Five-Year Results With Patisiran for Hereditary Transthyretin Amyloidosis With Polyneuropathy: A Randomized Clinical Trial With Open-Label Extension.

Importance: There is a lack of long-term efficacy and safety data on hereditary transthyretin amyloidosis with polyneuropathy (hATTR-PN) and on RNA interference (RNAi) therapeutics in general. This study presents the longest-term data to date on patisiran for hATTR-PN.

Objective: To present the long-term efficacy and safety of patisiran in adults with hATTR-PN.

Predictors of Early Death in Patients With Wild-Type Transthyretin Cardiac Amyloidosis.

Background: For the time being, tafamidis is the only approved treatment for wild-type transthyretin cardiac amyloidosis. However, benefits on all-cause death only emerge after ≈18 months. The current available staging systems are unable to specifically discriminate patients at high risk of death within 18 months from diagnosis, and the selection of patients who are expected to benefit from tafamidis is left to the clinical judgment of treating physicians, being often based primarily (and sometimes only) on age.

Feasibility of a Biomarker-Based Screening for Pre-Symptomatic AL Amyloidosis in Patients With Intermediate/High-Risk MGUS.

Biomarker-based screening enables early detection of AL amyloidosis in intermediate/high-risk MGUS patients. Our study shows that identifying pre-symptomatic AL through biomarker longitudinal monitoring allows early treatment, leading to significant organ function recovery.

SMaRT M-Seq: an optimized step-by-step protocol for M protein sequencing in monoclonal gammopathies.

In patients with monoclonal gammopathies, tumor B cells or plasma cells secrete a monoclonal antibody (M protein) that not only serves as a biomarker for tumor tracking but can also cause potentially life-threatening organ damage. This damage is driven by the patient-specific sequence of the M protein. Methods for sequencing M proteins have been limited by their high cost and time-consuming nature, and while recent approaches using next-generation sequencing or mass spectrometry offer advancements, they may require tumor cell sorting, are limited to subsets of immunoglobulin genes or patients, and/or lack extensive validation.

AA amyloidosis in vertebrates: epidemiology, pathology and molecular aspects.

AA amyloidosis is a prototypic example of systemic amyloidosis: it results from the prolonged overproduction of SAA protein produced in response to chronic inflammation. AA amyloidosis primarily affects the kidneys, liver, spleen, gastrointestinal tract, leading to a variety of symptoms. First, this review examines AA amyloidosis in humans, focusing on pathogenesis, clinical presentation, and diagnosis and then in animals.

Piecing together the intricate puzzle of organ recovery in AL amyloidosis.

In AL amyloidosis, the factors hindering organ recovery despite deep haematological responses to anti-clonal therapy remain elusive. The study by Staron and colleagues identifies tissue-specific factors influencing the lack of organ response, including host-related characteristics, the properties of the amyloidogenic precursor, the extent of organ compromise at diagnosis and the dynamics and depth of haematological response. While this study begins to unravel the complex mechanisms underlying organ recovery in AL amyloidosis, it also raises critical questions that warrant further investigation through future collaborative research.

Belantamab Mafodotin in Relapsed/Refractory AL Amyloidosis: Real-World Multi-Center Experience and Review of the Literature.

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.

The cellular prion protein does not affect tau seeding and spreading of sarkosyl-insoluble fractions from Alzheimer's disease.

The cellular prion protein (PrP) plays many roles in the developing and adult brain. In addition, PrP binds to several amyloids in oligomeric and prefibrillar forms and may act as a putative receptor of abnormal misfolded protein species. The role of PrP in tau seeding and spreading is not known.

International prevalence of transthyretin amyloid cardiomyopathy in high-risk patients with heart failure and preserved or mildly reduced ejection fraction.

Background: Transthyretin amyloid cardiomyopathy (ATTR-CM) is an underdiagnosed cause of heart failure (HF).

Methods: This epidemiology study assessed the international prevalence of ATTR-CM among patients aged ≥60 years with a history of HF, left ventricular ejection fraction (LVEF) >40%, an end-diastolic interventricular septum thickness (IVST) ≥12 mm, but without diagnosed amyloidosis, history of LVEF ≤40%, cardiomyopathy of known cause, severe valvular, or coronary heart disease. ATTR-CM was determined using cardiac scintigraphy alongside exclusionary testing for light chain amyloidosis.

The ASC inflammasome adapter governs SAA-derived protein aggregation in inflammatory amyloidosis.

Extracellularly released molecular inflammasome assemblies -ASC specks- cross-seed Aβ amyloid in Alzheimer's disease. Here we show that ASC governs the extent of inflammation-induced amyloid A (AA) amyloidosis, a systemic disease caused by the aggregation and peripheral deposition of the acute-phase reactant serum amyloid A (SAA) in chronic inflammatory conditions. Using super-resolution microscopy, we found that ASC colocalized tightly with SAA in human AA amyloidosis.

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.

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.

Response matters in light chain amyloidosis, whatever it takes.

Access to upfront daratumumab for AL amyloidosis is expanding, but it is not universal. Bomsztyk et al. show that patients who do not receive front-line daratumumab can be effectively rescued with this agent, indicating that deep haematological response should be pursued tenaciously.

Patients with a cardiac complete response in AL amyloidosis have survival rates similar to those of a matched general population.

The survival of patients achieving a cardiac complete response in light chain amyloidosis, defined as N-terminal pro B-type natriuretic peptide ≤350 pg/mL or B-type natriuretic peptide ≤80 pg/mL, was similar to that of a matched general population, with estimated 5-year survival rates of 93% and 95%, respectively.

International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T-cell-engaging bispecific antibodies in multiple myeloma.

Multiple myeloma remains an incurable disease, despite the development of numerous drug classes and combinations that have contributed to improved overall survival. Immunotherapies directed against cancer cell-surface antigens, such as chimeric antigen receptor (CAR) T-cell therapy and T-cell-redirecting bispecific antibodies, have recently received regulatory approvals and shown unprecedented efficacy. However, these immunotherapies have unique mechanisms of action and toxicities that are different to previous treatments for myeloma, so experiences from clinical trials and early access programmes are essential for providing specific recommendations for management of patients, especially as these agents become available across many parts of the world.