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. Commentary on: Staron et al. Factors impeding organ recovery despite a deep haematological response in patients with systemic AL amyloidosis. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19766.

Factors impeding organ recovery despite a deep haematological response in patients with systemic AL amyloidosis.

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.

Cytogenetic abnormality in non-systemic light chain amyloidosis monoclonal gammopathy of renal significance: A field needs to be explored.

The role of cytogenetic abnormalities in non-systemic light chain amyloidosis monoclonal gammopathy of renal significance diseases still needs to be clarified. Bhutani et al. present the results of a study investigating the underlying plasma cell cytogenetic abnormalities in monoclonal immunoglobulin deposition disease (MIDD). The results show that translocation (11;14) is a common abnormality in MIDD and affects the presentation and outcomes. Commentary on: Bhutani et al. Translocation (11;14) is a common cytogenetic abnormality in clonal plasma cells in monoclonal immunoglobulin deposition disease. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19748.

Prognostic value of CMR-derived extracellular volume in AL amyloidosis: a multicenter study.

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.

Gene Expression Sets and Renal Profiling from the Renal AL Amyloid Involvement and NEOD00 (RAIN) Trial.

Introduction: There is an unmet need to understand the mechanisms by which amyloid deposition drives alterations in the kidney. We leveraged renal biopsies from amyloid light-chain (AL) amyloidosis participants of the Renal AL Amyloid Involvement and NEOD00 (RAIN) trial (NCT03168906) to perform transcriptional profiling and to employ a novel histologic scoring tool. Our objective was to utilize a transcriptome-driven approach to identify AL molecular signatures that may be prognostic. Methods: Clinical data were correlated to histologic and molecular findings. A composite scarring injury and amyloid score (AS) were assigned to each biopsy. Glomerular and tubulointerstitial (TI) compartments were microdissected and sequenced separately. Expression data were compared to healthy living donors and focal segmental glomerulosclerosis (FSGS) profiles. Differentially expressed genes were determined. Results: Cluster analysis revealed 2 distinct patient clusters (G1 and G2) based on gene expression. The AS was higher in the TI compartment (6.5 vs. 4.5; P = 0.0290) of G2. Glomeruli showed activation of fibrotic pathways and increased canonical signaling of LPS/IL-1. TNF activation was noted in TI. Enriched ingenuity canonical pathways included "coagulation system," "GADD45 signaling," and "Wnt/Ca+ pathway," among others. For AL versus living donors, ingenuity pathway analysis identified enrichment in PI3K/Akt signaling. Gene regulators of cellular proliferation were enriched in the amyloid group. Conclusion: Despite the small sample size, we identified 2 distinct groups of patients with AL based on molecular signatures. Detailed studies of a larger cohort encompassing omics technologies at a single cell resolution will further help to identify the response of individual kidney cell types to amyloid deposits, potentially leading to the development of novel therapeutic targets.

Functional Status and Quality of Life in Light-Chain Amyloidosis: Advanced Imaging, Longitudinal Changes, and Outcomes.

BACKGROUND: In light-chain (AL) amyloidosis, whether functional status and heart failure-related quality of life (HF-QOL) correlate with cardiomyopathy severity, improve with therapy, and are associated with major adverse cardiac events (MACE) beyond validated scores is not well-known. OBJECTIVES: The authors aimed to: 1) correlate functional status and HF-QOL with cardiomyopathy severity; 2) analyze their longitudinal changes; and 3) assess their independent associations with MACE. METHODS: This study included 106 participants with AL amyloidosis, with 81% having AL cardiomyopathy. Functional status was evaluated using the NYHA functional class, the Karnofsky scale, and the 6-minute walk distance (6MWD), and HF-QOL using the MLWHFQ (Minnesota Living with Heart Failure Questionnaire). Cardiomyopathy severity was assessed by cardiac 18F-florbetapir positron emission tomography/computed tomography, cardiac magnetic resonance, echocardiography, and serum cardiac biomarkers. MACE were defined as all-cause death, heart failure hospitalization, or cardiac transplantation. RESULTS: NYHA functional class, Karnofsky scale, 6MWD, and MLWHFQ were impaired substantially in participants with recently diagnosed AL cardiomyopathy (P < 0.001), and correlated with all markers of cardiomyopathy severity (P ≤ 0.010). NYHA functional class, 6MWD, and MLWHFQ improved at 12 months in participants with cardiomyopathy (P ≤ 0.013). All measures of functional status and HF-QOL were associated with MACE (P ≤ 0.017), independent of Mayo stage for 6MWD and MLWHFQ (P ≤ 0.006). CONCLUSIONS: Functional status and HF-QOL were associated with AL cardiomyopathy severity, improved on therapy within 12 months, and were associated with MACE, independently of Mayo stage for 6MWD and MLWHFQ. They may be validated further in addition to prognostic scores and as surrogate outcomes for future studies.

Current and Emerging Immunotherapies for Systemic AL Amyloidosis.

Systemic light-chain (AL) amyloidosis is a rare and complex clonal plasma cell neoplasm characterized by the production of misfolded and unstable immunoglobulin light-chains leading to multisystem amyloid deposition, which progresses to organ dysfunction and eventual failure. The importance and urgency of AL amyloidosis depends on its potential to induce significant organ impairment, progressive course, risk of life-threatening complications, and the limited treatment options available. Treatment options and prognosis depend on the number and severity of organ involvement at the time of diagnosis with cardiac involvement carrying the worst outcomes. The treatments aim to target eliminating the underlying clonal plasma cell neoplasm and prevent the production and deposition of amyloid precursor immunoglobulin light-chain protein in the affected vital organs. Strategies for treating systemic AL amyloidosis have incorporated anti-plasma cell therapies approved in the management of multiple myeloma due to their shared cellular derivation. Quadruplet therapy of cyclophosphamide, bortezomib, dexamethasone and daratumumab (DaraCyborD) is the currently approved first-line induction therapy for systemic AL amyloidosis. Some patients need upfront autologous hematopoietic stem cell transplantation (HSCT) after high-dose melphalan conditioning particularly if DaraCyborD is not able to achieve complete hematologic response (CHR). Additionally, a promising treatment option involves disassembling amyloid deposits from the vital organs using monoclonal antibodies such as CAEL 101 or Birtamimab with the expectation of restoring damaged tissues of the vital organs affected thereby improving or reversing patients' symptoms. Both CAEL 101 and Birtamimab are currently being tested in phase 3 clinical trials for systemic AL amyloidosis patients with advanced cardiac involvement. This comprehensive review provides an up-to-date overview of AL amyloidosis therapy, with a particular focus on recent advances and future directions of immunotherapeutic strategies.

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.

A bibliometric analysis of light chain amyloidosis from 2005 to 2024: research trends and hot spots.

Background: Light chain (AL) amyloidosis stands as the most prevalent subtype of systemic amyloidosis, encompassing a group of rare diseases. Here, we evaluated the scientific landscape of AL amyloidosis to investigate research trends and identify hotspots within the field. Methods: Relevant studies on AL amyloidosis published over the past two decades were retrieved from the Web of Science Core Collection. The publications between 2005 and 2024 were subjected to bibliometric analyses, leveraging tools including CiteSpace, VOSviewer, RStudio and MS Excel to analyse and visualize the annual publication trend, co-occurrence patterns, collaborative networks among countries, organizations, and authors. Burst keywords and references were also examined to obtain the research history, and emerging hotspots. Results: The bibliometric analysis included 2,864 articles published between 2005 and 2024. The most productive journal is Amyloid-Journal of Protein Folding Disorders. The United States, along with several developed nations, emerges as a dominant force in international AL amyloidosis research. "AL amyloidosis" and "cardiac amyloidosis" were the primary hotspots over the past two decades, and "Biomarkers," "Cardiac amyloidosis," and "treatment" would be future trends. Conclusion: This bibliometric analysis examined the research developments in AL amyloidosis over the past two decades using bibliometric software. Recent research in this field primarily focuses on two main areas: clinical diagnosis and treatment of AL amyloidosis, as well as cardiac amyloidosis. Emphasis is placed on understanding the mechanisms underlying immunoglobulin light chain aggregation and deposition to mitigate organ involvement.

Localized AL amyloidosis of the breast in a geriatric female.

Localized breast amyloidosis is often found incidentally on mammography or ultrasound, as amyloid deposits can be calcified and mimic malignancy. Although rare, breast amyloidosis should be considered a possible etiology of abnormal mammography findings in older women.

Role of Autologous Stem Cell Transplantation in Systemic Light Chain Amyloidosis.

Systemic light chain (AL) amyloidosis is a multisystem disorder characterized by extracellular deposition of misfolded insoluble amyloid fibrils resulting in progressive organ dysfunction. AL. amyloidosis most commonly affects the heart, kidneys, gastrointestinal tract and peripheral nerves. Early mortality is chiefly determined by the degree of cardiac involvement. The aim of therapy is to rapidly reduce amyloidogenic light chain production by targeting the underlying clonal plasma or lymphoma cell population. High dose therapy with melphalan followed by autologous peripheral blood stem cell transplant (ASCT) continues to remain a highly effective treatment and is considered a standard of care for transplant eligible patients, which offers long term disease control in patients with AL amyloidosis. In recent years, several new therapeutic options have emerged (including anti-CD38 monoclonal antibodies) which are very effective alone or in combination in eradicating clonal plasma cells. In this review, we discuss the role of ASCT in the current setting of a rapidly evolving treatment landscape for patients with AL amyloidosis and provide our practice recommendations.

Clinical characterization of patients with cardiac amyloidosis in a referral center of Colombia.

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.

Objetivo: Describir las características de nuestra primera cohorte de amiloidosis en un centro de referencia cardiovascular de Latinoamérica en Colombia. Métodos: Los datos fueron tomados de los registros electrónicos de la Fundación Cardioinfantil- Instituto de cardiología; Se incluyeron pacientes adultos con diagnóstico de amiloidosis cardíaca y se presenta un análisis descriptivo. Resultados: Se incluyeron un total de 31 pacientes con amiloidosis. 17 eran ATTR y 14 eran AL. Se encontró una mortalidad global del 25%. La edad media al diagnóstico fue de 74 años, predominando el sexo masculino. Las comorbilidades más frecuentes fueron Hipertensión y Fibrilación auricular. La presentación clínica más frecuente fue insuficiencia cardíaca congestiva (75%), con fracción de eyección levemente reducida (41.94%), seguida de fracción de eyección reducida (32.26%) y fracción de eyección preservada (25.81%). En el subtipo ATTR, la fracción de eyección reducida se encontró en el 41.18% y la fracción de eyección levemente reducida en el 35.29%. Conclusión: Estos resultados brindan información sobre el tipo de amiloidosis más frecuente y el momento del diagnóstico, el cual fue tardío en nuestra cohorte, su prevalencia en el sexo masculino (61.29%), edad promedio al diagnóstico de 74 años, principal presentación clínica y abordaje más frecuente, mostrando el desafío que representa en la práctica clínica llegar al diagnóstico. Se necesitan mejoras en el diagnóstico y tratamiento precoz de estos pacientes.

Diagnostic performance of liver stiffness as marker of liver involvement in systemic immunoglobulin light chain (AL) amyloidosis.

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.

Long-Term Rehabilitation Therapy Is Effective for Physical Function in a Patient With Amyloid Light Chain Amyloidosis Complicated by Nephrotic Syndrome: A Case Report and Literature Review.

We report on the rehabilitation of a patient with amyloid light chain (AL) amyloidosis complicated by nephrotic syndrome. Various symptoms produced by AL amyloidosis, including nephrotic syndrome, complicate rehabilitation therapy. In this case report, long-term physical therapy was initiated prior to autologous peripheral blood stem cell transplantation owing to the risk of further decline in physical function due to decreased mobility and physical activity. Patients were instructed on how to perform home exercise therapy. Furthermore, compliance was monitored using a checklist and regular face-to-face feedback. There was no increase in skeletal muscle mass, but improvements in grip strength, lower extremity muscle strength, and phase angle were observed after 24 weeks of physical therapy. Despite the absence of partial remission (urinary protein level of 3.5 g/gCre or higher), nephrotic syndrome demonstrated a trend toward improvement. Since the effectiveness of physical therapy in such patients has not yet been fully established, this report suggests that long-term rehabilitation therapy for physical function in patients with nephrotic syndrome complicated by persistent proteinuria may be effective.

Safety and efficacy of B cell maturation antigen-directed CAR T-cell therapy in patients with relapsed/refractory multiple myeloma and concurrent light chain amyloidosis.

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.

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.