Immunoglobulin Light Chain (AL) Amyloidosis

Background

• AL amyloidosis is primarily a systemic disease manifested by progressive tissue and organ damage caused by the deposition of amyloid fibrils formed from the misfolding and aggregation of monoclonal immunoglobulin light chains.
• Any organ can be involved. The most commonly affected organs are the heart and kidneys.
• The disease most commonly affects adults > 60 years old.
• The age- and sex-adjusted incidence is about 12-13 cases per million person-years in the United States in 2015.
• Risk factors include preexisting monoclonal gammopathy of undetermined significance (MGUS), single nucleotide polymorphisms, and exposure to some chemicals.
• Prognosis is generally poor if it is untreated, unless it is localized disease.
• The most important baseline prognostic factors are cardiac involvement, hepatic involvement, the presence of autonomic neuropathy, a greater difference between disease-associated and uninvolved circulating FLC (dFLC), and bone marrow plasma cell burden, while hematologic and/or organ response is important for the prediction of prognosis after therapy.

Evaluation

• Perform a history and physical exam including the evaluation of orthostatic hypotension.
  • Patients usually present with nonspecific symptoms, such as, fatigue, peripheral edema, weight loss, pseudoclaudication or claudication, exertional dyspnea, and an alteration in taste.
  • Macroglossia and periorbital purpura are highly specific findings, but they are not uncommon.
• Clinical presentation may vary depending on the specific organs involved. The following presentations that are not attributed to other medical conditions should prompt a high suspicion of a diagnosis of AL amyloidosis:
  • heart failure with preserved ejection fraction and/or left ventricular hypertrophy not related to hypertension
  • nephrotic range proteinuria which is unrelated to diabetes
  • peripheral or autonomic neuropathy unrelated to diabetes (including bilateral carpal tunnel syndrome and/or orthostatic hypotension)
  • hepatomegaly and/or unexplained elevation in alkaline phosphatase
  • monoclonal gammopathy with unexplained elevated N-terminal pro-brain natriuretic peptide (NT-proBNP), proteinuria, and/or neuropathy
• For patients with presentation that is suspicious for AL amyloidosis, perform serum and urine protein electrophoresis, immunofixation, and serum FLC assay (Strong recommendation).
• For patients with cardiac presentation, consider ^99mtechnetium (^99mTc)-labeled pyrophosphate or ^99mTc-labeled 3,3-diphosphono-1,2-propanodicarboxylic acid (PYP or DPD) testing to rule out amyloid transthyretin (ATTR) amyloidosis.
• If monoclonal immunoglobulin is detected in the blood or urine and/or if the serum FLC assay is abnormal, confirm the diagnosis with a biopsy (generally with a bone marrow biopsy or aspirate and/or an abdominal fat aspirate) and histopathologic analyses (Strong recommendation).
  • Histopathologic analyses include Congo red staining to detect amyloid (Strong recommendation), and typing of amyloid with mass spectrometry (Strong recommendation), immunohistochemistry (Strong recommendation), or immunoelectron microscopy.
  • If the initial biopsy is negative but a high index of suspicion remains, consider additional workup, such as, cardiac magnetic resonance imaging (MRI), and a possible repeat biopsy (of involved tissues or organ or alternate site) (Weak recommendation).
• After the diagnosis of AL amyloidosis, perform a further evaluation of organ involvement to determine if it is localized AL amyloidosis and to determine the extent of organ involvement in systemic AL amyloidosis.

Management

• Patients should have rapid initiation of treatment.
• Manage patients primarily in designated centers with onsite multidisciplinary care and experience in the management of patients with amyloidosis.
• Offer enrollment in clinical trials as the preferred management approach (Strong recommendation). See a list of ongoing trials in patients with AL amyloidosis at clinicaltrials.gov.
• For the management of localized AL amyloidosis, either consider observation, or offer local resection, or radiation therapy if it is clinically indicated (Strong recommendation for local resection or radiation therapy).
• Management of systemic AL amyloidosis:
  • For newly diagnosed systemic AL amyloidosis, management is based on evaluation of eligibility for induction therapy and hematopoietic stem cell transplantation (HSCT).
    • Regardless of transplant eligibility, common induction therapy options include:
      • daratumumab and hyaluronidase-fihj plus bortezomib, cyclophosphamide, and dexamethasone (preferred) (Strong recommendation)
      • bortezomib-based regimens (Strong recommendation)
    • In patients who are ineligible for HSCT and at intermediate-risk with t[11;14] or neuropathy, administer melphalan and dexamethasone (Strong recommendation).
    • For transplant-eligible patients, offer high-dose chemotherapy with autologous HSCT generally after induction therapy (Strong recommendation).
    • Do not offer maintenance or consolidation therapy outside the context of a clinical trial (Strong recommendation).
  • For relapsed or refractory systemic AL amyloidosis:
    • For patients with long relapse-free duration from initial therapy, offer reuse of first-line therapy (Strong recommendation).
    • For patients who remain eligible, offer high-dose melphalan plus autologous HSCT (Strong recommendation).
    • Other therapy options depend on the agents to which patients are refractory as well as the safety of the agents based on organ involvement, and include:
      • proteasome inhibitor-based regimens (Weak recommendation)
      • daratumumab-based regimens (Weak recommendation)
      • immunomodulator-based regimens (Strong recommendation)
      • alkylator-based regimens (Weak recommendation)
      • venetoclax-based regimens for patients with t(11;14) (Weak recommendation)
• Supportive care should include management of the complications of organ involvement.
• Monitoring frequently during and after therapy is necessary to evaluate hematologic and organ responses.