Light-chain amyloidosis with dysphagia as the main symptom: a case report.

BACKGROUND: Immunoglobulin light-chain amyloidosis is a relatively rare condition with a worldwide incidence of 5.1-12.8 cases per million person-years (Baker, 2022). It is characterized by a clonal population of immunoglobulin-secreting cells that produce a monoclonal light chain of κ or λ type as either an intact molecule or a fragment. CASE PRESENTATION: A 69-year-old East Asian (Chinese) male patient who presented with progressive dysphagia visited multiple hospitals repeatedly for more than 2 years and was finally diagnosed with immunoglobulin light-chain amyloidosis. CONCLUSIONS: Otolaryngologists should consider immunoglobulin light-chain amyloidosis when encountering suspicious clinical manifestations and intervene early to avoid misdiagnosis.

Improving care for systemic light-chain amyloidosis patients: is a multidisciplinary approach best?

INTRODUCTION: Light chain (AL) amyloidosis is a rare and complex disease which can affect various systems of the body. In common with many rare and multisystemic diseases, the breadth of diagnostic, clinical, and supportive expertise required to care for such patients is best met by a multidisciplinary team. AREAS COVERED: We outline different phases of the patients' journey, including diagnosis, staging, treatment, and response assessment, to highlight common clinical issues best resolved by a multidisciplinary approach. EXPERT OPINION: To extend the benefit of multidisciplinary care to the majority of patients with AL amyloidosis, innovative healthcare models such as telehealth and multisite multidisciplinary team meetings need to be implemented. The need for a multidisciplinary approach where such a wide array of healthcare skills is required also highlights the shortcomings of our current diagnostic and monitoring assays. Better access to diagnostic and subtyping assays is necessary. The ability to characterize and measure the causative amyloidogenic light chain as well as imaging techniques to accurately diagnose and monitor response to therapy is also needed and is currently an area of research focus.

Prognostic factors in Chinese patients with immunoglobulin light chain amyloidosis: a scoping review and meta-analysis.

OBJECTIVE: This scoping review and meta-analysis aimed to map the evidence regarding prognostic factors in Chinese patients with immunoglobulin light chain (AL) amyloidosis and to identify current research gaps. METHODS: We searched EMBASE, PubMed, and CNKI databases from their inception to 15 September 2021. All studies investigated the association between any prognostic factor and target outcomes, including overall survival (OS), progression-free survival (PFS), and end-stage renal disease (ESRD) in Chinese patients with AL amyloidosis. RESULTS: This scoping review included 52 studies, of which 44 with 6,432 patients contributed to the multivariate prognostic analysis. Multivariate analysis identified a total of 106 factors that correlated with OS, 16 factors with PFS, and 18 factors with ESRD. Five prognostic factors were significantly associated with PFS, and 11 prognostic factors were significantly associated with ESRD. Meta-analysis was only available for prognostic factors without heterogeneous cutoff values, for which hazard ratios (HRs) and their 95% confidence intervals (CIs) were reported. Meta-analysis showed that bone marrow plasma cells (BMCs) (HR: 1.96, 95% CI: 1.21-3.19, p < 0.05) and interventricular septal thickness (IVST) (HR: 1.23, 95% CI: 1.10-1.38, p < 0.05) were independently associated with OS. CONCLUSION: The significant prognostic factors associated with OS, PFS, and ESRD in Chinese patients with AL amyloidosis were related to plasma cell tumor load, biological characteristics, cardiac involvement, renal involvement, population characteristics, and treatment. Further studies should explore additional prognostic factors in patients with AL amyloidosis to develop prognostic models.

The significant prognostic factors associated with OS, PFS, and ESRD in Chinese patients with AL amyloidosis were related to plasma cell tumor load, biological characteristics, cardiac involvement, renal involvement, population characteristics, and treatment.Meta-analysis showed there was a significant association between BMCs or interventricular septal thickness and OS.

Successes in translation.

Translational research is key in advancing the diagnosis and therapy of systemic amyloidoses. This paper summarises our presentations at the ISA Workshop on Translation in Systemic Amyloidoses held in Athens on September 25-26, 2023. The critical advances made by the pioneers in the field are reviewed, with particular attention to the discoveries and developments of utmost importance to our understanding of what amyloid is and how the substance affects functions. Examples of translational research regarding the mechanisms of cardiac damage in light chain amyloidosis, the role of biomarkers in improving our understanding of the biology of the disease and patients' management, and the molecular mechanisms involved in the cytotoxicity are described. Advances in basic research continue to open new therapeutic avenues.

Digital whole-slide imaging of changes in amyloid after peripheral blood stem cell transplantation in patients with amyloid light-chain amyloidosis.

Peripheral blood stem cell transplantation (PBSCT) has made amyloid light-chain (AL) amyloidosis treatable. After PBSCT, hematological complete remission (HCR) can be achieved, leading to improved renal prognosis. The purpose of this study was to evaluate whether whole slide imaging of biopsy samples shows a post-treatment reduction in amyloid deposits in patients with AL amyloidosis. Patients were divided into three groups: Group A (n = 8), not eligible for PBSCT and treated with other therapies; Group B (n = 11), treated with PBSCT and achieved HCR; and Group C (n = 5), treated with PBSCT but did not achieve HCR. Clinical findings and amyloid deposition in glomeruli, interstitium, and blood vessels were compared before and after treatment using digital whole-slide imaging. Proteinuria and hypoalbuminemia improved more in Group B than in the other groups, and in Group B, amyloid deposition improved more in the glomeruli than in the interstitium and blood vessels. The long-term renal and survival prognosis was better in Group B than in the other groups. PBSCT can be expected to improve long-term clinical and renal histological prognosis in patients with AL amyloidosis who achieve HCR. Amyloid disappearance from renal tissue may take a long time even after clinical HCR.

A patient with AL amyloidosis presenting with refractory tuberculosis, chest tightness and hypotension: case report.

INTRODUCTION: Immunoglobulin light chain (AL) amyloidosis presents a clinical spectrum characterized by diverse manifestations and involvement of multiple organs, posing a significant diagnostic challenge for physicians. METHODS AND RESULTS: We present a case of a patient admitted to our hospital due to recurrent cough and sputum, which was initially diagnosed as refractory tuberculosis. Throughout his hospitalization, the patient experienced distressing symptoms, including uncontrollable chest tightness, hypotension, and fever. Noteworthy observations included a persistent elevation in cardiac biomarkers, indicative of cardiac damage. Bronchoalveolar lavage revealed the presence of various pathogenic microorganisms, while bone marrow flow cytometry demonstrated the existence of clonal plasma cells. Additionally, the urine free light chain assay detected the presence of M protein, and the positive congo red staining of the abdominal wall fat biopsy confirmed amyloid deposition in the tissues. Taking into account the patient's clinical presentation and the examination findings, we reached a conclusive diagnosis of immunoglobulin light chain (AL) amyloidosis. CONCLUSION: This case serves as a reminder for physicians to consider rare diseases like AL amyloidosis when patients present with symptoms involving multiple organ systems such as heart, lung and kidney that are unresponsive to conventional treatment options.

Concurrent Acute Heart Failure and Renal Failure in Amyloid Light Chain Amyloidosis.

INTRODUCTION: Amyloid light chain (AL) amyloidosis is a multisystem disease with significant variability in patient presentation. This case describes the presentation and workup of a patient with unique multiorgan involvement on initial presentation. CASE PRESENTATION: A 69-year-old African American male presented with weakness, leg swelling, and shortness of breath. Initial workup demonstrated acute heart failure and acute-on-chronic renal failure with nephrotic range proteinuria (5.78 protein to creatinine ratio). Further workup showed elevated serum protein electrophoresis, urine protein electrophoresis, and light chains. Subsequent renal biopsy showed lambda-restricted AL-type renal amyloidosis. DISCUSSION: A variety of systemic presentations have been described in the literature; however, concurrent heart and renal failure as primary presentation is uncommon. CONCLUSIONS: This case emphasizes the importance of considering systemic inflammatory diseases, such as amyloidosis, in the differential diagnoses of patients with unexplained multiorgan disease. Early diagnosis and treatment initiation are essential for improving patient outcomes. Improved recognition of common clinical manifestations and laboratory abnormalities will likely improve outcomes through earlier diagnosis.

Skeletal muscle involvement in systemic amyloidosis is often overlooked.

AIM: Systemic amyloidosis is a condition in which misfolded amyloid fibrils are deposited within tissues. Amyloid myopathy is a rare manifestation of systemic amyloidosis. However, whether skeletal muscle involvement is underestimated and whether such deposition guarantees clinical and pathological myopathic features remain to be investigated. METHODS: We retrospectively reviewed patients with systemic amyloidosis, in whom skeletal muscle biopsies were performed at our centre between January 2018 and June 2023. In total, 28 patients with suspected systemic amyloidosis were included. Among these, 21 presented with cardiomyopathy but lacked myopathic symptoms. The clinical and pathological data of these patients were further analysed. The amyloid type was confirmed by immunohistochemistry. RESULTS: Twenty-eight patients with suspected systemic amyloidosis underwent muscle biopsy. Amyloid deposition in the skeletal muscle was confirmed in 24 patients, including 22 with light-chain amyloidosis (AL) and two with transthyretin amyloidosis (ATTR). Among the 24 patients, seven presented with muscle weakness and decreased muscle strength (Group 1, symptomatic myopathy), whereas the remaining 17 exhibited normal muscle strength (Group 2, asymptomatic myopathy). Group 1 included four patients with AL-λ, one with AL-κ and two with ATTR. Group 2 included 15 patients with AL-λ and two patients with AL-κ. In Group 1, six patients exhibited neuropathy, whereas only one patient in Group 2 presented with subclinical neuropathy on nerve conduction studies. Amyloid deposition in the interstitium was the most obvious change, observed in all 24 patients. Neuropathic changes, including denervation atrophy and muscle fibre grouping, were also common. Except for type 2 fibre atrophy, the other myopathic changes were mild and nonspecific. No sarcolemmal disruption was observed. Immunohistochemical analysis revealed marked positivity for MAC and MHC1 expression in the regions with amyloid deposits. Clinicopathological analysis revealed no significant differences in the extent of muscular amyloid deposition between the two groups. Nevertheless, patients in Group 1 displayed more pronounced neurogenic atrophy on skeletal muscle biopsies. CONCLUSIONS: Our study indicates that amyloid deposition in skeletal muscle is commonly observed but rarely causes symptomatic myopathy in systemic amyloidosis.

Internalisation of immunoglobulin light chains by cardiomyocytes in AL amyloidosis: what can biopsies tell us?

BACKGROUND: Cardiac involvement in systemic light chain amyloidosis (AL) leads to chronic heart failure and is a major prognosis factor. Severe cellular defects are provoked in cardiac cells by tissue-deposited amyloid fibrils of misfolded free immunoglobulin light chains (LCs) and their prefibrillar oligomeric precursors. OBJECTIVE: Understanding the molecular mechanisms behind cardiac cell cytotoxicity is necessary to progress in therapy and to improve patient management. One key question is how extracellularly deposited molecules exert their toxic action inside cardiac cells. Here we searched for direct evidence of amyloid LC uptake by cardiomyocytes in patient biopsies. METHODS: We immunolocalized LCs in cardiac biopsies from four AL cardiac amyloidosis patients and analysed histopathological images by high resolution confocal microscopy and 3D image reconstruction. RESULTS: We show, for the first time directly in patient tissue, the presence of LCs inside cardiomyocytes, and report their proximity to nuclei and to caveolin-3-rich areas. Our observations point to macropinocytosis as a probable mechanism of LC uptake. CONCLUSIONS: Internalisation of LCs occurs in patient cardiomyocytes. This event could have important consequences for the pathogenesis of the cardiac disease by enabling interactions between amyloid molecules and cellular organelles inducing specific signalling pathways, and might bring new insight regarding treatment.

Delayed identification of monoclonal protein is associated with early death in isolated cardiac AL amyloidosis.

BACKGROUND: Early identification of immunoglobulin light-chain amyloidosis (AL) is crucial due to its rapid progression. Monoclonal light-chain (M-LC) testing is the first step in the diagnostic workup for patients with suspected cardiac amyloidosis (CA). We aimed to determine whether the time interval between the first CA suspicion and M-LC testing can be related to AL amyloidosis survival outcomes. METHODS: All patients (n = 94) with isolated cardiac AL amyloidosis diagnosed at our center between 2016 and 2020 were included. Those with pre-existing known monoclonal protein (monoclonal gammopathy of undetermined significance or smoldering multiple myeloma) were excluded. Time intervals to diagnostic tests and diagnosis were calculated and assessed for their survival prediction ability. RESULTS: The time interval between first CA suspicion (on echocardiography) and M-LC testing correlated with early mortality, and the best cutoff predicting survival, was 6 weeks. The 26 patients (∼28% of entire cohort) who underwent M-LC-studies >6 weeks after first suspicion more frequently presented Mayo stage IIIb (65% vs. 35%, p = .008), showing poorer overall survival than those (n = 68, 72%) referred for early M-LC studies (median 3 vs. 14 months, p = .039). CONCLUSIONS: Monoclonal protein testing should be the first-step in the diagnostic workup for patients with echocardiographic/other instrumental red flags raising CA suspicion.

Prognostic Value of Left Ventricular 18F-Florbetapir Uptake in Systemic Light-Chain Amyloidosis.

BACKGROUND: Positron emission tomography/computed tomography (PET/CT) with 18F-florbetapir, a novel amyloid-targeting radiotracer, can quantify left ventricular (LV) amyloid burden in systemic light-chain (AL) amyloidosis. However, its prognostic value is not known. OBJECTIVES: The authors' aim was to evaluate the prognostic value of LV amyloid burden quantified by 18F-florbetapir PET/CT, and to identify mechanistic pathways mediating its association with outcomes. METHODS: A total of 81 participants with newly diagnosed AL amyloidosis underwent 18F-florbetapir PET/CT imaging. Amyloid burden was quantified using 18F-florbetapir LV uptake as percent injected dose. The Mayo stage for AL amyloidosis was determined using troponin T, N-terminal pro-B-type natriuretic peptide (NT-proBNP), and free light chain levels. Major adverse cardiac events (MACE) were defined as all-cause death, heart failure hospitalization, or cardiac transplantation within 12 months. RESULTS: Among participants (median age, 61 years; 57% males), 36% experienced MACE, increasing from 7% to 63% across tertiles of LV amyloid burden (P < 0.001). LV amyloid burden was associated with MACE (HR: 1.46; 95% CI: 1.16-1.83; P = 0.001). However, this association became nonsignificant when adjusted for Mayo stage. In mediation analysis, the association between LV amyloid burden and MACE was mediated by NT-proBNP (P < 0.001), a marker of cardiomyocyte stretch and heart failure, and a component of Mayo stage. CONCLUSIONS: In this first study to link cardiac 18F-florbetapir uptake to subsequent outcomes, LV amyloid burden estimated by percent injected dose predicted MACE in AL amyloidosis. This effect was not independent of Mayo stage and was mediated primarily through NT-proBNP. These findings provide novel insights into the mechanism linking myocardial amyloid deposits to MACE.

Healthcare resource utilisation and costs associated with AL amyloidosis: a retrospective matched cohort study.

We conducted a retrospective population-based, matched cohort study using the National Health Insurance Research Database to estimate healthcare resource utilisation (HRU) and costs in patients with newly diagnosed AL amyloidosis in Taiwan. Cases were matched 10:1 by age, sex, and area of residence to patients without AL amyloidosis (comparators) randomly selected from the database during the same time period. Annual all-cause HRU and costs for 3 years were quantified. AL amyloidosis-attributable costs were obtained by subtracting all-cause HRU costs incurred by comparators from cases. The mean age of all patients was 60.78 years and 59.07% were male. Co-morbidities were more frequent in cases than comparators. By 6 months after diagnosis, 12.1% of cases had died versus 0.9% of comparators. In the first year, cases had 103% more outpatient visits, 177% more emergency room visits, were hospitalised 4-times more frequently, and spent 5.5-times more days in hospital than comparators, and total healthcare costs were > sixfold higher. Costs incurred during the first year after diagnosis accounted for 55% of the 3-year cumulative cost. High HRU costs associated with delayed diagnosis and end-organ damage indicate a need for earlier diagnosis and more effective treatments for AL amyloidosis.

Helical superstructures between amyloid and collagen in cardiac fibrils from a patient with AL amyloidosis.

Systemic light chain (LC) amyloidosis (AL) is a disease where organs are damaged by an overload of a misfolded patient-specific antibody-derived LC, secreted by an abnormal B cell clone. The high LC concentration in the blood leads to amyloid deposition at organ sites. Indeed, cryogenic electron microscopy (cryo-EM) has revealed unique amyloid folds for heart-derived fibrils taken from different patients. Here, we present the cryo-EM structure of heart-derived AL amyloid (AL59) from another patient with severe cardiac involvement. The double-layered structure displays a u-shaped core that is closed by a ß-arc lid and extended by a straight tail. Noteworthy, the fibril harbours an extended constant domain fragment, thus ruling out the variable domain as sole amyloid building block. Surprisingly, the fibrils were abundantly concatenated with a proteinaceous polymer, here identified as collagen VI (COLVI) by immuno-electron microscopy (IEM) and mass-spectrometry. Cryogenic electron tomography (cryo-ET) showed how COLVI wraps around the amyloid forming a helical superstructure, likely stabilizing and protecting the fibrils from clearance. Thus, here we report structural evidence of interactions between amyloid and collagen, potentially signifying a distinct pathophysiological mechanism of amyloid deposits.

Prognostic value of plasma big endothelin-1 in patients with light chain cardiac amyloidosis.

BACKGROUND: Light chain cardiac amyloidosis (AL-CA) is associated with a high incidence of mortality. Big endothelin-1 (ET-1), the precursor of endothelial-vasoconstrictive ET-1, is closely related to the concentration of bioactive ET-1. Association between big ET-1 and prognosis of AL-CA has not yet been documented. The purpose of this study was to evaluate the prognostic value of big ET-1 for poor outcomes in moderate to severe AL-CA. METHODS: Big ET-1 levels were determined on admission in patients with newly diagnosed AL-CA with modified Mayo 2004 stage II or III. Primary outcome was all-cause mortality. The secondary outcomes included death from cardiac cause and the composite of the primary outcome or hospitalisations due to worsening heart failure. RESULTS: Overall, 141 patients were retrospectively included (57 stage II, 34 stage IIIa, 50 stage IIIb). During a median follow-up time of 25.7 months, 84 (59.6%) patients died. Patients with big ET-1 levels of ≤0.88 pmol/L had longer survival than those with >0.88 pmol/L (median survival time: 34.1 months vs 15.3 months, log-rank p<0.001), which was also observed in the validation cohort (log-rank p=0.026). Higher big ET-1 levels were predictive for all-cause mortality after multivariable adjustment (HR 1.91, 95% CI 1.05 to 3.49, p=0.035). Big ET-1 levels added an incremental prognostic value over modified Mayo 2004 stage (C-index: from 0.671 to 0.696, p=0.025; integrated discrimination improvement 0.168, p=0.047). CONCLUSIONS: Big ET-1 is a strong and independent predictor of mortality in patients with moderate to severe AL-CA, which may indicate a possible role for risk stratification in patients with this disease.

Outcomes of venetoclax-based therapy in patients with t(11;14) light chain amyloidosis after failure of daratumumab-based therapy.

BACKGROUND: Daratumumab's incorporation in the upfront treatment of light chain (AL) amyloidosis has led to daratumumab (dara) refractoriness early in disease course. Patients who experience relapse or have suboptimal response to dara-based-therapy, have limited options. OBJECTIVE: This study aimed to evaluate the outcomes of venetoclax-based therapy in t(11;14) positive AL patients who previously failed dara. METHODS: Thirty-one patients with AL were included in this bi-institutional retrospective analysis. RESULTS: Dara failure was due to inadequate response in 20 (65%) patients, haematologic relapse in 7 (22%), and both haematologic plus organ relapse in 4 (13%). Overall haematologic response rate to venetoclax-based therapy was 97%, with ≥ VGPR being 91%. Of the 19 evaluable patients with cardiac involvement, 14 (74%) achieved organ response. Of the 13 evaluable patients with renal involvement, 6 (46%) achieved organ response. With a median follow-up of 22 months, median time-to-next-treatment (TTNT) and overall survival (OS) were not reached. The 12- and 24-month TTNT rates were 74% and 56%, respectively. At data-cut-off, four patients had died, all from AL-related organ complications. The 12- and 24-month OS rates were 89% and 85%, respectively. Grade ≥3 adverse events occurred in 26% of patients, with 6% due to infections. CONCLUSION: These findings are encouraging for the use of venetoclax as salvage therapy post-dara failure.

Options for Rescue Treatment of Patients with AL Amyloidosis Exposed to Upfront Daratumumab.

PURPOSE OF REVIEW: This review aims to assess the therapeutic strategies available for relapsed/refractory patients with immunoglobulin light chain (AL) amyloidosis who received upfront daratumumab-based regimens. RECENT FINDINGS: The treatment landscape of AL amyloidosis has changed radically thanks to the introduction in the upfront setting of daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone (DaraCyBorD) which improved patients' outcomes increasing the rate of hematologic and organ responses. However, many patients eventually relapse or are refractory to daratumumab and the best salvage therapy is not well defined yet. In this contest, we reviewed the available therapeutic options after daratumumab failure, and we look towards the current advances in Bcl-2 inhibitors, novel immunotherapeutic agents as chimeric antigen receptor (CAR-T) therapy and bispecific antibodies (bsAbs). Relapsed/refractory AL amyloidosis represent an unmet clinical need and novel targeted drugs require urgent prospective assessment.

Evaluation of administration-related reactions with subcutaneous daratumumab with and without premedication.

BACKGROUND: Daratumumab-hyaluronidase-fihj (Dara-SQ) is frequently used in the treatment of plasma cell disorders and is associated with improved outcomes. Dara-SQ was shown to be non-inferior to intravenous daratumumab (Dara-IV) in efficacy, safety, and associated with fewer administration-related reactions (ARRs). Despite the lower ARR risk with Dara-SQ, package labeling still recommends indefinite premedication. In this study, we investigated the safety of premedication discontinuation after one cycle of Dara-SQ. MATERIALS AND METHODS: This pre-post interventional quality improvement study included all patients aged 18 years and older diagnosed with multiple myeloma or light chain (AL) amyloidosis who received at least one dose of Dara-SQ. Patients in Arm 1 received Dara-SQ per package labeling, while patients in Arm 2 had premedication omitted (excluding dexamethasone) after cycle 1. The primary endpoint was the incidence of ARR after cycle 1. Overall ARR rate and therapy time saved were also evaluated. RESULTS: A total of 102 patients (63 in Arm 1 and 39 in Arm 2) were included. There were zero reactions in either arm after cycle 1 across 1479 Dara-SQ doses administered over a 30-month period with or without premedication omission. The overall ARR rate was 2.9% (3/102), which all occurred prior to premedication omission. Therapy timed saved from premedication omission was 194 hours in a 6-month period, equating to approximately $140 000 USD. CONCLUSION: ARRs to Dara-SQ were rare, mild, and occurred during cycle 1 prior to premedication omission. Omission of noncorticosteroid premedication is safe, feasible, and carries substantial time and cost savings for patients and infusion centers.