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1.  A Case of Recurrent Cardiac Arrest and Light Chain Cardiac Amyloidosis 
Introduction:
Light chain amyloidosis is a clonal plasma cell disorder characterized by monoclonal light chain deposition in body organs. The diagnostic challenge belies the variable, often elusive nature of amyloid disease presentation. Cardiac involvement in particular may be seen in up to 50% of cases, and is associated with poor prognosis. We present a case of light chain cardiac amyloidosis, with multi-system derangements, leading to recurrent cardiac arrest despite resuscitative efforts.
Case Report:
A 59-year-old man with a history of end-stage renal disease presented with the complaint of sudden onset of shortness of breath. Atrial fibrillation with rapid ventricular response was noted. While undergoing treatment, complications arose on 3 separate occasions at which time the patient experienced a precipitous fall in heart rate, cardiac arrest, and successful resuscitation. An echocardiogram was performed which revealed a 25% reduction in ejection fraction and new left ventricular septal thickening in comparison to an evaluation 3 months prior. Cardiac catheterization was unremarkable for coronary artery disease. Over the course of hospitalization, there was progressive muscle weakness. Nerve conduction studies were performed, revealing diffuse axonal sensorimotor neuropathy. The link between diffuse polyneuropathy, autonomic instability, persistent hypotension requiring intravenous vasoactive support, and recurrent asystole remained unclear. Amyloidosis workup with immunofixation electrophoresis revealed free kappa light chain excess. Before further workup, the patient went into asystole, unresponsive to resuscitative efforts. Post-mortem findings suggest cardiac arrest due to amyloidosis of the heart secondary to multiple myeloma. Of note, amyloid deposits were found focally in blood vessels of the kidney and peripheral nerves.
Discussion:
Early detection of cardiac involvement is crucial as illustrated above. Advanced echocardiographic techniques including speckle tracking plus strain imaging, may lead to earlier, amyloid-specific identification. Gadolinium-enhanced cardiac MRI has also been employed, with futility reserved for infiltrative cardiac disease states without renal insufficiency. Potentially, utilizing the above imaging studies, in association with cardiac biomarkers such as NT-pro BNP, may lead to the development of prognostication tools to identify patient's at high risk for death. Goal for early detection and institution of prognosis models are aimed at early implementation of treatment strategies including heart transplantation, high-dose chemotherapy, and autologous stem cell support. For patients with a myriad of symptoms and suspicion of amyloidosis, we encourage early lab and imaging studies, because any delay in diagnosis and initiation of treatment is inevitably too late.
PMCID: PMC4175941
2.  Light chain (AL) amyloidosis: update on diagnosis and management 
Light chain (AL) amyloidosis is a plasma cell dyscrasia characterized by the pathologic production of fibrillar proteins comprised of monoclonal light chains which deposit in tissues and cause organ dysfunction. The diagnosis can be challenging, requiring a biopsy and often specialized testing to confirm the subtype of systemic disease. The goal of treatment is eradication of the monoclonal plasma cell population and suppression of the pathologic light chains which can result in organ improvement and extend patient survival. Standard treatment approaches include high dose melphalan (HDM) followed by autologous hematopoietic stem cell transplantation (SCT) or oral melphalan with dexamethasone (MDex). The use of novel agents (thalidomide, lenalidomide and bortezomib) alone and in combination with steroids and alkylating agents has shown efficacy and continues to be explored. A risk adapted approach to SCT followed by novel agents as consolidation reduces treatment related mortality with promising outcomes. Immunotherapeutic approaches targeting pathologic plasma cells and amyloid precursor proteins or fibrils are being developed. Referral of patients to specialized centers focusing on AL amyloidosis and conducting clinical trials is essential to improving patient outcomes.
doi:10.1186/1756-8722-4-47
PMCID: PMC3228694  PMID: 22100031
3.  Induction therapy with bortezomib and dexamethasone followed by autologous stem cell transplantation versus autologous stem cell transplantation alone in the treatment of renal AL amyloidosis: a randomized controlled trial 
BMC Medicine  2014;12:2.
Background
Although the use of bortezomib alone and in combination with steroids has shown efficacy in AL amyloidosis, its role in combination with high-dose melphalan and autologous stem cell transplantation (HDM/SCT) is unknown. In this study, we evaluated bortezomib in combination with dexamethasone (BD) for induction chemotherapy prior to HDM/SCT.
Methods
This was a single-center, prospective, randomized controlled trial comparing induction therapy consisting of two BD cycles followed by HDM/SCT (BD + HDM/SCT) with HDM/SCT alone in the treatment of patients with newly diagnosed AL amyloidosis. The hematological and organ responses of the patients were assessed every three months post HDM/SCT.
Results
Fifty-six patients newly diagnosed with renal (100%), cardiac (57.1%), liver (7.1%), or nervous system (8.9%) AL amyloidosis were enrolled in this study; 28 patients were assigned to each arm. Two patients died within 100 days of HDM/SCT (3.6% treatment-related mortality). The overall hematologic response rates in the BD + HDM/SCT arm and HDM/SCT arm at three, six and twelve months were 78.5% versus 50%, 82.1% versus 53.5% and 85.7% versus 53.5%, respectively. In the BD + HDM/SCT arm, 15 (53.5%) patients achieved a hematologic response after BD and before HDM/SCT. An intention-to-treat analysis revealed a higher rate of complete remission in the BD + HDM/SCT arm at both 12 and 24 months (67.9% and 70%, respectively) than with the HDM/SCT-only therapy (35.7% and 35%, respectively, P = 0.03). After a median follow-up of 28 months, the survival rates at 24 months post-treatment start were 95.0% in the BD + HDM/SCT group and 69.4% in the HDM/SCT alone group (P = 0.03).
Conclusions
Our preliminary data suggest that the outcome of treating AL amyloidosis with BD induction and HDM/SCT was superior to the outcome of the HDM/SCT treatment alone.
Trial registration
This trial has been registered at clinicaltrials.gov with the number NCT01998503.
doi:10.1186/1741-7015-12-2
PMCID: PMC3895846  PMID: 24386911
AL amyloidosis; Bortezomib; Autologous stem cell transplantation
4.  AL Amyloidosis 
Definition of the disease
AL amyloidosis results from extra-cellular deposition of fibril-forming monoclonal immunoglobulin (Ig) light chains (LC) (most commonly of lambda isotype) usually secreted by a small plasma cell clone. Most patients have evidence of isolated monoclonal gammopathy or smoldering myeloma, and the occurrence of AL amyloidosis in patients with symptomatic multiple myeloma or other B-cell lymphoproliferative disorders is unusual. The key event in the development of AL amyloidosis is the change in the secondary or tertiary structure of an abnormal monoclonal LC, which results in instable conformation. This conformational change is responsible for abnormal folding of the LC, rich in β leaves, which assemble into monomers that stack together to form amyloid fibrils.
Epidemiology
AL amyloidosis is the most common type of systemic amyloidois in developed countries with an estimated incidence of 9 cases/million inhabitant/year. The average age of diagnosed patients is 65 years and less than 10% of patients are under 50.
Clinical description
The clinical presentation is protean, because of the wide number of tissues or organs that may be affected. The most common presenting symptoms are asthenia and dyspnoea, which are poorly specific and may account for delayed diagnosis. Renal manifestations are the most frequent, affecting two thirds of patients at presentation. They are characterized by heavy proteinuria, with nephrotic syndrome and impaired renal function in half of the patients. Heart involvement, which is present at diagnosis in more than 50% of patients, leading to restrictive cardiopathy, is the most serious complication and engages prognosis.
Diagnostic methods
The diagnosis relies on pathological examination of an involved site showing Congo red-positive amyloid deposits, with typical apple-green birefringence under polarized light, that stain positive with an anti-LC antibody by immunohistochemistry and/or immunofluorescence. Due to the systemic nature of the disease, non-invasive biopsies such as abdominal fat aspiration should be considered before taking biopsies from involved organs, in order to reduce the risk of bleeding complications.
Differential diagnosis
Systemic AL amyloidosis should be distinguished from other diseases related to deposition of monoclonal LC, and from other forms of systemic amyloidosis. When pathological studies have failed to identify the nature of amyloid deposits, genetic studies should be performed to diagnose hereditary amyloidosis.
Management
Treatment of AL amyloidosis is based on chemotherapy, aimed at controlling the underlying plasma clone that produces amyloidogenic LC. The hematological response should be carefully checked by serial measurements of serum free LC. The association of an alkylating agent with high-dose dexamethasone has proven to be effective in two thirds of patients and is considered as the current reference treatment. New agents used in the treatment of multiple myeloma are under investigation and appear to increase hematological response rates. Symptomatic measures and supportive care is necessary in patients with organ failure. Noticeably, usual treatments for cardiac failure (i.e. calcium inhibitors, β-blockers, angiotensin converting enzyme inhibitors) are inefficient or even dangerous in patients with amyloid heart disease, that should be managed using diuretics. Amiodarone and pace maker implantation should be considered in patients with rhythm or conduction abnormalities. In selected cases, heart and kidney transplantation may be associated with prolonged patient and graft survival.
Prognosis
Survival in AL amyloidosis depends on the spectrum of organ involvement (amyloid heart disease being the main prognosis factor), the severity of individual organs involved and haematological response to treatment.
doi:10.1186/1750-1172-7-54
PMCID: PMC3495844  PMID: 22909024
AL amyloidosis; Immunoglobulinic amyloidosis; « Primary » amyloidosis
5.  Primary systemic amyloidosis as a real diagnostic challenge – case study 
Primary amyloidosis (AL) is a rare variety of plasma cell dyscrasia, the diagnosis of which is often difficult to establish. Pathogenesis of amyloidosis involves extracellular deposition of insoluble protein fibrils in tissues, leading to insufficiency of affected organs. According to various sources, mean survival rate of patients with primary amyloidosis ranges from 12 to 24 months, making primary amyloidosis a disease with a very poor prognosis. Survival rate is significantly lowered in case of cardiac manifestation of amyloidosis (about 6 months survival in untreated patients). In recent years a considerable progress in AL treatment has been observed. Nowadays we are able not only to delay progression of amyloidosis, but also to improve the function of the affected organs. Unfortunately as first signs and symptoms of AL are usually nonspecific, the diagnosis of AL is often delayed, resulting in late introduction of optimal therapy. There are many diagnostic tests which can be used in diagnostic process of amyloidosis, i.e. electrophoresis, serum and urine immunofixation or affected organs and bone marrow biopsy. On establishing the diagnosis in a patient with suspected amyloidosis it should be remembered that particular diagnostic methods vary considerably in sensitivity.
The aim of this paper is to present a case report of a 27-year-old patient with primary amyloidosis focusing on diagnostic aspect of this condition. On the basis of this case, the authors would like to emphasize the value of precise diagnostic process, with immunological techniques playing undoubtedly a crucial role.
doi:10.5114/ceji.2014.42126
PMCID: PMC4439975  PMID: 26155101
AL amyloidosis; Congo red stain; bone marrow trepanobiopsy; immunofixation
6.  Advances in the treatment of monoclonal gammopaties: The emerging role of targeted therapy in plasma cell dyscrasias 
Biologics : Targets & Therapy  2008;2(3):419-431.
The paradigm for the treatment of monoclonal gammopaties has dramatically changed: therapeutic options in multiple myeloma (MM) have evolved from the introduction of melphalan and prednisone in the 1960s, high-dose chemotherapy and stem cell transplantation in the late 1980s and 1990s, to the rapid introduction of small novel molecules within the last seven years. Based on the understanding of the complex interaction of the MM cells with the bone marrow microenvironment and the signaling pathways that are dysregulated in this process, a number of novel therapeutic agents are now available. Specifically, three novel agents with a specific-targeted anti-MM activity, have been FDA-approved for the treatment of this disease, namely Bortezomib, thalidomide, and lenalidomide which are now all playing a key role in the treatment of MM. The success of targeted therapy in MM has since led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias such as Waldenström’s macroglobulinemia and primary amyloidosis, both in the preclinical settings and as part of clinical trials.
PMCID: PMC2721375  PMID: 19707373
monoclonal gammopaties; targeted therapies
7.  Spontaneous rupture of the liver in a patient with systemic AL amyloidosis undergoing treatment with high-dose melphalan and autologous stem cell transplantation: A case report with literature review 
A 55-year-old woman with primary Immunoglobulin light chain (AL) systemic amyloidosis died due to spontaneous rupture of her liver following treatment with high-dose melphalan and autologous stem cell transplant (HDM/SCT). She was first diagnosed after developing nephrotic-range proteinuria. Spontaneous rupture of her liver occurred 10 days after treatment with HDM/SCT and was complicated by septic shock. She was not eligible for surgical intervention and died shortly after. Amyloid fibrils were extracted from the autopsied liver sample (05-135L) and the biochemical nature of the fibrils was analyzed using electrophoretic and immunohistochemical techniques. Our testing showed that the fibrils were composed of immunoglobulin lambda light chains that were not glycosylated.
While the liver is often involved in AL amyloidosis, this is the first documented case of a spontaneous hepatic rupture in a patient during treatment with HDM/SCT. A literature review of spontaneous liver rupture in patients with amyloidosis is presented.
doi:10.1080/13506120902879574
PMCID: PMC2911629  PMID: 20536404
AL amyloidosis; liver rupture; stem cell transplantation
8.  Extracorporeal Membrane Oxygenation as Bridge-to-Decision in Acute Heart Failure due to Systemic Light-Chain Amyloidosis 
Patient: Female, 58
Final Diagnosis: Acute hear failure
Symptoms: Dispnoea • edema • fatigue
Medication: —
Clinical Procedure: Bone marrow biopsy • endomyocardial biopsy • abdominal subcutaneous fat biopsy under ECMO support
Specialty: Cardiology
Objective:
Rare disease
Background:
Cardiac amyloidosis results from the amyloid deposition in heart tissue, either in the context of a systemic disease or as a localized form. Several pro-amyloid proteins can produce amyloid deposits in the heart. Each of these amyloidoses has characteristic clinical (cardiac and extracardiac) features, and a specific diagnosis and treatment.
Case Report:
A 58-year-old woman who presented with acute heart failure and echocardiographic findings strongly suggestive of infiltrative cardiomyopathy needed percutaneous veno-arterial extracorporeal membrane oxygenation (ECMO) as bridge-to-decision. Amyloid deposition was found on endomyocardial and bone marrow biopsies. Bone marrow plasma cell infiltrate with acute renal lesion and hypercalcemia confirmed the diagnosis of multiple myeloma-associated systemic light-chain amyloidosis (AL). Refractory shock with multi-organic failure syndrome persisted and no improvements in left ventricular function and structure were seen. After extensive discussion by a multidisciplinary team, and with the patients’ family, she was not considered eligible for high-dose chemotherapy and/or autologous stem cell transplantation, heart transplantation, or sequential heart with autologous stem cell transplantation. The patient died a few hours after ECMO withdrawal. During the 14 days of ECMO support no major bleeding or thrombotic complications occurred.
Conclusions:
The clinician must consider a diagnosis of cardiac amyloidosis in patients with heart failure, a restrictive type of cardiomyopathy with ventricular hypertrophy in the absence of valve abnormalities, or uncontrolled arterial hypertension. Although developments in chemotherapy have greatly improved the outcomes in AL amyloidosis, the prognosis of patients with severe cardiac involvement remains very poor. ECMO is potentially a reliable bridge-to-diagnosis and bridge-to-decision in these patients. An experienced ECMO team, careful patient selection, and rigorous management protocols with objective criteria to wean or stop ECMO are needed.
doi:10.12659/AJCR.892772
PMCID: PMC4373156  PMID: 25803181
Amyloidosis; Cardiomyopathy, Restrictive; Extracorporeal Membrane Oxygenation; Heart Failure; Shock, Cardiogenic
9.  Cardiac Transplantation Followed by Dose-Intensive Melphalan and Autologous Stem Cell Transplantation for AL Amyloidosis and Heart Failure 
Transplantation  2010;90(8):905-911.
Background
Patients with AL amyloidosis who present with severe heart failure due to cardiac involvement rarely survive more than six months. Survival after cardiac transplantation is markedly reduced due to the progression of amyloidosis. Autologous stem cell transplantation (ASCT) has become a common therapy for AL amyloidosis, but there is an exceedingly high treatment-related mortality in patients with heart failure.
Methods
We developed a treatment strategy of cardiac transplant followed by ASCT. 26 patients were evaluated, and of 18 eligible patients, nine patients underwent cardiac transplantation. Eight of these patients subsequently received an ASCT.
Results
Six of seven evaluable patients achieved a complete hematologic remission, and one achieved a partial remission. At a median follow-up of 56 months from cardiac transplant, five of seven patients are alive without recurrent amyloidosis. Their survival is comparable to 17,389 patients who received heart transplants for non-amyloid heart disease: 64% in non-amyloid vs. 60% in amyloid patients at seven years (p= 0.83). Seven of eight transplanted patients have had no evidence of amyloid in their cardiac allograft.
Conclusions
This demonstrates that cardiac transplantation followed by ASCT is feasible in selected patients with AL amyloidosis and heart failure, and that such a strategy may lead to improved overall survival. (clinicaltrials.gov, NCT00456040)
doi:10.1097/TP.0b013e3181f10edb
PMCID: PMC2964067  PMID: 20733534
Amyloid; Cardiac Amyloidosis; Stem Cell Transplantation
10.  Reactivation of hepatitis B (reverse seroconversion) after melphalan/dexamethasone therapy for primary amyloidosis: a case report 
Introduction
Hepatitis B virus (HBV) reactivation (so-called reverse seroconversion) is a rare but known complication of hematopoietic stem cell transplantation, immunosuppressive therapy, or high-dose chemotherapy plus rituximab. This event is linked to a treatment-related fall in titers of antibodies to hepatitis B surface antigen (HBsAb) below the protective threshold level.
Case presentation
A 77-year-old Korean man diagnosed with primary amyloidosis was started on melphalan/dexamethasone combination therapy. During treatment, laboratory indices of hepatic function suddenly deteriorated, and he developed acute hepatitis through reverse HBV seroconversion, becoming positive for hepatitis B surface antigen (HBsAg) and negative for HBsAb. HBV DNA was also detectable in serum to a profound extent. Normal liver function was gradually restored during the course of antiviral therapy (entecavir).
Conclusions
HBV reactivation may lead to fatal liver disease in a significant percentage of patients. As a result, physicians often screen for HBsAg and HBsAb prior to initiating chemotherapy, advising antiviral treatment in patients seropositive for HBsAg, even in the absence of hepatitis B e antigen. Here, a case of HBV reactivation is described, involving a patient given relatively low-dose chemotherapy (melphalan/dexamethasone) for primary amyloidosis.
doi:10.1186/s13256-015-0610-z
PMCID: PMC4460636  PMID: 26031455
Hepatitis B; Immunity; Innate; Amyloidosis; Dexamethasone; Melphalan
11.  Amyloid Deposits in the Bone Marrow of Patients with AL Amyloidosis Do Not Impact Stem Cell Mobilization or Engraftment 
Amyloid deposits are often found in the bone marrow in patients with AL amyloidosis; we sought to determine whether this affects stem cell collection or engraftment following high dose melphalan and autologous stem cell transplantation (HDM/SCT). Data on 361 patients with AL amyloidosis who had Congo red staining of the pre-treatment bone marrow biopsy and underwent HDM/SCT from July 1994 to December 2011 were reviewed. Data were analyzed for stem cell yield, number of days of stem cell collection, neutrophil and platelet engraftment post SCT. Sixty-five % of patients (n=233) had bone marrow amyloid deposits. There were no significant differences in median number of stem cells collected, days to neutrophil or platelet engraftment between patients with and without bone marrow amyloid deposits. Thus, while amyloid involvement of the bone marrow is common, it does not negatively impact stem cell mobilization or neutrophil and platelet engraftment after HDM/SCT.
doi:10.1016/j.bbmt.2012.07.016
PMCID: PMC4161277  PMID: 22842332
Amyloidosis; light-chain; melphalan; stem cell transplantation; stem cell mobilization; stem cell collection; engraftment; bone marrow
12.  Ten-year follow-up after autologous stem cell transplantation of a patient with immunoglobulin light-chain (AL) amyloidosis with deposits in the heart, liver and gastrointestinal tract 
BMJ Case Reports  2011;2011:bcr0320114007.
The prognosis in amyloid light chain (AL)-amyloidosis and multiorgan involvement is poor, with a high-treatment-related mortality after high-dose melphalan and autologous stem cell transplantation (HDM/SCT). Some patients, however, might benefit from the therapy. We report a case of cardiac AL-amyloidosis with multiorgan involvement where the progressive cardiomyopathy was halted after successful treatment with HDM/SCT in 2001. The patient is in an excellent cardiac condition with a good quality of life, receiving treatment with angiotensinogen receptor blockers and a flexible diuretics regimen at follow-up after 10 years.
doi:10.1136/bcr.03.2011.4007
PMCID: PMC3171029  PMID: 22688930
13.  Autologous Stem Cell Transplant for AL Amyloidosis 
Bone Marrow Research  2012;2012:238961.
AL amyloidosis is caused by clonal plasma cells that produce immunoglobulin light chains which misfold and get deposited as amyloid fibrils. Therapy directed against the plasma cell clone leads to clinical benefit. Melphalan and corticosteroids have been the mainstay of treatment for a number of years and the recent availability of other effective agents (IMiDs and proteasome inhibitors) has increased treatment options. Autologous stem cell transplant (ASCT) has been used in the treatment of AL amyloidosis for many years. It is associated with high rates of hematologic response and improvement in organ function. However, transplant carries considerable risks. Careful patient selection is important to minimize transplant related morbidity and mortality and ensure optimal patient outcomes. As newer more affective therapies become available the role and timing of ASCT in the overall treatment strategy of AL amyloidosis will need to be continually reassessed.
doi:10.1155/2012/238961
PMCID: PMC3361989  PMID: 22675637
14.  POEMS Syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy and Skin Changes) Treated with Autologous Hematopoietic Stem Cell Transplantation: A Case Report and Literature Review 
Patient: Male, 62
Final Diagnosis: POEMS syndrome
Symptoms: General malaise • pretibial edemas • weight loss
Medication: —
Clinical Procedure: Autologous hematopoietic stem cell transplantation
Specialty: Hematology
Objective:
Rare disease
Background:
POEMS syndrome is a rare systemic pathology of paraneoplastic origin that is associated with plasma cell dyscrasia. It is characterized by the presence of sensorimotor polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes, and other systemic manifestations. The pathogenesis of the syndrome is unknown but over-production of vascular endothelial growth factor is probably responsible for most of the more characteristic symptoms.
There is no standard treatment for POEMS syndrome and no randomized controlled clinical trials of treatment exist in the available literature. High-dose melphalan with autologous hematopoietic stem cell transplantation should be considered for younger patients with widespread osteosclerotic lesions, and for patients with rapidly progressive neuropathy.
Case Report:
This is the case of a 62-year-old Caucasian man who was admitted to our center presenting pretibial edema accompanied by significant weight loss and difficulty walking. POEMS criteria were present and an immunofixation test confirmed the presence of a monoclonal plasmaproliferative disorder. After autologous hematopoietic stem cell transplantation, the monoclonal component disappeared and the patient’s clinical status improved markedly.
Conclusions:
Autologous hematopoietic stem cell transplantation following high-dose melphalan is an effective therapy for younger patients with widespread osteosclerotic lesions in POEMS syndrome.
doi:10.12659/AJCR.892837
PMCID: PMC4349133  PMID: 25726020
Paraproteinemias; POEMS Syndrome; Polyneuropathies; Transplantation, Autologous; Vascular Endothelial Growth Factor A
15.  Successful long-term outcome of the first combined heart and kidney transplant in a patient with systemic AL amyloidosis 
Simultaneous cardiac and renal involvement is associated with a particularly poor prognosis in patients with AL amyloidosis (AL-A). We report the first case of a successful long-term outcome of combined heart and kidney transplantation not followed by autologous stem cell transplantation in a patient with systemic AL-A. The recipient was a 46-year-old man with end-stage renal failure associated with serious cardiac involvement in the context of AL-A. Before transplantation, two courses of oral melphalan plus prednisone induced partial hematologic remission, as shown by the decrease in circulating free light chain with no improvement of renal or heart function. The patient underwent combined heart and kidney transplantation as a rescue treatment. Three years after organ transplantation, plasma cell dyscrasia remains in complete remission, with normal free lambda light chain levels and no recurrence of amyloid deposition on heart and kidney grafts. This case report demonstrates that successful long-term outcome of combined heart and kidney transplantation not systematically associated with stem cell transplantation may be considered an additional therapeutic option in AL-A patients with severe organ dysfunction and partial hematologic remission.
doi:10.1111/j.1600-6143.2008.02469.x
PMCID: PMC2810314  PMID: 19067666
Amyloidosis; surgery; Heart Transplantation; Humans; Kidney Transplantation; Male; Melphalan; administration & dosage; Middle Aged; Prednisone; administration & dosage; Transplantation Conditioning; Treatment Outcome; combine Heart and Kidney transplantation; Amyloidosis
16.  Current Trends in the Diagnosis, Therapy and Monitoring of the Monoclonal Gammopathies 
The Clinical Biochemist Reviews  2009;30(3):93-103.
This paper provides an overview of developments in the diagnosis, therapy and monitoring of the monoclonal gammopathies, particularly multiple myeloma and AL amyloidosis. Consensus statements outlining diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS), myeloma and amyloidosis have been recently published. Understanding of the biology and pathogenesis of myeloma has accelerated in the last decade and provides the basis for improved prognostication and therapeutic interventions. Myeloma therapy has progressed with the introduction of autologous and allogeneic stem cell transplantation and the recent introduction of the novel agents, thalidomide, lenalidomide and bortezomib. Each of these therapeutic advances has contributed to the improved survival seen in this patient population. Similar treatment advances are occurring in AL amyloidosis. While serum and urine electrophoretic analysis remain the “gold standard” laboratory techniques for the accurate and cost-effective monitoring of the monoclonal gammopathies, new tests such as the free light chain assays have a complementary role. New guidelines for the monitoring of both myeloma and AL amyloidosis have been produced that incorporate these newer tests.
PMCID: PMC2755006  PMID: 19841691
17.  Clinical Features and Treatment Response of Light Chain (AL) Amyloidosis Diagnosed in Patients With Previous Diagnosis of Multiple Myeloma 
Mayo Clinic Proceedings  2010;85(3):232-238.
OBJECTIVE: To identify and assess the clinical features and treatment response of light chain (AL) amyloidosis diagnosed in patients with previous diagnosis of multiple myeloma (MM).
PATIENTS AND METHODS: From a prospectively maintained database, we identified 47 patients seen between January 1, 1990, and August 31, 2008, with a diagnosis of AL amyloidosis that was made at least 6 months after MM diagnosis; these patients form the study group.
RESULTS: Among the 47 patients, 36 developed typical features, 3 had atypical features, and 8 had an incidental finding of amyloidosis. Amyloid deposits were demonstrated in bone marrow, subcutaneous fat aspirate, or organ biopsy in 24, 19, and 12 patients, respectively. One organ was involved in 29 patients (62%), whereas 11 patients (23%) had involvement in more than one organ. At diagnosis of AL amyloidosis, treatment was changed or started in 22 patients, whereas the same treatment was continued in 21 patients, and no treatment data were available for the rest. The best hematologic response included partial response or better in 11 patients (23%) and stable disease in 18 patients (38%). Improvement in an organ was seen in 3 of the 21 evaluable patients. The median overall survival from diagnosis of AL amyloidosis was 9.1 months (95% confidence interval, 4-14). Of the 6 patients still alive, 2 underwent peripheral blood stem cell transplant, and none had cardiac involvement or involvement in more than one organ.
CONCLUSION: Delayed onset of AL amyloidosis is rarely seen in patients with MM and requires a high index of suspicion for prompt diagnosis. Outcome of these patients is poor, especially in the presence of cardiac involvement.
Delayed onset of light chain (AL) amyloidosis is rarely seen in patients with multiple myeloma and requires a high index of suspicion for prompt diagnosis; outcome of these patients is poor, especially if they have cardiac involvement.
doi:10.4065/mcp.2009.0547
PMCID: PMC2843113  PMID: 20194151
18.  Advanced POEMS syndrome treated with high-dose melphalan followed by autologous blood stem cell transplantation: a single-center experience 
Blood research  2014;49(1):42-48.
Background
POEMS syndrome is a rare paraneoplastic syndrome associated with plasma cell dyscrasia. High-dose chemotherapy followed by autologous stem cell transplantation has shown encouraging efficacy in the treatment of patients with POEMS syndrome. However, there are minimal reports on clinical outcomes after autologous stem cell transplantation for patients with advanced disease and very poor performance status.
Methods
We retrospectively evaluated 9 advanced POEMS syndrome patients, who had an Eastern Cooperative Oncology Group performance status score of 3 or 4, and were treated with high-dose melphalan therapy followed by autologous stem cell transplantation from 2004 to 2011.
Results
Eight patients achieved initial hematologic response, 4 of whom had complete responses. At a median follow-up of 44 months (range, 8-94 months), 7 patients were alive, with 3-year overall survival rate of 77.8%. There were no hematologic relapses in the survivors. One patient died of disease progression; the other died of pneumonia despite a hematologic response 3 months after autologous stem cell transplantation. All survivors achieved improvement in general performance status and in clinical response.
Conclusion
High-dose melphalan followed by autologous stem cell transplantation can be considered a valid treatment option even for patients with advanced POEMS syndrome.
doi:10.5045/br.2014.49.1.42
PMCID: PMC3974956  PMID: 24724066
POEMS syndrome; Stem cell transplantation; Chemotherapy; Severity; Illness index
19.  Endoscopic and histopathological features of gastrointestinal amyloidosis 
Amyloidosis is a rare disorder, characterized by the extracellular deposition of an abnormal fibrillar protein, which disrupts tissue structure and function. Amyloidosis can be acquired or hereditary, and systemic or localized to a single organ, such as the gastrointestinal (GI) tract. Clinical manifestations may vary from asymptomatic to fatal forms. Primary amyloidosis (monoclonal immunoglobulin light chains, AL) is the most common form of amyloidosis. AL amyloidosis has been associated with plasma cell dyscrasias, such as, multiple myeloma. Secondary amyloidosis is caused by the deposition of fragments of the circulating acute-phase reactant, serum amyloid A protein (SAA). Common causes of AA amyloidosis are chronic inflammatory disorders. Although GI symptoms are usually nonspecific, histopathological patterns of amyloid deposition are associated with clinical and endoscopic features. Amyloid deposition in the muscularis mucosae, submucosa, and muscularis propria has been dominant in AL amyloidosis, leading to polypoid protrusions and thickening of the valvulae conniventes, whereas granular amyloid deposition mainly in the propria mucosae has been related to AA amyloidosis, resulting in the fine granular appearance, mucosal friability, and erosions. As a result, AL amyloidosis usually presents with constipation, mechanical obstruction, or chronic intestinal pseudo-obstruction while AA amyloidosis presents with diarrhea and malabsorption Amyloidotic GI symptoms are mostly refractory and have a negative impact on quality of life and survival. Diagnosing GI amyloidosis requires high suspicion of evaluating endoscopists. Because of the absence of specific treatments for reducing the abundance of the amyloidogenic precursor protein, we should be aware of certain associations between patterns of amyloid deposition and clinical and endoscopic features.
doi:10.4253/wjge.v3.i8.157
PMCID: PMC3180620  PMID: 21954412
Amyloidosis; Amyloid; Congo red; Endoscopy; Gastrointestinal tract; Histopathology
20.  A Phase I Dose-Escalation Trial of High-Dose Melphalan with Palifermin for Cytoprotection Followed by Autologous Stem Cell Transplantation for Patients with Multiple Myeloma with Normal Renal Function 
Melphalan 200 mg/m2 is the standard conditioning regimen for patients with multiple myeloma (MM) with normal renal function (NRF) undergoing autologous stem cell transplant (ASCT). In an effort to escalate the dose of melphalan and to improve the efficacy, we designed a dose-escalation study of melphalan in conjunction with palifermin in patients with NRF, with the hope that a higher dose of melphalan can be administered with an acceptable degree of oral mucositis (OM). We enrolled 19 patients (18 evaluable) with NRF. Dose-escalation of melphalan administered on day –2 began at 200 mg/m2 with palifermin administered at a fixed dose of 60 mcg/kg/day. Palifermin was given as an i.v. bolus on day −5, −4, and −3, and then on day +1, +2, and +3. Subsequent dose escalations of melphalan were done at 20 mg/m2 increments up to a maximum dose of 280 mg/m2. Of 18 evaluable patients, there were no treatment-related deaths by day 100. The median age was 48.5 years (range, 33-65 years). The most common adverse events related to palifermin included rash (18 events, no ≥grade 3 events), elevation of amylase (10 events, 4 were grade 3 but asymptomatic), and lipase (5 events, 2 were grade 3 but asymptomatic), edema (11 events, no ≥grade 3). The overall incidence of OM grade 3 was 44% (8/18) with a median duration of severe mucositis of 5 days (range, 3-6 days). Eleven patients (61%) required opioid analgesics. None of the patients received total parenteral nutrition (TPN)/nasogastric feeding. Two of 6 patients who were given melphalan 280 mg/m2 did not develop OM. Cardiac dose-limiting toxicity (DLT) in the form of atrial fibrillation did occur in 1 of 6 patients treated with melphalan 280 mg/m2. Palifermin has permitted safe dose escalation of melphalan up to 280 mg/m2, thus reaching the cumulative dosage of melphalan administered in tandem ASCT. This higher dose of melphalan has the potential to improve the efficacy and, hopefully, outcomes of patients with MM with a single ASCT. A phase 2 trial is necessary to better delineate the antimyeloma efficacy of this regimen.
doi:10.1016/j.bbmt.2012.08.003
PMCID: PMC3786738  PMID: 22892551
Palifermin; Oral mucositis; High-dose melphalan
21.  Myeloma (multiple) 
BMJ Clinical Evidence  2006;2006:2403.
Introduction
Multiple myeloma is the most common primary cancer of the bones in adults, representing about 1% of all cancers diagnosed in the US in 2004, and 14% of all haematological malignancies. In the UK, multiple myeloma accounts for 1% of all new cases of cancer diagnosed each year.
Methods and outcomes
We conducted a systematic review and aimed to answer the following clinical questions: What are the effects of treatment in people with asymptomatic early stage multiple myeloma (stage I)? What are the effects of first-line treatments in people with advanced stage multiple myeloma (stages II and III)? What are the effect of salvage treatments, or supportive therapy, in people with advanced stage multiple myeloma (stages II and III)? We searched: Medline, Embase, The Cochrane Library and other important databases up to November 2004 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA).
Results
We found 71 systematic reviews, RCTs, or observational studies that met our inclusion criteria.
Conclusions
In this systematic review we present information relating to the effectiveness and safety of the following interventions: allogenic transplant (non-myeloablative), autologous stem cell transplant (early or late transplantation, double or single, purging of), bisphosphonates, bone marrow stem cells, bortezomib, chemotherapy (combination, conventional dose, intermediate dose plus stem cell rescue, high-dose plus stem cell rescue), combination chemotherapy plus corticosteroids, deferred treatment (in stage I disease), early chemotherapy plus corticosteroids (in stage I disease), epoetin alpha, first-line treatments, infection prophylaxis, interferon, maintenance therapy (in advanced multiple myeloma), melphalan (normal dose, high dose before autologous stem cell transplantation, plus total body irradiation), optimum priming regimen, peripheral blood stem cells, plasmapheresis, salvage therapy regimens, single-agent chemotherapy (adding prednisolone), single-agent chemotherapy (bendamustine, melphalan, cyclophosphamide, lomustine, carmustine) with or without corticosteroid (prednisolone, dexamethasone), syngeneic transplantation, and thalidomide (and derivatives).
Key Points
Multiple myeloma is a neoplastic proliferation of plasma cells, mainly within the bone marrow, causing anaemia, renal dysfunction, infections and bone lesions. Monoclonal protein is found in serum and/or urine in 97% of people.
Early chemotherapy plus corticosteroids have not been shown to improve survival in people with asymptomatic, early stage multiple myeloma.
In people with advanced multiple myeloma, combination chemotherapy or single agent chemotherapy plus prednisolone improves survival more effectively than single agent chemotherapy alone, and adding corticosteroids to combination chemotherapy is more effective still High or intermediate dose chemotherapy with bone marrow or peripheral blood stem cell rescue improves progression free and overall survival compared with conventional dose chemotherapy. Syngeneic (from a twin) or autologous stem cell transplantation may increase event free, but not overall, survival if given early rather than late.An optimum priming regimen with stem cell factor may increase the yield of CD34+ cells for transplantation, but increases the risk of adverse effects. Very high dose melphalan may increase overall survival and have fewer adverse effects compared with high dose melphalan plus total body irradiation.
Adding interferon to chemotherapy increases response rates and progression free, but not overall, survival, but increases toxicity. We don't know which are the most effective salvage regimens,or if thalidomide increases survival, but bortezomib may increase response rates and overall short term survival.
In people with advanced disease, bisphosphonates reduce skeletal fractures and pain, epoetin alpha may improve anaemia, prophylactic treatment with antibiotics and immunoglobulin may reduce infections, and plasmapheresis may improve renal function when added to forced diuresis plus chemotherapy. However, we don't know whether any of these treatments improve survival, and they may increase adverse effects.
PMCID: PMC2907638
22.  Pathologic improvement after high-dose melphalan and autologous stem cell transplantation for primary systemic amyloidosis 
NDT Plus  2008;1(6):414-416.
Although primary systemic amyloid light-chain amyloidosis was considered intractable, recent advances in therapy have been reported to result in better clinical outcomes including remission of nephrotic syndrome. However, changes in renal pathologic findings after high-dose chemo- therapy have not been characterized. We describe a patient who underwent serial renal biopsies and had complete remission after high-dose melphalan and autologous stem cell transplantation for this form of amyloidosis. Successive renal biopsy specimens showed reduction in amyloid staining mainly in interlobular arterial and arteriolar walls. Thus, amyloid light-chain amyloidosis resolved both clinically and pathologically after high-dose chemotherapy.
doi:10.1093/ndtplus/sfn144
PMCID: PMC3840819  PMID: 24282444
AL amyloidosis; autologous stem cell transplantation; high-dose melphalan; pathologic improvement
23.  Febrile reactions occurring with second cycle of high-dose melphalan and SCT in patients with AL amyloidosis: a ‘melphalan recall’ reaction 
Bone marrow transplantation  2009;45(1):21-24.
Aggressive treatment with high-dose i.v. melphalan followed by auto-SCT (HDM/SCT) is effective in inducing hematological and clinical remissions, and in extending survival in AL amyloidosis. Tandem cycles of HDM/SCT have been shown to increase hematologic complete response rates in patients with AL amyloidosis. Between April 1994 and July 2008, 57 patients with AL amyloidosis at the Boston University Medical Center were treated with a second cycle of HDM/SCT after failing to achieve a complete response after a first transplantation. A total of 11 of 57 patients (19%) treated with tandem transplantation developed high fever 12–24 h after melphalan administration. The average peak temperature was 39.1 °C. Other clinical features include hypotension, acute renal failure and skin rash. No infectious etiology was identified. One of the patients had serum available for measurement of cytokines before, during and after the febrile reaction. The concentration of several pro-inflammatory cytokines, including IL-6 and TNFα, increased significantly, showing a clear physiological response correlating with the clinical findings. We conclude that an unusual cytokine-mediated febrile reaction can occur in patients with AL amyloidosis exposed to a second cycle of high-dose melphalan, which we have termed a ‘melphalan recall’ reaction.
doi:10.1038/bmt.2009.94
PMCID: PMC3672063  PMID: 19421171
AL amyloidosis; stem cell transplantation; melphalan recall
24.  Haematopoietic stem cell transplantation as first-line treatment in myeloma: a global perspective of current concepts and future possibilities 
Oncology Reviews  2012;6(2):e14.
Stem cell transplantation forms an integral part of the treatment for multiple myeloma. This paper reviews the current role of transplantation and the progress that has been made in order to optimize the success of this therapy. Effective induction chemotherapy is important and a combination regimen incorporating the novel agent bortezomib is now favorable. Adequate induction is a crucial adjunct to stem cell transplantation and in some cases may potentially postpone the need for transplant. Different conditioning agents prior to transplantation have been explored: high-dose melphalan is most commonly used and bortezomib is a promising additional agent. There is no well-defined superior transplantation protocol but single or tandem autologous stem cell transplantations are those most commonly used, with allogeneic transplantation only used in clinical trials. The appropriate timing of transplantation in the treatment plan is a matter of debate. Consolidation and maintenance chemotherapies, particularly thalidomide and bortezomib, aim to improve and prolong disease response to transplantation and delay recurrence. Prognostic factors for the outcome of stem cell transplant in myeloma have been highlighted. Despite good responses to chemotherapy and transplantation, the problem of disease recurrence persists. Thus, there is still much room for improvement. Treatments which harness the graft-versus-myeloma effect may offer a potential cure for this disease. Trials of novel agents are underway, including targeted therapies for specific antigens such as vaccines and monoclonal antibodies.
doi:10.4081/oncol.2012.e14
PMCID: PMC4419629  PMID: 25992212
myeloma; stem cell transplantation; autologous; melphalan; bortezomib.
25.  Heart Transplantation and End-Stage Cardiac Amyloidosis: A Review and Approach to Evaluation and Management 
Cardiac amyloidosis is one of the most common of the infiltrative cardiomyopathies and is associated with a poor prognosis. The extent of cardiac involvement with amyloid deposition is an important determinant of treatment options and is the major determinant of outcome in patients with amyloidosis. Several small case series with sequential orthotopic heart transplantation and autologous stem cell transplant have demonstrated an improvement in post-transplant outcome and have revived enthusiasm about heart transplantation for patients with end-stage heart failure due to AL amyloidosis. The purpose of this review is to summarize the evaluation and management of cardiac amyloidosis and to provide our single-center experience with end-stage heart failure due to AL amyloidosis treated with heart transplantation followed by an autologous stem cell transplant.
PMCID: PMC3487570  PMID: 23227279
Cardiac amyloidosis; amyloid protein; AL amyloidosis; autologous hematopoietic stem cell transplant; end-stage cardiac amyloidosis

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