What about evaluating and managing amyloidosis in the patient (pt) with multiple myeloma?

Evaluating and Managing Amyloidosis in Multiple Myeloma Patients

In patients with multiple myeloma, screen for AL amyloidosis when cardiac, renal, or neurologic symptoms emerge, as approximately 10-15% of multiple myeloma patients have concurrent AL amyloidosis, and this overlap fundamentally changes treatment approach and prognosis. 1

Recognition of the MM-Amyloidosis Overlap

The relationship between multiple myeloma and AL amyloidosis is bidirectional and clinically critical:

• Approximately 10-15% of multiple myeloma patients also have AL amyloidosis 1
• Conversely, 10% of AL amyloidosis cases are associated with multiple myeloma 1
• The plasma cell burden in multiple myeloma is generally higher than in AL amyloidosis, but amyloid deposition remains an uncommon clinical feature in typical myeloma 1
• Patients with both conditions are more fragile than those with myeloma alone due to multiple severe organ dysfunctions 1

Clinical Red Flags Requiring Amyloidosis Evaluation

Any multiple myeloma patient presenting with the following should undergo immediate evaluation for AL amyloidosis: 1

• Restrictive cardiomyopathy or unexplained heart failure 1
• Unexplained proteinuria or nephrotic syndrome 1
• Macroglossia or submandibular gland enlargement 1
• Periorbital purpura (periorbital ecchymoses) 1
• Peripheral neuropathy with autonomic features or bilateral carpal tunnel syndrome 1
• Hepatomegaly with mildly elevated alkaline phosphatase 1, 2
• Acquired factor X deficiency with coagulopathy 1
• Unexplained weight loss with gastrointestinal symptoms 1, 2

Diagnostic Approach

Step 1: Monoclonal Protein Screening

Perform comprehensive monoclonal protein screening with all three tests simultaneously: 1, 3

• Serum free light chain assay (sFLC) with kappa/lambda ratio 1, 3
• Serum immunofixation electrophoresis (SIFE) 1, 3
• Urine immunofixation electrophoresis (UIFE) 1, 3

Critical pitfall: Standard protein electrophoresis (SPEP/UPEP) alone is inadequate, as it fails to show a monoclonal spike in nearly 50% of AL amyloidosis cases. 1, 3

Step 2: Tissue Diagnosis

AL amyloidosis diagnosis requires BOTH demonstration of amyloid deposits AND evidence of plasma cell dyscrasia—unlike ATTR amyloidosis, tissue biopsy cannot be avoided. 1

Two acceptable biopsy approaches: 1

1. Start with surrogate site biopsy (abdominal fat aspiration or bone marrow), then proceed to affected organ biopsy if negative 1

   • Abdominal fat aspiration sensitivity: 84% for AL-CM 1
   • Bone marrow biopsy sensitivity: 69% for systemic AL amyloidosis 1

2. Direct biopsy of affected organ (kidney, heart, GI tract) 1

Step 3: Amyloid Typing

Mass spectrometry (LC-MS/MS) is the gold standard for identifying the amyloid precursor protein, with 88% sensitivity and 96% specificity. 1

Critical pitfall: Over 10% of patients with monoclonal gammopathy can have ATTR deposits rather than AL deposits, making precise typing essential. 1

Step 4: Exclude Multiple Myeloma Criteria

Collaborate with hematology to determine if the patient meets full multiple myeloma criteria or has isolated AL amyloidosis: 1

• Bone marrow plasma cell percentage
• Presence of CRAB criteria (hypercalcemia, renal insufficiency, anemia, bone lesions) 1
• Imaging for lytic lesions (whole-body low-dose CT or FDG PET/CT preferred over skeletal survey) 1

Treatment Implications

For Patients with Both MM and AL Amyloidosis

Treatment must target the plasma cell clone using anti-plasma cell therapies derived from multiple myeloma regimens: 1, 3

First-line therapy options based on transplant eligibility: 3

• ASCT-eligible patients: Consider daratumumab-CyBorD (cyclophosphamide, bortezomib, dexamethasone) or high-dose melphalan with autologous stem cell transplantation 3
• ASCT-ineligible patients: Daratumumab-CyBorD is the preferred first-line option 3

For patients aged <60 years with AL amyloidosis and ≤2 organs involved without severe cardiac involvement, high-dose chemotherapy followed by stem cell transplantation should be considered. 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. 1

Alternative Regimens for Non-Transplant Candidates

Melphalan 0.22 mg/kg plus high-dose dexamethasone 40 mg orally days 1-4 every 28 days achieves high response rates (67% hematologic response, 33% complete remission). 1

Patients ineligible for high-dose dexamethasone (those with refractory ventricular arrhythmias, GI bleeding, or psychosis) should receive standard melphalan-prednisone. 1

For refractory or relapsing disease: Intermediate-dose dexamethasone 20 mg orally days 1-4 every 21 days plus thalidomide 100-200 mg/day, with mandatory monthly Holter monitoring for dangerous bradycardia. 1

Cardiac Monitoring During Treatment

Close collaboration between hematology and cardiology is mandatory for: 1

• Monitoring for cardiotoxicity of AL amyloidosis therapies 1
• Daratumumab carries cardiac risks: heart failure (12%), arrhythmias (8%), atrial fibrillation (6%) 3
• Proteasome inhibitors (bortezomib, carfilzomib) risk Grade 3 heart failure and decreased LVEF 3
• Assessment of cardiovascular fitness for high-dose melphalan with stem cell transplantation 1

Critical pitfall: There are no absolute contraindications to plasma cell-directed therapies based on ejection fraction or cardiac status in AL cardiac amyloidosis—treatment should not be withheld based solely on cardiac function. 3

Organ-Specific Management Considerations

Renal Involvement

Approximately 70% of AL amyloidosis patients have renal involvement, presenting as nephrotic syndrome with heavy proteinuria. 4

• Avoid NSAIDs and IV contrast to prevent further renal dysfunction 1
• Proteinuria typically decreases progressively over months to years after complete or very good hematologic response 4
• Renal function usually stabilizes but rarely improves after stopping amyloidogenic light chain production 4
• Plasmapheresis for adjunctive treatment of renal dysfunction remains controversial (category 2B) 1

Cardiac Involvement

Cardiac involvement is the main driver of disease prognosis and mortality in AL amyloidosis. 3, 5

• Standard heart failure medications (calcium channel blockers, β-blockers, ACE inhibitors) are inefficient or dangerous in amyloid heart disease 5
• Manage with diuretics as primary therapy 5
• Consider amiodarone and pacemaker implantation for rhythm or conduction abnormalities 5

Gastrointestinal Involvement

Refer to gastroenterology for: 1

• Significant malnutrition or unexplained weight loss
• Severe nausea, vomiting, diarrhea, constipation, or GI bleeding
• Assessment for potential GI contraindications to heart transplantation (malabsorption with significant malnutrition is a relative contraindication) 1

Prognosis and Follow-Up

Survival depends on: 5

• Spectrum of organ involvement (cardiac disease being the main prognostic factor)
• Severity of individual organ involvement
• Hematologic response to treatment

Monitor hematologic response with serial serum free light chain measurements. 5

Deep hematologic responses correlate with improved organ function and survival. 3