Primary systemic amyloidosis

Opinion statement Patients with unexplained heart failure, hepatomegaly, nephrotic syndrome, or peripheral neuropathy should be evaluated for primary systemic (amyloid lightchain, or AL) amyloidosis by first seeking evidence of a clonal plasma cell disorder with serum and urine immunofixation studies, as well as a bone marrow biopsy. Immunostaining of the marrow biopsy for lambda and kappa isotypes will usually demonstrate a dominant clonal population of plasma cells if immunofixation studies are negative (less than 10% of cases). Tissue diagnosis of amyloidosis should be sought by biopsy of the abdominal fat or an involved organ. In addition, patients with stable myeloma or monoclonal gammopathy of undetermined significance who develop such conditions or become progressively ill should be evaluated for amyloidosis. We recommend that newly diagnosed patients with AL amyloidosis, who meet criteria for autologous hematopoietic cell transplantation, be considered for highdose melphalan with stem cell support. Criteria usually include adequate cardiac, pulmonary, and hepatic function. AL amyloidosis patients treated with autologous transplantation frequently achieve durable complete remissions of the plasma cell disease and marked improvement in amyloid-related organ dysfunction. AL amyloidosis patients with dominant cardiac amyloid, who are without symptomatic pleural effusions and have no history of cardiac syncope or symptomatic arrhythmias, may be considered for autologous transplantation but are at increased risk of peritransplant mortality. Autologous transplantation should not routinely be offered to patients with dominant cardiac amyloid with recurrent effusions or histories of syncope or arrhythmias or to patients older than 50 years of age with more than two major organ systems involved (eg, heart, kidneys, liver, and peripheral nerves). We recommend that AL patients with isolated advanced cardiac or hepatic amyloidosis be considered for solid organ replacement followed by autologous transplantation. Otherwise, AL patients who are elderly or ineligible for autologous transplantation may be treated with oral melphalan (Alkeran, GlaxoWellcome, Middlesex, UK) and prednisone; however, because the response rate is only about 25% and the prognosis poor, such patients might also be enrolled on clinical trials of emerging therapies.     

A Comprehensive Multidisciplinary Diagnostic Algorithm for the Early and Efficient Detection of Amyloidosis

Amyloidosis is a rare protein misfolding disease caused by the accumulation of amyloid fibrils in various tissues and organs. There are different subtypes of amyloidosis, with light chain (AL) amyloidosis being the most common. Amyloidosis is notoriously difficult to diagnose because it is clinically heterogeneous, no single test is diagnostic for the disease, and diagnosis typically involves multiple specialists. Here, we propose an integrated, multidisciplinary algorithm for efficiently diagnosing amyloidosis. Drawing on research from several medical disciplines, we have combined clinical decisions and best practices into a comprehensive algorithm to facilitate the early detection of amyloidosis. Currently, many patients are diagnosed more than 6 months after symptom onset, yet early diagnosis is the major predictor of survival. Our algorithm aims to shorten the time to diagnosis with efficient sequencing of tests and minimizing uninformative investigations. We also recommend typing and staging of confirmed amyloidosis to guide treatment. By reducing time to diagnosis, our algorithm could lead to earlier and more targeted treatment, ultimately improving prognosis and survival.     

Cardiac Amyloidosis: Diagnosis and Treatment Strategies

Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective.     

Continuously elevated cardiac troponin I in two patients with multiple myeloma and fatal cardiac amyloidosis

Myeloma-associated systemic amyloidosis (AL) with cardiac involvementhas a poor prognosis, with a median survival of <1year [1]. Standard therapy with oral melphalan and prednisoloneis unsatisfactory, with an overall response rate for AL of 20%.The diagnosis of cardiac amyloidosis in patients with multiplemyeloma is most commonly based on     

MASS-FIX for the detection of monoclonal proteins and light chain N-glycosylation in routine clinical practice: a cross-sectional study of 6315 patients

Immunoenrichment-based matrix assisted laser desorption ionization time-of-flight mass spectrometry (MALDI-TOF-MS), termed MASS-FIX, offers several advantages over immunofixation for the detection and isotyping of serum monoclonal protein, including superior sensitivity and specificity, the ability to differentiate therapeutic monoclonal antibodies, and the rapid identification of light chain (LC) N-glycosylation. We identified 6315 patients with MASS-FIX performed at our institution since 2018. Of these, 4118 patients (65%) with a wide array of plasma cell disorders (PCD), including rare monoclonal gammopathies of clinical significance, had a positive MASS-FIX. Two-hundred twenty-one (5%) of the MASS-FIX positive patients had evidence of LC N-glycosylation, which was more commonly identified in IgM heavy chain isotype, kappa LC isotype, and in diagnoses of immunoglobulin light chain (AL) amyloidosis and cold agglutinin disease (CAD) compared to other PCD. This cross-sectional study describes the largest cohort of patients to undergo MASS-FIX in routine clinical practice. Our findings demonstrate the widespread utility of this assay, and confirm that LC N-glycosylation should prompt suspicion for AL amyloidosis and CAD in the appropriate clinical context.Subject terms: Myeloma, Translational research     

Focused review on nutritional status of patients with immunoglobulin light chain amyloidosis

Background: Immunoglobulin light chain (AL) amyloidosis is a complex disease marked by a poor clinical portrait and prognosis generally leading to organ dysfunction and shortened survival. We aimed to review the available evidence on whether AL amyloidosis can lead to malnutrition, thus having a negative impact on quality of life (QoL) and survival.Materials: We searched Pubmed for studies that assessed malnutrition in amyloidosis patients, with no restrictions to the year of publication or language. Retrospective or prospective, observational, and interventional studies that reported data regarding AL amyloidosis and nutritional status were included.Results: From 62 articles retrieved, 23 were included. Malnutrition was prevalent in up to 65% of patients with AL Amyloidosis. Prevalence of weight loss of 10% or more ranged from 6 to 22% of patients, while a body mass index of < 22 kg/m2 was found in 22 to 42%. Weight loss, lower BMI and other indicators of poor nutritional status were negatively associated with quality of life and survival. Only one RCT focused on nutritional counseling was found and reported positive results on patients QoL and survival.Conclusion: Despite inconsistencies across assessment criteria, the available data reveal that weight loss and malnutrition are common features in patients with AL amyloidosis. This review reinforces the premise that an impaired nutritional status can be negatively associated with QoL and survival in patients with AL amyloidosis, and therefore should be further investigated.     

Light-chain cardiac amyloidosis

Cardiac amyloidosis is an underrecognized condition, in which delays to diagnosis have great implications on management options, prognosis, and morbidity. Once cardiac tissue is infiltrated by amyloid fibrils, there is a cascade of pathologic changes that can display an array of clinical manifestations, from impaired relaxation of the ventricular myocardium to severe restrictive disease or even progressive systolic heart failure. Management is guided not only by recognizing the subtype of amyloidosis (primary, hereditary, and wild-type transthyretin amyloidosis), but also the clinical stage of the disease. It is important for those managing such patients to understand and differentiate disease associated with fibrils composed of transthyretin vs light-chain proteins. Kappa- and lambda-light chains of primary amyloidosis are particularly toxic to myocytes, leading to accelerated clinical illness in the face of intolerance to treatment and poor survival. Limitations to treatment of primary cardiac amyloidosis are related to multiorgan dysfunction and the inability to tolerate appropriate chemotherapy. Bortezomib, a selective protease inhibitor, has been shown to be and an effective and tolerable option for those with myocardial amyloid infiltration. Standard goal-directed optimal medical management for cardiomyopathy (such as beta-blockers and ace inhibitors) does not offer a survival benefit with cardiac amyloidosis, and often is associated with adverse effects. Despite advances in treatment of advanced heart failure therapy, end-stage cardiomyopathy in the setting of amyloidosis is not well stabilized by inotropes or mechanical circulatory support, and offers restricted candidacy for heart transplantation. We review the salient features of cardiac amyloidosis to help general practitioners and subspecialists manage this unique clinical condition.     

Safety and Efficacy of Triplet Regimens in Newly Diagnosed Light Chain Amyloidosis

BackgroundThe prognosis of patients with systemic light chain (AL) amyloidosis, particularly cardiac, is poor. Treatments have been derived from multiple myeloma, but there are few studies that use triplet regimens in AL amyloidosis because of concern of greater toxicity than seen in myeloma.Patients and MethodsWe conducted a retrospective review of patients with newly diagnosed AL amyloidosis who were initially treated with a triplet regimen.ResultsFor the 9 patients included, the median age was 64 years, and 8 were ineligible for stem cell transplantation. At least 2 organs were involved in 4 patients, including 7 with kidney and 4 with heart involvement, 2 of whom had New York Heart Association class 3 heart failure. All the patients received bortezomib, cyclophosphamide or lenalidomide/thalidomide, and dexamethasone. With a median follow-up of 13 months, 8 of 9 patients had a hematologic response, including 2 who achieved complete response, with a median time to response of 2.7 months. An organ response was seen in 7 of 9 patients, including all 4 patients with cardiac involvement. There were no deaths, and only 1 patient had progressive disease. The major toxicity observed was fluid overload and syncope, seen only in patients with heart failure, who eventually achieved a partial or complete response.ConclusionsDose-attenuated triplet regimens achieved rapid hematologic responses with manageable and reversible toxicity in patients with newly diagnosed AL amyloidosis.     

Urinary Findings in Renal Light Chain–Derived Amyloidosis and Light Chain Deposition Disease

BackgroundEarly recognition of light chain—derived (AL) amyloidosis and light chain deposition disease (LCDD) is essential for optimal therapy. However, clinical and laboratory manifestations of these unusual conditions often go unrecognized. Renal protein deposits in AL amyloidosis and LCDD can cause both heavy albuminuria and Bence Jones proteinuria. Absent separate etiologies, this combined finding is rare and provides a clue to the diagnosis of these conditions.Materials and MethodsWe retrospectively reviewed test results of urine immunoelectrophoreses and urine immunofixation electrophoreses performed at a single institution from 1977 to 2006. Patients with both heavy albuminuria and Bence Jones proteinuria were investigated further to determine whether these findings were predictive of renal AL amyloidosis or LCDD. We reviewed the patients' clinical histories, laboratory data, and pathology reports and included patients with biopsy-confirmed renal AL amyloidosis or LCDD in this series.ResultsWe identified 6 patients with renal amyloidosis or LCDD who presented with the dual findings of Bence Jones proteinuria and heavy albuminuria. We report their demographic information, laboratory data, and case histories.ConclusionThe simultaneous presence of heavy albuminuria and Bence Jones proteinuria justifies a workup for AL amyloidosis or LCDD. Prompt recognition of these rare conditions would permit earlier initiation of therapy and potentially limit organ dysfunction. In addition, patients might be spared unnecessary clinical investigation and unwarranted treatment.     

Pitfalls in the Diagnosis of Primary Amyloidosis

Primary (AL) amyloidosis is the most prevalent type of systemic amyloidosis, and management of this disease has evolved through the years from supportive care to aggressive treatments that include immunomodulatory agents and high-dose chemotherapy with hematopoietic stem cell transplantation. However, other types of amyloidosis are increasingly recognized, such as familial amyloidosis and senile cardiac amyloidosis, and management of these conditions is different from that of AL amyloidosis. Congo red staining with exhibition of an apple-green birefringence is diagnostic of amyloid. Immunohistochemistry can detect amyloid deposits but has limitations, and newer molecular techniques such as mass spectrometry show promise in determining types of amyloidosis. Physicians need to be aware of clinical scenarios that can mimic AL amyloidosis to avoid misdiagnosis and harm to the patient.     

Novel Approaches for the Management of AL Amyloidosis

Purpose of Review

Light-chain-associated (AL) amyloidosis is a rare disease with a poor prognosis. However, we have made recent strides in more accurate diagnosis and effective treatment. Here, we discuss the most recent updates and advancements during the past year in the diagnosis, prognostication, and management of AL amyloidosis both in the upfront and relapsed setting.

Recent Findings

New imaging modalities, such as cardiac magnetic resonance (CMR) and use of fluorine-labeled radiotracers, are emerging as an important diagnostic tool in conjunction with biomarkers in the diagnosis, prognosis, and monitoring of the effects of therapy. In addition, ongoing evaluation of plasma cell-directed therapeutics, including daratumumab, pomalidomide, and ixazomib, as well as promising targeted novel therapies, such as the monoclonal antibody NEOD001, are in development.

Summary

In conclusion, incorporating the use of plasma cell-directed therapy and novel agents targeting the amyloid deposits itself hold enormous potential in achieving improved outcomes in AL amyloidosis.

     

轻链淀粉样变性的诊治更新及存在的问题

轻链淀粉样变性(AL)主要是免疫球蛋白轻链错误折叠形成的淀粉样物质,引起人体多脏器损害的一种克隆性浆细胞病,其发生机制不清楚.临床上通常以患者心、肾等某一脏器衰竭为突出表现.治疗主要为美法仑联合地塞米松或硼替佐米等靶向新药化疗或进行自体干细胞移植治疗.疗效的判断不仅以血清游离轻链及M蛋白水平判断血液学反应,更要以氨基末端B型脑钠肽前体和肌钙蛋白I判断心脏等重要脏器功能改善情况.在新药时代,心脏受累是生存和预后的决定因素.AL的现代治疗,不仅要给予抗浆细胞的新药靶向治疗,更要结合抗淀粉样变治疗,以清除AL的伴侣蛋白.尽管治疗上有很多可喜进展,但也有不少问题亟待解决.     

Immunoglobulin light chain amyloidosis diagnosis and treatment algorithm 2021

Immunoglobulin light chain amyloidosis (AL) commonly presents with nephrotic range proteinuria, heart failure with preserved ejection fraction, nondiabetic peripheral neuropathy, unexplained hepatomegaly or diarrhea, and should be considered in patients presenting with these symptoms. More importantly, patients being monitored for smoldering multiple myeloma and a monoclonal gammopathy of undetermined significance (MGUS) are at risk for developing AL amyloidosis. MGUS and myeloma patients that have atypical features, including unexplained weight loss; lower extremity edema, early satiety, and dyspnea on exertion should be considered at risk for light chain amyloidosis. Overlooking the diagnosis of light chain amyloidosis leading to therapy delay is common, and it represents an error of diagnostic consideration. Herein we provide a review of established and investigational treatments for patients with AL amyloidosis and provide algorithms for workup and management of these patients.Subject terms: Myeloma, Chemotherapy     

Immunotherapy in systemic primary (AL) amyloidosis using amyloid-reactive monoclonal antibodies

Heretofore, treatment of patients with primary or light chain-associated (AL) amyloidosis has been directed toward reducing the synthesis of the amyloidogenic precursor protein through conventional or high-dose cytotoxic antiplasma cell chemotherapy. Although such efforts have extended survival, most often the prognosis remains exceedingly poor due to the persistence (or progression) of the pathologic deposits. The development of murine amyloid-reactive monoclonal antibodies (mAbs) has provided another therapeutic approach; namely, passive immunotherapy. These reagents, prepared against human light chain-related fibrils, recognize an epitope common to the beta-pleated structure of AL and other types of amyloid proteins and can effect rapid amyloidolysis when administered to mice injected with human AL amyloid extracts. One such prototypic antibody, the IgG1kappa mAb 11-1F4, has now been chimerized and is undergoing GMP production for an eventual phase I and II clinical trial in patients with AL amyloidosis. Demonstration of the therapeutic efficacy of this amyloid-reactive mAb would provide an important proof-of-principle that this form of immunotherapy also could benefit individuals with other types of inherited or acquired amyloid-associated disease.     

Single Center Experience of Autologous Stem Cell Transplantation in Patients with Systemic Light Chain Amyloidosis in Korea

BackgroundSystemic light chains is the most common systemic amyloidosis. In patients with AL amyloidosis, the prognosis is influenced by the extent of organ damage, especially cardiac involvement. Autologous stem cell transplantation (ASCT) is a highly effective treatment for AL amyloidosis for selective patientMethodsOne hundred patients treated with ASCT for AL amyloidosis were reviewed in the Samsung Medical Center amyloidosis cohort. The cardiac, renal, and hematologic response was analyzed, and survival results compared based on organ involvement and hematologic response.ResultsThe most common involved organ was kidney (n = 62) followed by heart (n = 50). The organ response rate was 44.0% and 37.1% in the patients with cardiac and renal involvement, respectively. In hematologic response, overall response rate (ORR) was 79.0%, including 48.0% complete response (CR). Median overall survival (OS) in patients with and without hematologic CR were not reached and 64.2 months (95% CI, 19.5 to 109.0), respectively (P < .001). The survival rate was not significantly different between patients with or without cardiac or renal involvement. Treatment-related mortality (TRM) in 30 days and 100 days was 2.0% and 3.0%, respectively.ConclusionsASCT is an effective treatment option for eligible patients with AL amyloidosis. Achieving hematologic CR is essential for long-term survival.     

原发性轻链型淀粉样变的治疗进展

原发性轻链(AL)型淀粉样变是一种少见的、致死性、克隆性浆细胞疾病。基于硼替佐米的治疗虽然已经显著改善了AL型淀粉样变患者的预后,但是晚期患者的预后仍较差,临床迫切需要更为有效的治疗药物。第62届美国血液学会(ASH)年会报道了治疗AL型淀粉样变的多种新药(如抗CD38单抗、bcl-2抑制剂联合他汀类药物、CAEL-101等)的临床数据。     

Light Chain Amyloidosis (AL) Associated With B Cell Lymphoma a Single Center Experience

IntroductionLight chain (AL) amyloidosis and B‐cell lymphoma represent 5% to 7% of all AL, Systemic amyloidosis, deposits in sites remote from the underlying lymphoma, and peritumoral amyloidosis deposition is within the immediate vicinity.Materials and MethodsWe conducted a retrospectively study to identify and describe AL with B cell lymphoma at Princess Margaret Cancer Center from 01 January 1997 to 31 July 2019.ResultsThirty-five patients with AL and lymphoma, an incidence of 6, 2%, median age of diagnosis of 66 (range 47 to 86), majority male, most had underlying Waldestrom's Macroglobulinemia. 21 patients with peritumoral AL (PAL), and 15 with systemic AL. 42.8% of the patients had major organ involvement. 35% got treatment with Rituximab with alkylator, 20% received proteasome inhibitors, 17% patients were on a watch and wait approach, amyloid response showed very good partial response > 45.8%, and lymphoma ORR was 42.8%, with a median follow up of 31.5 months. A 36 month overall survival (OS) and progression-free survival (PFS) showed worse outcomes for heart involvement OS (P = .002), PFS (0.057) and IgM subtype OS (P = .02), PFS (0.01).ConclusionWe have shown adverse outcome with IgM AL and to document a differences in OS and PFS not previously reported for PAL.     

Clinical Characteristics and Outcome of Primary Systemic Light-Chain Amyloidosis in Greece

Background:Primary systemic light-chain (AL) amyloidosis is characterized by the deposition of immunoglobulin light chain–derived amyloid fibrils in various tissues leading to multiorgan dysfunction.Patients and Methods:In order to define characteristics, treatment, and outcome of Greek patients with AL amyloidosis, we analyzed 112 unselected patients with AL from several hospitals.Results:The heart was involved in 59% of patients and kidneys in 71%. Patients were treated with several different treatment regimens; high-dose dexamethasone-based regimens were used as primary treatment in 43% and melphalan-based regimens in 37%, while 12% received up-front bortezomib with dexamethasone. A hematologic response to first-line therapy was documented in 50% (complete response, 14.5%), and organ responses were observed in 25% of patients, the latter being strongly associated with achievement of hematologic response. Median overall survival was 34.2 months and was independently affected by heart involvement, creatinine, age, involvement of ≥ 2 organs, and bone marrow plasmacytosis > 30%. In patients with cardiac involvement, advanced age and extended bone marrow plasmacytosis were associated with an even worse outcome, while for patients without heart involvement, only bone marrow plasmacytosis was independently associated with survival. Hematologic response was associated with improved survival in patients with heart involvement but mostly in patients with less bone marrow infiltration.Conclusion:In this first series of patients from Greece with AL amyloidosis, disease features and outcome appeared similar to those reported from tertiary centers. Heart involvement and bone marrow plasma cell infiltration comprise adverse prognostic factors but also indicate the heterogeneity of the disease and the need for individual treatment approaches.     

淀粉样变治疗学研究的最新进展

既往10-15年中系统性淀粉样变新治疗的发展取得了实质性进展。这些进展改善了患者的转归,但亦带来新的临床问题。例如,由于淀粉样轻链(或)(AL)淀粉样变对自体造血干细胞移植的作用不太肯定,为此正在开发广泛途径的治疗研究和提供最佳支持治疗。现认为淀粉样前体和成熟原纤维促使淀粉样变相关的器官病变,显示完全清除AL淀粉样变患者促淀粉样(amyloidogenic)轻链生成的重要性,同时治疗前后需作淀粉样前体蛋白和器官病变标记的监测。     

淀粉样变治疗学研究的最新进展

既往10—15年中系统性淀粉样变新治疗的发展取得了实质性进展。这些进展改善了患者的转归，但亦带来新的临床问题。例如，由于淀粉样轻链（K或入）（AL）淀粉样变对自体造血干细胞移植的作用不太肯定，为此正在开发广泛途径的治疗研究和提供最佳支持治疗。现认为淀粉样前体和成熟原纤维促使淀粉样变相关的器官病变，显示完全清除AL淀粉样变患者促淀粉样（amyloidogenic）轻链生成的重要性，同时治疗前后需作淀粉样前体蛋白和器官病变标记的监测。