How can a localized plasma cell clone in AL amyloidosis progress to a systemic disorder?

Progression of Localized AL Amyloidosis to Systemic Disease

A localized plasma cell clone in AL amyloidosis can progress to systemic disease through the evolution of monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) to symptomatic disease, with a risk of approximately 10% per year for SMM patients during the first 5 years.1

Mechanisms of Progression

• Localized AL amyloidosis involves amyloid deposits confined to a single organ or tissue site, with no evidence of clonal plasma cells in bone marrow or systemic disease 2
• The progression from localized to systemic disease occurs when the underlying plasma cell clone evolves and expands, producing higher quantities of amyloidogenic light chains that circulate and deposit in multiple organs 3
• The size of the serum monoclonal protein and the number of plasma cells in the bone marrow are the most important risk factors for progression from MGUS/SMM to systemic disease 1
• The free light chain (FLC) ratio is an independent additional risk factor for progression, with abnormal ratios indicating higher risk 1

Risk Stratification

• Patients with both ≥10% bone marrow plasma cells and ≥30 g/L of monoclonal protein have an 87% probability of progression to systemic disease at 15 years 1
• Patients with ≥10% bone marrow plasma cells and <30 g/L of monoclonal protein have a 70% risk of progression at 15 years 1
• The cumulative probability of progression from SMM to active multiple myeloma or AL amyloidosis is 51% at 5 years, 66% at 10 years, and 73% at 15 years 1
• The risk of progression is highest in the first 5 years (10% per year), decreasing to approximately 3% per year for the next 5 years, and 1% per year thereafter 1

Diagnostic Considerations

• When localized AL amyloidosis is diagnosed, comprehensive screening for systemic involvement is essential, including serum free light chain assay, serum and urine immunofixation electrophoresis 4, 5
• Bone marrow biopsy is necessary to assess plasma cell burden and exclude systemic involvement 4
• Mass spectrometry-based analysis (LC-MS/MS) is the gold standard for typing amyloid deposits, with 88% sensitivity and 96% specificity 1
• In cases of suspected concomitant systemic AL and ATTR cardiac amyloidosis (such as MGUS with abnormal nuclear scintigraphy), cardiac biopsy is recommended to definitively establish the cardiac pathology 1

Monitoring and Follow-up

• Patients with localized AL amyloidosis require regular monitoring for progression to systemic disease 2
• For intermediate and high-risk MGUS patients, follow-up should include serum protein electrophoresis, complete blood count, calcium and creatinine measurements every 6 months initially, then annually if stable 1
• For SMM patients, more intensive monitoring is recommended every 4-6 months for the first year, and if stable, evaluation can be extended to every 6-12 months 1
• Skeletal survey should be performed if there is evidence of progression in routine studies 1

Clinical Implications and Management

• Early detection of progression from localized to systemic disease is crucial for timely intervention before irreversible organ damage occurs 4, 5
• Treatment is not indicated for MGUS or localized AL amyloidosis unless there is evidence of progression to systemic disease 1, 2
• For systemic AL amyloidosis, treatment targets the underlying plasma cell clone with chemotherapy and/or immunomodulatory agents 4, 6
• Daratumumab-CyBorD (cyclophosphamide, bortezomib, and dexamethasone) is recommended as first-line therapy for most patients with systemic AL amyloidosis 4
• High-dose melphalan followed by autologous stem cell transplantation may be considered for eligible patients with systemic disease 4

Pitfalls and Caveats

• Distinguishing between localized and systemic AL amyloidosis is crucial as management approaches differ significantly 5
• Standard protein electrophoresis (SPEP/UPEP) should not be used alone to exclude a monoclonal protein in suspected AL amyloidosis due to lower sensitivity 4
• Patients with AL amyloidosis are at higher risk for treatment-related toxicity than those with multiple myeloma, requiring careful monitoring during therapy 4
• The presence of a monoclonal gammopathy does not always indicate systemic amyloidosis, as over 10% of patients with monoclonal gammopathy can have ATTR deposits in the bone marrow 1