What is the treatment approach for cardiac amyloidosis?

Treatment of Cardiac Amyloidosis

The treatment approach for cardiac amyloidosis is fundamentally determined by the amyloid type: for AL (light-chain) cardiac amyloidosis, daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is now the standard first-line therapy, while for ATTR (transthyretin) cardiac amyloidosis, tafamidis is the FDA-approved disease-modifying treatment. 1, 2

Critical First Step: Accurate Amyloid Typing

Before initiating any disease-specific therapy, you must definitively identify the amyloid protein type, as AL and ATTR amyloidosis require completely different treatments. 3, 4

• Mass spectrometry (LC-MS/MS) of tissue biopsy is the gold standard for amyloid typing, with 88% sensitivity and 96% specificity. 3, 4
• Immunohistochemistry can be performed on tissue samples with antibodies against amyloid A, κ- and λ-light chains, and TTR amyloid. 1
• If TTR amyloid is detected, DNA mutational analysis should differentiate between wild-type (senile) and hereditary amyloidosis. 1, 4

Disease-Specific Treatment for AL Cardiac Amyloidosis

First-Line Therapy

Daratumumab-CyBorD (daratumumab plus cyclophosphamide, bortezomib, and dexamethasone) has emerged as the standard of care for newly diagnosed AL amyloidosis, achieving very good partial response or better in 78.5% of patients compared to 49.2% with CyBorD alone in the landmark ANDROMEDA trial. 1, 3

• Daratumumab is the only FDA-approved agent specifically for AL amyloidosis. 1
• The goal is to eradicate the pathological plasma cell clone and remove amyloidogenic light chains from circulation. 3

Autologous Stem Cell Transplantation (ASCT)

For highly selected patients, high-dose melphalan followed by autologous stem cell transplantation offers the possibility of long-lasting remission, with median survival exceeding 15 years in those achieving complete response. 1

• Treatment-related mortality in experienced centers is approximately 3%. 1
• An ejection fraction <40% is generally considered a contraindication to SCT due to risk of hemodynamic decompensation. 1
• Only about 25% of newly diagnosed AL amyloidosis patients are eligible for this intensive treatment due to advanced cardiac and other organ involvement. 1
• Daratumumab-CyBorD may be used as induction therapy (2-4 cycles) before HDM/SCT in transplant-eligible patients. 1, 3

Special Considerations for Advanced Cardiac Involvement

Patients with advanced cardiac involvement (NT-proBNP >8,500 pg/mL) may receive single-agent daratumumab with minimal dexamethasone to minimize potential cardiotoxicity. 1, 4

Monitoring Treatment Response

Assess both hematologic and organ responses regularly: 1

• Complete hematologic response: Absence of amyloidogenic light chains (negative serum and urine immunofixation) AND FLC ratio within reference range. 1
• Cardiac response: Decrease in NT-proBNP by >30% and to <300 ng/L (if baseline NT-proBNP >650 ng/L). 1

Important Toxicity Considerations

Daratumumab carries cardiac toxicities including cardiac failure (12%), arrhythmias (8%), and atrial fibrillation (6%). 3

• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma. 3
• Close monitoring for cardiac decompensation during therapy is essential. 3

Disease-Specific Treatment for ATTR Cardiac Amyloidosis

Tafamidis: The FDA-Approved Standard

Tafamidis (either VYNDAQEL 80 mg or VYNDAMAX 61 mg orally once daily) is indicated for treatment of ATTR cardiomyopathy in adults with NYHA Class I-III symptoms to reduce cardiovascular mortality and cardiovascular-related hospitalization. 2

• Tafamidis is a TTR stabilizer that prevents dissociation of the transthyretin tetramer into amyloidogenic monomers. 3, 5
• This applies to both wild-type and hereditary transthyretin-mediated amyloidosis. 2
• VYNDAMAX and VYNDAQEL are not substitutable on a per mg basis. 2

Alternative and Emerging Therapies for ATTR

Patisiran (an RNA-interfering drug) should be considered in hereditary ATTR cardiomyopathy with polyneuropathy. 5

• For hereditary ATTR amyloidosis, combined cardiac and liver transplantation may be considered, with 5-year survival rates of 50% to 80%. 4

Supportive Cardiac Management (All Types)

Heart Failure Management

Judicious diuresis remains the cornerstone of heart failure therapy in cardiac amyloidosis, but standard heart failure medications must be used with extreme caution or avoided. 1, 3, 4

• Diuretics and vasodilators should be used cautiously because hypotension can result from underfilling of a stiff, restrictive heart. 1, 4
• β-blockers are usually avoided because cardiac output is heart rate dependent in severe restrictive physiology. 1
• ACE inhibitors and ARBs should be used with caution in patients with amyloidosis. 1

Medications to AVOID

Digoxin should be avoided because it binds to amyloid fibrils and can cause toxicity even with normal serum digoxin levels. 1, 4

Calcium channel antagonists should be avoided because they bind to amyloid fibrils, resulting in exaggerated hypotensive and negative inotropic responses. 1, 4

Anticoagulation

Anticoagulation is reasonable in patients with cardiac amyloidosis and atrial fibrillation to reduce stroke risk, independent of CHA₂DS₂-VASc score. 3, 4

• Warfarin or direct thrombin inhibitors are strongly indicated for patients with atrial fibrillation or history of embolic stroke. 4

Multidisciplinary Care Requirements

Effective management requires close collaboration between hematologists and cardiologists, as cardiac involvement is the main driver of disease prognosis and mortality. 3

• The hematologist directs anti-plasma cell therapies and coordinates overall care in AL amyloidosis. 3
• The cardiologist manages cardiac manifestations, which are present in most cases. 3
• Nephrologists manage kidney involvement when present. 3
• Gastroenterologists address GI tract involvement and malabsorption. 1, 3

Common Pitfalls to Avoid

There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis—even patients with advanced cardiac disease may benefit from treatment. 3

Delayed diagnosis is common due to nonspecific symptoms; maintain high clinical suspicion in patients with unexplained heart failure and increased wall thickness, especially with low QRS voltage on ECG. 1, 3

Fragmented care without coordination between specialists leads to suboptimal treatment—early referral to an expert center is often necessary for timely diagnosis and treatment initiation. 3, 6