Immunoglobulin Light Chain Amyloidosis Research Articles

Characteristics and outcomes of COVID-19 in patients with plasma cell dyscrasias during the first Omicron wave in Beijing since December 2022: a retrospective study at a National Clinical Research Center for Hematologic Disease.

The wave of coronavirus disease 2019 (COVID-19) with Omicron variant reached its first peak in Beijing, China in December 2022. We delineated characteristics and factors associated with adverse outcome of patients with plasma cell dyscrasias (PCDs) and COVID-19 during the first month of the wave. A total of 104 patients with a median age of 65 years were included in the study, with multiple myeloma (74%, n=77) and primary Immunoglobulin light chain amyloidosis (16.3%, n=17) being the two most common disease. Overall, severe or critical COVID-19 was developed in 18 (17.3%) patients, with a total all-cause mortality rate of 4.8% (n=5). The vaccination coverage was 41% and 48.1%, before and during the upsurge of Omicron, respectively, calling for the improvement of vaccination in PCD patients. Multivariable analysis revealed that age was the only independent risk factors (OR=1.14, 95% CI: 1.06-1.26, p = 0.002) associated with the development of severe or critical disease. Among patients with severe or critical group, low levels of albumin (HR=18.29; 95% CI: 1.82-183.44, p = 0.013) and high levels of lactic dehydrogenase (LDH) (HR=0.08; 95% CI: 0.01-0.65, p = 0.018) were associated with longer time to negative conversion of COVID-19.

Prevalence and Treatment of Arrhythmias in Patients With Transthyretin and Light-Chain Cardiac Amyloidosis.

Background: Various types of arrhythmia are observed in patients with cardiac amyloidosis, but the prevalence of arrhythmia has not been fully investigated. This study investigated the prevalence and treatment of arrhythmias in patients with cardiac amyloidosis before the introduction of new agents for amyloidosis, such as tafamidis. Methods and Results: Of 53 patients who were histologically diagnosed with cardiac amyloidosis at 10 centers in western Japan between 2009 and 2021, 43 who were diagnosed on the basis of immunohistochemical staining were evaluated in this study. Of these 43 patients, 13 had immunoglobulin light-chain (AL) amyloidosis and 30 had transthyretin (ATTR) amyloidosis; further, 27 had atrial tachyarrhythmia, 13 had ventricular tachyarrhythmia, and 17 had bradyarrhythmia. Atrial fibrillation (AF) was the most common arrhythmia in patients with cardiac amyloidosis (n=24; 55.8%), especially among those with ATTR amyloidosis (70.0% of ATTR vs. 23.1% of AL). Eleven (25.6%) patients were treated with a cardiac implantable device. All 3 patients with pacemakers were alive at the last follow-up (median 76.7 months; interquartile range [IQR] 4.8-146.4 months). Of the 8 patients who underwent AF ablation, there was no recurrence in 6 (75%) after a median of 39.3 months (IQR 19.8-59.3 months). Conclusions: The prevalence of various arrhythmias was high in patients with cardiac amyloidosis. AF occurred most frequently in patients with cardiac amyloidosis, especially among patients with ATTR.

Rare Forms of Cardiac Amyloidosis: Diagnostic Clues and Phenotype in Apo AI and AIV Amyloidosis.

Apo AI amyloidosis (AApoAI) and Apo AIV amyloidosis (AApoAIV) are rare but increasingly recognized causes of cardiac amyloidosis (CA). We sought to define the cardiac phenotype in AApoAI and AApoAIV using multimodality imaging. We identified all patients with AApoAI and AApoAIV assessed at our center between 2000 and 2021, and 2 cohorts of patients with immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis matched for age, sex, and cardiac involvement. Forty-five patients had AApoAI, 13 (29%) of whom had cardiac involvement, 32 (71%) renal involvement, 28 (62%) splenic involvement, 27 (60%) hepatic involvement, and 7 (16%) laryngeal involvement. AApoAI-CA commonly presented with heart failure (n=8, 62%) or dysphonia (n=7, 54%). The Arg173Pro variant universally caused cardiac and laryngeal involvement (n=7, 100%). AApoAI-CA was associated with right-sided involvement, with a thicker right ventricular free wall (8.6±1.9 versus 6.3±1.3 mm versus 7.7±1.2 mm, P=0.004), greater incidence of tricuspid stenosis (4 [31%] versus 0 [0%] versus 0 [0%], P=0.012) and tricuspid regurgitation (6 [46%] versus 1 [8%] versus 2 [15%], P=0.048) than AL-CA and transthyretin CA. Twenty-one patients had AApoAIV, and cardiac involvement was more common than in AApoAI (15 [71%] versus 13 [29%], P=0.001). AApoAIV-CA most commonly presented with heart failure (n=12, 80%), and a lower median estimated glomerular filtration rate than AL-CA and transthyretin CA (36 mL/[min·1.73 m²] versus 65 mL/[min·1.73 m²] versus 63 mL/[min·1.73 m²], P<0.001). All AApoAIV-CA patients had classical CA features on echocardiography/cardiac magnetic resonance, including an apical-sparing strain pattern, which was less common in AApoAI-CA (15 [100%] versus 7 [54%], P=0.003), whereas cardiac uptake on bone scintigraphy was less common in AApoAIV-CA than AApoAI-CA (all grade 1) (14% versus 82%, P<0.001). Patients with AApoAI and AApoAIV had a good prognosis (median survival >172 and >30 months, respectively), and a lower risk of mortality than matched patients with AL-amyloidosis (AL versus AApoAI: hazard ratio, 4.54 [95% CI, 2.02-10.14]; P<0.001; AL versus AApoAIV: hazard ratio, 3.07 [95% CI, 1.27-7.44]; P=0.013). Dysphonia, multisystem involvement, or right-sided cardiac disease should raise suspicion of AApoAI-CA. AApoAIV-CA presents most commonly with heart failure and always displays classical CA imaging features, mimicking common forms of CA. Both AApoAI and AApoAIV are associated with a good prognosis and a lower risk of mortality than matched patients with AL-amyloidosis.

Prevalence of MGCS Among Patients With Monoclonal Gammopathies.

Prevalence of MGCS Among Patients With Monoclonal Gammopathies.

Updated OS of patients with AL amyloidosis after CAEL-101.

8026 Background: Morbidity and mortality remain high in immunoglobulin light chain (AL) amyloidosis due to organ involvement despite hematologic remission. Few anti-amyloid fibril therapies for AL amyloidosis exist. We previously published the results of the phase 1a/1b study of CAEL-101 in AL amyloidosis showing significant improvement in organ response rates.1 We report long-term outcomes. Methods: Patients enrolled in NCT02245867 with relapsed/refractory AL amyloidosis received in phase 1a, a one-time dose-finding CAEL-101 infusion and in phase 1b, 4 weekly CAEL-101 infusions with preplanned dose escalation. Patients were evaluated for organ response for 12 weeks after last infusion. We extracted clinical, laboratory, and pathology data regarding clinical course beyond 12 weeks after last treatment. We performed a review of all AL amyloidosis patients at our center not treated with CAEL-101 1/01/2012-12/30/19 as clinical comparisons. Results: 22 patients were enrolled in CAEL-101. 5 patients were treated in both phase 1a and phase 1b. With median follow-up of 81.3 months (IQR 60.4-87.7), long term follow-up data are available for 19/22 patients. 5 patients died during long term follow-up: 3 from progressive AL amyloidosis; 1 from organ transplantation complication; and 1 from venous thromboembolism sequelae. Among patients with organ data available, 10/17 had hematologic progression and received next line therapy. 5/17 patients had organ progression. All patients with organ PD had previous/concomitant hematologic PD. Median OS was not reached; median organ PFS was 93.3 months (38.9-NR). No delayed adverse events occurred. Comparison with historical control groups revealed trends toward improved OS: HR 0.42 (0.09-1.81 p=0.23) in all comers AL amyloid controls, and HR 0.20 (0.03-1.16 p=0.07) in cardiac controls. Kaplan-Meier analysis and Cox regression were performed. Conclusions: Patients with relapsed/refractory AL amyloidosis who received a low cumulative amount of the novel anti-amyloid CAEL-101 in a phase 1a/1b study had lengthy overall and progression-free survival compared to historical controls. Patterns of organ progression after initial response may reflect intrinsic differences in organ vulnerability. The CAEL101-301 and CAEL101-302 phase 3 clinical trials are underway to confirm these findings. Reference: 1. Edwards CV, Rao N, Bhutani D, et al: Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood 138:2632-2641, 2021. [Table: see text]

Cardiac Amyloidosis Imaging, Part 3: Interpretation, Diagnosis, and Treatment.

Cardiac amyloidosis was thought to be rare, undiagnosable, and incurable. However, recently it has been discovered to be common, diagnosable, and treatable. This knowledge has led to a resurgence in nuclear imaging with 99mTc-pyrophosphate-a scan once believed to be extinct-to identify cardiac amyloidosis, particularly in patients with heart failure but preserved ejection fraction. The renewed interest in 99mTc-pyrophosphate imaging has compelled technologists and physicians to reacquaint themselves with the procedure. Although 99mTc-pyrophosphate imaging is relatively simple, interpretation and diagnostic accuracy require an in-depth knowledge of amyloidosis etiology, clinical manifestations, disease progression, and treatment. Diagnosing cardiac amyloidosis is complicated because typical signs and symptoms are nonspecific and usually attributed to other cardiac disorders. In addition, physicians must be able to differentiate between monoclonal immunoglobulin light-chain amyloidosis (AL) and transthyretin amyloidosis (ATTR). Several clinical and noninvasive diagnostic imaging (echocardiography and cardiac MRI) red flags have been identified that suggest a patient may have cardiac amyloidosis. The intent of these red flags is to raise physician suspicion of cardiac amyloidosis and guide a series of steps (a diagnostic algorithm) for narrowing down and diagnosing the specific amyloid type. One element in the diagnostic algorithm is to identify monoclonal proteins indicative of AL. Monoclonal proteins are detected by serum or urine immunofixation electrophoresis and serum free light-chain assay. Another element is identifying and grading cardiac amyloid deposition using 99mTc-pyrophosphate imaging. When monoclonal proteins are present and the 99mTc-pyrophosphate scan is positive, the patient should be further evaluated for cardiac AL. The absence of monoclonal proteins and a positive 99mTc-pyrophosphate scan is diagnostic for cardiac ATTR. Patients with cardiac ATTR need to undergo genetic testing to differentiate between wild-type ATTR and variant ATTR. This article is the third in a 3-part series in this issue of the Journal of Nuclear Medicine Technology Part 1 reviewed amyloidosis etiology and outlined 99mTc-pyrophosphate study acquisition. Part 2 described 99mTc-pyrophosphate image quantification and protocol technical considerations. This article discusses scan interpretation along with cardiac amyloidosis diagnosis and treatment.

The correlation of left atrial dysfunction and amyloid load in patients with immunoglobulin light-chain cardiac amyloidosis: a 3T cardiac magnetic resonance study.

To investigate the left atrial (LA) changes in immunoglobulin light-chain cardiac amyloidosis (AL-CA) patients with different risk stratifications and to explore the correlation between LA function and the degree of amyloid load using cardiac magnetic resonance (CMR) imaging. Forty-three AL-CA patients were retrospectively enrolled and were divided into low-to-moderate-risk group (n = 16, increased NT-proBNP or troponin I, or both normal) and high-risk group (n = 27, increased NT-proBNP and troponin I). 20 healthy individuals matched for age and gender were included. The function, myocardial deformation of left heart, and left ventricular (LV) tissue characterization among the three groups were compared. The correlation between LA function and LV tissue characterization was investigated. Compared with the controls, the AL-CA patients had a larger LA volume, lower left atrial emptying fraction (LAEF) and impaired left atrial strain (LAS). The high-risk group exhibited lower reservoir and booster function and increased LV extracellular volume (LV-ECV) than the low-to-moderate-risk group (p < 0.05). LV-ECV was significantly correlated with LAS and LAEF (all p < 0.05) but not LAEFconduit. The LAS and LAEF had a good diagnostic ability for risk stratification of AL-CA patients (area under the curve, 0.70 ~ 0.72). High-risk AL-CA patients showed more severe LA function impairment than low-to-moderate-risk AL-CA patients. LAS and LAEF were closely associated with LV-ECV in AL-CA patients, LAS and LAEF exhibited good capability to differentiate AL-CA patients of different risk stratifications. CMR-derived LAS and LAEF were correlated with amyloid load, allowing for differentiation of AL-CA patients at different risk stages.

Role of complementarity-determining regions 1 and 3 in pathologic amyloid formation by human immunoglobulin κ1 light chains

Background Immunoglobulin light chain (LC) amyloidosis is a life-threatening disease complicated by vast numbers of patient-specific mutations. We explored 14 patient-derived and engineered proteins related to κ1-family germline genes IGKVLD-33*01 and IGKVLD-39*01. Methods Hydrogen-deuterium exchange mass spectrometry analysis of conformational dynamics in recombinant LCs and their fragments was integrated with studies of thermal stability, proteolytic susceptibility, amyloid formation and amyloidogenic sequence propensity. The results were mapped on the structures of native and fibrillary proteins. Results Proteins from two κ1 subfamilies showed unexpected differences. Compared to their germline counterparts, amyloid LC related to IGKVLD-33*01 was less stable and formed amyloid faster, whereas amyloid LC related to IGKVLD-39*01 had similar stability and formed amyloid slower, suggesting different major factors influencing amyloidogenesis. In 33*01-related amyloid LC, these factors involved destabilization of the native structure and probable stabilization of amyloid. The atypical behavior of 39*01-related amyloid LC stemmed from increased dynamics/exposure of amyloidogenic segments in βC′V and βEV that could initiate aggregation and decreased dynamics/exposure near the Cys23–Cys88 disulfide. Conclusions The results suggest distinct amyloidogenic pathways for closely related LCs and point to the complementarity-defining regions CDR1 and CDR3, linked via the conserved internal disulfide, as key factors in amyloid formation.

Monoclonal antibodies and amyloid removal as a therapeutic strategy for cardiac amyloidosis.

Cardiac amyloidosis (CA) is an infiltrative disease caused by progressive deposition of amyloid fibres in the heart. The most common forms include immunoglobulin light-chain and transthyretin amyloidosis. Current therapies for CA either stabilize or block the production of amyloidogenic precursors, preventing further amyloid deposition. This approach, while reducing cell damage and disease progression, does not target pre-existing amyloid deposits. Conversely, amyloid removal might stimulate functional recovery of the affected organ, thus improving quality of life and survival. A therapeutic strategy based on monoclonal antibodies capable of selectively binding amyloid deposits and inducing their removal has recently been tested in various clinical trial, with promising results, and could represent a key treatment for CA in the near future.

Amylo-AFFECT-QOL, a self-reported questionnaire to assess health-related quality of life and to determine the prognosis in cardiac amyloidosis.

Self-reported questionnaires are useful for estimating the health-related quality of life (HR-QoL), impact of interventions, and prognosis. To our knowledge, no HR-QoL questionnaire has been developed for cardiac amyloidosis (CA). This study aimed to validate Amylo-AFFECT-QOL questionnaire to assess HR-QoL and its prognostic value in CA. A self-reported questionnaire, "Amylo-AFFECT" had been designed and validated for CA symptoms evaluation and screening by physicians. It was adapted here to assess HR-QoL (Amylo-AFFECT-QOL) and its prognostic value in CA. To validate the theoretical model, internal consistency and convergent validity were assessed, particularly correlations between Amylo-AFFECT-QOL and the HR-QoL Minnesota Living Heart Failure (MLHF) questionnaire. Amylo-AFFECT-QOL was completed by 515 patients, 425 of whom (82.5%) had CA. Wild-type and hereditary transthyretin amyloidosis (ATTRwt and ATTRv) and immunoglobulin light-chain amyloidosis (AL) were diagnosed in 47.8, 14.7, and 18.8% of cases, respectively. The best HR-QoL evaluation was obtained with five dimensions: "Heart failure," "Vascular dysautonomia," "Neuropathy," "Ear, gastrointestinal, and urinary dysautonomia," and "Skin or mucosal involvement." The global Amylo-AFFECT-QOL and MLHF scores showed significant positive correlations (rs = 0.72, p < 0.05). Patients with a final diagnosis of CA had a global Amylo-AFFECT-QOL score significantly higher than the control group composed by patients with other diagnoses (22.2 ± 13.6 vs. 16.2 ± 13.8, respectively, p-value < 0.01). According to the Amylo-AFFECT-QOL global results, ATTRv patients' QoL was more affected than AL patients' QoL or ATTRwt patients' QoL. Patients with a higher HR-QoL score had a greater risk of death or heart transplant after 1 year of follow-up (log-rank < 0.01). Amylo-AFFECT-QOL demonstrates good psychometric properties and is useful for quantifying HR-QoL and estimating CA prognosis. Its use may help to improve overall management of patients with CA.

Daratumumab plus bortezomib, cyclophosphamide, and dexamethasone in Asian patients with newly diagnosed AL amyloidosis: subgroup analysis of ANDROMEDA

Subcutaneous daratumumab plus bortezomib/cyclophosphamide/dexamethasone (VCd; D-VCd) improved outcomes versus VCd for patients with newly diagnosed immunoglobulin light-chain (AL) amyloidosis in the phase 3 ANDROMEDA study. We report a subgroup analysis of Asian patients (Japan; Korea; China) from ANDROMEDA. Among 388 randomized patients, 60 were Asian (D-VCd, n = 29; VCd, n = 31). At a median follow-up of 11.4 months, the overall hematologic complete response rate was higher for D-VCd versus VCd (58.6% vs. 9.7%; odds ratio, 13.2; 95% confidence interval [CI], 3.3–53.7; P < 0.0001). Six-month cardiac and renal response rates were higher with D-VCd versus VCd (cardiac, 46.7% vs. 4.8%; P = 0.0036; renal, 57.1% vs. 37.5%; P = 0.4684). Major organ deterioration progression-free survival (MOD-PFS) and major organ deterioration event-free survival (MOD-EFS) were improved with D-VCd versus VCd (MOD-PFS: hazard ratio [HR], 0.21; 95% CI, 0.06–0.75; P = 0.0079; MOD-EFS: HR, 0.16; 95% CI, 0.05–0.54; P = 0.0007). Twelve deaths occurred (D-VCd, n = 3; VCd, n = 9). Twenty-two patients had baseline serologies indicating prior hepatitis B virus (HBV) exposure; no patient experienced HBV reactivation. Although grade 3/4 cytopenia rates were higher than in the global safety population, the safety profile of D-VCd in Asian patients was generally consistent with the global study population, regardless of body weight. These results support D-VCd use in Asian patients with newly diagnosed AL amyloidosis. ClinicalTrials.gov Identifier: NCT03201965.

Diagnostic Challenges and Solutions in Systemic Amyloidosis

Amyloidosis refers to a clinically heterogeneous group of disorders characterized by the extracellular deposition of amyloid proteins in various tissues of the body. To date, 42 different amyloid proteins that originate from normal precursor proteins and are associated with distinct clinical forms of amyloidosis have been described. Identification of the amyloid type is essential in clinical practice, since prognosis and treatment regimens both vary according to the particular amyloid disease. However, typing of amyloid protein is often challenging, especially in the two most common forms of amyloidosis, i.e., the immunoglobulin light chain amyloidosis and transthyretin amyloidosis. Diagnostic methodology is based on tissue examinations as well as on noninvasive techniques including serological and imaging studies. Tissue examinations vary depending on the tissue preparation mode, i.e., whether it is fresh-frozen or fixed, and they can be carried out by ample methodologies including immunohistochemistry, immunofluorescence, immunoelectron microscopy, Western blotting, and proteomic analysis. In this review, we summarize current methodological approaches used for the diagnosis of amyloidosis and discusses their utility, advantages, and limitations. Special attention is paid to the simplicity of the procedures and their availability in clinical diagnostic laboratories. Finally, we describe new methods recently developed by our team to overcome limitations existing in the standard assays used in common practice.

Immunoglobulin Light Chain Amyloidosis: Diagnosis and Risk Assessment.

Immunoglobulin light chain (AL) amyloidosis is a clonal plasma cell disorder with multiple clinical presentations. The diagnosis of AL amyloidosis requires a high index of suspicion, making a delay in diagnosis common, which contributes to the high early mortality seen in this disease. Establishing the diagnosis of AL amyloidosis requires the demonstration of tissue deposition of amyloid fibrils. A bone marrow biopsy and fat pad aspirate performed concurrently have a high sensitivity for the diagnosis of AL amyloidosis and negate the need for organ biopsies in most patients. An accurate diagnosis requires amyloid typing via additional testing, including tissue mass spectrometry. Prognostication for AL amyloidosis is largely driven by the organs impacted. Cardiac involvement represents the single most important prognostic marker, and the existing staging systems are driven by cardiac biomarkers. Apart from organ involvement, plasma cell percentage on the bone marrow biopsy, specific fluorescence in situ hybridization findings, age at diagnosis, and performance status are important prognostic markers. This review elaborates on the diagnostic testing and prognostication for patients with newly diagnosed AL amyloidosis.

The Clinical Characteristics of Immunoglobulin Light Chain Amyloidosis in the Chinese Population: A Systematic Scoping Review

Immunoglobulin light chain (AL) amyloidosis is the most common type of systemic amyloidosis in China and is associated with increased morbidity and a poor prognosis. However, the clinical characteristics of Chinese patients with AL amyloidosis have not been systematically investigated. This scoping review aimed to summarize the available literature regarding the clinical characteristics of patients with AL amyloidosis and identify potential knowledge gaps. We searched three electronic databases from inception to 7 February 2021. PICOS (Patient, Intervention, Comparison, Outcome and Study) design structure was used to formulate the data extraction. All statistical calculations and analyses were performed with R (version 3.6.0). Sixty-seven articles with 5022 patients were included. Results suggest Chinese patients were younger (57 years) at the time of diagnosis when compared with other patient populations and were predominantly male (61.2%). The time interval from the onset of symptoms to diagnosis was between 6 and 12 months. It was found that 41.1% of Chinese patients with AL amyloidosis were diagnosed with an advanced stage III disease when diagnosed, and 20.2% had a concurrent disease. The most involved organs were the kidneys (84.3%) and the heart (62.5%). In conclusion, our study shows some similarities and differences with other studies on the clinical characteristics of Chinese patients with AL amyloidosis, including the age at diagnosis, Mayo stage, and organ involvement. However, a nationwide epidemiological investigation is still needed to provide a comprehensive overview of this patient population in China.

Diagnosis and management of AL amyloidosis due to B-cell non-Hodgkin lymphoma.

Immunoglobulin light chain (AL) amyloidosis may be caused by a B-cell non-Hodgkin lymphoma (NHL) rather than a plasma cell neoplasm in rare cases, which presents unique diagnostic and management considerations. NHL associated with AL will often have an IgM paraprotein; thus, this disease is termed IgM-related AL amyloidosis (IgM AL). The clinical presentation of IgM AL is more likely to involve the lungs, peripheral nerves, and soft tissue; cardiac involvement is less common. Patients with IgM AL amyloidosis should undergo a lymphoma-directed work-up including evaluation for nodal and extranodal disease. Additionally, patients with an IgM paraproteinemia should be screened for AL amyloidosis through history and physical examination. Treatment regimens active against underlying lymphoma, rather than plasma cell-directed regimens, are recommended. Historical response rates in IgM AL have been poor; prospective studies of novel antineoplastic regimens may improve treatment outcomes.

Current approaches to the diagnosis and management of amyloidosis.

Amyloidosis is a collection of diseases caused by the misfolding of proteins that aggregate into insoluble amyloid fibrils and deposit in tissues. While these fibrils may aggregate to form insignificant localised deposits, they can also accumulate in multiple organs to the extent that amyloidosis can be an immediately life-threatening disease, requiring urgent treatment. Recent advances in diagnostic techniques and therapies are dramatically changing the disease landscape and patient prognosis. Delays in diagnosis and treatment remain the greatest challenge, necessitating physician awareness of the common clinical presentations that suggest amyloidosis. The most common types are transthyretin (ATTR) amyloidosis followed by immunoglobulin light-chain (AL) amyloidosis. While systemic AL amyloidosis was previously considered a death sentence with no effective therapies, significant improvement in patient survival has occurred over the past 2 decades, driven by greater understanding of the disease process, risk-adapted adoption of myeloma therapies such as proteosome inhibitors (bortezomib) and monoclonal antibodies (daratumumab) and improved supportive care. ATTR amyloidosis is an underdiagnosed cause of heart failure. Technetium scintigraphy has made noninvasive diagnosis much easier, and ATTR is now recognised as the most common type of amyloidosis because of the increased identification of age-related ATTR. There are emerging ATTR treatments that slow disease progression, decrease patient hospitalisations and improve patient quality of life and survival. This review aims to update physicians on recent developments in amyloidosis diagnosis and management and to provide a diagnostic and treatment framework to improve the management of patients with all forms of amyloidosis.

Case report of Paraproteinemia

Different peripheral neuropathies are linked to paraproteinemia. Anti-myelin-associated glycoprotein (MAG) neuropathy, immunoglobulin or its fragment deposition in the interstitium, immunoglobulin light chain amyloidosis (AL amyloidosis) and paraneoplastic mechanisms that cannot be solely attributed to immunoglobulin or its fragment deposition, represented by polyneuropathy, organotypic, are the three main causes of neuropathy correlated with paraproteinemia. Nerve conduction metrics slow down in patients with POEMS syndrome and anti-MAG neuropathy. An approximately (3.2%) of people over the age of 45-50 have paraproteins in their bodies. Plasma cell diseases can be thought of as a continuum of illnesses ranging from asymptomatic myeloma to symptomatic monoclonal gammopathy of unknown significance (MGUS). A low amount of paraprotein (30 g/L), a low percentage of plasma cells in the bone marrow, and the absence of organ or tissue damage from myeloma are the characteristics of MGUS (predominantly renal, skeletal or bone marrow impairment.) No treatment is necessary for MGUS, and there is a 1% annual risk.

Localized light chain amyloidosis: A self-limited plasmacytic B-cell lymphoproliferative disorder.

Immunoglobulin light chain amyloidosis can be either systemic or localized. Although these conditions share a similar name, they are strikingly different. Localized light chain amyloidosis has been challenging to characterize due to its lower incidence and highly heterogeneous clinical presentation. Here, we review the emerging literature, emphasizing recent reports on large cohorts of patients with localized amyloidosis, and provide insights into this condition's pathology and natural history. We find that patients with localized amyloidosis have an excellent prognosis with overall survival similar to that of the general population. Furthermore, the risk of progression to systemic disease is low and likely represents initial mischaracterization as localized disease. Therefore, we argue for the incorporation of more sensitive techniques to rule out systemic disease at diagnosis. Despite increasing mechanistic understanding of this condition, much remains to be discovered regarding the cellular clonal evolution and the molecular processes that give rise to localized amyloid formation. While localized surgical resection of symptomatic disease is typically the treatment of choice, the presentation of this disease across the spectrum of plasmacytic B-cell lymphoproliferative disorders, and the frequent lack of an identifiable neoplastic clone, can make therapy selection a challenge in the uncommon situation that systemic chemotherapy is required.

IgM-Related Immunoglobulin Light Chain (AL) Amyloidosis

Waldenström macroglobulinemia (WM) is a rare lymphoplasmacytic disorder characterized by an IgM paraprotein. The clinical presentation of WM varies and can include common manifestations such as anemia and hyperviscosity, in addition to less common features such as cryoglobulinemia, IgM-related neuropathy, and immunoglobulin light chain (AL) amyloidosis. Amyloidosis is a protein-folding disorder in which vital organ damage occurs due to the accumulation of misfolded protein aggregates. The most common type of amyloidosis in patients with an IgM paraprotein is AL amyloidosis, although other types of amyloidosis may occur. IgM-related amyloidosis has distinct clinical features when compared with other subtypes of AL amyloidosis. This review highlights the diagnostic criteria of IgM-related AL amyloidosis, as well as the clinical characteristics and treatment options for this disorder.

Understanding AL amyloidosis with a little help from in vivo models.

Monoclonal immunoglobulin (Ig) light chain amyloidosis (AL) is a rare but severe disease that may occur when a B or plasma cell clone secretes an excess of free Ig light chains (LCs). Some of these LCs tend to aggregate into organized fibrils with a β-sheet structure, the so-called amyloid fibrils, and deposit into the extracellular compartment of organs, such as the heart or kidneys, causing their dysfunction. Recent findings have confirmed that the core of the amyloid fibrils is constituted by the variable (V) domain of the LCs, but the mechanisms underlying the unfolding and aggregation of this fragment and its deposition are still unclear. Moreover, in addition to the mechanical constraints exerted by the massive accumulation of amyloid fibrils in organs, the direct toxicity of these variable domain LCs, full-length light chains, or primary amyloid precursors (oligomers) seems to play a role in the pathogenesis of the disease. Many in vitro studies have focused on these topics, but the variability of this disease, in which each LC presents unique properties, and the extent and complexity of affected organs make its study in vivo very difficult. Accordingly, several groups have focused on the development of animal models for years, with some encouraging but mostly disappointing results. In this review, we discuss the experimental models that have been used to better understand the unknowns of this pathology with an emphasis on in vivo approaches. We also focus on why reliable AL amyloidosis animal models remain so difficult to obtain and what this tells us about the pathophysiology of the disease.