What are the treatment options for amyloidosis?

Treatment Options for Amyloidosis

For AL (light-chain) amyloidosis, daratumumab combined with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the preferred first-line treatment for most patients, achieving very good partial response or better in 78.5% of cases, while ATTR (transthyretin) cardiac amyloidosis requires tafamidis to reduce cardiovascular mortality and hospitalization. 1, 2, 3

Critical First Step: Accurate Amyloid Typing

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

• Mass spectrometry (LC-MS/MS) of tissue biopsy is the gold standard for amyloid typing, with 88% sensitivity and 96% specificity 2, 4
• Perform comprehensive monoclonal protein screening with serum free light chain assay (sFLC), serum immunofixation electrophoresis (SIFE), and urine immunofixation electrophoresis (UIFE) simultaneously 2
• Standard protein electrophoresis (SPEP/UPEP) alone has insufficient sensitivity and should not be used 2
• Bone marrow biopsy demonstrates clonal proliferation of lambda or kappa-producing plasma cells in AL amyloidosis 2

AL Amyloidosis Treatment Algorithm

First-Line Therapy for Most Patients

Daratumumab-CyBorD (daratumumab with cyclophosphamide, bortezomib, and dexamethasone) is the preferred first-line option for both ASCT-eligible and ASCT-ineligible patients. 1, 2, 3

• This regimen achieved very good partial response or better in 78.5% of patients compared to 49.2% with CyBorD alone in the ANDROMEDA trial 3
• The treatment goal is to eradicate pathological plasma cells and remove amyloidogenic light chains from circulation 1, 2

High-Dose Melphalan with Autologous Stem Cell Transplantation (HDM/SCT)

For highly selected patients, consider HDM/SCT, though Dara-CyBorD may supplant this as first-line therapy. 1

• Eligibility criteria: Age <60 years, ≤2 organs involved, no severe cardiac involvement, adequate cardiac function, good performance status 2
• Treatment-related mortality is approximately 3% in experienced centers 1, 4
• Offers possibility of long-lasting remission and high organ response rates 1
• For patients aged 60-65 years with serum creatinine ≥2 mg/dL, reduce melphalan dose to 100 mg/m² and proceed with extreme caution 2

Alternative Regimen

CyBorD (cyclophosphamide, bortezomib, and dexamethasone) without daratumumab remains an option when daratumumab is unavailable or contraindicated. 1, 2

ATTR Amyloidosis Treatment

ATTR Cardiac Amyloidosis

Tafamidis is indicated for ATTR cardiomyopathy in adults with NYHA Class I-III symptoms to reduce cardiovascular mortality and cardiovascular-related hospitalization. 3

• Demonstrated lower all-cause mortality (29.5% versus 42.9%) and lower cardiovascular-related hospitalization (0.48 versus 0.70 per year) after 30 months compared to placebo 3
• Differentiate hereditary variant from wild-type ATTR using TTR gene sequencing 3

Critical Monitoring for Cardiac Toxicities

Close collaboration between hematology and cardiology is mandatory, as AL amyloidosis therapies carry significant cardiac risks. 1, 2

Specific Agent Toxicities to Monitor

Daratumumab: 1, 4

• 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%)

Proteasome Inhibitors (Bortezomib): 1

• Grade 3 heart failure in 6.4%

• 10% decrease in LVEF in 23%

Cyclophosphamide: 1

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

Corticosteroids (Dexamethasone): 1

• Peripheral edema, pulmonary edema, fluid overload

Immunomodulatory agents (Lenalidomide, Pomalidomide): 1

• Paradoxical increase in cardiac biomarkers (86% with >30% increase in BNP for lenalidomide)
• Kidney dysfunction in 66% with lenalidomide, 26% with pomalidomide

Supportive Cardiac Management

Judicious diuresis remains the cornerstone of heart failure therapy in cardiac amyloidosis, but standard heart failure medications require extreme caution. 3

• Anticoagulation is reasonable in patients with cardiac amyloidosis and atrial fibrillation to reduce stroke risk, independent of CHA₂DS₂-VASc score 3
• There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis 2

Response Monitoring Timeline

• Hematologic response assessment: 3-6 months 4
• Organ-specific response assessment: 6-12 months 4
• Regular monitoring should include NT-proBNP, troponin levels, echocardiography with strain measurements, ECG, and Holter monitoring 3

Common Pitfalls to Avoid

• Delayed diagnosis due to nonspecific symptoms—maintain high index of suspicion 2
• Fragmented care without coordination between hematology, cardiology, and nephrology specialists leads to suboptimal outcomes 2
• Overlooking cardiac involvement, which is the main driver of disease prognosis and mortality 2, 3
• Using standard protein electrophoresis alone for diagnosis—always include serum free light chains and immunofixation 2
• Failing to differentiate AL from ATTR amyloidosis—management differs significantly 2, 3
• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma 2

Organ-Specific Considerations

Renal Involvement

• Avoid NSAIDs and IV contrast to prevent further renal dysfunction 2
• Supportive care includes blood pressure control and dialysis if needed 2

Gastrointestinal Involvement

• Refer to gastroenterology for significant malnutrition, unexplained weight loss, severe nausea, vomiting, diarrhea, constipation, or GI bleeding 2