What is the treatment approach for a patient with cardiac amyloidosis, presenting with heart failure and a granular, sparkling appearance on echocardiogram, with urine light chain presence?

Treatment of AL Cardiac Amyloidosis

This patient with cardiac amyloidosis and urine light chain positivity has AL (light chain) amyloidosis and requires immediate hematology-oncology consultation for plasma cell-directed chemotherapy, with daratumumab plus cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) as the preferred first-line regimen. 1

Immediate Management Steps

Confirm AL Subtype and Initiate Hematology Referral

• The presence of urine light chains confirms this is AL amyloidosis, not ATTR amyloidosis 1
• Urgent hematology-oncology consultation is mandatory as AL amyloidosis is rapidly fatal without treatment of the underlying plasma cell disorder 1
• Complete serum and urine immunofixation electrophoresis with serum free light chains to quantify disease burden 1
• Consider cardiac or other tissue biopsy if diagnosis confirmation is needed 1

Disease-Directed Therapy Selection

First-line chemotherapy options depend on stem cell transplant (SCT) candidacy: 1

For SCT Candidates (Highly Selected Patients):

• High-dose melphalan with autologous stem cell transplantation was historically standard of care 1
• However, Dara-CyBorD may now supplant this as preferred first-line therapy even in SCT candidates 1
• Only ~25% of newly diagnosed AL patients are eligible for SCT due to advanced cardiac and organ involvement 1

For Non-SCT Candidates (Majority of Patients):

• Daratumumab plus CyBorD (Dara-CyBorD) is the preferred regimen based on the landmark ANDROMEDA trial showing 78.5% very good partial response or better versus 49.2% with CyBorD alone 1
• Daratumumab is the only FDA-approved agent specifically for AL amyloidosis 1
• Alternative: CyBorD alone (cyclophosphamide, bortezomib, dexamethasone) or bortezomib-melphalan-dexamethasone 1

For Advanced Cardiac Involvement:

• If NT-proBNP >8,500 pg/mL, consider single-agent daratumumab with minimal dexamethasone to minimize cardiotoxicity 1

Monitoring Treatment Response

Hematologic Response Assessment (3-6 months):

• Monitor serum free light chain difference (dFLC) 1
• Complete response: Negative serum and urine immunofixation with normal FLC ratio 1
• Very good partial response: dFLC <40 mg/L 1
• Partial response: dFLC decrease ≥50% 1

Cardiac Response Assessment (6-12 months after hematologic response):

• Cardiac response defined as: NT-proBNP decrease >30% and <300 ng/L (if baseline NT-proBNP >650 ng/L) 1
• Serial echocardiography and troponin monitoring 1

Critical Cardiotoxicity Considerations

Chemotherapy agents carry significant cardiac risks that require close monitoring: 1

• Corticosteroids (dexamethasone): Peripheral edema, pulmonary edema, fluid overload 1
• Bortezomib: Grade 3 heart failure in 6.4%, >10% LVEF decrease in 23% 1
• Cyclophosphamide: Myocarditis, pericardial effusion, cardiac tamponade, arrhythmias including severe QT prolongation 1
• Daratumumab: Cardiac failure in 12% (grade 3-4 in 6%), atrial fibrillation in 6% 1
• Avoid lenalidomide: Paradoxical BNP increase in 86%, kidney dysfunction in 66% 1

Heart Failure Management

Supportive Cardiac Care:

• Diuretics for volume management, but use cautiously as patients are preload-dependent 2
• Anticoagulation is reasonable for atrial fibrillation regardless of CHA₂DS₂-VASc score to reduce stroke risk 1
• Avoid ACE inhibitors, ARBs, and beta-blockers as they are poorly tolerated due to hypotension 2
• Avoid digoxin due to binding to amyloid fibrils and increased toxicity risk 3

Advanced Heart Failure Options:

• Assess candidacy for heart transplantation in collaboration with transplant specialists 1
• Systemic AL amyloidosis with 5-year survival <75% or 10-year survival <50% is a contraindication to heart transplant alone 1
• Consider combined heart and stem cell transplantation in select cases 3

Relapsed/Refractory Disease

If disease relapses or is refractory to initial therapy: 1

• Daratumumab (if not used first-line) is generally preferred due to lower cardiac and renal toxicity 1
• Alternative immunomodulatory agents: lenalidomide, pomalidomide, thalidomide (use with extreme caution given cardiac toxicity) 1
• Ixazomib (oral proteasome inhibitor) 1
• Venetoclax for patients with t(11;14) cytogenetic alteration 1
• Enroll in clinical trials whenever possible 1

Key Pitfalls to Avoid

• Do not delay hematology referral: Untreated AL cardiac amyloidosis is rapidly fatal with median survival <6 months without treatment 3
• Do not use tafamidis: This is only indicated for ATTR cardiac amyloidosis, not AL amyloidosis 1, 4
• Do not use standard heart failure medications reflexively: Many are poorly tolerated or contraindicated 2, 3
• Do not miss the window for SCT evaluation: Early assessment is critical even if most patients won't qualify 1