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Light chain (AL) amyloidosis is a serious systemic disease caused by the deposition of free misfolded immunoglobulin light chains (LCs) in the form of amyloid fibrils within tissues. Cardiac involvement determines prognosis and mortality. An important cytotoxic impact of amyloidogenic prefibrillar LC oligomers on cardiomyocytes is by now established in isolated rodent cardiomyocytes, simple animal models, or cardiomyocyte-like cell lines. However, the response of human cardiomyocytes to this pathogenic condition is currently unknown. In this work, we have set up a human cellular disease model of AL cardiac amyloidosis (AL-CA) in the form of cardiac spheroids, to study the cytotoxic effects of amyloidogenic LCs with regard to contractile function and calcium handling. To mimic the disease in a reconstituted system, soluble amyloidogenic LCs purified from urine of AL-CA patients were added to a mixture of induced pluripotent stem cell-issued human cardiomyocytes (hiPSC-CM) and human primary cardiac fibroblasts, which resulted in formation of spheroids within 7 days. This procedure ensured a uniform pericellular LC distribution within spheroids. LC-treated hiPSC-CM cultures and LC-containing spheroids presented structural and functional defects including: (1) decreased levels and subcellular disorganization of sarcomeric protein alpha-actinin; (2) abnormal accumulation of calcium handling SERCA2a protein; (3) impaired contractility of spheroids and altered calcium transients. Three independent patient-derived LCs had similar effects, albeit to varying degrees, highlighting the patient-specific properties of this type of amyloids. Taken together, these results indicate that the present cardiac spheroid disease model could be appropriate to the study of cardiac cytotoxicity caused by different amyloidogenic LCs in AL-CA patients, contributing to a better understanding and therapeutic handling of the disease. [ABSTRACT FROM AUTHOR]

Due to the large size and rapid growth of the global therapeutic antibody market, there is major interest in understanding the aggregation of protein products as it can compromise efficacy, concentration, and safety. Various production and storage conditions have been identified as capable of inducing aggregation of polyclonal and monoclonal antibody (mAb) therapies such as low pH, freezing, light exposure, lyophilisation and increased ionic strength. The addition of stabilising excipients to these therapeutics helps to combat the formation of aggregates with future aggregation inhibition mechanisms involving the introduction of point mutations and glycoengineering within aggregation prone regions (APRs). Antibody aggregation also plays an integral role in the pathogenesis of a condition known as amyloid light chain (AL) amyloidosis which is characterised by the production of improperly folded and amyloidogenic immunoglobulin light chains (LCs). Current diagnostic tools rely heavily on histological staining with their future moving towards amyloid component identification and proteomic analysis. For many years, treatment options designed for multiple myeloma (MM) have been applied to AL amyloidosis patients by depleting plasma cell numbers. More recently, treatment strategies more specific to this condition have been developed with many designed to recognize amyloid fibrils and trigger their degradation without causing systemic plasma cell cytotoxicity. Amyloid fibrils in AL disease and aggregates in antibody therapeutics are both formed through the oligomerisation of misfolded / modified proteins attempting to reach a thermodynamically stable, free energy minimum that is lower than the respective monomers themselves. Although the final morphologies are different, by understanding the principles underlying such aggregation, we expect to find common insights that may contribute to the development of new and effective methods of antibody aggregation and/or amyloidosis management. We envision that this area of research will continue to be very relevant in both industry and clinical settings. [ABSTRACT FROM AUTHOR]

Daratumumab and bortezomib, the first-line drugs for AL amyloidosis, typically yield a complete hematologic response (CHR) rate of nearly 60% when used in combinations. An early achievement of CHR is crucial in amyloidosis. We retrospectively evaluated the relationship between dFLC (the difference between free light chain) reduction by Day 7 in Cycle 1 (C1D7) and CHR, organ response, and survival in 48 newly diagnosed AL amyloidosis patients receiving daratumumab, bortezomib, and dexamethasone. The CHR rate within six months was 66.7%. Using Receiver Operating Characteristic Curve curve analysis, we predicted CHR based on a dFLC reduction in C1D7 (67.0% change, optimal sensitivity 87.5%, specificity 81.3%). We introduce the novel concept of "rapid hematologic dFLC response", defined as a reduction in dFLC levels ≥ 67% in C1D7. The CHR rate in rapid responders' groups was higher than that in slow responders' group (90.3% vs. 23.5%, P<0.01). After a median follow-up of 19 months (range: 0.3–57), the renal response rate in rapid responders was higher than that in slow responders (72.0% vs. 27.5%, P = 0.025). The median major organ deterioration event-free survival in the rapid responders' group (not reached) was significantly superior to that in the slow responders' group (19 m, 95% CI: 1.79–23.14 m, P = 0.048). In conclusion, early dFLC reduction in C1D7 indicates a high possibility of CHR and organ response and may allow for early modification of therapy in selected patients. Key points: We propose a new concept of "the rapid dFLC response" in AL amyloidosis, based on treatment with daratumumab, bortezomib, and dexamethasone. Rapid dFLC response in C1D7 (67.0% change, sensitivity 87.5%, specificity 81.3%) can predict complete hematologic response. [ABSTRACT FROM AUTHOR]

Objective: To investigate the diagnostic performance of liver stiffness for detecting liver involvement in immunoglobulin light chain (AL) amyloidosis. Methods: Liver stiffness was measured using transient elastography in 71 patients with systemic AL amyloidosis and 18 patients with wild type transthyretin (ATTRwt) amyloidosis with cardiomyopathy. Both non-invasive consensus criteria and serum amyloid P component (SAP) scintigraphy were used as substitute standards instead of liver biopsy for establishing liver involvement. Results: Liver stiffness was higher in AL amyloidosis patients with liver involvement than in those without: this was observed using both consensus criteria (median 14.4 kPa vs. 8.1 kPa; p = 0.001) and SAP scintigraphy (median 20.9 kPa vs. 6.2 kPa; p < 0.001). Liver stiffness was also higher in AL amyloidosis patients with liver involvement compared to AL and ATTRwt amyloidosis patients with cardiac involvement. Based on receiver operating characteristic (ROC) curves a cut-off value of 14.4 kPa for stiffness was optimal to indicate liver involvement, providing sensitivity and specificity of 50% and 74%, respectively, using the consensus criteria and 63% and 90%, respectively, using SAP scintigraphy as standard. Conclusion: Liver stiffness is a promising tool to establish liver involvement in AL amyloidosis having potential to become part of updated criteria for liver involvement. [ABSTRACT FROM AUTHOR]

Summary Systemic light chain (AL) amyloidosis is a rare clonal plasma cell disorder characterized by the production of amyloidogenic immunoglobulin light chains, which causes the formation and deposition of amyloid fibrils, leading to multi‐organ dysfunction. Current treatment is directed at the underlying plasma cell clone to achieve a profound reduction in the monoclonal free light chain production. The standard‐of‐care first‐line therapy is a combination of daratumumab, cyclophosphamide, bortezomib and dexamethasone (D‐VCd regimen), resulting in high rates of haematological and organ responses. However, AL amyloidosis remains incurable, and all patients inevitably relapse. Hence, novel treatment options are needed for patients with an inadequate response or relapsed/refractory disease. B‐cell maturation antigen (BCMA) is a tumour necrosis factor (TNF receptor superfamily receptor overexpressed on plasma cells in multiple myeloma (MM) and AL amyloidosis. Recently, several novel anti‐BCMA immunotherapies have been approved for the treatment of relapsed/refractory MM, including antibody–drug conjugate belantamab mafodotin, bispecific antibodies teclistamab and elranatamab and chimeric antigen receptor T‐cell therapies idecabtagene vicleucel and ciltacabtagene autoleucel. Despite lower expression than in MM, BCMA is also a promising target in AL amyloidosis. This review aims to provide up‐to‐date information on the efficacy and toxicity of anti‐BCMA therapy in AL amyloidosis. [ABSTRACT FROM AUTHOR]

Amyloidosis is a group of complex diseases caused by the misfolding and aggregation of proteins into amyloid fibrils. Light-chain (AL) amyloidosis is one of the most prevalent forms of amyloidosis, characterized by the gradual proliferation of light chains from plasma cell clones. A growing body of evidence has contributed to our understanding of its pathogenesis, presentation and clinical course. Increased recognition of its clinical sequelae has increased the prevalence of AL amyloidosis. Renal involvement, seen in up to 70% of cases, is particularly challenging due to its impact on quality of life and access to treatment options. Thus, early recognition of its unique sequelae, appropriate staging and a comprehensive understanding of treatment options balanced by their organ toxicities are crucial to managing this disease. We review the current treatment standards and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of AL amyloidosis for the Nephrologist. [ABSTRACT FROM AUTHOR]

Background. Research related to the state of blood vessels in systemic AL amyloidosis (AL-A) is mostly done on experimental models. The pathogenetic and clinical significance of vascular dysfunction in patients with AL-A is poorly understood. Aim. To study the levels of endothelial dysfunction markers in patients with AL-A at the onset of the disease and after anti-tumor therapy. Materials and methods. The study group included 30 patients with AL-A. The comparison group consisted of 10 patients with multiple myeloma (MM), and the control group included 10 healthy individuals. Patients with AL-A were divided into 2 groups: the first group included 20 patients who underwent the full planned induction therapy, and the second group included 10 patients whose treatment was stopped due to a significant increase in N-terminal pro-brain natriuretic peptide (NTproBNP) levels. The levels of asymmetric dimethylarginine (ADMA), big endothelin (bET), and E-selectin were measured by enzyme-linked immunosorbent assay in serum before and after completion (or premature cessation) of anti-tumor therapy. Results. Patients with AL-A had significantly higher levels of E-selectin and ADMA in serum compared to patients with MM and healthy individuals. An increase in at least one marker of endothelial dysfunction (E-selectin and ADMA) was observed in 27 (90%) patients with AL-A at disease onset. There were no differences in bET levels. In all patients in the first group, reaching hematologic remission was associated with a decrease in E-selectin and ADMA levels compared to baseline values (p0.001). In 5 (55%) out of 9 patients with hematologic and organ response, ADMA levels decreased to normal values. In all patients of the second group, the increase in NTproBNP was accompanied by a significant increase in ADMA (p=0.005) and E-selectin (p=0.007) levels compared to baseline values. Adverse cardiovascular events were observed in 80% of patients with elevated NTproBNP levels. The increase in cardiac markers during anti-tumor therapy was more common in advanced stages of heart involvement. Stage IIIA AL-A was present in 23% of patients in the first group and 70% in the second group (p=0.003). After discontinuation of therapy, the levels of cardiac markers decreased to baseline values, which ruled out disease progression. Conclusion. A pronounced endothelial dysfunction was observed in 90% of patients with AL-A. Reduction in endothelial dysfunction markers was observed upon achieving hematologic and organ response. Anti-tumor therapy in patients with amyloid cardiomyopathy can cause additional endothelial damage, resulting in increased NTproBNP levels and cardiovascular complications.

Abstract Aims Systemic amyloidosis represents a heterogeneous group of diseases resulting from amyloid fibre deposition. The purpose of this study is to establish a differential diagnosis algorithm targeted towards the two most frequent subtypes of CA. Methods and results We prospectively included all consecutive patients with ATTR and AL evaluated between 2018 and 2022 in two centres in a score derivation cohort and a different validation sample. All patients had a complete clinical, biomarker, electrocardiographic, and imaging evaluation. Confirmation of the final diagnosis with amyloid typing was performed according to the current international recommendations. The study population included 81 patients divided into two groups: ATTR (group 1, n = 32: 28 variant and 4 wild type) and AL (group 2, n = 49). ATTR patients were younger (50.7 ± 13.9 vs. 60.2 ± 7.3 years, P = 0.0001), and significantly different in terms of NT‐proBNP [ATTR: 1472.5 ng/L (97–4218.5) vs. AL 8024 ng/L (3058–14 069) P = 0.001], hs‐cTn I [ATTR: 10 ng/L (4–20) vs. AL 78 ng/L (32–240), P = 0.0002], GFR [ATTR 95.4 mL/min (73.8–105.3) vs. AL: 68.4 mL/min (47.8–87.4) P = 0.003]. At similar left ventricular (LV) wall thickness and ejection fraction, the ATTR group had less frequently pericardial effusion (ATTR: 15% vs. AL: 33% P = 0.0027), better LV global longitudinal strain (ATTR: −13.1% ± 3.5 vs. AL: −9.1% ± 4.3 P = 0.04), RV strain (ATTR: −21.9% ± 6.2 vs. AL: −16.8% ± 6 P = 0.03) and better reservoir function of the LA strain (ATTR: 22% ± 12 vs. AL: 13.6% ± 7.8 P = 0.02). Cut‐off points were calculated based on the Youden method. We attributed to 2 points for parameters having an AUC > 0.75 (NT‐proBNP AUC 0.799; hs‐cTnI AUC 0.87) and 1 point for GFR (AUC 0.749) and TTE parameters (GLS AUC 0.666; RV FWS AUC 0.649, LASr AUC 0.643). A score of equal or more than 4 points has been able to differentiate between AL and ATTR (sensitivity 80%, specificity 62%, AUC = 0.798). The differential diagnosis score system was applied to the validation cohort of 52 CA patients showing a sensitivity of 81% with specificity of 77%. Conclusions CA is a complex entity and requires extensive testing for a positive diagnosis. This study highlights a series of non‐invasive checkpoints, which can be useful in guiding the decision‐making process towards a more accurate and rapid differential diagnosis.

Summary: Patients with AL amyloidosis can have persistent organ dysfunction despite achieving a haematological complete response (hemCR). We aimed to identify factors for organ non‐response among 143 patients who achieved hemCR for ≥6 months. Kidney, heart and liver non‐response were observed in 40/117 (34%), 19/68 (28%) and 3/17 (18%) patients respectively. Predisposing factors varied by organ system. Kidney non‐responders had more advanced organ dysfunction at diagnosis, whereas heart non‐responders had disproportionately more lambda‐typic amyloidogenic light chains. Most patients without an apparent reason for organ non‐response had detectable residual clonal disease. The interplay of factors impeding organ recovery in AL amyloidosis is complex. [ABSTRACT FROM AUTHOR]

Clinical trials evaluating chimeric antigen receptor (CAR) T‐cell therapy in relapsed/refractory multiple myeloma (RRMM) have typically excluded patients with AL amyloidosis. As a result, there are limited data on the safety and efficacy of CAR T‐cell therapy in this patient population. We retrospectively reviewed eight consecutive patients with RRMM and AL amyloidosis who were treated with standard of care CAR T‐cell therapy. Cytokine release syndrome was seen in 75% of patients (grade ≥3: 0%) and immune effector cell‐associated neurotoxicity syndrome (grade 1) in only one patient. Low‐grade cytopenias were common (any grade/grade ≥3: neutropenia 62.5%/37.5%, anemia 37.5%/0%, thrombocytopenia 25%/0%). CAR T‐cell therapy led to rapid and deep responses with a median time to best response of 43 days and a hematologic very good partial response or better rate of 62.5%. Overall, we found that commercial CAR T‐cell therapy was feasible, and effective in patients with RRMM and concurrent AL amyloidosis. [ABSTRACT FROM AUTHOR]

Introduction: Although sudden death (SD) is a recognized complication of cardiac amyloidosis, there is scarce data about its incidence, mechanisms, and predictors. The aim of this study was to describe incidence of SD and to analyze possible risk factors. Methods: Consecutive patients with ATTR or AL cardiac amyloidosis evaluated at two European centers were identified. SD was defined as unexpected death in clinically stable patients. Cox proportional hazard regression was performed to assess risk factors in univariate analysis. Those statistically significant were then assessed through age-adjusted multivariate analysis. Results: Analysis included 784 patients, 569 with ATTR amyloidosis (mean age 74.1 ± 12.1 years) and 215 with AL amyloidosis (mean age 64.5 ± 10.8 years). After a median follow-up of 1.9 years, SD rate at 2 years was 1.8% in ATTR. Previous pacemaker implantation (PPM) was associated with increased risk after age-adjusted analysis (HR 4.97; 95%CI: 1.39–17.7; p = 0.01). SD rate in AL amyloidosis patients at 2 years was 8.0% after a median follow-up of 1.2 years. Betablockers and NYHA III-IV were independently associated with an increased risk after age-adjusted multivariate analysis (HR 7.06 95%CI (2.31–21.5) p = 0.001) and (HR 4.56 95%CI (1.51–13.8) p = 0.007) respectively. Conclusions: SD is more frequent in AL than in ATTR cardiac amyloidosis. SD is associated with different risk factors in both entities. [ABSTRACT FROM AUTHOR]

Background: This study aimed to assess the prognostic value of cardiac magnetic resonance (CMR) variables and compare them with biological and echocardiographic markers in patients with AL cardiac amyloidosis (CA). Methods: We conducted a prospective study across three tertiary centres, where patients underwent clinical examination, blood tests, echocardiography, and CMR. The primary endpoint was all-cause mortality. Results: A total of 176 patients with AL CA were included, with a median age of 68 years (IQR 58-75). According to the 2004 Mayo Clinic staging, 121 patients (69%) were in stage 3. During a median follow-up of 22 months (IQR 8–48), 45 patients died, and 55 were hospitalized for heart failure. Patients who died had higher NT-proBNP and troponin levels, and lower LVEF, cardiac output, and longitudinal strain. Among CMR variables, extracellular volume (ECV) was most strongly associated with all-cause mortality. In multivariate Cox models, including Mayo Clinic staging, ECV ≥ 0.45 was independently associated with mortality (HR 2.36, CI 95% 1.47–5.60) and also with heart failure hospitalizations (HR 4.10, 95%CI 2.15–8.8). Conclusion: ECV is a powerful predictor of outcomes in AL CA, providing additional prognostic value on top of Mayo Clinic staging. [ABSTRACT FROM AUTHOR]

ABSTRACT AL amyloidosis is a rare, complex and often challenging disease for both patients and healthcare providers. The availability of accurate medical information is crucial for effective diagnosis and management. In recent years, artificial intelligence (AI) has emerged as a potential tool for providing medical information. This study aims to assess the accuracy of AI ChatGPT responses for AL amyloidosis related common questions and compare them to expert opinions. A scoring system was developed to evaluate responses provided by five participating expert physicians. AI ChatGPT demonstrated an overall accuracy rate of 82% in answering AL amyloidosis‐related questions. Responses on prognosis and patient support received the highest scores (100%), while questions related to treatment options showed lower accuracy (30%–60%). The results indicate that while the AI ChatGPT demonstrates overall accuracy, there are areas for improvement and potential discrepancies compared to expert opinions. These findings highlight the importance of ongoing refinement and validation of AI‐powered medical tools and cannot yet replace the advice of experts in the disease. [ABSTRACT FROM AUTHOR]

Introduction: Amyloid-specific antibodies have been shown to opsonize and enhance amyloid clearance in systemic amyloidosis mouse models. However, the immunological mechanisms by which amyloid is removed have not been clearly defined. Previous reports from preclinical in vivo studies suggest polymorphonuclear cells (i.e. , neutrophils) can affect amyloid removal. Therefore, we sought to analyze how neutrophils may contribute to the clearance of human AL amyloid extracts, using a murine amyloidoma model. Methods: Immunocompromised nude mice injected subcutaneously with patient-derived AL amyloid extract (generating a localized "amyloidoma") were used to circumvent confounding factors contributed by the adaptive immune system and served as the model system. Two representative AL amyloid extracts were used, ALλ(CLA), which is refractory to clearance, and ALκ(TAL), which is readily cleared in mice. Neutrophil recruitment to the amyloid masses, cellular activation, and propensity to engulf amyloid were assessed. Results: Immunophenotyping of amyloidomas from animals implanted with 2 mg of either ALλ or ALκ revealed that more neutrophils were recruited to ALκ amyloid masses as compared to the ALλ material, which was generally devoid of neutrophils. Ex vivo analyses indicated neutrophils do not efficiently phagocytose amyloid directly. However, histological evaluation of the ALκ amyloidoma revealed the abundant presence of neutrophil extracellular traps, which were absent in the ALλ amyloidomas. Using neutrophil depletion experiments in mice, we determined that mice devoid of neutrophils cleared the human amyloid lesions less efficiently. Moreover, mice devoid of neutrophils also had significantly reduced intra-amyloid expression of inflammatory cytokines. Discussion: Neutrophils may not directly mediate amyloid clearance through phagocytosis; however, these cells can be stimulated by the amyloid and may function to facilitate phagocytosis and amyloid clearance by professional phagocytes (e.g. , macrophages). [ABSTRACT FROM AUTHOR]

ABSTRACT Introduction Methods Results Conclusions Teclistamab has demonstrated deep responses in patients with multiple myeloma in the MajesTEC‐1 study. However, the safety and efficacy of teclistamab in patients with AL amyloidosis are unknown.We retrospectively analyzed patients with biopsy‐proven relapsed/refractory AL amyloidosis who were treated with teclistamab from December 2022 to February 2024 at the University of Pennsylvania. The data cutoff was 2/29/24. Adverse events (AE) were extracted from the electronic medical record. Patients were assessed for hematologic and organ response per consensus guidelines.Eight patients were included in this case series: median age 63 (range 59–67), 75% female, 88% White. All eight patients achieved at least very good partial response (VGPR) and had normalization of free light chains (FLC), and six (75%) patients achieved undetectable FLC levels. Of the six patients with immunofixation completed, all six (100%) achieved hematologic complete response (hCR). The median time to hematologic VGPR and hCR was 13 days (range 12–18 days) and 88 days (range 32–150 days), respectively. The median duration of follow‐up was 8.5 months (range 1–14 months). Of the five patients with cardiac involvement, four (80%) achieved a cardiac response. Of the seven patients with renal involvement, two patients already achieved renal response prior to teclistamab, and of the remaining five, three (60%) achieved renal response. Six patients (75%) developed low‐grade cytokine release syndrome (CRS). No patients developed ICANS. Neutropenia and AKI both occurred in 25% of patients, respectively.In this series of patients, teclistamab showed outstanding depth of response and was well‐tolerated. Teclistamab shows promise in treating patients with relapsed AL amyloidosis. [ABSTRACT FROM AUTHOR]

Introduction: Treatment for relapsed/refractory AL amyloidosis (AL) is an unmet need. The safety and efficacy of belantamab mafodotin (BLM) in multiple myeloma are known, whereas in AL data are limited. Methods: We report a multi-center cohort of AL patients receiving BLM, and review all previous data on BLM therapy in AL. Results: Twelve patients with a median of 3 (range 2–9) prior lines of therapy were included. The overall hematological response rate (ORR) was 75% (9/12), including 5 complete responses. Six of the 10 evaluable patients had organ responses. The median event-free survivals/overall survivals were 22.3 and 28.8 months, respectively. Grade 3 toxicities were mostly infections and keratopathy, occurring in 7/12 (58%). Hematological toxicities were rare. No grade 4/5 toxicities occurred. The review of the previous series reveals BLM provides an ORR of 60–83% with similar rates of corneal toxicity. Conclusion: BLM, being an off-the-shelf therapy, with acceptable toxicity even in frail patients, may be a valuable option in AL, with a high ORR, and a signal for durable responses and high-quality organ responses. [ABSTRACT FROM AUTHOR]

Further line treatment of patients with advanced stage AL amyloidosis with cardiac involvement is challenging. Venetoclax is a promising option, especially in t(11;14) and BCL2 expression. In our multicentre observational study, we report the 3-year follow-up of Venetoclax treatment in 9 patients with advanced, relapsed or refractory AL amyloidosis with t(11;14) and BCL-2 expression in > 50% of plasma cells. At baseline, all patients had been previously treated with daratumumab, all had cardiac involvement with revised Mayo stage III or IV/ European modification of Mayo 2004 IIIA or IIIB (1/9 unclassified due to missing troponin T), 5/9 patients had renal involvement. After a median of 35 months (range 25–49) since the start of Venetoclax, 8/9 patients were still alive (OS 89%). First and best hematological responses were observed after a median of 26 days (11–125) and 106 days (35–659), overall response rate was 100% (7/9 CR, 2/9 VGPR). Where observed, organ response was documented within the first 6 months of therapy, including cardiac (6/9) and renal (3/5) improvements. Venetoclax was discontinued in 6/9 patients after a median of 15 months (11–48) due to toxicity (2/9), disease progression (2/9), fixed treatment duration (1/9), or safety concerns (1/9). In conclusion, Venetoclax induces a rapid and deep hematologic response with consistent improvement in organ function with an acceptable safety profile in patients with pretreated, advanced stage AL amyloidosis with cardiac involvement and BCL2 expression with and potentially without detected t(11:14), which warrants further investigation. [ABSTRACT FROM AUTHOR]

Objective: The objective of the study is to describe the characteristics of our first cohort of amyloidosis in a Latin America cardiovascular reference center in Colombia. Methods: This is a historic cohort study and data were taken from the electronic records of the Fundación Cardioinfantil-Instituto de cardiología; adult patients with a diagnosis of cardiac amyloidosis were included and a descriptive analysis was presented. Results: A total of 31 patients with amyloidosis were included. 17 were Transthyretin Amyloidosis (ATTR) subtype and 14 were AL subtype. An overall mortality of 25% was found. The mean age at diagnosis was 74 years, male sex predominant. More frequent comorbidities were hypertension and atrial fibrillation. The most frequent clinical presentation was congestive heart failure (75%), with mildly reduced ejection fraction (41.94%), followed by reduced ejection fraction (32.26%), and preserved ejection fraction (25.81%). In the ATTR subtype, a reduced ejection fraction was found at 41.18% and a mildly reduced ejection fraction at 35.29%. Conclusion: These results provide information on the most frequent type of amyloidosis and the late timing to diagnose in our historic cohort study, we present some of the baseline characteristics and most frequent approaches to diagnose Cardiac Amyloidosis that represents all challenges in clinical practice. Improvements are needed in the diagnosis and early treatment of these patients. [ABSTRACT FROM AUTHOR]

Aims: Systemic amyloidosis represents a heterogeneous group of diseases resulting from amyloid fibre deposition. The purpose of this study is to establish a differential diagnosis algorithm targeted towards the two most frequent subtypes of CA. Methods and results: We prospectively included all consecutive patients with ATTR and AL evaluated between 2018 and 2022 in two centres in a score derivation cohort and a different validation sample. All patients had a complete clinical, biomarker, electrocardiographic, and imaging evaluation. Confirmation of the final diagnosis with amyloid typing was performed according to the current international recommendations. The study population included 81 patients divided into two groups: ATTR (group 1, n = 32: 28 variant and 4 wild type) and AL (group 2, n = 49). ATTR patients were younger (50.7 ± 13.9 vs. 60.2 ± 7.3 years, P = 0.0001), and significantly different in terms of NT‐proBNP [ATTR: 1472.5 ng/L (97–4218.5) vs. AL 8024 ng/L (3058–14 069) P = 0.001], hs‐cTn I [ATTR: 10 ng/L (4–20) vs. AL 78 ng/L (32–240), P = 0.0002], GFR [ATTR 95.4 mL/min (73.8–105.3) vs. AL: 68.4 mL/min (47.8–87.4) P = 0.003]. At similar left ventricular (LV) wall thickness and ejection fraction, the ATTR group had less frequently pericardial effusion (ATTR: 15% vs. AL: 33% P = 0.0027), better LV global longitudinal strain (ATTR: −13.1% ± 3.5 vs. AL: −9.1% ± 4.3 P = 0.04), RV strain (ATTR: −21.9% ± 6.2 vs. AL: −16.8% ± 6 P = 0.03) and better reservoir function of the LA strain (ATTR: 22% ± 12 vs. AL: 13.6% ± 7.8 P = 0.02). Cut‐off points were calculated based on the Youden method. We attributed to 2 points for parameters having an AUC > 0.75 (NT‐proBNP AUC 0.799; hs‐cTnI AUC 0.87) and 1 point for GFR (AUC 0.749) and TTE parameters (GLS AUC 0.666; RV FWS AUC 0.649, LASr AUC 0.643). A score of equal or more than 4 points has been able to differentiate between AL and ATTR (sensitivity 80%, specificity 62%, AUC = 0.798). The differential diagnosis score system was applied to the validation cohort of 52 CA patients showing a sensitivity of 81% with specificity of 77%. Conclusions: CA is a complex entity and requires extensive testing for a positive diagnosis. This study highlights a series of non‐invasive checkpoints, which can be useful in guiding the decision‐making process towards a more accurate and rapid differential diagnosis. [ABSTRACT FROM AUTHOR]

BackgroundIn Colombia, the characteristics of cardiac amyloidosis (CA)—including wild-type transthyretin amyloidosis (ATTRwt), immunoglobulin light chain amyloidosis (AL), and genetic variant transthyretin amyloidosis (ATTRv)—are underexplored.MethodsThis case series at a Colombian university hospital analyzed demographic, clinical, laboratory, radiological, and genetic data of CA patients diagnosed between 2018 and 2022. Patients with incomplete data underwent further testing.ResultsOf 24 identified patients, 14 were included after exclusions. The majority were male (73.3%), with an average age of 70.6 years. ATTRv and AL were equally prevalent (42.8%), followed by ATTRwt (14.2%). The p.Val142Ile TTR mutation was found among all ATTRv patients. Most presented with functional capacity NYHA I-II and common electrocardiographic findings included low voltage, atrial fibrillation, and first-degree AV block. Echocardiography and cardiac magnetic resonance imaging revealed ventricular hypertrophy, diastolic dysfunction, reduced longitudinal strain, and late myocardial enhancement.ConclusionsAL and ATTRv were the most common causes of CA followed by ATTRwt. This distribution, along with the clinical, and radiological characterization is consistent with previous reports of other regions. The p.Val142Ile mutation was the only one found in patients with ATTRv, suggesting a strong African genetic influence. These findings enhance our understanding of CA in the region.

[Display omitted] [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Amyloid Light Chain (AL) Amyloidosis is a rare disorder of protein misfolding and metabolism characterized by insoluble fibrils deposition in various tissues and organs, which could quickly progress and become fatal. The most frequently affected organ is heart being its involvement the most adverse prognostic feature. Kidney and liver could be other organ localizations, defining AL Amyloidosis as a multisystem disorder. Being Budd-Chiari syndrome (BCS) an uncommon congestive hepatopathy caused by blockage of hepatic veins in the absence of cardiac disorders, it could be rarely caused by a massive deposition of amyloid proteins into hepatic sinusoidal spaces, giving an uncommon clinical presentation of AL Amyloidosis. [ABSTRACT FROM AUTHOR]

AL amyloidosis is a rare and serious disease that chronically affects vital organs. The lives of people with this disease are severely affected. We asked ourselves how this disease affects the daily lives of patients and their carers. To do this, we conducted qualitative human and social science research with 33 patients and their carers to investigate their perceptions of AL amyloidosis, their quality of life, their medical care, their treatments, their future and their passions. The results show that AL amyloidosis imposes a genuine biographical transition on both sufferers and their families, with many patients identifying new needs, new resources and new ways of managing their day-to-day lives. [ABSTRACT FROM AUTHOR]

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). Summary: Relapsed/refractory AL amyloidosis represent an unmet clinical need and novel targeted drugs require urgent prospective assessment. [ABSTRACT FROM AUTHOR]

Amyloid light chain (AL) amyloidosis is a progressive plasma cell disorder caused by amyloid deposition resulting in organ damage and failure. Current standard-of-care treatments target clonal plasma cells, the source of misfolded light chains (amyloid precursors), yet only half of patients with advanced disease survive ≥6 months. The amyloid depleter birtamimab is an investigational humanized monoclonal antibody that binds misfolded κ and λ light chains with high specificity and was designed to neutralize soluble toxic light chain aggregates and promote phagocytic clearance of deposited amyloid. Post hoc analyses from the Phase 3 VITAL trial suggested birtamimab plus standard of care confers a survival benefit in patients with advanced (Mayo Stage IV) AL amyloidosis. AFFIRM-AL (NCT04973137), a Phase 3 confirmatory trial of birtamimab plus standard of care in patients with Mayo Stage IV AL amyloidosis, is ongoing. This review summarizes birtamimab's mechanism of action, attributes, and potential clinical utility. [ABSTRACT FROM AUTHOR]

Serum immunofixation electrophoresis (IFE) is often performed for screening monoclonal proteins (M proteins) in immunoglobulin light-chain amyloidosis (AL amyloidosis). However, the performance of serum IFE for detecting M protein in AL amyloidosis patients is often insufficient. In this study, we examined the detection rate of serum M protein in newly diagnosed AL amyloidosis patients and analyzed differences in M protein detection between IFE methods. Among 60 patients newly diagnosed with AL amyloidosis, 22 had undetectable serum M protein by IFE with the Epalyzer2 system. Samples with undetectable M protein had significantly lower involved serum-free light-chain (iFLC) and a smaller difference between involved and uninvolved serum-free light-chain (dFLC) values than samples with IFE-detectable monoclonal light chains. When samples that tested negative for M protein by the Epalyzer2 system were retested by IFE with the HYDRASYS 2 system, 50% had IFE-detectable monoclonal light chains. The IFE system and reagents used may affect serum monoclonal immunoglobulin light-chain detection in AL amyloidosis patients, especially those with low iFLC or low dFLC samples. More attention should be paid to the performance of IFE systems, since it may affect the diagnostic and therapeutic evaluation of AL amyloidosis patients. [ABSTRACT FROM AUTHOR]

Background: The morbidity and mortality from AL amyloidosis has significantly improved with the development of novel treatments. Daratumumab is a highly effective treatment for AL amyloidosis, but end-stage kidney disease is a common complication of this condition. Kidney transplantation is the ideal form of renal replacement therapy but has historically been contraindicated in this group of patients. Methods: Given the improved survival and better treatments of both conditions, we argue that it is time to reconsider transplanting these patients. Results: We report our experience of transplanting four patients with AL amyloidosis who had achieved stable remission through treatment with daratumumab. Conclusions: We highlight the key challenges involved and discuss important clinical issues for patients receiving daratumumab, particularly the difficulties with interpreting the crossmatch in light of daratumumab and immunoglobulin therapy interference. We also discuss the complexities involved in balancing the risks of infection, relapse, rejection, and immunosuppression in such patients. [ABSTRACT FROM AUTHOR]

Light chain (AL) amyloidosis is a plasma cell disorder distinguished from multiple myeloma (MM) by the degree of organ involvement due to tissue deposition of misfolded proteins. Treatments for AL amyloidosis have largely been borrowed from those developed for patients with MM. High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has historically been associated with the best outcomes. The recent incorporation of daratumumab into up front therapy represents a significant advance and has changed the treatment paradigm, calling into question the role of ASCT. The development of very active novel immune and cellular therapies, specifically B cell maturation antigen (BCMA)-directed therapies, has similarly been transformative for patients with MM and is now being studied in patients with AL amyloidosis. These include chimeric antigen receptor (CAR) T cells, bispecific antibodies, and antibody drug conjugates. Although limited, preliminary data in patients with relapsed and refractory AL amyloidosis are showing promising results, and it is expected that the treatment landscape for AL amyloidosis will continue to evolve. Particular attention to safety, potential for organ recovery, and quality of life will be important when evaluating new treatments and/or treatment paradigms. [ABSTRACT FROM AUTHOR]

Background: Isoelectric focusing (IEF) is a method with an exquisite resolution, and coupled with affinity immunoblotting (AIB), it can provide superior sensitivity to detect monoclonal free light chains (FLC). Methods: We tested the hypothesis that IEF/AIB is more sensitive and specific for monoclonal FLC detection in serum and urine samples than conventional methods, that is, electrophoresis (ELP), immunofixation (IF) and serum FLC ratio assessment. Investigation included 107 samples of 68 patients, among which 21 multiple myeloma patients were recently tested for minimal residual disease and 18 patients with AL amyloidosis. Results: Monoclonal FLC were detected by IEF/AIB in 37% of serum samples negative for monoclonal FLC on ELP/IF. As for urine samples, significant advantage of the IEF/AIB over ELP/IF was not demonstrated. Considering both serum and urine results, IEF/AIB definitely revealed monoclonal FLC in 20/83 (24%) of ELP/IF-negative samples. FLC ratio was abnormally high (>1.65) in all 11 patients definitely positive for monoclonal FLC kappa by IEF/AIB but also in 16/47 (34%) IEF/AIB-negative samples. Abnormally low values (<0.26) were found only in 10/28 samples (36%) positive for monoclonal FLC lambda. Appropriate use of renal FLC ratio reference range reduced the number of presumably false positives (6/47, i.e. 13%) but not false negatives (17/28, i.e. 61%). Conclusions: The IEF/AIB method is more sensitive than IF and might be used in patients with negative IF results before deciding whether to proceed to minimal residual disease testing. [ABSTRACT FROM AUTHOR]

Immunoglobin light chain (AL) amyloidosis is a rare disease in which a plasma cell dyscrasia leads to deposition of insoluble amyloid fibrils in multiple organs. To facilitate development of new therapies for this heterogenous disease, a public–private partnership was formed between the nonprofit Amyloidosis Research Consortium and the US Food and Drug Administration Center for Drug Evaluation and Research. In 2020, the Amyloidosis Forum launched an initiative to identify clinical trial endpoints and analytic strategies across affected organ systems and life impacts via specialized working groups. This review summarizes the proceedings of the Statistical Group and proposes a pathway for development and validation of multi-domain endpoints (MDEs) for potential use in AL amyloidosis clinical trials. Specifically, drawing on candidate domain-specific endpoints recommended by each organ-specific working group, different approaches to constructing MDEs were considered. Future studies were identified to assess the validity, meaningfulness and performance of MDEs through use of natural history and clinical trial data. Ultimately, for drug development, the context of use in a regulatory evaluation, the specific patient population, and the investigational therapeutic mechanism should drive selection of appropriate endpoints. MDEs for AL amyloidosis, once developed and validated, will provide important options for advancing patient-focused drug development in this multi-system disease. [ABSTRACT FROM AUTHOR]

Daratumumab‐based regimens are the new standard of care for newly diagnosed patients with AL amyloidosis based on the results of the ANDROMEDA study. However, real‐world data on daratumumab efficacy in upfront therapy in unselected patients are scanty. In the framework of a prospective observational study, we investigated the efficacy and safety of daratumumab in 88 newly diagnosed patients, including subjects with IIIb cardiac stage (26%) or myeloma defining events (29%). Daratumumab was administered with bortezomib in 50 (56%) patients, lenalidomide in 31 (35%), and monotherapy in 7 (8%). The rate of serious adverse events was low (16%). The overall hematologic response rate was 75% with 52 (59%) patients attaining at least a very good partial response (VGPR) at six months. Amongst patients evaluable for organ response, the rate of cardiac and renal responses at 6 months was 31% and 21%, respectively. Comparing stage IIIb patients with the remaining ones, the rate of profound hematologic response was not significantly different (≥VGPR 57% vs. 59%, p 0.955) likewise the rate of cardiac (33% vs. 30%, p 0.340) and renal (40% vs. 16%, p 0.908) responses. Daratumumab‐based regimens demonstrated to be safe and effective in treatment‐naïve AL amyloidosis even in advanced stage disease. [ABSTRACT FROM AUTHOR]

BackgroundA 63-year-old Black woman presented with progressive exertional dyspnea and chronic lower back pain. The course and findings in her case are instructive.Case reportFamily history was notable for cardiac deaths. An echocardiogram demonstrated ventricular wall thickening with diastolic dysfunction. The patient’s N-terminal pro b-type natriuretic peptide level was 1,691 pg/ml with a troponin I level of 0.36 ng/ml. Transthyretin (TTR) sequencing detected a heterozygous V122I variant. The patient’s free κ light chain level in serum was 664 mg/L with a ratio of 16.5. Bone marrow analysis showed 20%–30% κ-restricted plasma cells with amyloid deposits. A technetium-99m sodium pyrophosphate scan was performed and was negative. Magnetic resonance imaging of the total spine showed ligamentum flavum (LF) thickening at L4–5, causing severe spinal stenosis. In both the abdominal fat and the LF, liquid chromatography-coupled tandem mass spectrometry confirmed κ-type immunoglobulin light chain (AL) amyloidosis; the quantitative estimate of amyloid content in the LF was 5%. She was diagnosed with AL amyloidosis with Mayo Stage IIIA cardiac and soft tissue involvement, enrolled in the Aquarius trial (NCT05250973) in Cohort 2, and received daratumumab, cyclophosphamide, bortezomib, and dexamethasone. She achieved a partial hematological response with a cardiac response and is now pain-free and fully functional.ConclusionIn patients with amyloidosis who have both monoclonal gammopathy and a TTR variant, it is imperative to discern the tissue type of the amyloid to deduce the correct diagnosis. ATTR and AL amyloidosis can both cause spinal stenosis with minimal degenerative changes. The LF tissue must be stained for amyloids and, if present, typing must be performed.

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

IntroductionAmyloid-specific antibodies have been shown to opsonize and enhance amyloid clearance in systemic amyloidosis mouse models. However, the immunological mechanisms by which amyloid is removed have not been clearly defined. Previous reports from preclinical in vivo studies suggest polymorphonuclear cells (i.e., neutrophils) can affect amyloid removal. Therefore, we sought to analyze how neutrophils may contribute to the clearance of human AL amyloid extracts, using a murine amyloidoma model.MethodsImmunocompromised nude mice injected subcutaneously with patient-derived AL amyloid extract (generating a localized “amyloidoma”) were used to circumvent confounding factors contributed by the adaptive immune system and served as the model system. Two representative AL amyloid extracts were used, ALλ(CLA), which is refractory to clearance, and ALκ(TAL), which is readily cleared in mice. Neutrophil recruitment to the amyloid masses, cellular activation, and propensity to engulf amyloid were assessed.ResultsImmunophenotyping of amyloidomas from animals implanted with 2 mg of either ALλ or ALκ revealed that more neutrophils were recruited to ALκ amyloid masses as compared to the ALλ material, which was generally devoid of neutrophils. Ex vivo analyses indicated neutrophils do not efficiently phagocytose amyloid directly. However, histological evaluation of the ALκ amyloidoma revealed the abundant presence of neutrophil extracellular traps, which were absent in the ALλ amyloidomas. Using neutrophil depletion experiments in mice, we determined that mice devoid of neutrophils cleared the human amyloid lesions less efficiently. Moreover, mice devoid of neutrophils also had significantly reduced intra-amyloid expression of inflammatory cytokines.DiscussionNeutrophils may not directly mediate amyloid clearance through phagocytosis; however, these cells can be stimulated by the amyloid and may function to facilitate phagocytosis and amyloid clearance by professional phagocytes (e.g., macrophages).

Abstract Aims Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. Methods and results This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision‐making regarding therapy. Over the 12‐year study period, among the 233 patients included, 133 were NYHA III‐IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT‐proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut‐off values for Stage 1: hsTnT ≤ 107 ng/L and NT‐proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT‐proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT‐proBNP then CB 4 μmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 μmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2–24]. At 1 year, 102 (44%) patients died and the Kaplan–Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11–18]) and stage 3, 6.6 months (95% CI [1–13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2. Conclusions The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis.

Introduction: AL amyloidosis can involve the gastrointestinal (GI) tract in a sporadic manner, affecting certain anatomical areas while sparing others. Case Presentation: Our patient with AL amyloidosis and confirmed colonic involvement was found to have new odynophagia, GI bleeding, and imaging findings that might suggest AL amyloidosis. However, negative pathology results from esophageal biopsies suggested the patient’s new ulcerations were more likely a side effect of her autologous stem cell transplant (SCT) and chemotherapy meant to target amyloidosis, as opposed to an effect of amyloid infiltration itself. Conclusion: GI involvement of amyloidosis requires a high degree of clinical suspicion and should be considered in patients with systemic diseases affecting the kidney, heart, and GI tract; however, when satisfactory biopsies obtained from endoscopy results are negative, other causes should be considered.

AL amyloidosis (AL) results from the misfolding of immunoglobulin light chains (IG LCs). Aim of this study was to comprehensively analyse kappa LC sequences from AL patients in comparison with multiple myeloma (MM). We analysed IGKV/IGKJ usage and associated organ tropism and IGKV1/D-33 in terms of mutational analysis and theoretical biochemical properties. cDNA and bulk RNA sequencing of the LCs of AL and MM patients. We studied 41 AL and 83 MM patients showing that IGKV1 was most expressed among kappa AL and MM, with higher frequency in AL (80% vs. 53%, p =.002). IGKV3 was underrepresented in AL (10% vs. 30%, p =.014). IGKJ2 was more commonly used in AL than in MM (39% vs. 29%). Patients with IGKV1/D-33 were associated with heart involvement (75%, p =.024). IGKV1/D-33-segments of AL had a higher mutation count (AL = 12.0 vs. MM = 10.0). FR3 and CDR3 were most frequently mutated in both, with a median mutation count in FR3 being the highest (AL = 4.0; MM = 3.5) and one mutation hotspot (FR3 (83I)) for IGKV1/D-33/IGKJ2 was associated with cardiac involvement. This study confirmed that germline usage has an influence on AL amyloidosis risk and organ involvement. [ABSTRACT FROM AUTHOR]

Aims: Predicting mortality in severe AL cardiac amyloidosis is challenging due to elevated biomarker levels and limited thresholds for stratifying severe cardiac damage. Methods and results: This prospective, observational, cohort study included de novo, confirmed cardiac AL amyloidosis patients at the Henri Mondor National Reference Centre. The goal was to identify predictors of mortality to enhance prognostic stratification and improve informed decision‐making regarding therapy. Over the 12‐year study period, among the 233 patients included, 133 were NYHA III‐IV and 179 Mayo 2004 III. The independent predictors for mortality identified were hsTnT, NT‐proBNP, cardiac output, and conjugated bilirubin. A novel prognostic, conditional stratification, Mondor amyloidosis cardiac staging (MACS) was developed with biomarker cut‐off values for Stage 1: hsTnT ≤ 107 ng/L and NT‐proBNP ≤ 3867 ng/L (n = 77; 33%); for stage 2 NT‐proBNP > 3867 ng/L (n = 72; 30%). For stage 3, if troponin >107 ng/L, regardless of NT‐proBNP then CB 4 μmol/L, was added (n = 41; 17.5%) and stage 4: CB > 4 μmol/L (n = 43; 18.5%). The median overall survival was 8 months 95% CI [2–24]. At 1 year, 102 (44%) patients died and the Kaplan–Meier median survival with MACS Stage 1 was not reached, while stage 2 was 15.2 months (95% CI [11–18]) and stage 3, 6.6 months (95% CI [1–13]). Notably, among European stage II patients, 17.1%, n = 8 were MACS stage 3 and European stage IIIb 21.4% (n = 23) were MACS stage 4. Importantly, among European stage IIIb patients 42.2% (n = 29) were classified MACS stage 4 and 12.5% n = 9 were only MACS stage 2. Conclusions: The Mondor prognostic staging system, including conjugate bilirubin may significantly improve prognostic stratification for patients with severe cardiac amyloidosis. [ABSTRACT FROM AUTHOR]

Summary: Haemostatic abnormalities and deregulated coagulation are common complications in AL amyloidosis. The relevant risks of thromboembolic and haemorrhagic events have not been thoroughly evaluated. To describe clinically significant thrombotic/haemorrhagic events in 450 consecutive patients with AL amyloidosis. Venous thromboembolic events (VTEs) were reported in 6% and arterial embolic events (AEEs) in 5% of patients, respectively, during a 55‐month median follow‐up. Lower albumin, lower eGFR, higher BM infiltration, soft tissue involvement, IMiD‐based therapy and prior thrombosis were associated with VTE risk. Prior thrombosis was the only independent prognostic variable (HR 9.3, p = 0.001). Coronary arterial disease, prior AEE, 24‐h proteinuria and higher platelet counts were associated with AEE risk. Significant bleeding events were reported in 9%, and associated mortality was 19%. Liver involvement, higher serum creatinine and higher baseline VWF:Ag levels were linked to bleeding risk. Using competing risk analysis, the cumulative probability of thrombosis/bleeding was higher during the first year following diagnosis, but a stable lower risk for both events remained for the duration of follow‐up. In AL amyloidosis patients, the risk of thrombotic/arterial embolic events is significant, but the bleeding risk is also high. A multiparametric assessment is required to initiate anti‐thrombotic or anti‐platelet therapy appropriately. [ABSTRACT FROM AUTHOR]

Amyloidosis is a disease characterized by the deposition of protein fibrils. Cardiac involvement is a significant factor in determining prognosis. This study aimed to examine the clinical profile, outcomes, and long-term mortality rates in patients with transthyretin (ATTR) and amyloid light-chain (AL) amyloidosis. The retrospective cohort study included 94 patients with amyloidosis (69 with AL and 25 with ATTR amyloidosis) diagnosed between 2010 and 2022. The study involved multimodality imaging (ECG, echocardiography and cardiac magnetic resonance (CMR) data and survival analyses. Patients with ATTR amyloidosis were older and had a higher proportion of males compared to those with AL amyloidosis. Cardiac involvement was more prevalent in the ATTR group, including atrial fibrillation (AF), while pleural and pericardial effusion were more frequent in the AL group. Biomarkers such as NT-proBNP and troponin T were significantly elevated in both groups and were associated with all-cause mortality only in univariate analyses. CMR data, especially typical late gadolinium enhancement (LGE) was not associated with increased mortality, while pleural effusion and left atrial dilatation on echocardiography were identified as powerful predictors of mortality. In conclusion, both AL and ATTR amyloidosis exhibited poor outcomes. Cardiac involvement, particularly dilated left atrium and pleural effusion on echocardiography were associated with an increased risk of mortality, while typical LGE on CMR was not. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite a lack of standardization and some open questions, a growing body of evidence supports the use of frailty to optimize the clinical management of patients with hematological malignancies. Several scores have been applied particularly to multiple myeloma, an entity that shares many characteristics with AL amyloidosis, both being frequently associated. To date, no study has focused on frailty in patients with AL amyloidosis. We aimed to define a practical evaluation of frailty and estimate its impact in survival in patients with systemic AL amyloidosis. Systemic AL amyloidosis is a challenging disease for which many patients are considered frail in daily clinical practice. However, no study has so far addressed frailty and its impact on the outcome of these patients. We built a simple score to predict mortality based on three frailty-associated variables: age, ECOG performance status (<2 vs. ≥2) and NT-proBNP (<8500 vs. ≥8500 ng/L). Four-hundred and sixteen consecutive newly diagnosed patients diagnosed at ten sites from the Spanish Myeloma Group were eligible for the study. The score was developed in a derivation cohort from a referral center, and it was externally validated in a multicenter cohort. Multivariate analysis showed that the three variables were independent predictors of survival. The score was able to discriminate four groups of patients in terms of overall survival and early mortality in both cohorts. Comorbidity was also analyzed with the Charlson comorbidity index, but it did not reach statistical significance in the model. A nomogram was created to easily estimate the mortality risk of each patient at each time point. This score is a simple, robust, and efficient approach to dynamically assess frailty-dependent mortality both at diagnosis and throughout follow-up. The optimal treatment for frail AL amyloidosis patients remains to be determined but we suggest that the estimation of frailty-associated risk could complement current staging systems, adding value in clinical decision-making in this complex scenario. [ABSTRACT FROM AUTHOR]

Light chain amyloidosis is a rare disease caused by clonal plasma cells in the bone marrow generating an excessive amount of immunoglobulin light chains. These chains misfold and produce insoluble fibrils that deposit in various organs, including the heart, kidneys, liver, nervous system, and digestive tract. Life expectancy and symptoms during the course of the disease vary depending on which and how many organs are affected. Targeted plasma cell therapy has significantly advanced the clinical management of amyloidosis, with ongoing progress. However, current clinical studies are investigating innovative targets, drug combinations and treatment strategies to improve therapeutic outcomes by minimizing adverse effects and refining patient prognosis in these challenging hematological conditions. In this paper, we review the state of the art regarding the use of anti‐amyloid antibodies, as a revolutionary and innovative approach in the current scenario of amyloid treatment. [ABSTRACT FROM AUTHOR]