Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

ACUTE

immunoglobulin light chain (AL) amyloidosis

1st line – observation

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ACUTE
|
immunoglobulin light chain (AL) amyloidosis
|
without organ involvement
1st line – 

observation

Patients with an incidental finding of amyloid deposits in the bone marrow and no organ involvement do not require immediate treatment.[112]​​

Patients can be closely observed with monitoring for progression in haematological parameters and vital organ function.[112]

1st line – high-dose melphalan plus stem cell transplantation

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ACUTE
|
immunoglobulin light chain (AL) amyloidosis
|
with organ involvement, and eligible for stem cell transplantation
1st line – 

high-dose melphalan plus stem cell transplantation

Patients should be managed in a specialist amyloidosis centre by a multidisciplinary team (including haematology, cardiology, nephrology, gastroenterology, and neurology specialists).[110]

Treatment (including supportive care measures) should be personalised, and all treatment decisions should involve the patient.[110]

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.[62][110][111]

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

Eligibility criteria for ASCT in patients with AL amyloidosis are: 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), and bilirubin <2 mg/dL.[111][112][113]​​​​​​ 

Observational data suggest that ASCT may be safe and effective in carefully selected patients aged 70-75 years.[114] Therefore, patients aged >70 years should be evaluated for eligibility for ASCT by a multi-disciplinary team at a specialist amyloidosis centre.[111]

Definite exclusions for ASCT include: 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.[62][111]

Most patients (approximately 80%) will not be eligible for ASCT.[49][64]​ Eligibility criteria for ASCT may vary depending on the individual centre.

There is a preponderance of observational data suggesting that ASCT is effective in AL amyloidosis.[115][116][117][118] Randomised trials comparing ASCT with systemic therapy are lacking.[119][120][121]​

Risks associated with ASCT include sudden cardiac death, gastrointestinal tract bleeding, and renal failure. The treatment-related mortality rate is <3%.[122][123]

Stem cell harvesting (with use of growth factors for mobilisation) should be performed before administering conditioning regimens for ASCT.[111]

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 haematological responses and prolonged survival in selected patients.[124]​

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.[62][125][126]

See local specialist protocol for dosing guidelines.

Primary options

melphalan

Plus – induction therapy (pre-stem cell transplantation)

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ACUTE
|
immunoglobulin light chain (AL) amyloidosis
|
with organ involvement, and eligible for stem cell transplantation
Plus – 

induction therapy (pre-stem cell transplantation)

Treatment recommended for ALL patients in selected patient group

Use of induction therapy prior to autologous stem cell transplantation (ASCT) should be considered for all patients to reduce disease burden and improve response rate.[62][111][112]

Use of induction therapy may also permit certain patients to undergo ASCT who would otherwise be ineligible.[127]​​

The recommended regimen for induction therapy is daratumumab plus cyclophosphamide plus bortezomib plus dexamethasone (Dara-CyBorD) for 2-4 cycles.[62][111][112]

Daratumumab (an anti-CD38 monoclonal antibody) 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).[62]

If a haematological complete response (CR) is achieved with induction therapy, ASCT may be deferred.[62][111][112]​​​ See Criteria for haematological response criteria.

Patients should be screened for hepatitis B and C and HIV (as clinically indicated) before initiating systemic therapy.[62] Herpes zoster prophylaxis is recommended if treatment includes a proteasome inhibitor (e.g., bortezomib) or daratumumab.[62]

Enrolment in a clinical trial should be considered wherever possible.[62]

See local specialist protocol for dosing guidelines.

Primary options

daratumumab

or

daratumumab/hyaluronidase

-- AND --

cyclophosphamide

-- AND --

bortezomib

-- AND --

dexamethasone

Consider – consolidation and maintenance therapy (post-stem cell transplantation)

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ACUTE
|
immunoglobulin light chain (AL) amyloidosis
|
with organ involvement, and eligible for stem cell transplantation
Consider – 

consolidation and maintenance therapy (post-stem cell transplantation)

Additional treatment recommended for SOME patients in selected patient group

Consolidation and maintenance therapy following autologous stem cell transplantation (ASCT) are not routinely recommended due to lack of evidence.[62]

Consolidation therapy may, however, be considered if only a haematological partial response (PR) or very good partial response (VGPR) is achieved after ASCT, and there is no improvement in organ function.[62][111][112][128][129]

Achieving a rapid and deep haematological response is associated with improved outcomes (including improved organ function and survival).[106][107][130][131][132]​​​​​ Patients can be observed (without consolidation) if they achieve a haematological VGPR or CR and improved organ function with ASCT.​[112][122]

Maintenance therapy, to prevent haematological progression and organ deterioration after ASCT with minimal toxicity, may be considered in patients with 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).[62][111][112]​​

Consolidation and maintenance regimens include bortezomib or lenalidomide, or both combined.[129][133]​​ However, if bortezomib was used for induction therapy and did not result in a deep haematological 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.[62][112][134][135][136]​ Lenalidomide should not be used in patients with advanced heart or autonomic nerve involvement.

Patients should be screened for hepatitis B and C and HIV (as clinically indicated) before initiating systemic therapy.[62] Herpes zoster prophylaxis is recommended if treatment includes a proteasome inhibitor (e.g., bortezomib).[62]

Enrolment in a clinical trial should be considered wherever possible.

See local specialist protocol for dosing guidelines.

Primary options

bortezomib

OR

lenalidomide

OR

bortezomib

and

lenalidomide

1st line – systemic therapy

Back
ACUTE
|
immunoglobulin light chain (AL) amyloidosis
|
with organ involvement, and not eligible or declining stem cell transplantation
1st line – 

systemic therapy

Patients should be managed in a specialist amyloidosis centre by a multidisciplinary team (including haematology, cardiology, nephrology, gastroenterology, and neurology specialists).[110]

Treatment (including supportive care measures) should be personalised, and all treatment decisions should involve the patient.[110]

All patients with newly diagnosed AL amyloidosis and organ involvement (i.e., heart, liver, kidney, nerve, lung, or intestine) are considered candidates for systemic therapy.[62][110][111]

The goal of systemic therapy is to achieve a haematological CR.[62][110]

Recommended regimens for patients undergoing initial systemic therapy (e.g., those ineligible or declining autologous stem cell transplantation [ASCT]) include: daratumumab plus cyclophosphamide plus bortezomib plus dexamethasone (Dara-CyBorD); daratumumab alone (for Mayo stage IIIb patients); and melphalan plus dexamethasone (for patients with AL amyloidosis with significant neuropathy who are ineligible for ASCT).[62][110]

Other regimens that may be considered for initial systemic therapy include: cyclophosphamide plus bortezomib plus dexamethasone (CyBorD); bortezomib plus melphalan plus dexamethasone (BMDex); lenalidomide plus dexamethasone; and carfilzomib plus dexamethasone (for patients with significant neuropathy who do not have advanced cardiac involvement).[62][110]

Dara-CyBorD and CyBorD may require dose modification depending on stage (e.g., Mayo stage IIIb), presence of neuropathy, fluid retention status, and patient functional status.[62][110]

Daratumumab (an anti-CD38 monoclonal antibody) 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).[62]

Patients should be screened for hepatitis B and C and HIV (as clinically indicated) before initiating systemic therapy.[62] Herpes zoster prophylaxis is recommended if treatment includes a proteasome inhibitor (e.g., bortezomib) or daratumumab.[62]

Enrolment in a clinical trial should be considered wherever possible.

See local specialist protocol for dosing guidelines.

Primary options

daratumumab

or

daratumumab/hyaluronidase

-- AND --

cyclophosphamide

-- AND --

bortezomib

-- AND --

dexamethasone

OR

daratumumab

OR

daratumumab/hyaluronidase

OR

melphalan

and

dexamethasone

Secondary options

cyclophosphamide

and

bortezomib

and

dexamethasone

OR

bortezomib

and

melphalan

and

dexamethasone

OR

lenalidomide

and

dexamethasone

OR

carfilzomib

and

dexamethasone

secondary (AA) amyloidosis (non-familial)

1st line – treatment of underlying condition

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ACUTE
|
secondary (AA) amyloidosis (non-familial)
1st line – 

treatment of underlying condition

Treatment generally involves control of the underlying systemic inflammatory process.

Tumour necrosis factor (TNF)-alpha inhibitors (e.g., infliximab, etanercept) are used to treat inflammatory arthropathies, with a mean duration of therapy of 20 months.[153]

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.[153][154][155]

When AA amyloidosis is due to Castleman's disease, resection of the tumour is effective.[23][156]​​

Consult specialist for guidance on dose.

Primary options

infliximab

OR

etanercept

Secondary options

anakinra

OR

canakinumab

OR

rilonacept

OR

tocilizumab

familial periodic fever syndromes

1st line – colchicine or canakinumab or rilonacept

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ACUTE
|
familial periodic fever syndromes
1st line – 

colchicine or canakinumab or rilonacept

Colchicine effectively reduces the frequency and duration of attacks (including abdominal pain, swollen joints, fever) and prevents the development of secondary (AA) amyloidosis in patients with familial Mediterranean fever.[157][158]

Interleukin-1 and interleukin-6 inhibitors improve clinical signs and symptoms of familial periodic fever syndromes.[159][160][161][162][163][164][165][166][167]

Canakinumab (an interleukin-1 inhibitor) is approved for the treatment of familial periodic fever syndromes (including familial Mediterranean fever, tumour necrosis factor [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).

Consult specialist for guidance on dose.

Primary options

colchicine

OR

canakinumab

OR

rilonacept

transthyretin (TTR) amyloidosis

1st line – liver transplantation or pharmacotherapy

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ACUTE
|
transthyretin (TTR) amyloidosis
|
with polyneuropathy
1st line – 

liver transplantation or pharmacotherapy

Liver transplantation is the most established treatment for hereditary TTR (ATTRv) amyloidosis.[168][169]

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.[170][171][172][173]​​​ However, the number of liver transplantations performed is declining due to the increasing availability of systemic therapies for this condition (e.g., patisiran, vutrisiran, inotersen, tafamidis, and diflunisal).[174]

Patisiran and vutrisiran: small interfering ribonucleic acids (siRNAs) that inhibit the production of TTR in the liver. In an 18-month randomised controlled trial, patisiran reduced neurological impairment and improved quality of life compared with placebo in patients with ATTRv amyloidosis with polyneuropathy.[175] Longer-term data suggest that efficacy and safety are maintained.[176] Vutrisiran has similar efficacy to patisiran; non-inferiority to patisiran has been reported.[177]​ ​Patisiran is administered as an intravenous infusion every 3 weeks; pre-medication with a corticosteroid, paracetamol, 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) programme. In Europe, inotersen is approved for the treatment of stage 1 or stage 2 polyneuropathy in adults with ATTRv amyloidosis. In a 15-month randomised controlled trial, inotersen reduced neurological impairment and improved quality of life compared with placebo in patients with TTR amyloidosis with polyneuropathy.[178] Severe thrombocytopenia and glomerulonephritis have been reported with this agent. Longer-term data suggest that efficacy and safety are maintained.[179]

Tafamidis: an orally administered TTR stabiliser 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 neurological impairment and improving quality of life in an 18-month placebo-controlled randomised clinical trial.[180] Long-term tafamidis meglumine was associated with a continued reduction in neurological progression.[181] 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. Tafamidis meglumine is approved in Europe for the treatment of stage 1 symptomatic polyneuropathy in adults with TTR amyloidosis.

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

Consult specialist for guidance on dose.

Primary options

patisiran

OR

vutrisiran

OR

inotersen

OR

tafamidis meglumine

Secondary options

diflunisal

1st line – liver transplantation or pharmacotherapy

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ACUTE
|
transthyretin (TTR) amyloidosis
|
with cardiac involvement
1st line – 

liver transplantation or pharmacotherapy

Liver transplantation is the most established treatment for hereditary TTR (ATTRv) amyloidosis.[168][169]

Progression of cardiac disease may occur after liver transplantation in patients with ATTRv amyloidosis with cardiac involvement.[185][186]

Systemic therapies are increasingly available for patients with ATTRv amyloidosis, which means the number of liver transplants performed will likely fall.[174]

In one 30-month randomised controlled trial of patients with TTR cardiac amyloidosis (ATTRv or ATTRwt), tafamidis (a TTR stabiliser that is administered orally) significantly reduced all-cause mortality and cardiac-related hospitalisations (approximately 30% reduction for each outcome) compared with placebo.[187] 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.[188][189]

Tafamidis is available as a free acid or salt formulation (tafamidis meglumine); the dose for each formulation is different, and they are not interchangeable on a per mg basis. 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.

Consult specialist for guidance on dose.

Primary options

tafamidis

OR

tafamidis meglumine

ONGOING

refractory or relapsed AL amyloidosis

1st line – salvage therapy

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ONGOING
|
refractory or relapsed AL amyloidosis
|
following initial stem cell transplantation
1st line – 

salvage therapy

Salvage therapy can be given if there is no response to autologous stem cell transplantation (i.e., less than a haematological partial response [PR]), or if relapse occurs after stem cell transplantation (i.e., reappearance of a detectable monoclonal protein or an abnormal immunoglobulin free light chain [FLC] ratio after having achieved a haematological complete response [CR]).

Salvage regimens include: melphalan plus dexamethasone; bortezomib plus dexamethasone; pomalidomide plus dexamethasone; lenalidomide plus dexamethasone; bortezomib alone.[62][112]

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).

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.[62][112][134][135][136]​​​​​​​ Lenalidomide should not be used in patients with advanced heart or autonomic nerve involvement.

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

See local specialist protocol for dosing guidelines.

Primary options

melphalan

and

dexamethasone

OR

bortezomib

and

dexamethasone

OR

pomalidomide

and

dexamethasone

OR

lenalidomide

and

dexamethasone

OR

bortezomib

1st line – salvage therapy

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ONGOING
|
refractory or relapsed AL amyloidosis
|
following initial systemic therapy
1st line – 

salvage therapy

Salvage therapy should be considered if: haematological response to initial systemic therapy is less than a partial response (PR) by cycle 2 or less than a very good partial response (VGPR) by cycle 3, or relapse occurs after initial systemic therapy (i.e., reappearance of a detectable monoclonal protein or an abnormal immunoglobulin free light chain [FLC] ratio after having achieved a haematological complete response [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.[62]​

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 daratumumab plus cyclophosphamide plus bortezomib plus dexamethasone (Dara-CyBorD), then pomalidomide plus dexamethasone, or lenalidomide plus dexamethasone, or bendamustine (with or without dexamethasone) can be considered.[134][136][148][149][150]​​​​​ Ixazomib may be considered in combination with dexamethasone, or with dexamethasone plus lenalidomide.[62][151][152]​​​ 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.[62][110][112]​​​​

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

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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