The systemic amyloidoses are a group of complex diseases caused by tissue deposition of misfolded proteins that results in progressive organ damage.1 The incidence of immunoglobulin light chain (AL) amyloidosis (also referred to as primary amyloidosis) is approximately one-tenth that of multiple myeloma,1 a more common cancer of the bone marrow plasma cells. In approximately 10% of patients, both AL amyloidosis and multiple myeloma are present at the time of diagnosis.2 The process of amyloid formation results in cellular injury, tissue damage, and organ dysfunction through mechanisms that are not completely understood.1 Patients with amyloidosis usually present with a small plasma cell clone with evidence of dysfunction in 1 or more involved organs.1 Most commonly, this includes renal involvement in approximately 70% of amyloidosis patients, with nephrotic range proteinuria or renal failure; cardiomyopathy in approximately 60%; and peripheral neuropathy in approximately 20%.1 Among newly diagnosed patients, 30% have 3 or more major organ systems involved.3
The prognosis for patients with amyloidosis varies considerably depending on the nature, number, and extent of organ involvement.2 Median survival may be as short as 4 to 6 months, with cardiac failure, hepatic failure, and/or infection being the major causes of death.2 However, those patients with limited organ involvement can expect a median survival in excess of 5 years.2
Types of Amyloid Diseases
To date, at least 28 different proteins have been identified as causative agents of amyloid diseases.4 AL amyloidosis is the most common form of amyloid disease and is due to deposition of protein derived from immunoglobulin light chain fragments.4 It is considered a plasma cell dyscrasia in which a monoclonal protein is detectable in the serum or urine in approximately 80% of cases.4 AA (or secondary) amyloidosis is characterized by extracellular tissue deposition of fibrils composed of fragments of serum amyloid A (SAA) protein, an acute-phase reactant. AA amyloidosis is related to a chronic disease in which there is ongoing or recurring inflammation, such as rheumatoid arthritis or inflammatory bowel disease.4 Dialysis-related amyloidosis is due to deposition of fibrils derived from beta-2 microglobulin, which accumulates in patients with end-stage renal disease on long-term dialysis therapy.4 Amyloid deposition may also be isolated to a single organ, such as the skin, eye, heart, etc, and has been shown to be biochemically identical to systemic forms of amyloid.4
Early diagnosis is the key to effective therapy, allowing reversal of the organ damage and better tolerability of adverse effects of therapy.1 Approximately 40% of patients have light chain–only disease, and therefore diagnosis is often missed if only serum protein electrophoresis is performed.1 However, the combination of serum and urine immunofixation electrophoresis with serum free light chain assay approaches 100% sensitivity for diagnosis.1 If a serum monoclonal protein is present, a bone marrow biopsy should be performed to rule out multiple myeloma.1 Congo red staining performed on the biopsy will be positive for amyloid in <60% of patients.1 Congo red staining of tissue from an involved organ or surrogate site (fat pad, gingiva, or rectum) may also lead to diagnosis.3 Deciphering the type of amyloidosis is essential in establishing the appropriate intervention and treatment.3
Treatment for AL amyloidosis is highly individualized and is based on age, organ dysfunction, and regimen toxicities.1 The goals of therapy are prompt elimination of the misfolded amyloidogenic light chains, minimization of treatment toxicity, and support of the function of target organs.1 For many years, melphalan plus prednisone was considered the standard therapy for patients with AL amyloidosis who are not candidates for autologous stem cell transplantation.2 More recently, dexamethasone has been substituted for prednisone in association with melphalan, resulting in much higher hematologic responses.1 A reduction in proteinuria has been noted in up to 50% of patients treated with these regimens, though they are not without risk.2 Melphalan-induced cytogenetic abnormalities can lead to pancytopenia and/or secondary myelodysplastic syndromes, with an incidence of these complications of up to 6.5%.2 However, the actual risk may exceed 20% in those who appear to have a good amyloid response and survive for more than 3.5 years.2
Thalidomide as a single agent has limited efficacy and is poorly tolerated, with fatigue and sedation being the major dose-limiting toxicities, followed by fluid retention, constipation, orthostasis, peripheral neuropathy, and worsening renal function.1 Somewhat better results have been obtained when thalidomide was combined with dexamethasone.2 Thalidomide/dexamethasone can be considered an option alone or in combination with cyclophosphamide for the treatment of patients who relapse after melphalan/dexamethasone or stem cell transplantation.2 Lenalidomide in combination with dexamethasone may also be reasonable for patients who relapse after melphalan/dexamethasone or stem cell transplantation.2 The most common adverse effects of this combination are cytopenia, fatigue, and rash.1 Hematologic responses have ranged from 41% to 47%.1 In addition, bortezomib has significant activity in AL amyloidosis, with the most common nonhematologic toxicities including peripheral sensory neuropathy with or without neuropathic pain, exacerbation of orthostatic hypotension, peripheral edema, and constipation or diarrhea.2 A phase 3 study comparing bortezomib/melphalan/dexa - methasone with melphalan/dexa - methasone is currently in progress.2
A significant advance in myeloma chemotherapy has been the addition of stem cell transplantation, and this approach has since been adapted for patients with AL amyloidosis.1 The fragility of the amyloidosis patient population was soon evident, however, when some transplant centers reported treatment-related mortality exceeding 40% or more in those with cardiac involvement.1 In an attempt to reduce treatment-related toxicity, attenuated melphalan dosing has been used in high-risk and older patients, resulting in reduced toxicity but generally lower response rates.1 Both cardiac and renal transplantation have been successfully carried out in AL amyloidosis patients with associated organ involvement.1 The Amyloidosis Clinical Trials Network should also be explored for those patients considering clinical trial participation, as novel agents and regimens are showing great promise in the treatment of amyloidosis.
- Merlini G, Seldin DC, Gertz MA. Amyloidosis: pathogenesis and new therapeutic options. J Clin Oncol. 2011;29:1924-1933.
- Rajkumar SV. Prognosis and treatment of immunoglobulin light chain (AL) amyloidosis and light and heavy chain deposition diseases. UpToDate 19.2. http://www.uptodate.com/contents/prognosis-andtreatment-of-immunoglobulin-light-chain-al-amyloidosis-and-light-and-heavy-chain-deposition-diseases. Updated June 3, 2011. Accessed November 7, 2011.
- Comenzo RL. How I treat amyloidosis. Blood. 2009;114:3147-3157.
- Gorevic PD. An overview of amyloidosis. UpToDate 19.2. http://www.uptodate.com/contents/an-overview-ofamyloidosis?source=search_result&search=An+overview+of+amyloidosis.&selectedTitle=1~150. Updated November 2, 2010. Accessed November 7, 2011.