What are the treatment options for amyloidosis?

From the Guidelines

Treatment for amyloidosis should be individualized based on the specific type, affected organs, disease stage, and the patient's overall health status, with a focus on early diagnosis and treatment to slow disease progression and prevent further organ damage. For AL amyloidosis, the most common form, standard treatment involves chemotherapy regimens such as CyBorD (cyclophosphamide, bortezomib, and dexamethasone) or daratumumab-based combinations to target abnormal plasma cells, as recommended by the European Myeloma Network 1. Autologous stem cell transplantation may be recommended for eligible patients, with a treatment-related mortality of approximately 3% and a median survival of over 15 years in those patients achieving a complete response 1.

Some key considerations in the treatment of AL amyloidosis include:

• The use of bortezomib-based regimens, which have been shown to be effective in achieving deep and durable responses 1
• The incorporation of daratumumab into upfront treatment for patients who are not eligible for autologous stem cell transplantation 1
• The importance of supportive care, including diuretics for fluid retention, pain management, and specific organ support as needed 1
• The need for individualized treatment plans, taking into account the patient's overall health status, disease stage, and affected organs 1

In terms of specific treatment options, the European Myeloma Network recommends the following:

• For low-risk patients who are eligible for transplantation, melphalan 200 mg/m2, with consideration of induction with cyclophosphamide/dexamethasone/bortezomib if bone marrow infiltration is > 10% 1
• For intermediate-risk patients who are not eligible for transplantation, bortezomib-based combinations, such as MDex or BMDex 1
• For high-risk patients, dose and schedule adjustments at lower doses, with consideration of bortezomib-based combinations 1

Overall, the goal of treatment for amyloidosis is to achieve deep and durable responses, with a focus on reducing amyloid protein production and managing symptoms, while also providing supportive care to improve quality of life and prevent further organ damage.

From the FDA Drug Label

VYNDAQEL and VYNDAMAX are indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization. VYNDAQEL and VYNDAMAX are transthyretin stabilizers indicated for the treatment of the cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis in adults to reduce cardiovascular mortality and cardiovascular-related hospitalization.

The treatment options for amyloidosis include:

• Tafamidis (VYNDAQEL and VYNDAMAX): a transthyretin stabilizer that reduces cardiovascular mortality and cardiovascular-related hospitalization in adults with cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) 2, 2, 2. Key points to consider:
• Indication: treatment of cardiomyopathy of wild-type or hereditary transthyretin-mediated amyloidosis (ATTR-CM) in adults.
• Mechanism of action: transthyretin stabilizer.
• Dosage: VYNDAQEL 20-mg or 80-mg, VYNDAMAX 61-mg, taken once daily.

From the Research

Treatment Options for Amyloidosis

• The management of immunoglobulin light chain (AL) amyloidosis is complex, and emerging data have shown promising results for several novel agents 3.
• For carefully selected patients, high-dose melphalan and stem cell transplantation is recommended 3.
• Transplant eligibility criteria generally include biopsy-proven amyloidosis, evidence of a plasma cell dyscrasia, involvement of at least one major organ, and adequate performance status 3.
• For transplant-ineligible patients, bortezomib-based regimens are recommended, including:
  • bortezomib, oral melphalan, and dexamethasone (BMDex)
  • bortezomib, cyclophosphamide, and dexamethasone (CyBorD or VCd)
  • subcutaneous daratumumab (DARA SC) and VCd 3.
• For relapsed/refractory disease, novel therapeutics including proteosome inhibitors, immunomodulatory agents, and monoclonal antibodies have shown promising results 3.

Etiological Treatment of Cardiac Amyloidosis

• The standard of care for transthyretin (ATTR) cardiac amyloidosis includes agents capable of selectively stabilizing the precursor protein (e.g., tafamidis) 4.
• Recent data from ATTRibute-CM led to the approval of acoramidis, whereas patisiran received refusal based on the APOLLO-B trial 4.
• Novel CRISPR-Cas9-based drugs (i.e., NTLA-2001) hold great potential in the setting of ATTR cardiac amyloidosis 4.
• Several hematological regimens are available to treat immunoglobulin light chain (AL) cardiac amyloidosis 4.
• The investigation of monoclonal antibodies targeting misfolded ATTR (e.g., PRX004, NI301A) or AL (e.g., birtamimab, anselamimab) has led to encouraging results 4.

Current Approaches to Diagnosis and Management

• Delays in diagnosis and treatment remain the greatest challenge, necessitating physician awareness of the common clinical presentations that suggest amyloidosis 5.
• Significant improvement in patient survival has occurred over the past 2 decades, driven by greater understanding of the disease process, risk-adapted adoption of myeloma therapies, and improved supportive care 5.
• ATTR amyloidosis is an underdiagnosed cause of heart failure, and technetium scintigraphy has made noninvasive diagnosis much easier 5.
• Emerging ATTR treatments slow disease progression, decrease patient hospitalizations, and improve patient quality of life and survival 5.

Confirming the Diagnosis of Amyloidosis

• Most patients with amyloidosis will require biopsy of an involved organ or tissue to confirm the diagnosis 6.
• Cardiac transthyretin amyloidosis may be diagnosed without a biopsy provided stringent criteria are met 6.
• Laser capture microdissection and tandem mass spectrometry (LCM-MS) has revolutionized amyloid subtyping, being able to identify the amyloidogenic protein more reliably than antibody-based methods such as immunohistochemistry 6.

Diagnosis and Treatment of an Underdiagnosed Disease

• Systemic amyloidosis is a multi-system disease caused by fibrillary protein deposition with ensuing dysfunction of the affected organ systems 7.
• Its diagnosis is often delayed because the manifestations of the disease are variable and non-specific 7.
• The diagnostic algorithm is complex and generally requires histological confirmation of the diagnosis 7.
• AL amyloidosis can be considered a complication of a plasma cell dyscrasia and treated with reference to patterns applied in multiple myeloma 7.
• Three drugs (tafamidis, patisiran, and inotersen) are now available to treat grade 1 or 2 polyneuropathy in ATTRv amyloidosis, and further agents are now being tested in clinical trials 7.