• This manual is not a substitute for consultation with an appropriate specialist.
• The contents of this manual have been developed through consensus of a Provincial Tumour Group. Please note the various update dates for each section as some of the content of the manual may not be up to date.

Revised 25 January 2012 

Amyloidosis is a term for diseases where there is extracellular deposition of pathological insoluble fibrillar proteins in organs and tissues. Amyloid deposits stain with Congo red, appearing red microscopically in normal light but apple green when viewed in polarized light. Under electron microscopy amyloid deposits have a characteristic beta-pleated-sheet configuration.

Amyloidosis can be divided into four major subtypes:

1. Light chain amyloidosis (AL): Also known as primary amyloidosis. Precursor protein is monoclonal immunoglobulin light chains. Associated with plasma cell dyscrasias or mature B-cell neoplasms
2. Secondary amyloidosis (AA): Precursor protein is serum amyloid A protein. Reactive amyloidosis secondary to chronic inflammation, infection or certain neoplasia
3. Familial amyloidosis (FAP): Precursor protein is a variant protein such as transthyretin, fibrinogen and apolipoprotein. The most common familial amyloidosis is transthyretin-associated (ATTR type)
4. Senile systemic amyloidosis (SSA): Precursor protein is transthyretin wild type. Age related (>65), found predominantly in males and affecting the heart.

Accurate diagnosis of the amyloid and subtype of amyloid is imperative for proper treatment. AL amyloidosis is a plasma cell dyscrasia (neoplasm) closely related to multiple myeloma with an anticipated incidence of 10 to 20 cases per year in BC.

Patients with AL amyloidosis requiring treatment typically receive chemotherapy whereas chemotherapy would be inappropriate for the other subtypes of amyloidosis. Patients with amyloidosis which is not due to light chains (AL) should be referred to appropriate specialists and do not require treatment or follow up at the BCCA. Given the rarity of AL amyloidosis, patients should be discussed with a member of the Leukemia/BMT Program of BC or a medical oncology member of the Lymphoma Tumour Group at one of the BCCA Centres.

Required tests:

• Pathology: Amyloid deposition must be found on a tissue biopsy. Light chain composition of the amyloid deposit can be confirmed by immunohistochemistry but this test is known to be unreliable in AL amyloidosis. Direct testing of the amyloid deposit by mass spectrometry-based proteomic analysis may be required to confirm AL-amyloid subtype (Vrana, Blood, 2009;114:4957-4959). This test is not done in British Columbia, but can be performed at reference laboratories such as the Mayo Clinic Laboratories.
• Bone marrow aspiration and biopsy: This test will determine if the amyloid is associated with multiple myeloma or another B-cell neoplasm.
• Serum and urine protein studies:
  • serum protein electrophoresis (SPE)
  • serum protein immunofixation
  • quantitative immunoglobulins
  • serum free light chain levels
  • urine protein 24 hour quantitation and electrophoresis.
  • urine protein immunofixation

The combination of serum and urine immunofixation with serum free light chain assay approaches 100% sensitivity for identifying a monoclonal protein in patients with AL amyloidosis (Palladini, Clin Chem 2009;55;499-504).

• Serum calcium, uric acid, creatinine
• beta-2-microglobulin (required at diagnosis only for associated myeloma)
• Troponin, brain naturetic peptide, or N-terminal pro-brain naturetic peptide level
• CBC
• Skeletal radiographic survey (skull, spine, humeri, pelvis, femora, ribs) with routine x-ray imaging or preferably low dose CT scan as used for myeloma: to rule out multiple myeloma
• Echocardiogram

Non-AL amyloidosis should be considered even if a monoclonal immunoglobulin protein is found (Lachman, NEJM 2002; 346:1786-1791). The incidence of MGUS increases with age and the monoclonal protein may be a finding which is unrelated to the diagnosis of amyloid. If the subtype of amyloid remains uncertain after clinical and laboratory assessment, consideration should be made for direct testing of the amyloid by mass spectrometry-based proteomic analysis. 

Genetic testing may be performed on the peripheral blood should familial amyloidosis be suspected. Although testing for transthyretin amyloid is available in British Columbia (Molecular Genetics Laboratory; C & W Health Center of BC), testing for less common familial amyloid requires sending blood samples to reference laboratories. Direct testing of the amyloid deposit by mass spectrometry-based proteomic analysis remain the most accurate test even in this circumstance.

If the amyloidosis is found to be associated with a B-cell neoplasm other than myeloma staging evaluation should be performed as appropriate for the lymphoma.​

Cardiac involvement with amyloid is the major determinant of outcome. Cardiac biomarkers have been used to prognosticate patients and determine appropriateness of therapies (particularly high-dose chemotherapy followed by stem cell rescue) (Dispenzieri, Blood, 2004;104:1881-1887). 

Using threshold values of Troponin < 0.035μg/L and NT-proBNP < 332 ng/L:

• Stage 1: Both Troponin and NT-proBNP are below the threshold
  
• Stage 2: Either Troponin or NT-proBNP are above the threshold
• Stage 3: Both Troponin and NT-proBNP are above the threshold

Immunizations

All patients should receive the immuni​zations recommended in Appendix III.

Standard Treatment

For older or unfit patients who are not eligible for transplantation, a bortezomib based treatment (UMYMPBOR) (Kastritis J Clin Onc, 2010;28:1031-1037) or melphalan with dexamethasone is used (Palladini Blood, 2004;103:2936-2938). Younger, fit patients (up to approximately 70 years of age) may be offered high dose chemotherapy and autologous hematopoietic stem cell transplant. Such patients should NOT be treated with melphalan prior to stem cell collection as it may affect the ability to collect adequate amounts of stem cells to support transplantation.

Hematopoietic stem cell transplantation

The Bone Marrow Transplantation Team offers treatment with high dose chemotherapy and hematopoietic stem cell transplantation to selected patients depending upon the level of organ dysfunction and cardiac involvement (Sanchorawala Blood, 2007;110:3561-3563). Physicians with potentially eligible patients should initiate referral with a member of the Bone Marrow Transplant Team. Induction chemotherapy may be considered with a bortezomib containing regimen (UMYBORPRE) but may not be necessary. Patients who are candidates for high dose chemotherapy and hematopoietic stem cell transplantation should NOT be treated with melphalan or other alkylating agents because this may make it impossible to gather adequate stem cells to support transplantation.

Secondary Chemotherapy

Secondary treatments for recurrent AL amyloid may include the following:

• Lenalidomide and Dexamethasone (UMYLENDEX)
• Bortezomib with Dexamethasone (UMYBORREL)
• Thalidomide (MYTHALID) (currently drug funding is not available with the BCCA)

Currently evidence for second line treatment is limited but options remain similar to that available for myeloma. The choice of the timing and order of these drugs must be individualized.

Radiation

Radiation may be useful for symptomatic focal lesions which will stop progressing if irradiated but often do not regress.