How to discuss amyloidosis with a patient, including its treatment options such as melphalan (Alkeran) and dexamethasone for light-chain (AL) amyloidosis and tafamidis (Vyndaqel) for transthyretin (ATTR) amyloidosis?

How to Discuss Amyloidosis with Patients

Start with Disease Type Classification

Begin by explaining that amyloidosis is not a single disease but rather a group of conditions where abnormal proteins deposit in organs, and the specific type determines both prognosis and treatment.

The two main types you'll discuss are:

• Light-chain (AL) amyloidosis: Caused by abnormal plasma cells producing misfolded light chain proteins that deposit in organs, particularly the heart, kidneys, liver, and nervous system 1
• Transthyretin (ATTR) amyloidosis: Caused by misfolded transthyretin protein, either hereditary (ATTRv) or wild-type/age-related (ATTRwt), predominantly affecting the heart 2, 3

The distinction is critical because AL amyloidosis requires chemotherapy targeting plasma cells, while ATTR amyloidosis requires medications that stabilize or silence the transthyretin protein 4, 2.

Explaining AL Amyloidosis Treatment

For Transplant-Eligible Patients

Daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) has emerged as the standard of care for newly diagnosed AL amyloidosis, achieving unprecedented deep responses with 78.5% of patients achieving very good partial responses or better 1, 4.

When discussing this with patients, explain:

• Daratumumab is the only FDA-approved medication specifically for AL amyloidosis 1
• Treatment targets the abnormal plasma cells producing the toxic light chains 1
• The goal is to eliminate the light chains from circulation, which typically occurs within 3-6 months, followed by organ improvement 6-12 months later 1
• Only about 25% of patients are eligible for the more intensive option of high-dose melphalan with stem cell transplantation due to advanced organ involvement 1

For Transplant-Ineligible Patients

For patients with advanced cardiac involvement (NT-proBNP >8,500 pg/mL), single-agent daratumumab with minimal dexamethasone minimizes cardiotoxicity risk 1.

Alternative regimens include:

• CyBorD (cyclophosphamide, bortezomib, dexamethasone) without daratumumab 1
• Bortezomib-melphalan-dexamethasone 1
• Oral melphalan with dexamethasone, which achieved 67% hematologic response and 33% complete remission in one study 1

Important Cardiac Monitoring Points

Warn patients that chemotherapy itself can stress the heart, requiring close collaboration between their hematologist and cardiologist 1:

• Daratumumab carries risks of cardiac failure (12%), arrhythmias (8%), and atrial fibrillation (6%) 4
• Bortezomib can cause Grade 3 heart failure in 6.4% and >10% decrease in ejection fraction in 23% 1
• Corticosteroids (dexamethasone) can cause peripheral edema, pulmonary edema, and fluid overload 1
• Cyclophosphamide can cause myocarditis, pericardial effusion, and arrhythmias 1

Explaining ATTR Amyloidosis Treatment

Tafamidis as Disease-Modifying Therapy

For ATTR cardiac amyloidosis, tafamidis (Vyndaqel/Vyndamax) is the only FDA-approved therapy and should be started as soon as possible to delay disease progression and improve survival 2, 3.

Key points to communicate:

• Tafamidis cannot reverse existing damage but delays progression and forestalls decline in quality of life 2
• The benefit is attenuated in advanced disease, making early treatment critical 2
• Dosing is either Vyndaqel 80 mg (four 20-mg capsules) or Vyndamax 61 mg (one capsule) once daily 3
• These formulations are not interchangeable on a per-mg basis 3
• Capsules must be swallowed whole, not crushed or cut 3

TTR Silencers for Neuropathy

For patients with hereditary ATTR with peripheral neuropathy, TTR silencers offer disease-modifying therapy, but emphasize they are only proven for ATTRv polyneuropathy, not wild-type ATTR 5:

• Patisiran: 0.3 mg/kg IV infusion every 3 weeks with premedication 5
• Inotersen: subcutaneous injection requiring monitoring for thrombocytopenia and glomerulonephritis 5
• Vutrisiran: 25 mg subcutaneous injection every 3 months 5
• All TTR silencers require daily vitamin A supplementation (3,000 IU) 5

Critical Medication Warnings

Explicitly warn patients to avoid certain medications that bind to amyloid fibrils and cause toxicity 2:

• Digoxin should never be used as it binds to amyloid fibrils and causes toxicity even at normal serum levels 2
• Calcium channel blockers should be avoided as they bind to amyloid and cause exaggerated hypotensive responses 2

Managing Symptoms and Quality of Life

Gastrointestinal Symptoms

Explain that GI symptoms from amyloidosis require symptomatic management, as disease-modifying therapies have limited impact on GI involvement 1:

For nausea and early satiety:

• Ondansetron 4-8 mg every 4-8 hours or promethazine 12.5-25 mg every 4-6 hours 1
• Metoclopramide 10-20 mg every 6-8 hours or prucalopride 2 mg daily 1

For diarrhea:

• Loperamide 2-4 mg four times daily 1
• Rifaximin 550 mg three times daily for bacterial overgrowth 1
• Cholestyramine 4 g 1-4 times daily for bile salt malabsorption 1

For constipation:

• Polyethylene glycol 17 g daily 1
• Linaclotide 145 mg daily 1

Dietary Modifications

Recommend practical dietary changes:

• Small evening meals with predominantly liquid consistency for faster gastric transit 1
• Lengthening time between dinner and lying down to reduce reflux 1
• Low-FODMAP diet to reduce gas-producing foods and relieve cramping, diarrhea, and bloating 1
• Calorie-rich supplements and shakes for weight loss from malabsorption 1

Neuropathic Pain Management

For sensory neuropathy symptoms, pregabalin or gabapentin are first-line options 5:

• Pregabalin as first-line 5
• Gabapentin as alternative first-line 5
• Duloxetine as alternative 5
• Avoid tricyclic antidepressants as they can worsen orthostatic hypotension and autonomic symptoms 5

Orthostatic Hypotension

Start with non-pharmacological measures:

• Increased salt and fluid intake 5
• Compression stockings 5
• Abdominal binders 5

If inadequate, add medications:

• Fludrocortisone 0.05-0.1 mg daily, titrated to 0.1-0.3 mg daily 5
• Midodrine for refractory cases 5
• Droxidopa as alternative 5
• Pyridostigmine is preferred in patients with cardiac involvement as it doesn't cause fluid retention 5

Setting Realistic Expectations

Prognosis Discussion

Be direct that cardiac involvement is the main driver of mortality in AL amyloidosis 4:

• Deep hematologic responses correlate with improved organ function and survival 4
• Organ response typically lags 6-12 months behind hematologic response 1
• Patients with advanced cardiac involvement (NT-proBNP >8,500 pg/mL) have higher treatment-related mortality risk 1

Response Monitoring

Explain the two-part monitoring approach 1:

Hematologic response (measured by serum free light chains):

• Complete response: negative immunofixation and normal free light chain ratio 1
• Very good partial response: difference in free light chains <40 mg/L 1
• Partial response: ≥50% decrease in free light chain difference 1

Organ response (measured 6-12 months after hematologic response):

• Cardiac: >30% decrease in NT-proBNP to <300 ng/L 1
• Renal: ≥30% decrease in proteinuria or drop below 0.5 g/24h 1
• Hepatic: 50% decrease in alkaline phosphatase or ≥2 cm reduction in liver size 1

Common Pitfalls to Address

Emphasize that standard protein electrophoresis alone is inadequate for diagnosis, as it misses the monoclonal spike in nearly 50% of AL amyloidosis cases 1, 4. All three tests are required: serum free light chain assay, serum immunofixation, and urine immunofixation 4.

Clarify that there are no absolute contraindications to plasma cell-directed therapy based on ejection fraction or cardiac status, though close monitoring is essential 1, 4.

Stress the importance of early treatment, as patients treated earlier show better outcomes and quality of life in both AL and ATTR amyloidosis 5, 2.