomers is required for efficient amyloid formation. The kinetics of AL LC displayed a transition point in concentration dependence, which MM LC lacked. The lack of concentration dependence of MM LC aggregation kinetics suggests that conformational change of the light chain is rate-limiting for these proteins. Aggregation kinetics displayed two distinct phases, which corresponded to the formation of oligomers and amyloid fibrils, respectively. EGCG specifically inhibited the second aggregation phase and induced the formation of SDS-stable, non-amyloid LC aggregates. Our data suggest that EGCG intervention does not depend on the individual LC sequence and is similar to the mechanism observed for amyloid-? and ?-synuclein.
| S-EPMC5313104 | biostudies-literature
Project description:The immunoglobulin light-chain amyloidosis is a multisystemic disease which manifests by damage to the vital organs by light chain-derived amyloid fibril. Traditionally, the treatment has been directed to the underlying plasma cell clone with or without high dose chemotherapy followed by autologous stem cell transplantation using melphalan based conditioning. Now with the approval of highly tolerable anti-CD38 monoclonal antibody daratumumab based anti-plasma cell therapy in 2021, high rates of hematologic complete responses are possible even in patients who are otherwise deemed not a candidate for autologous stem cell transplantation. However, despite the progress, there remains a limitation in the strategies to improve symptoms particularly in patients with advanced cardiac involvement, those with nephrotic syndrome and autonomic dysfunction due to underlying systemic AL amyloidosis. The symptoms can be an ordeal for the patients and their caregivers and effective strategies are urgently needed to address them. The supportive care is aimed to counteract the symptoms of the disease and the effects of the treatment on involved organs' function and preserve patients' quality of life. Here we discuss multidisciplinary approach in a system-based fashion to address the symptom management in this dreadful disease. In addition to achieving excellent anti-plasma cell disease control, using treatment directed to remove amyloid from the vital organs can theoretically hasten recovery of the involved organs thereby improving symptoms at a faster pace. Ongoing phase III clinical trials of CAEL-101 and Birtamimab will address this question.
| S-EPMC9242830 | biostudies-literature
Project description:Amyloid formation and deposition of immunoglobulin light-chain proteins in systemic amyloidosis (AL) cause major organ failures. While the ? light-chain is dominant (?/?=1:2) in healthy individuals, ? is highly overrepresented (?/?=3:1) in AL patients. The structural basis of the amyloid formation and the sequence preference are unknown. We examined the correlation between sequence and structural stability of dimeric variable domains of immunoglobulin light chains using molecular dynamics simulations of 24 representative dimer interfaces, followed by energy evaluation of conformational ensembles for 20 AL patients' light chain sequences. We identified a stable interface with displaced N-terminal residues, provides the structural basis for AL protein fibrils formation. Proline isomerization may cause the N-terminus to adopt amyloid-prone conformations. We found that ? light-chains prefer misfolded dimer conformation, while ? chain structures are stabilized by a natively folded dimer. Our study may facilitate structure-based small molecule and antibody design to inhibit AL. This article is part of a Special Issue entitled: Accelerating Precision Medicine through Genetic and Genomic Big Data Analysis edited by Yudong Cai & Tao Huang.
| S-EPMC5927852 | biostudies-literature
Project description:Dysphagia is an uncommon presentation of systemic immunoglobulin light-chain (AL) amyloidosis with multiple myeloma (MM). Gastrointestinal (GI) involvement usually manifests with altered motility, malabsorption or bleeding. Furthermore, patients identified with GI amyloidosis, without previous diagnosis of a plasma cell disorder, are extremely rare. We report an elderly woman who presented with acute on chronic cardiac dysfunction, sick sinus syndrome and acute renal failure. While admitted, she developed intermittent dysphagia to both solids and liquids. Oesophagogastroduodenoscopy showed ulcerations of oesophagus and duodenum. Biopsies revealed focal amyloid deposition, stained with Congo red. Renal biopsy revealed amyloid deposition in renal arterioles. She underwent a bone marrow biopsy confirming MM, represented by more than 15% plasma cell population. She was started on treatment for heart failure, induction chemotherapy for MM and percutaneous gastrostomy tube for feeding. However, she continued to deteriorate, eventually opting for hospice, and ultimately died 2?days after discharge from hospital.
| S-EPMC6202992 | biostudies-literature
Project description:Light chain (AL) amyloidosis is caused by a usually small plasma-cell clone that is able to produce the amyloidogenic light chains. They are able to misfold and aggregate, deposit in tissues in the form of amyloid fibrils and lead to irreversible organ dysfunction and eventually death if treatment is late or ineffective. Cardiac damage is the most important prognostic determinant. The risk of dialysis is predicted by the severity of renal involvement, defined by the baseline proteinuria and glomerular filtration rate, and by the response to therapy. The specific treatment is chemotherapy targeting the underlying plasma-cell clone. It needs to be risk-adapted, according to the severity of cardiac and/or multi-organ involvement. Autologous stem cell transplant (preceded by induction and/or followed by consolidation with bortezomib-based regimens) can be considered for low-risk patients (~20%). Bortezomib combined with alkylators is used in the majority of intermediate-risk patients, and with possible dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents were investigated in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. In addition, the use of novel approaches based on antibodies targeting the amyloid deposits or small molecules interfering with the amyloidogenic process gave promising results in preliminary studies. Some of them are under evaluation in controlled trials. These molecules will probably add powerful complements to standard chemotherapy. The understanding of the specific molecular mechanisms of cardiac damage and the characteristics of the amyloidogenic clone are unveiling novel potential treatment approaches, moving towards a cure for this dreadful disease.
| S-EPMC5841939 | biostudies-literature
Project description:Systemic immunoglobulin light chain (AL) amyloidosis is a disorder characterized by the production of clonal serum free light chains that misfold, aggregate, and deposit in vital organs. Treatment of this disease is typically targeted at the abnormal plasma cell clone in the bone marrow which is the source of the amyloidogenic light chain. First-line therapies in this disease are well established, but in the relapsed or refractory setting, there are many treatment options, including immunomodulatory agents, proteasome inhibitors, alkylating agents, and monoclonal antibodies. Decisions regarding treatment choice should be made by a multidisciplinary team with consideration of the patient's functional status, disease stage, degree of organ dysfunction, and potential treatment toxicities. Herein we review the current treatment options available for patients with relapsed or refractory AL amyloidosis.
| S-EPMC6815750 | biostudies-literature
Project description:In patients with immunoglobulin light-chain (AL) amyloidosis, depth of hematologic response correlates with both organ response and overall survival. Our group has demonstrated that screening with a matrix-assisted laser desorption/ionization-time-of-flight (TOF) mass spectrometry (MS) is a quick, sensitive, and accurate means to diagnose and monitor the serum of patients with plasma cell disorders. Microflow liquid chromatography coupled with electrospray ionization and quadrupole TOF MS adds further sensitivity. We identified 33 patients with AL amyloidosis who achieved amyloid complete hematologic response, who also had negative bone marrow by six-color flow cytometry, and who had paired serum samples to test by MS. These samples were subjected to blood MS. Four patients (12%) were found to have residual disease by these techniques. The presence of residual disease by MS was associated with a poorer time to progression (at 50 months 75% versus 13%, p?=?0.003). MS of the blood out-performed serum and urine immunofixation, the serum immunoglobulin free light chain, and six-color flow cytometry of the bone marrow in detecting residual disease. Additional studies that include urine MS and next-generation techniques to detect clonal plasma cells in the bone marrow will further elucidate the full potential of this technique.
| S-EPMC7042300 | biostudies-literature
Project description:ObjectivesThe purpose of this study was to determine phenotypes characterizing cardiac involvement in AL amyloidosis by using direct (fluorine-18-labeled florbetapir {[18F]florbetapir} positron emission tomography [PET]/computed tomography) and indirect (echocardiography and cardiac magnetic resonance [CMR]) imaging biomarkers of AL amyloidosis.BackgroundCardiac involvement in systemic light chain amyloidosis (AL) is the main determinant of prognosis and, therefore, guides management. The hypothesis of this study was that myocardial AL deposits and expansion of extracellular volume (ECV) could be identified before increases in N-terminal pro-B-type natriuretic peptide or wall thickness.MethodsA total of 45 subjects were prospectively enrolled in 3 groups: 25 with active AL amyloidosis with cardiac involvement (active-CA), 10 with active AL amyloidosis without cardiac involvement by conventional criteria (active-non-CA), and 10 with AL amyloidosis with cardiac involvement in remission for at least 1 year (remission-CA). All subjects underwent echocardiography, CMR, and [18F]florbetapir PET/CT to evaluate cardiac amyloid burden.ResultsThe active-CA group demonstrated the largest myocardial AL amyloid burden, quantified by [18F]florbetapir retention index (RI) 0.110 (interquartile range [IQR]: 0.078 to 0.139) min-1, and the lowest cardiac function by global longitudinal strain (GLS), median GLS -11% (IQR: -8% to -13%). The remission-CA group had expanded extracellular volume (ECV) and [18F]florbetapir RI of 0.097 (IQR: 0.070 to 0.124 min-1), and abnormal GLS despite hematologic remission for >1 year. The active-non-CA cohort had evidence of cardiac amyloid deposition by advanced imaging metrics in 50% of the subjects; cardiac involvement was identified by late gadolinium enhancement in 20%, elevated ECV in 20%, and elevated [18F]florbetapir RI in 50%.ConclusionsEvidence of cardiac amyloid infiltration was found based on direct and indirect imaging biomarkers in subjects without CA by conventional criteria. The findings from [18F]florbetapir PET imaging provided insight into the preclinical disease process and on the basis of interpretation of expanded ECV on CMR and have important implications for future research and clinical management of AL amyloidosis. (Molecular Imaging of Primary Amyloid Cardiomyopathy [MICA]; NCT02641145).
| S-EPMC8218539 | biostudies-literature
Project description:Light chain (AL) amyloidosis is the most common form of amyloidosis involving the kidney. It is characterized by albuminuria, progressing to overt nephrotic syndrome and eventually end-stage renal failure if diagnosed late or ineffectively treated, and in most cases by concomitant heart involvement. Cardiac amyloidosis is the main determinant of survival, whereas the risk of dialysis is predicted by baseline proteinuria and glomerular filtration rate, and by response to therapy. The backbone of treatment is chemotherapy targeting the underlying plasma cell clone, that needs to be risk-adapted due to the frailty of patients with AL amyloidosis who have cardiac and/or multiorgan involvement. Low-risk patients (?20%) can be considered for autologous stem cell transplantation that can be preceded by induction and/or followed by consolidation with bortezomib-based regimens. Bortezomib combined with alkylators, such as melphalan, preferred in patients harboring t(11;14), or cyclophosphamide, is used in most intermediate-risk patients, and with cautious dose escalation in high-risk subjects. Novel, powerful anti-plasma cell agents, such as pomalidomide, ixazomib, and daratumumab, prove effective in the relapsed/refractory setting, and are being moved to upfront therapy in clinical trials. Novel approaches based on small molecules interfering with the amyloidogenic process and on antibodies targeting the amyloid deposits gave promising results in preliminary uncontrolled studies, are being tested in controlled trials, and will likely prove powerful complements to chemotherapy. Finally, improvements in the understanding of the molecular mechanisms of organ damage are unveiling novel potential treatment targets, moving toward a cure for this dreadful disease.
| S-EPMC5976806 | biostudies-literature
Project description:The amyloidoses are protein misfolding diseases characterized by the deposition of amyloid that leads to cell death and tissue degeneration. In immunoglobulin light chain amyloidosis (AL), each patient has a unique monoclonal immunoglobulin light chain (LC) that forms amyloid deposits. Somatic mutations in AL LCs make these proteins less thermodynamically stable than their non-amyloidogenic counterparts, leading to misfolding and ultimately the formation of amyloid fibrils. We hypothesize that location rather than number of non-conservative mutations determines the amyloidogenicity of light chains.We performed sequence alignments on the variable domain of 50 kappa and 91 lambda AL light chains and calculated the number of non-conservative mutations over total number of patients for each secondary structure element in order to identify regions that accumulate non-conservative mutations. Among patients with AL, the levels of circulating immunoglobulin free light chain varies greatly, but even patients with very low levels can have very advanced amyloid deposition.Our results show that in specific secondary structure elements, there are significant differences in the number of non-conservative mutations between normal and AL sequences. AL sequences from patients with different levels of secreted light chain have distinct differences in the location of non-conservative mutations, suggesting that for patients with very low levels of light chains and advanced amyloid deposition, the location of non-conservative mutations rather than the amount of free light chain in circulation may determine the amyloidogenic propensity of light chains.
| S-EPMC2664898 | biostudies-literature