Primary amyloidosis

Systemic AA amyloidosis results from tissue deposition of fibrils of serum amyloid A protein.

AA amyloidosis occurs primarily in patients with chronic inflammatory disorders such as rheumatoid arthritis, juvenile idiopathic arthritis, or inflammatory bowel disease, or chronic infections such as osteomyelitis or tuberculosis in some patients.

In some patients, the cause of AA amyloidosis is not identified.

In recent years there has been a reduction in the relationship of the above disorders with AA amyloidosis but there has been an increase in the fraction of patients who have chronic skin  or soft tissue infections related to injection drug use.

Patients with local immunoglobulin light chain amyloidosis typically have no circulating monoclonal immunoglobulins in the serum or urine and no evidence of bone marrow involvement by clonal plasma cells.

Localized immunoglobulin light chain amyloidosis is uncommon and constitutes approximately 12% of all amyloid cases.

Localized immunoglobulin light chain amyloidosis is rare and can cause significant morbidity and in rare cases mortality.

In immunoglobulin light chain (AL) amyloidosis, the amyloidogenic protein is a misfolded light chain or light chain fragment produced by clonal plasma cells.

Characterized by deposition of misfolded immunoglobulin light chains or fragments of light or heavy chains in fibrillar form.

This protein configuration is responsible for the apple-green birefringence observed under polarized microscopic examination of involved tissue stained with Congo red dye, the hallmark essential for diagnosis.

Congo red staining of a subcutaneous fat aspirate is a reliable and noninvasive test that can identify amyloid deposits in approximately 85% of patients.

Amyloid deposits can be identified by bone marrow aspiration in biopsy followed by Congo red staining: a bone marrow evaluation has a sensitivity of only 56 to 70% for establishing a diagnosis of systemic amyloidosis.

The next most used biopsy is a fat pad aspiration which has a diagnostic sensitivity for AL amyloidosis of 70 to 80%.

A bone marrow biopsy and fat pad aspiration performed concurrently can reach the diagnostic sensitivity for AL amyloidosis of 80 to 90%.

Proteins that are found in amyloid deposits are most commonly serum amyloid protein, Apolipoprotein E, , apolipoprotein A1, and Apolipoprotein A4

Amyloid aggregates can affect multiple organs: heart approximately 70%, kidneys 70%, liver 17%, soft tissue 17%, nervous system 15%, and gastrointestinal tract 10%.

Deposition of light chains can occur in any organ and tissue.

Identification of free light chains in the serum, a urine without confirmation of the amyloid composition in tissue is not adequate for diagnosis.

Fatigue is the communist symptom in AL amyloidosis.

In AL amyloid deposition can affect any organ system, and the presenting symptoms are largely related to organ dysfunction caused by amyloid deposition.

In AA amyloidosis, kidney involvement is nearly universal, resulting in reduced kidney function and proteinuria that may be in the nephrotic range.

Cardiac involvement in the degree of abnormal free light protein production are important prognostic factors with AL.

Cardiac involvement is the main determinant of patient survival and most commonly presents with heart failure with preserved ejection fraction and symmetric cardiac wall, thickening on echocardiography.

Cardiac amyloidosis presents with heart failure, and initial suspicion is noted during echocardiographic evaluation with finding suggestive of an infiltrative cardiomyopathy.

Concentric cardiac hypertrophy, increase in interventricular, septum thickness, and normal to low voltage on EKG is classically described in amyloidosis.

Diffuse and subendocardial, late gadolinium enhancement on cardiac magnetic resonance imaging is highly sensitive and specific for cardiac amyloidosis.

Staging systems, incorporate anti-pro BNP 1800 ng/L or greater or BNP greater than 400 ng/L, cardiac troponins, T .025 µL or greater and the difference between involved and uninvolved serum free light chains of 18 mg/deciliter as risk factors.

Patients with no risk factors are classified as stage 1, those with    0ne elevated risk factor is stage II, those with two elevated risk factors has stage III, and those with three elevated risk factors as stage IV.

For patient classified as having stage I, II, III, IV disease, the median overall survival from diagnosis is 94, 40, 14, and six months, respectively.

The median survival of patients from stage I to IV is 94.1, 40.3, 14, and 5.8 months respectively.

Electrocardiograms may show low voltage and rhythm abnormalities and cardiac biomarkers, including troponins, and BNP levels are important predictors of outcome in amyloidosis, as well as part of the cardiac response criteria.

Coaglation studies are clinically indicated in evaluation, and patients with systemic light chain amyloidosis, are at risk of developing acquired Factor X  deficiency due to binding affect 10 to amyloid  fibrils.

Only 5% of the patients with primary amyloidosis survive beyond 10 years.

This protein is a result of a transformed, clonal plasma cell with low to absent proliferative potential.

Relatively low plasma cell burden.

It is distinguished from secondary amyloidosis (AA), where the amyloidogenic precursor is a normal acute phase reactant serum amyloid A (SAA), which is produced as a result of chronic inflammation or infection (Rajkumar SV).

Hereditary amyloidosis refers to amyloid fibrils derived from genetic variants of mutant proteins, with the most common being transthyretin (TTR).

Transthyroitin amyloidosis is found in as many as 25% of adults older than 85 years on autopsy.

Higher incidence of monoclonal gammopathy with transthyretin (TTR) amyloidosis.

Classification of systemic amyloidoses is based on the misfolded precursor proteins, and at least 30 different precursors have been identified.

The clinical course, affected organ systems, prognosis, and treatment considerations are determined by the type of precursor protein involved.

A wild-type TTR may cause senile cardiac amyloidosis (Westermark P).

Mutant transthyretin amyloidosis have involvement of the heart, nerves, and eyes, while all organs except the brain can be involved in immunoglobulin light chain amyloidosis.

TTR affects about 50,000 patients worldwide and causes a buildup of abnormal transthyretin proteins in the peripheral nerves, heart, kidneys, eyes and G.I. tract.

TTR can be treated with RNA inhibitors with the first drug approved patisiran infusion.

Monoclonal immunoglobulin light chain with a 3:1 predominance of lambda:kappa light chains.

Lambda is intrinsically more amylidogenic than kappa light chains.

Serum and urine protein electrophoresis is not adequate for laboratory evaluation, as it does not show a monoclonal spike in nearly 50% of cases.

Serum immunofixation electrophoresis and 24 hour urine immunofixation electrophoresis is essential along with serum free light chain ratio analysis.

The majority if patients with light chain amyloidosis have immunoglobulin abnormalities of kappa or lambda chains or Kappa/lambda ratio.

Workup should include urinalysis and quantification of proteinuria  by 24 hour urine collection, and measurement of creatinine clearance, serum electrophoresis and immunofixation, and serum for the light chain assay.

Free light chains were cleared by the kidney and renal insufficiency increases the concentrations of free light chains.

Incidence of approximately 3-10 per million persons per year.

AL is uncommon in non-white individuals and persons younger than 40 years,

and it affects men and women equally.

Muscle involvement is rare and not well categorized which may lead to a delay in diagnosis.

Most common systemic amyloidosis in the U.S.

Incidence approximately one case per hundred thousand person-years in Western countries.

Without treatment has in excess inexorable progress of course due to uncontrolled damage of organs.

Prognosis is predominately determined by the presence of heart involvement.

Patients with severe heart involvement, stage II-IIIB by the Mayo staging system have the shortest survival, with the median of about six months.

The Mayo Clinic staging system is based on the levels of NT-pro BNP and cardiac troponins, and the clonal burden, assess as the difference between involved and uninvolved circulating free light chains.

Cause of death in patients with cardiac amyloidosis is usually sudden cardiac death.

As amyloid accumulates it progressively affects organs structure and function.

Amyloid arthropathy occurs in 1-5% of patients.

Diagnosis is often delayed because of subtle symptomology common in other more common conditions.

Diagnosis of systemic amyloidosis should be suspected in patients with non-diabetic proteinuria, heart failure with preserved ejection fraction, unexplained peripheral neuropathy, or atypical monoclonal gammopathy of undetermined significance.

Incidence about one-fifth that of myeloma.

Progression to myeloma is uncommon, because of the short survival.

The precursor protein is bone marrow plasma cell-derived immunoglobulin light, or rarely heavy, chains, and targeting plasma cells is the mainstay of therapy.

The next most common recognized form of systemic amyloidosis are due to the precursor protein, transthyretin which is made in the liver.

Patients may present with features of amyloidosis or myeloma and subsequently develop symptoms of the other.

In a series of 1596 patients with amyloidosis during 35 years progression to multiple myeloma occurred in 6 cases (Rajkumur SV).

Incidence similar to Hodgkin’s disease and polycythemia rubra vera.

Median age at presentation 65 years.

Prognosis worse than for multiple myeloma.

Unlike multiple myeloma, where the tumor burden of proliferative plasma cells drives the clinical course, the natural history of primary amyloidosis is determined by the degree and type of organ involvement by the amyloid protein produced by the non-proliferating transformed plasma cells.

AL amyloidosis is typically associated with a plasma cell disorder, responsible for production of lambda immunoglobin light change in 75 to 80% of cases and Kappa light chains in the remaining 20 to 25%.

No known risk factors or sexual or racial predisposition.

Characterized by deposition of a congophilic beta-pleated fibrillary protein with monoclonal light-chain fragments in affected tissues.

Results from the misfolding of a protein derived from native alpha helical state into a proteolysis resistant beta-pleated sheet.

The inability to degrade these proteins results in their extracellular deposition of amyloid.

Virtually all patients have elevated levels of free light chains.

Beta-pleated sheets allow for binding of Congo Red stain, which emits an anpple green birefringence under polarized light.

Amorphous hyaline appearing material in the intercellular space.

Amyloid defined by Congo red dye and green birefringence under polarized light.

Extracellular deposits in kidneys, heart, liver, gastrointestinal tract, peripheral nervous system and other tissues result in organ dysfunction and death.

Nervous system symptoms include: small fiber, neuropathy, and automatic dysfunction with G.I. motility disturbances, early satiety, dry eyes and mouth, orthostatic hypotension, and neurogenic bladder.

Macroglossia is seen in approximately 10 to 20% of patients.

Hepatic involvement causes cholestasis and hepatomegaly, and hyperbilirubinemia can occur as a terminal event with liver liver involvement.

Splenic involvement may result in hyposplenism.

Easy bruising may occur due to amyloid deposits or factor X deficiency.

When patients present with a protein spike and findings consistent with a monoclonal gammopathy of undetermined significance but there is albuminuria, CHF, renal insufficiency, peripheral neuropathy, orthostatic hypotension, carpal tunnel syndrome, hepatomegaly, malabsorption syndrome, or any combination of these problems, the most likely diagnosis is primary systemic amyloidosis.

The process results from the deposition of amyloid light chains in organs and tissues.

Life expectancy dependent on degree of organ involvement and ranges from 6 months for patients with severe cardiac involvement to a few years.

Goal is to diagnosis amyloidosis as early as possible and utilizing chemotherapy and supportive care for individual patients.

Supportive care includes: salt restriction, diuretics, management of hyperlipidemia, ACE inhibitors, or angiotensin receptor blockers may help with proteinuria, dialysis is an option for end-stage renal disease, diarrhea management for patients with autonomic nervous system involvement, oral or intravenous, feeding in undernourished patients, neuropathic pain control with gabapentin, bleeding complications may require clotting  factor replacement’

Diagnosis requires evidence of amyloid deposits in tissue and evidence of plasma cell dyscrasia.

Reduction in amyloid light chains associated with improved organ function and patient survival.

Serum free light chains are a marker of clonal response with treatment (Caillard S).

Patients with greater than 10% bone marrow plasmacytosis have inferior outcomes relative to patients with 10% or less plasma cells and are considered to have amyloidosis with multiple myeloma.

The 10% cut off point markedly affects prognosis independent of serum immunoglobulin free light chains and cardiac biomarkers

Presence of translocation t(;11) is associated with inferior survival.

Serum free light chains levels are utilized in the assessment of plasma cell dyscrasias.

Serum light chains have prognostic value, and is the most important tool to monitor responses to treatment and predict outcomes after therapy.

Serum free light chains have been incorporated into prognostic tools that include cardiac troponin T and NT-pro-BNP levels.

Patients that present with advanced disease and involvement with more than one organ have significantly shorter survival and reduced quality-of-life.

Cardiac biomarkers BNP or troponins reflect heart involvement (Jain AB).

Cardiac involvement contributes approximately 75% of deaths.

The absence of treatment for AL amyloidosis in patients with heart failure symptoms have a median survival time of six months.

Light chain amyloid has toxic direct effect on cardiac myocytes (Brenner DA).

Cardiac improvement with treatment may be subtle, and echocardiographic changes can be delayed ().

Serial measurement of BNP showing reduction in levels indicate cardiac response and improved outcome (Palladini G).

Responses to treatment associated with improvement in NYHA classification as toxic light chain reduction occurs.

Patients with amyloidosis who present with heart failure or syncope have a survival of 4-6 months.

Serum immunoglobulin free light chains levels are prognostic.

Immunoglobulin free light chains are the mainstay for evaluating hematological response.

Treatment of amyloidosis targets a reduction of involved free light chains to less than 4 mg/dL as the desired goal, and failure to achieve this level may prompt a change of therapy.

Renal involvement, presenting as hypoalbuminemia and albuminuria occurs in approximately 58% of patients with light chain amyloidosis.

Effective treatment may be associated with renal improvement in 25% of patients and may occur as long as 1 year after initiation of treatment.

Survival with light chain amyloidosis is best predicted by a combination of high sensitivity cardiac troponins T at presentation and changes in N-terminal pro-B-type natriuretic peptide (NT-proBNP) after chemotherapy: after treatment progression of NT-proBNP and a more than 75% increase of high sensitivity cardiac troponin T were independent prognostic determinants of survival (Palladini G et al).

High sensitivity cardiac troponin T is the best baseline prognostic marker.

Almost all patients require systemic therapy.

Treatment improves organ function, quality-of-life, and survival in patients with primary amyloidosis.

Survival improvements have improved with each decade, however mortality in the first six months has not improved in the last 30 years.

Overall survival 1.5 years with conventional chemotherapy.

5 year overall survival 28%.

Median survival 13.2 months.

Fewer than 5% of patients survive 10 years or longer.

Early mortality, with nearly half of patients dying within a year of diagnosis.

Frequent presentation with vague and nonspecific symptoms.

The majority of patients have a rapidly progressive disease.

Kidney involvement is the most common organ abnormality with proteinuria and nephrotic syndrome seen in up to 90% of patients.

Should be considered in every patient with nephrotic syndrome in the absence of diabetes and hypertension.

May involve renal blood vessels, and tubules and have only modest proteinuria.

In cases of AA amyloidosis associated with injection drug use, heroin is the most commonly implicated agent.

Patients with AAA amyloidosis associated with heroin usually have HCV, HIV infections.

Cardiac involvement is the second most common organ involvement and is associated with a poor prognosis.

Survival of patients with systemic AL amyloidosis is dependent on the severity of cardiac dysfunction at the time of diagnosis.

Patients who were diagnosed late in the clinical course have a median survival of 3 to 6 months versus patients without cardiac involvement that can survive for many years.

The heart is frequently involved in 70 to 80% of patients and cardiac involvement is leading cause of death.

Cardiac findings include low voltage on EKG, concentric ventricular thickening, and diastolic dysfunction.

In patients with congestive heart failure or cardiomyopathy in the absence of ischemic or valvular heart disease should be considered for the diagnosis of cardiac amyloidosis.

Poor atrial contractility, increased risk for atrial thrombi and thromboembolic complications, elevated levels of serum cardiac troponin, NT – proBNP and  bradyarrhythmia are common.

Prognosis of primary cardiac amyloidosis with light chain disease has a median survival of less than 1 year after presentation.

Patients with cardiac involvement typically have low-voltage complexes on electrocardiogram evaluation.

Patients with cardiac amyloidosis with conduction or arrhythmias have a high risk for sudden death.

A misleading pseudoinfarction pattern on EKG may suggest the diagnosis of ischemic heart disease in patients with cardiac amyloidosis.

Echocardiogram in cardiac amyloidosis may show concentric thickening of ventricle wall or septum or both with reduced or normal chamber size, abnormal left ventricular relaxation, diastolic dysfunction or restrictive hemodynamics.

Cardiac MRI contributes information on myocardial thickness, late gallium, enhancement, and T1 weight mapping for extra cellular volume.

PET scans with radiotracers target amyloid deposits, especially in the myocardium.

Median survival 4 months for those presenting with congestive heart failure, 12 months for those presenting with orthostatic hypotension, 16months for those presenting with nephrotic syndrome and 26 months for those presenting with peripheral neuropathy.

Primary systemic amyloidosis can be treated with autologous peripheral blood stem cell transplantation with improvement in target organ function, hematological response and improved survival.

Primary systemic amyloidosis treated by peripheral blood stem cell transplantation is associated with a mortality rate of 13-14%.

With refined eligibility criteria transplants related mortality drops to approximately 3% and hematologic response can be attained in 84% of patients, with a very good partial response and 33% of cases and complete response in 39%.

25% of patients receiving stem cell transplantation have been 10 year survivors, and for patients who achieve a complete response, the 10 year survival rate is 53% (Sanchorawala V et al)

A prospective randomized study of 100 patients with stem cell transplantation showed no survival benefit (Jaccard a et al).

Advanced cardiac involvement and renal insufficiency are both contraindications to high-dose therapy before transplantation, and high-risk patients should not receive transplantation.

Diagnostic biopsy samples may be from the heart, kidneys, or more accessible tissues such as subcutaneous fat or bone marrow.

Biopsy sample sensitivity from symptomatic organs is higher that from more accessible tissues, that is more than 95% for symptomatic organs, 75-80% fat, and 50-65% from bone marrow.

Other tissues that allow for relatively non-invasive biopsies include minor, salivary glands, gingiva, rectum, and skin.

Examination of abdominal fat and bone marrow biopsies can identify 85% of patients with AL amyloidosis.

Special stains such is Congo red, thioflavin T and sulfated alcianblue are required to recognize amyloidosis.

Congo red binding is the gold standard for diagnosing amyloidosis with Apple-green birefringence on the polarized light.

Electron microscopy can be helpful to identify 8-11 nm meter nonbrancing fibrils.

Once a diagnosis of amyloidosis the protein should unergo direct sequencing by mass spectrometry or immunostains.

Mass spectrophotometry is the preferred method of typing I am a boy proteins from tissues.

Localized amyloidosis is the term that applies to cases which the amyloidosis precursor protein is made at the site of the amyloid deposition other than the bone marrow, and it is typically not associated with detectable circulating monoclonal protein in serum or urine.

Localized them like those is usually involves tracheobronchial tree, urinary tract, cutaneous tissue, lymph nodes, and nodular cutaneous involvement and make up that proximally 8% of cases of amyloidosis.

Evaluation includes a bone marrow examination to determine the extent that class of plasmacytosis, along with fluorescent in situ hybridization with the standard myeloma panel looking for trisomies, IgH translocations, chromosome 1 duplication and deletions.

The most commonly affected organs with symptomatology are the heart, kidneys, skin, peripheral nerves, autonomic nerves, and liver.

Baseline laboratory for serum and urine protein electrophoresis with immunofixation, serum immunoglobulin free light chains, bone marrow aspiration biopsy and terminal brain natririuretic peptide, either troponin T or high sensitive troponin T, serum alkaline phosphatase, creatinine, and 24 hour total urine protein.

In a setting of mono clonal abnormalities imaging with whole body, low-dose CT scan or PET/CT scan can detect osteolytic bone lesions.

Prognosis with amyloidosis depends on the burden of the amyloid in the tissues, especially the heart, and the size of plasma cell clone and it’s biology which predicts hematologic and organ response.

Cardiac involvement predicts most early deaths.

Plasma cell biology deaths occurring after the first year.

Proportion of patients dying within 12 months of diagnosis is approximately 30 to 40%.

Early and deep hematologic responses lead to significantly prolonged survival.

Improved organ function may be evident only after 6 to 12 months following treatment.

The time from initiation of treatment against plasma cell dyscrasia to the best organ response varies from 24 months for cardiac response, 29 months for a renal response, and 35 months for a hepatic response.

Continuous oral low-dose melphalan provides palliation with low response rates..

Low-dose daily melphalan is one of the standard therapies for patients not eligible for stem cell transplantation with 48% organ responses, six year actuarial survival rate of 50% progression free survival rate of 40% and median overall survival time 5.1 years. (Palladini G et al).

Oral melphalan and dexamethasone had a median survival time of 10.5 months (Lebovic D et al).

Parenteral melphalan with dexamethasone and 61 patients had a median survival of 17.5 months and the three-month all cause mortality of 28% percent (Dietrich S et al).

Treatment currently is based on chemotherapy/immunotherapy targeting of the amyloid clone.

Principles of treatment or to rapidly reduce causative  amyloidogenic monoclonal protein production, to provide therapy on the basis of organ involvement, to anticipate toxic effects, and provide or specific supportive care to minimize treatment complications and reduce the risk of death and maximize the quality of life.

Treatment aimed at suppressing monoclonal B cell dyscrasia.

Treatment options include: high-dose chemotherapy with autologous stem cell transplant, alkylating agnets, steroids, proteasome inhibitors, and immunomodulatory drugs.

Treatments reduce the production of immunoglobulin light chain precursor proteins by targeting the plasma cells that synthesize them, but they do not directly improved to soluble aggregates or the deposited amyloid.

Basis of treatment is suppression of immunoglobulin light chain synthesis by controlling the underlying plasma cell disorder with chemotherapy.

Supportive care includes treatment for amyloid cardiomyopathy with sodium restriction, diuretic use, possible use of angiotensin, converting enzyme inhibitors for after load reduction.

Digoxin is generally not beneficial except in certain cases of atrial fibrillation.

Use  of anticoagulants requires caution due to the increased risk of bleeding.

Calcium channel blockers are typically avoided.

Amyloid deposit regression is seen with chemotherapy normalization of serum free light chains, and is most readily achieved with high dose chemotherapy.

Primary type renal involvement 48-82% of patients.

Primary type renal involvement associated with nephrotic syndrome with dialysis required at a median of 13.8 months.

Primary systemic amyloidosis can be treated with autologous peripheral blood stem cell transplantation with improvement in target organ function, hematological response and improved survival.

Stem cell transplantation is associated with complete hematologic responses of 39%, organ responses to 47%.

Pre-transplant induction with daratumumab/cyclophosphamide/bortezomib/dexamethasone is generally advised, and specifically recommended in patients whose bone marrow plasma infiltrate is greater than 10%.

The most important predictor of outcome with stem cell transplantation is the stage of the disease.

A systematic review did not demonstrate the efficacy of stem cell transplantation (Mhaaskar R et al).

Primary systemic amyloidosis treated by peripheral blood stem cell transplantation is associated with a mortality rate of 13-14%, although recent studies have reduced this number to as low as 7%.

Stem cell transplantation associated with significant mortality in patients with cardiac disease and the presence of cardiomyopathy makes them ineligible for such a transplant.

Stem cell transplantation leads the hematologic complete response in 40% of patients with a median duration of complete response of 12.3 years.

Patients with the hematologic complete response from stem cell transplant have a median overall survival of 15 years, and 30% of these patient survive more than 20 years.

Only 10 to 20% of patients with newly diagnosed AL are eligible for stem cell transplant.

Heart transplantation followed by stem cell transplant in selected patients with primarily cardiomyopathy associated with a median survival of 95 months.

Therapy for cardiac involvement does not respond to treatment for other cardiomyopathies because of continued deposition of amyloid in the heart and other organs.

Current standard treatment is oral melphalan and prednisone with a response rate of 20-25% which occurs slowly at a median time of 12 months.

With traditional melphalan and prednisone it is difficult to document responses and improvement in end-organ damage is not seen frequently.

Thalidomide and lenalidomide based treatment effective management (Wechalekar AD, Sanchorawaia V).

Low dose oral chemotherapy response rates in primary systemic amyloidosis is 15-40%.

Most patients do not demonstrate objective responses to treatment and ultimately succumb.

Therapy for systemic amyloidosis is directed for recovering the function of the affected organs by targeting the abnormal plasma cell clone and slowing deposition of harmful amyloid fibrils.

About 69% of patients with newly diagnosed systemic amyloidosis have more than one organ involved at the time of diagnosis.

The incidence of systemic amyloidosis ranges from 9 to 14 cases per million person-years.

Treatment:

All new patients diagnosed with systemic amyloidosis should be assessed for autologous hematopoetic cell transplant (HCT) eligibility.

Those with low tumor burden can proceed to receive HCT immediately.

Others are eligible for systemic therapy first and reassessed for transplant possibilities based on the responsiveness of functional status and organ response.

Treatment strategy strategies are designed to destroy the plasma, cell population responsible for synthesis of immunoglobulin chains.

Goals of therapy are to eliminate the misfolded amyloid like chains as promptly as possible

In a randomized controlled French study (Jaccard et al) of 100 patients comparing high dose melphalan with autologous hematopoietic stem cell transplant with standard dose melphalan plus high dose dexamethasone the estimated median overall survival after a median follow up of 3 years was 22.3 months for the high dose melphalan group and 56.9 months in the standard treatment group.

Stem cell transplantation with high dose melphalan may improve kidney function in patients with amyloid kidney in about one third of survivors.

Stem cell transplantation associated with a complete remission of 39% and a median overall survival of 15 years in patients who receive a complete remission.

Bortezomib used with or without dexamethasone in amyloidosis associated with rapid hematologic response and organ responses (Kastritis E).

In amyloidosis, Bortezomib associated with a 71% hematologic response with a 25% complete remission rate (Kastritis E).

For  patients who are ineligible for stem cell transplant, which is approximately 80% of patients, receive treatment with combination of cyclophosphamide, bortezomib, dexamethasone plus Daratumumab:78% of patients have a very good partial response or better and approximately 50 to 55% have an organ response 18 months after treatment.

Prolonged alkylator therapy is required to maintain control and this is associated with an increased risk for the development of myelodysplasia, with an estimated risk of 21% at 3.5 years.

Induction treatment with dexamethasone and alpha interferon reportedly associated with 24% complete hematologic remissions and improvement in 45% of patients with amyloid-related organ dysfunction.

A combination of lenalidomide and dexamethasone in 23 patients resulted in 10 responses at a median follow-up of 17 months (Dispenzieri).

Daratumumab plus hyaluronidase combined with bortezomib, cyclophosphamide, and dexamethasone (VCd) for the treatment of patients with newly diagnosed light chain (AL) amyloidosis.

Daratumumab an anti-CD 38 monoclonal antibody when added to frontline bortezomid,cyclophosphamide, and dexamethasone in the ANDROMEDA study show response rates of up to 53%.

The combination of Daratumumab, and VCD is presently the mainstay of AL amyloidosis treatment.

ANDROMEDA clinical trial. In this study, 388 patients with newly-diagnosed AL amyloidosis, measurable disease, and at least 1 affected organ according to consensus criteria were randomized to receive VCd or D-VCd.

Findings demonstrated hematologic complete response rates of 42.1% and 13.5% for the D-VCd and VCd arms, respectively.

The most common (≥20%) adverse events among recipients of the D-VCd regimen: respiratory tract infection, diarrhea, peripheral edema, constipation peripheral sensory neuropathy, fatigue, nausea, insomnia, dyspnea, and cough.

Other agents with advocacy include lenalidomide, Ixazomib, melphalan, bendamustine carfilozomib and venetoclax.

Chemotherapy targets, plasma cell dyscrasia, and the production of amyloidogenic precursor proteins, but does not resolve or degrade amyloid fibril deposits in tissues: anti-fibril antibodies are presently being investigated. (Birtamimab, Anselamimab).