Managing systemic light-chain amyloidosis

Amyloidosis is a rare disease in which a specific protein is deposited as aggregated interstitial fibrils that can compromise organ function and lead to death. Immunoglobulin (Ig) light-chain amyloidosis (AL), caused by the monoclonal gammopathy of a plasma cell dyscrasia, is the most common type. A hereditary type is also caused by mutant transthyretin and other proteins. Rarely, a patient with amyloid has both a monoclonal gammopathy and a hereditary protein. In AL, circulating monoclonal Ig light chains can be measured with the free light-chain (FLC) assay and provide a target for therapy to eliminate the underlying plasma cell dyscrasia while supporting the patient's organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor FLC is eliminated. For patients with limited organ involvement, intravenous melphalan in doses from 100 to 200 mg/m2 with autologous stem cell support (SCT) is an effective approach and, when followed at 3 months post-SCT with adjuvant thalidomide and dexamethasone for persistent plasma cell disease, has a 1-year hematologic response rate of 77%. Monthly oral melphalan and dexamethasone for 1 year can also be effective therapy for patients too sick for SCT (67% response rate). Hematologic complete responses are usually durable and result in long-term survival and a variable degree of organ recovery. For patients with advanced cardiac involvement, the prognosis remains guarded even with treatment. Drugs effective in multiple myeloma are usually active in AL, depending on side effects. New agents such as bortezomib and lenalidomide have shown promising activity, and novel antibody-based approaches for imaging amyloid and accelerating removal of deposits are being actively investigated.     

New Insights and Modern Treatment of AL Amyloidosis

Systemic amyloidosis is a rare disease that is rarely cured. Systemic immunoglobulin light-chain amyloidosis (AL) is the most common type, usually the result of monoclonal light chains produced by a relatively indolent small plasma cell clone in the bone marrow. In AL, the direct toxicity of light chains, their misfolded intermediates, and deposition as amyloid fibrils in vital organs cause organ dysfunction and death. Often the diagnosis is delayed and the disease is advanced at presentation. Early diagnosis is possible with vigilance in clinical situations such as for patients with monoclonal gammopathy of undetermined significance who develop albuminuria or elevated cardiac biomarkers. Treatment is aimed at eradicating the clonal disease and restoring organ function; options include high dose melphalan followed by autologous stem cell transplantation, oral melphalan and dexamethasone, bortezomib-based combination chemotherapy and immunomodulatory agents such as lenalidomide or pomalidomide combined with dexamethasone. Cardiac involvement at baseline and the free light-chain hematologic response to therapy determine overall survival. Following measures of organ disease with cardiac and other biomarkers and of hematologic disease with serum free light chains is necessary to gauge organ and hematologic responses to therapy.     

Amyloidosis

Opinion statement Amyloidosis is a disease in which abnormal proteins form fibrillar tissue deposits that can compromise key viscera and lead to early death. In order to treat amyloidosis, the type of abnormal protein must be identified. The most common type is monoclonal immunoglobulin light chain or AL amyloidosis; the other important type is hereditary, caused by variant forms of transthyretin and other proteins, whereas amyloid associ-ated with chronic inflammation (“secondary≓) is rare in the developed world. AL can be misdiagnosed if a monoclonal gammopathy and a hereditary variant are present in the same patient. The aim of therapy in systemic AL amyloidosis is to reduce the amyloid-forming monoclonal light chain, measured with the serum free light chain assay, by suppressing the underlying plasma cell dyscrasia, while using supportive measures to sustain organ function. Amyloid deposits can be resorbed and organ function restored if the amyloid-forming precursor light chain is eliminated. The most effective treatment for systemic AL amyloidosis is risk-adapted melphalan with peripheral blood stem cell transplant (SCT). The hematologic response rate is 75% at 12 months when adjuvant therapy with thalidomide and dexamethasone is used post-SCT. Patients can achieve long-term durable remissions with organ recovery. Drugs effective in multiple myeloma are usually helpful in AL amyloidosis if tolerated. The use of novel antibody-based approaches for imaging amyloid and possibly for accelerating removal of deposits is under active investigation.     

Time to Redefine Risk-Stratification and Response Criteria in Immunoglobulin Light Chain Amyloidosis?

Immunoglobulin light chain (AL) amyloidosis results from clonal plasma cell (PC)-derived immunoglobulin light chain–mediated end-organ dysfunction, the extent and severity of which predicts survival. Anti-PC therapies reduce clonal light chain burden, which usually results in improvement of organ function, and consequently overall survival. Response assessment is critical to gauge therapeutic efficacy, to report clinical trial outcomes, and to switch therapy in those without response. Response in AL amyloidosis is 2-fold: hematologic response and organ response (OR). Depth of hematologic response is graded on the basis of serum free light chain (sFLC) parameters, but assessment of OR is binary. The role of normal sFLC ratio or complete remission as a treatment end point has been challenged, thus highlighting the need to quantify involved FLC and residual PC beyond the normal sFLC ratio to possibly account for the ongoing organ damage seen in some patients with complete remission. Mass spectrometry and urinary exosome represent ultrasensitive strategies to estimate involved FLC below the detection threshold of current sFLC assays. The role of new sFLC parameters and minimal residual disease as potential prognostic parameters has been recognized. Brain natriuretic peptide (BNP) and 24-hour proteinuria:estimated glomerular filtration rate ratio were identified to overcome certain limitations of N-terminal-Pro-BNP, 24-hour proteinuria, and estimated glomerular filtration rate for cardiac and renal response assessment, respectively. Use of monoclonal antibodies targeting PC and amyloid deposits has expanded the therapeutic armamentarium of AL amyloidosis, and given their excellent efficacy, early ORs are reported. This review provides insights into recent advances in the risk-stratification and response assessment of patients with AL amyloidosis in light of the changing therapeutic paradigms. Incorporation of these advancements into formal consensus guidelines would require further validation.     

Oral cyclic melphalan and dexamethasone for patients with AL amyloidosis

PurposeAggressive treatment of amyloid light chain (AL) amyloidosis with high-dose intravenous melphalan followed by autologous stem cell transplantation (HDM/SCT) is effective in inducing hematologic remission and clinical improvement. However, only selected patients with AL amyloidosis are eligible for HDM/SCT because of amyloid-associated organ dysfunction.Patients and MethodsWe report on 70 patients with AL amyloidosis treated with oral cyclic melphalan and dexamethasone.ResultsOf 48 evaluable patients who survived and returned for follow-up assessment, 6 patients (13%) achieved a complete hematologic response and 12 patients (25%) a partial hematologic response. Responses were non-inferior for patients receiving weekly “low-dose” dexamethasone compared with those receiving 4 day pulses. Median survival for the 70 patients has not yet been reached with a median follow-up of 17 months. Nineteen patients (27%) received additional treatment leading to improvement in survival.ConclusionMelphalan/dexamethasone can lead to hematologic responses and improvement in survival, particularly for those who can receive additional treatment for AL amyloidosis.     

Dual Monoclonal Antibody Therapy in Patients With Systemic AL Amyloidosis and Cardiac Involvement

BackgroundSystemic AL amyloidosis (AL) is a rare disease in which clonal immunoglobulin light chains produced by monoclonal plasma cells circulate and misfold, resulting in direct toxicity and fibrillar deposition of amyloid in numerous tissues. Early mortality from cardiac damage remains high. As depth of organ response carries a prognostic significance, combining anti-plasma cell and anti-amyloid therapies might hold the key to achieving long lasting responses. We report a series of patients who received 2 monoclonal antibodies, anti-CD38 and anti-amyloid, simultaneously.Materials and MethodsWe describe the characteristics and outcomes of 19 patients who received daratumumab (anti-CD38) on progression with front-line therapy for AL, 9 of whom were on concurrent dual monoclonal antibody treatment with daratumumab and NEOD001 (anti-amyloid), and also provide data on the schedule, safety, and tolerability of intravenous infusions of these monoclonal antibodies.ResultsThe 9 patients who received treatment with dual monoclonal antibodies achieved a high rate (100%) of hematologic response in a median of 33 days. There was no significant toxicity to dual monoclonal antibody therapy. Seven of the 8 met criteria for cardiac response, achieved in less than 3 months of combined therapy. Ten patients who received daratumumab alone also had high rates of hematologic and organ responses.ConclusionsMonoclonal antibodies with distinctly different targets can be safely combined in patients with AL and cardiac involvement. Patients experienced high rates of hematologic and cardiac response with combined anti-CD38 and anti-amyloid monoclonal antibody therapies. Further study of this combined approach is warranted.     

Fibril-directed Therapies in Systemic Light Chain AL Amyloidosis

Immunoglobulin light chain amyloidosis (AL amyloidosis) is a plasma cell disorder leading to the production and extracellular deposition of abnormal immunoglobulin light chains called amyloid. The pathogenesis of the disorder is driven by an abnormal plasma cell clone producing excessive monoclonal immunoglobulin light chains, which undergo deposition in various organs of the body such as the heart, kidney, and gastrointestinal tract. The outcome of the disease remains poor, with significant morbidity and mortality associated with the organ dysfunction. The mainstay of therapy remains targeting the plasma cell clone to decrease or eliminate the production of the abnormal light chains. These therapies include agents such as proteasome inhibitors, immunomodulators, and use of autologous stem cell transplantation. Although current therapies offer potential for disease control and improvement in survival, they cannot reverse light chain deposits in the organs. Newer therapies targeting the light chain fibrils in the form of antibodies binding to the amyloid protein in the organ have recently been developed and have shown early efficacy in clinical trials. In this review, we outline the preclinical work, mechanisms of action, and the clinical efficacy of fibril-directed therapies for light chain amyloidosis.     

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.     

Primary systemic amyloidosis

Opinion statement Primary amyloidosis is a plasma cell dyscrasia in which insoluble immunoglobulin light chain fragments are produced and polymerize into fibrils that deposit extracellularly, causing visceral organ dysfunction and death. The disorder is rare. Its recognition requires understanding the association between nephrotic syndrome, cardiomyopathy, peripheral neuropathy, and hepatomegaly with amyloidosis. The most important screening test for amyloidosis is immunofixation of the serum and urine to detect a monoclonal immunoglobulin light chain. All patients need the diagnosis confirmed histologically. The least invasive source of tissue for amyloid detection is the subcutaneous fat. The most important prognostic factor is whether there is cardiac involvement, which is best assessed by echocardiography with Doppler studies. Therapies used include oral melphalan/prednisone and high-dose corticosteroids. High-dose chemotherapy followed by stem cell reconstitution seems to provide the highest reported response rates. Transplant is associated with unique morbidities not seen in the transplantation of patients with other hematologic malignancies.     

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.     

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.     

Idelalisib plus rituximab is effective in systemic AL amyloidosis secondary to chronic lymphocytic leukaemia

Light chain amyloidosis is characterized by the progressive deposition of immunoglobulin light chains into the extracellular tissue, leading to organ dysfunction. Usually, it is associated with an underlying clonal plasma cell dyscrasia and rarely with chronic lymphocytic leukaemia. Herein, we described the first report of a patient with relapsed chronic lymphocytic leukaemia harbouring TP53 abnormalities who developed, histologically proven, systemic light chain amyloidosis who was treated with the PI3K inhibitor, idelalisib, and rituximab. Unfortunately, the patient had sudden death during sleep, likely caused by arrhythmia secondary to amyloid cardiomyopathy. Idelalisib was at least effective in reducing secretory free light chain, chronic lymphocytic leukaemia burden, and to improve the survival of patient.     

Stem cell transplantation for immunoglobulin light chain amyloidosis

Systemic chemotherapy aimed at eradicating transformed plasma cells is the mainstay of treatment for immunoglobulin light chain amyloidosis (AL). Autologous stem cell transplantation (SCT) is a highly effective treatment for AL and can lead to long term survival in excess of 10 years in patients who achieve complete remission. Since AL is a unique disease characterized by multiple organ dysfunction, SCT poses unique challenges in this disease. Morbidity and mortality of SCT has remarkably improved over time primarily due to careful selection of patients and evolution of predictive and prognostic models based on serum immunoglobulin light chains and cardiac biomarkers. In this review we focus on the historical evolution of SCT as a treatment for AL and unique challenges it poses in the management of this rare disease and provide guidelines for managing these challenges.     

Immunoglobulin light-chain amyloidosis: growing recognition, new approaches to therapy, active clinical trials

Immunoglobulin light-chain amyloidosis needs to be considered in any patient presenting with cardiomyopathy with preserved systolic function, heavy albuminuria, an unexplained sensorimotor peripheral neuropathy, hepatomegaly, or atypical MGUS (monoclonal gammopathy of undetermined significance) or myeloma.The prognosis of the disease is determined by the levels of cardiac biomarkers and the pretreatment levels of immunoglobulin free light chains. All patients with systemic light-chain amyloid require therapy. There is no presymptomatic phase that warrants observation. Stem-cell transplantation produces a high response rate but is a viable option in only 20% of patients. Corticosteroids, alkylating agents, immunomodulatory drugs, and proteasome inhibitors all have shown activity in this disorder, and combinations are currently being explored in clinical trials. Despite advances in the past decade, 30% of patients still die within a year of diagnosis, suggesting that failure to recognize this disorder prior to advanced organ dysfunction remains a major impediment to improving outcomes.     

Tolerability and efficacy of thalidomide for the treatment of patients with light chain-associated (AL) amyloidosis

Thalidomide is an effective therapy for multiple myeloma, although its mechanisms of action remain unclear. Light chain-associated (AL) amyloidosis is a plasma cell disorder related to multiple myeloma, but in AL amyloidosis, fibrillar tissue deposits of clonal immunoglobulin light chains produce organ dysfunction. To test the toxicity and efficacy of thalidomide in AL amyloidosis we initiated a phase I/II trial for patients with AL amyloidosis, most of whom had failed prior therapy with high-dose melphalan and autologous stem cell transplantation. This trial was designed as an individualized 6-month dose-escalation study with reevaluation of bone marrow plasmacytosis and serum and urine monoclonal proteins after 3 and 6 months. Sixteen patients were enrolled in the study with a median age of 62 years (range, 37-70 years). Fourteen patients had renal involvement, 4 had cardiac involvement, 4 had liver involvement, and 2 had predominant soft tissue or lymph node involvement. The median maximum tolerated dose was 300 mg, with fatigue and other central nervous system side effects being the major dose-limiting toxicities. Side effects not frequently reported for other patient populations included exacerbation of peripheral and pulmonary edema and worsening azotemia. In all, 50% of patients experienced grade 3/4 toxicity, and 25% had to discontinue the study drug. No complete hematologic responses were seen, but 25% of patients had a significant reduction in Bence-Jones proteinuria. Thus, while thalidomide has activity in AL amyloidosis, it also has significant toxicity in this patient population.     

Biological features of the clone involved in primary amyloidosis (AL).

Primary light chain-associated amyloidosis (AL) is a plasma cell dyscrasia that causes morbidity via systemic tissue deposition of monoclonal light chains in the form of fibrils (amyloid). It is the most common form of systemic amyloidosis in Western countries and is rapidly fatal. Knowledge of the pathobiology of the underlying B cell clone is of primary importance for the design and optimization of therapeutic strategies.     

意义未明的单克隆免疫球蛋白血症的病程演变、鉴别诊断及其干预策略:第54届美国血液学会年会报道

 【摘要】　意义未明的单克隆免疫球蛋白血症（monoclonal gammopathy of undetermined significances,MGUS）被界定为癌前克隆性疾病。其在50岁以上人群中的发病率达到4.2 %,且以每年1 %的高风险向多发性骨髓瘤（multiple myeloma,MM）和相关的恶性疾病转化。确定其病程演变将指导临床诊断和治疗。大多数MGUS患者仅需随访观察。而少部分患者则经过冒烟型骨髓瘤（smoldering multiple myeloma,SMM）阶段进展为MM,或者因M蛋白导致终末器官损害,发展为轻链型疾病,如轻链型淀粉样变性、轻链沉淀病等,需要启动药物干预措施。2012年第54届美国血液学会（ASH）年会进行了这部分内容的详细报道。     

Troponin in hematologic oncology

In cardiology practice, the standard method of evaluating patients with suspected ischemic myocardial injury is an assay that measures the release of troponin into the bloodstream. In hematologic oncology practice, troponin has been investigated extensively as a measure of myocardial injury after therapy with radiation and anthracyclines and after myeloablative therapies with stem cell replacement. This review describes the current literature on use of troponin for monitoring early and late complications of systemic chemotherapy. The use of troponin to assess the value of cardioprotective agents (used for prevention of chemotherapy-induced myocardial injury) also is reviewed. Because a number of nonmalignant hematologic disorders such as hypereosinophilic syndrome, thrombotic thrombocytopenic purpura, and immunoglobulin light-chain amyloidosis can affect the heart, the use of the troponin in assessing these patients' prognoses is also covered.     

Daratumumab Plus Bortezomib and Dexamethasone in Newly Diagnosed Systemic Light Chain Amyloidosis

Light chain amyloidosis (AL) is a plasma cell dyscrasia characterized by organ dysfunction, morbidity, and early mortality. Daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone is now standard frontline AL therapy; however, not all patients are candidates for this intensive regimen. Given the potency of Daratumumab, we evaluated an alternative frontline regimen: daratumumab, bortezomib, and limited-duration dexamethasone (Dara-Vd). Over a 3 year period, we treated 21 patients with Dara-Vd. At baseline, all patients had cardiac and/or renal dysfunction, including 30% of patients with Mayo stage IIIB cardiac disease. Nineteen of 21 patients (90%) achieved a hematologic response with 38% achieving a complete response. The median time to response was 11 days. Ten of 15 (67%) evaluable patients achieved a cardiac response and 7 of 9 (78%) achieved a renal response. The 1-year overall survival was 76%. In untreated systemic AL amyloidosis, Dara-Vd produces rapid and deep hematologic and organ responses. Dara-Vd was well-tolerated and efficacious, even among patients with extensive cardiac dysfunction.     

AL Amyloidosis Associated with IgM Monoclonal Protein: A Distinct Clinical Entity

IgM-associated AL amyloidosis is rare and may represent a distinct entity. Sixty (7%) of 868 consecutive AL patients referred to our center had an IgM monoclonal protein. They were significantly older than non-IgM patients (median, 67 years vs. 62 years), had a higher frequency of lymph-node involvement (25% vs. 2%) and significantly lower median proteinuria (1.2 g/24h vs. 3.4 g/24h), N-terminal pro-natriuretic peptide type-B (1177 ng/L vs. 2135 ng/L) and troponin I (0.02 ng/mL vs. 0.05 ng/mL). In IgM patients, κ light-chains were more frequent (42% vs. 23%) and the involved free light-chain concentration was lower (median 63 mg/L vs. 182 mg/L). Serum albumin and NT-proBNP were independent prognostic determinants. Response to treatment improved survival. The 14 patients who received melphalan/dexamethasone showed a 64% hematologic (complete remissions, 29%) and a 43% organ response rate. IgM-associated AL amyloidosis is a distinct entity, with less advanced organ dysfunction. Treatment with melphalan/dexamethasone might be effective in these patients.