What is the treatment approach for patients with amyloidosis?

Treatment of Amyloidosis

Immediate Priority: Accurate Amyloid Typing Before Any Treatment

Accurate typing of the amyloid protein using mass spectrometry is mandatory before initiating any disease-specific therapy, as AL and ATTR amyloidosis require completely different treatments. 1, 2

• Mass spectrometry (LC-MS/MS) of tissue biopsy is the gold standard with 88% sensitivity and 96% specificity 2
• Histopathologic confirmation requires Congo red staining showing characteristic apple-green birefringence under polarized light 3, 4, 5
• Essential next steps after confirming amyloid include monoclonal protein screening (serum free light chain assay, serum immunofixation electrophoresis, urine immunofixation electrophoresis) and bone marrow biopsy 3, 2

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Treatment Algorithm for AL Amyloidosis

First-Line Treatment Selection

Daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line treatment for most patients with AL amyloidosis, achieving very good partial response or better in 78.5% of patients. 1, 3, 2, 6

• This regimen is FDA-approved and represents the current standard of care 2, 6
• The goal is to eradicate pathological plasma cells and remove amyloidogenic light chains from circulation 1, 2

Transplant-Eligible Patients (Minority of Cases)

For highly selected patients meeting strict eligibility criteria, consider high-dose melphalan followed by autologous stem cell transplantation (HDM/SCT): 1, 3, 2, 6

Eligibility criteria include:

• Age typically <60 years (extreme caution if 60-65 years) 2
• Ejection fraction >40% 6
• ≤2 organs involved without severe cardiac involvement 2
• Adequate performance status and ability to tolerate fluid shifts and infections 6

Important limitations:

• Only approximately 25% of newly diagnosed AL amyloidosis patients qualify for this intensive approach 6
• Treatment-related mortality is approximately 3% in experienced centers 1, 3, 6
• Prior to transplant, administer 2-4 cycles of bortezomib-based induction if bone marrow plasma cells >10% 6

Alternative Regimen

CyBorD (cyclophosphamide, bortezomib, dexamethasone) without daratumumab is an alternative option, though inferior to Dara-CyBorD (49.2% vs 78.5% very good partial response rate) 2, 6

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Critical Cardiac Toxicity Monitoring

Close collaboration between hematology and cardiology is mandatory for monitoring cardiotoxicity during AL amyloidosis treatment, as cardiac involvement drives prognosis and mortality. 1, 2

Specific Toxicities by Agent:

Daratumumab: 1, 2, 6

• Cardiac failure in 12% (grade 3-4 in 6%)
• Cardiac arrhythmia in 8% (grade 3-4 in 2%)
• Atrial fibrillation in 6% (grade 3-4 in 2%)

Bortezomib: 1

• Grade 3 heart failure in 6.4%

• 10% decrease in LVEF in 23%

Corticosteroids (dexamethasone): 1

• Peripheral edema, pulmonary edema, fluid overload

Cyclophosphamide: 1

• Myocarditis, myopericarditis, pericardial effusion, cardiac tamponade
• Supraventricular and ventricular arrhythmias
• Risk increases with high doses, advanced age, and prior cardiac radiation

Critical caveat: There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis 2

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Response Assessment Timeline

Hematologic response typically occurs within 3-6 months, while organ-specific response generally occurs 6-12 months after hematologic response. 3, 6

Hematologic Response Criteria: 6

• Complete response (CR): Absence of amyloidogenic light chains and normalized free light chain ratio
• Very good partial response (VGPR): dFLC <40 mg/L
• Partial response (PR): dFLC decrease ≥50%
• No response (NR): dFLC decrease <50%

Cardiac Response: 6

• Decrease in NT-proBNP by >30% and <300 ng/L (if baseline NT-proBNP >650 ng/L)

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Treatment of ATTR Amyloidosis (Completely Different Approach)

Tafamidis is indicated for treatment of ATTR cardiomyopathy in adults with NYHA Class I-III symptoms to reduce cardiovascular mortality and cardiovascular-related hospitalization. 2

• This is FDA-approved and represents disease-specific therapy for ATTR, not AL amyloidosis 2
• TTR silencers (patisiran, inotersen, vutrisiran) are alternatives for ATTR with neuropathy 1
• Critical distinction: Anti-plasma cell therapies used for AL amyloidosis have no role in ATTR amyloidosis 2

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Supportive Cardiac Management (All Types)

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. 2

• Anticoagulation is reasonable in patients with cardiac amyloidosis and atrial fibrillation to reduce stroke risk, independent of CHA₂DS₂-VASc score 2
• Avoid NSAIDs and IV contrast to prevent further renal dysfunction in patients with renal involvement 2

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Management of Gastrointestinal Involvement

There is currently no strong evidence that disease-modifying therapies for amyloidosis (tafamidis, patisiran, inotersen, vutrisiran) impact GI involvement or symptoms. 1

Symptom-Directed Therapies: 1

For nausea/early satiety:

• Antiemetics: ondansetron 4-8 mg every 4-8 hours, promethazine 12.5-25 mg every 4-6 hours
• Prokinetics: metoclopramide 10-20 mg every 6-8 hours, prucalopride 2 mg daily

For diarrhea:

• Loperamide 2-4 mg 4 times daily
• Rifaximin 550 mg 3 times daily for small intestinal bacterial overgrowth
• Octreotide 50-250 mcg 3 times daily subcutaneously

For constipation:

• Polyethylene glycol 17 g daily
• Linaclotide 145 mg daily

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Common Pitfalls and Critical Caveats

Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma, requiring close monitoring for cardiac decompensation during therapy. 2, 6

• Delayed diagnosis occurs frequently due to nonspecific symptoms; maintain high clinical suspicion 2
• Fragmented care without coordination between hematology, cardiology, and nephrology leads to suboptimal outcomes 1, 2
• Standard protein electrophoresis (SPEP/UPEP) should not be used alone due to lower sensitivity 2
• Approximately 10-15% of multiple myeloma patients also have AL amyloidosis; evaluate any myeloma patient with restrictive cardiomyopathy, unexplained proteinuria, macroglossia, periorbital purpura, or peripheral neuropathy with autonomic features 2