Approach

Treatment of amyloidosis depends on the type of amyloidosis present. There is no cure for amyloidosis.

Patients should be managed in a specialist amyloidosis center by a multidisciplinary team (including hematology, cardiology, nephrology, gastroenterology, and neurology specialists).[112] Treatment (including supportive care measures) should be personalized, and all treatment decisions should involve the patient.[112]

Patients should be screened for hepatitis B and C, and HIV (as clinically indicated), before initiating systemic therapy.[61] Herpes zoster prophylaxis is recommended if treatment includes a proteasome inhibitor (e.g., bortezomib) or daratumumab (an anti-CD38 monoclonal antibody).[61]

Immunoglobulin light chain (AL) amyloidosis: treatment aim and approaches

The goal of treatment is to achieve a hematologic complete response (CR).[61][112]

See Criteria for hematologic response criteria.

Treatment for AL amyloidosis is aimed at suppressing the plasma cell clone responsible for producing the immunoglobulin light chain causing amyloidosis. Interruption of light chain deposition allows the body to solubilize and eliminate the amyloid deposit. This prevents further amyloid deposition, which would result in progressive organ failure.

All patients with newly diagnosed AL amyloidosis who have organ involvement (i.e., heart, liver, kidney, nerve, lung, or intestine) should be considered for treatment with autologous stem cell transplantation (ASCT) or systemic therapy, or both.[61][112][113]​​ Enrollment in a clinical trial should be considered wherever possible.​

Patients with an incidental finding of amyloid deposits in the bone marrow and no organ involvement do not require immediate treatment.[114] These patients can be closely observed with monitoring for progression in hematologic parameters and vital organ function.[114]

AL amyloidosis: autologous stem cell transplantation (ASCT)

Patients should be carefully assessed for eligibility for ASCT so that treatment-related complications and mortality are minimized.

Eligibility criteria for ASCT in patients with AL amyloidosis are:[113][114][115]​​​​​  

  • Age ≤70 years

  • ≥1 major vital organ involvement

  • Performance score ≤2

  • Systolic blood pressure ≥90 mmHg (supine)

  • Troponin T <0.06 microgram/L (or high-sensitivity troponin T <75 microgram/L)

  • N-terminal pro-B-type natriuretic peptide (NT-proBNP) <5000 ng/L

  • Left ventricular ejection fraction ≥40%; New York Heart Association (NYHA) class <III

  • Oxygen saturation 95% on room air; diffusing capacity of the lungs for carbon monoxide (DLCO) >50%

  • Creatinine clearance ≥30 mL/min (unless undergoing long-term dialysis)

  • Bilirubin <2 mg/dL

Observational data suggest that ASCT may be safe and effective in carefully selected patients ages 70-75 years.[116]​ Therefore, patients ages >70 years should be evaluated for eligibility for ASCT by a multidisciplinary team at a specialist amyloidosis center.[113]​ 

Definite exclusions for ASCT include:[61][113]

  • Symptomatic and/or medically refractory arrhythmias (ventricular and atrial) or pleural effusions

  • Uncompensated heart failure

  • Medically refractory orthostatic hypotension

  • Factor X deficiency with factor X level <25% or/and evidence of active bleeding

  • Extensive gastrointestinal involvement with evidence of active gastrointestinal bleeding or risk of bleeding

Most patients (approximately 80%) will not be eligible for ASCT.[48][63]​​​ Eligibility criteria for SCT may vary depending on the individual center.

There is a preponderance of observational data suggesting that ASCT is effective in AL amyloidosis.[117][118][119][120]​​​ Randomized trials comparing ASCT with systemic therapy are lacking.[121][122][123]​​​​ 

Risks associated with ASCT include sudden cardiac death, gastrointestinal tract bleeding, and renal failure. The treatment-related mortality rate is <3%.[124][125]

Stem cell harvesting and conditioning

Stem cell harvesting (with use of growth factors for mobilization) should be performed before administering conditioning regimens for ASCT.[113]​  

The standard conditioning regimen for ASCT is a single administration of high-dose melphalan. One longitudinal study reported that high-dose melphalan plus ASCT induces durable hematologic responses and prolonged survival in selected patients.[126]

Dosing of melphalan can be modified based on factors such as age, performance status, renal function, number of organs involved, and cardiac involvement; however, evidence for dose modifications is limited.[61][127][128]

Induction therapy

Use of induction therapy prior to ASCT should be considered for all patients to reduce disease burden and improve response rate.[61][113][114]

​​​Use of induction therapy may also permit certain patients to undergo ASCT who would otherwise be ineligible.[129]

The recommended regimen for induction therapy is daratumumab plus cyclophosphamide plus bortezomib plus dexamethasone (Dara-CyBorD) for 2-4 cycles.[61][113][114]​​ Daratumumab is available as an intravenous formulation, or a subcutaneous formulation (daratumumab/hyaluronidase). Dosing and administration are different for each formulation, but either formulation can be used in daratumumab-containing regimens (in all settings).[61]

If a hematologic CR is achieved with induction therapy, ASCT may be deferred.[61][113][114]​​​ 

Consolidation and maintenance therapy

Consolidation and maintenance therapy following ASCT are not routinely recommended due to lack of evidence.[61]

Consolidation therapy may, however, be considered if only a hematologic partial response (PR) or very good partial response (VGPR) is achieved after ASCT, and there is no improvement in organ function.[61][113][114][130][131]

Achieving a rapid and deep hematologic response is associated with improved outcomes (including improved organ function and survival).[105][106][132]​​​[133][134]​​​ Patients can be observed (without consolidation) if they achieve a hematologic VGPR or CR and improved organ function with ASCT.[114][124]​​

Maintenance therapy, to prevent hematologic progression and organ deterioration after ASCT with minimal toxicity, may be considered in patients with:[61][113][114]​​

  • concurrent multiple myeloma,

  • bone marrow plasma cells ≥20%, or

  • high-risk cytogenetic abnormalities (e.g., del(17p), t(4;14), t(14;16), t(14;20), 1q gain/amplification).

Consolidation and maintenance regimens include bortezomib or lenalidomide, or both combined.[131][135]​​​​ However, if bortezomib was used for induction therapy and did not result in a deep hematologic response after 4 months, then using it after ASCT is unlikely to provide any incremental value. Lenalidomide is not well-tolerated in patients with AL amyloidosis at doses used for multiple myeloma patients. Dose-adjustment and continuous renal function monitoring are required.[61][114][136][137][138]​​​ Lenalidomide should not be used in patients with advanced heart or autonomic nerve involvement.

Treatment of refractory or relapsed AL amyloidosis post-ASCT

Salvage therapy can be given if there is no response to ASCT (i.e., less than a hematologic PR), or if relapse occurs after ASCT (i.e., reappearance of a detectable monoclonal protein or an abnormal immunoglobulin free light chain [FLC] ratio after having achieved a hematologic CR). Salvage regimens include:[61][114]

  • Melphalan plus dexamethasone

  • Bortezomib plus dexamethasone

  • Pomalidomide plus dexamethasone

  • Lenalidomide plus dexamethasone

  • Bortezomib alone

The salvage therapy regimen should differ from that used for induction therapy (and consolidation or maintenance therapy, if used). The optimal approach for salvage therapy is unknown; it should be guided by prior treatments, depth and duration of response to prior treatments, safety and efficacy of alternative regimens, and patient factors (e.g., fitness, frailty). Enrollment in a clinical trial should be considered wherever possible.

AL amyloidosis: systemic therapy

All patients with newly diagnosed AL amyloidosis and organ involvement are considered candidates for systemic therapy.

The goal of systemic therapy is to achieve a hematologic CR.[61][112]​​​

Initial treatment

Recommended regimens for patients undergoing initial systemic therapy (e.g., those ineligible or declining ASCT) include:[61][112]

  • Daratumumab plus cyclophosphamide plus bortezomib plus dexamethasone (Dara-CyBorD): overall hematologic response rate >90% (CR rate: 53%).[139]​ Dose modification may be required depending on stage (e.g., Mayo stage IIIb), presence of neuropathy, fluid retention status, and patient functional status.

  • Daratumumab alone (for Mayo stage IIIb patients): overall hematologic response rate 67% (at median follow-up of 8 months) in stage IIIb patients.[140]​ 

  • Melphalan plus dexamethasone: overall hematologic response rate >65% and long-lasting remission.[141][142]​​​ May be considered for patients with significant neuropathy who are ineligible for ASCT.​[61]

Other regimens that may be considered for initial systemic therapy include:[61][112]

  • Cyclophosphamide plus bortezomib plus dexamethasone (CyBorD): hematologic response rate of 60% to 80%.[143][144][145][146][147] Dose modification may be required depending on stage (e.g., Mayo stage IIIb), presence of neuropathy, fluid retention status, and patient functional status.

  • Bortezomib plus melphalan plus dexamethasone (BMDex): improved hematologic response rate (79% vs. 52%; CR or VGPR rate: 64% vs. 39%) and improved overall survival (hazard ratio: 0.5) compared with melphalan plus dexamethasone.[148]​ 

  • ​Lenalidomide plus dexamethasone: reported to be efficacious, but lenalidomide is not well-tolerated in patients with AL amyloidosis at doses used for multiple myeloma patients. Dose-adjustment and continuous renal function monitoring are required.[61][114][136][137][138] Lenalidomide should not be used in patients with advanced heart or autonomic nerve involvement.

  • Carfilzomib plus dexamethasone: reported to be efficacious in patients with neuropathy, but associated with cardiac and pulmonary toxicity.[149] May be considered for patients with significant neuropathy who do not have advanced cardiac involvement.

Refractory or relapsed disease following initial systemic therapy

Salvage therapy should be considered if:[61][112][114]

  • hematologic response to initial systemic therapy is less than PR by cycle 2 or less than VGPR by cycle 3, or

  • relapse occurs after initial systemic therapy (i.e., reappearance of a detectable monoclonal protein or an abnormal immunoglobulin FLC ratio after having achieved a hematologic CR).

Salvage therapy should be a different regimen to that used for initial treatment. Repeating the initial treatment regimen may be an option for patients with relapsed disease who have had a long relapse-free period (at least several years) following initial treatment.[61]

The optimal approach for salvage therapy is unknown; therefore, it should be guided by prior treatments, depth and duration of response to prior treatments, safety and efficacy of alternative regimens, and patient factors (e.g., fitness, frailty). For example, if salvage therapy is required after initial treatment with Dara-CyBorD, then pomalidomide plus dexamethasone, or lenalidomide plus dexamethasone, or bendamustine (with or without dexamethasone) can be considered.[136][138][150][151][152]​​​​​​​​ Ixazomib may be considered in combination with dexamethasone, or with dexamethasone plus lenalidomide.[61]​​[153][154]​​​​ Venetoclax (an oral BCL-2 inhibitor) alone or in combination with dexamethasone can be considered in the relapsed/refractory setting for patients with the t(11;14) chromosome abnormality.[61][112]​​​[114]​​

There are no approved treatments for salvage therapy for patients with AL amyloidosis. Enrollment in a clinical trial should be considered wherever possible.[61]

Secondary (AA) amyloidosis

Treatment generally involves control of the underlying systemic inflammatory process.

AA amyloidosis (non-familial)

Tumor necrosis factor (TNF)-alpha inhibitors (e.g., infliximab, etanercept) are used to treat inflammatory arthropathies, with a mean duration of therapy of 20 months.[155] Interleukin-1 inhibitors (e.g., anakinra, canakinumab, rilonacept) and interleukin-6 inhibitors (e.g., tocilizumab) may be considered if TNF-alpha inhibitors are not effective or not tolerated.[155][156][157]​ 

When AA amyloidosis is due to Castleman disease, resection of the tumor is effective.[22][158]​​

Familial periodic fever syndromes leading to AA amyloidosis

Colchicine effectively reduces the frequency and duration of attacks (including abdominal pain, swollen joints, fever) and prevents the development of AA amyloidosis in patients with familial Mediterranean fever.[159][160]

Interleukin-1 and interleukin-6 inhibitors improve clinical signs and symptoms of familial periodic fever syndromes.[161][162][163][164][165][166][167][168][169]

Canakinumab (an interleukin-1 inhibitor) is approved for the treatment of familial periodic fever syndromes (including familial Mediterranean fever, TNF-receptor-associated periodic fever syndromes [TRAPS], cryopyrin-associated periodic syndromes [CAPS; e.g., Muckle-Wells syndrome], and mevalonate kinase deficiency [formerly known as hyper-IgD syndrome]).

Rilonacept (an interleukin-1 inhibitor) is approved for the treatment of CAPS (including Muckle-Wells syndrome).

Transthyretin (TTR) amyloidosis

Liver transplantation is the most established treatment for hereditary TTR (ATTRv) amyloidosis.[111][170]

ATTRv amyloidosis with polyneuropathy

Long-term regression of amyloid deposits, and long-term improvements in clinical outcomes (e.g., nerve function) and survival, have been reported after liver transplantation in patients with ATTRv amyloidosis with polyneuropathy, particularly those with Val30Met mutations.[171][172][173][174]​​ However, the number of liver transplantations performed is declining due to the increasing availability of systemic therapies for this condition.[175]

Systemic therapies for ATTRv amyloidosis with polyneuropathy includes:

  • Patisiran and vutrisiran: small interfering ribonucleic acids (siRNAs) that inhibit the production of TTR in the liver. In an 18-month randomized controlled trial, patisiran reduced neurologic impairment and improved quality of life compared with placebo in patients with ATTRv amyloidosis with polyneuropathy.[176] Longer-term data suggest that efficacy and safety are maintained.[177] ​Vutrisiran has similar efficacy to patisiran; noninferiority to patisiran has been reported.[178]​ Patisiran is administered as an intravenous infusion every 3 weeks; premedication with a corticosteroid, acetaminophen, and an antihistamine is recommended to reduce the risk of infusion-related reactions. Vutrisiran is administered by subcutaneous injection at 3-month intervals and does not require additional monitoring.

  • Inotersen: a subcutaneously administered antisense oligonucleotide drug that inhibits the production of TTR in the liver. Inotersen is available in the US only through a Risk Evaluation and Mitigation Strategy (REMS) program. In a 15-month randomized controlled trial, inotersen reduced neurologic impairment and improved quality of life compared with placebo in patients with TTR amyloidosis with polyneuropathy.[179] Severe thrombocytopenia and glomerulonephritis have been reported with this agent. Longer-term data suggest that efficacy and safety are maintained.[180]

  • Tafamidis: an orally administered TTR stabilizer drug that interferes with the misfolding of TTR and reduces amyloid formation. Available as a free acid (tafamidis) or salt formulation (tafamidis meglumine); the dose for each formulation is different, and they are not interchangeable on a per mg basis. Tafamidis meglumine did not meet the primary end points of reducing neurologic impairment and improving quality of life in an 18-month placebo-controlled randomized clinical trial.[181] Long-term tafamidis meglumine was associated with a continued reduction in neurologic progression.[182] In the US, both tafamidis and tafamidis meglumine are approved for the treatment of TTR amyloidosis with cardiac involvement, but not for TTR amyloidosis with polyneuropathy (see ATTRv and wild-type [ATTRwt] amyloidosis with cardiac involvement below). Tafamidis meglumine is approved in Europe for the treatment of stage 1 symptomatic polyneuropathy in adults with TTR amyloidosis.  

  • Diflunisal: a nonsteroidal anti-inflammatory drug that stabilizes TTR.[183] In one randomized controlled trial, diflunisal given for 2 years reduced the rate of progression of neurologic impairment and preserved quality of life compared with placebo in patients with ATTRv amyloidosis with polyneuropathy.[184] Renal function and blood cell counts should be carefully monitored.[185]​ Use of diflunisal for ATTRv amyloidosis is off-label.

ATTRv and wild-type (ATTRwt) amyloidosis with cardiac involvement

Progression of cardiac disease may occur after liver transplantation in patients with ATTRv amyloidosis with cardiac involvement.[186][187]​ Systemic therapies are increasingly available for patients with ATTRv amyloidosis, which means the number of liver transplants performed will likely fall.[175]

In one 30-month randomized controlled trial of patients with TTR cardiac amyloidosis (ATTRv or ATTRwt), tafamidis significantly reduced all-cause mortality and cardiac-related hospitalizations (approximately 30% reduction for each outcome) compared with placebo.[188] Results from an extension study and pre-specified analysis indicate that tafamidis is effective for both ATTRv and ATTRwt cardiac amyloidosis, and that benefit is maintained in the long term.[189][190]

In the US, both tafamidis and tafamidis meglumine are approved for the treatment of TTR cardiac amyloidosis. In Europe, only tafamidis is approved for TTR cardiac amyloidosis. The dose for each tafamidis formulation is different, and they are not interchangeable on a per mg basis.

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