How does localized AL (Amyloid Light-chain) amyloidosis progress to systemic disease?

Mechanism of Progression from Localized to Systemic AL Amyloidosis

Localized AL amyloidosis does not progress to systemic disease through detachment or circulation of plasma cells; rather, true localized disease remains confined to the site of origin without systemic involvement. 1, 2

Understanding the Distinction Between Localized and Systemic Disease

The critical concept here is that localized AL amyloidosis and systemic AL amyloidosis are fundamentally different entities from the outset, not sequential stages of the same disease process 2:

• Localized AL amyloidosis is defined by Congo red-positive tissue deposits with negative serum and urine immunofixation, indicating no detectable monoclonal protein in circulation 2
• Systemic AL amyloidosis requires both tissue amyloid deposits AND evidence of a plasma cell dyscrasia with circulating monoclonal light chains 3

What Actually Happens: No Systemic Progression from True Localized Disease

In a comprehensive Mayo Clinic study of 413 patients with localized AL amyloidosis followed over 46 years, there were zero cases of systemic progression 2. This finding is definitive and demonstrates that:

• The plasma cell clone in localized disease remains confined to the local tissue site 2
• There is no mechanism by which these cells "detach and begin circulating" 2
• When localized disease recurs (17% of patients), it recurs locally at the same anatomic site, not systemically 2

The Real Clinical Scenario: Misdiagnosis vs. True Progression

What may appear as "progression" from localized to systemic disease is typically one of two scenarios:

Scenario 1: Initial Misdiagnosis (Most Common)

• The patient had systemic disease from the beginning, but initial workup was inadequate 1, 4
• A single negative test is insufficient to exclude systemic disease—the combination of serum immunofixation, urine immunofixation, AND serum free light chain ratio is required for 100% sensitivity 4
• Approximately 4% of systemic AL cases are missed when relying on commercial immunofixation alone 4

Scenario 2: Concurrent MGUS/SMM Evolution (Different Process)

• A patient may have both localized amyloid deposits AND a separate, unrelated monoclonal gammopathy of undetermined significance (MGUS) or smoldering multiple myeloma (SMM) 1
• The MGUS/SMM can independently progress to symptomatic systemic disease at a rate of approximately 10% per year for the first 5 years 1
• This represents two coexisting conditions, not progression of one to the other 1

Risk Stratification for MGUS/SMM Progression (When Present)

If a patient has documented localized AL amyloidosis AND concurrent MGUS/SMM, monitor for systemic progression using these risk factors 1:

• Bone marrow plasma cells ≥10% AND monoclonal protein ≥30 g/L: 87% progression risk at 15 years 1
• Bone marrow plasma cells ≥10% AND monoclonal protein <30 g/L: 70% progression risk at 15 years 1
• Abnormal free light chain ratio: independent additional risk factor 1

Diagnostic Approach to Definitively Exclude Systemic Disease

To ensure a patient truly has localized (not systemic) disease, the following comprehensive workup is mandatory 3, 4:

• Serum free light chain assay (sFLC) with kappa/lambda ratio 3, 4
• Serum immunofixation electrophoresis (SIFE) 3, 4
• Urine immunofixation electrophoresis (UIFE) 3, 4
• Bone marrow biopsy to assess for clonal plasma cells 3
• Mass spectrometry (LC-MS/MS) of tissue biopsy for definitive amyloid typing (88% sensitivity, 96% specificity) 3, 1

Critical pitfall: Standard protein electrophoresis (SPEP/UPEP) has inadequate sensitivity and should never be used alone to exclude systemic disease 3, 5

Clinical Implications and Prognosis

For patients with true localized AL amyloidosis 2:

• 10-year survival is 78%, equivalent to the general population 2
• Treatment is typically local excision of deposits (61% of cases) 2
• Systemic chemotherapy is not indicated unless systemic disease develops 1
• Recurrence occurs locally in 17% but never systemically 2

For patients who develop systemic disease (either misdiagnosed initially or MGUS/SMM progression) 5, 1:

• Daratumumab-CyBorD is first-line therapy 5, 1
• Cardiac involvement drives prognosis and mortality 3, 5
• Treatment targets the plasma cell clone, not the amyloid deposits directly 5