New and developing therapies for AL amyloidosis

ABSTRACT

Introduction: Systemic light-chain (AL) amyloidosis is an infiltrative disorder associated with an underlying plasma cells dyscrasia, in which monoclonal immunoglobulin light chains accumulate in an abnormal misfolded form as amyloid fibrils in the extracellular space. Symptoms and prognosis are governed by which organs are affected, and cardiac involvement is the major determinant of survival. Diagnosis requires demonstration of amyloid deposition and confirmation of the fibril protein type.

Areas covered: This review will focus on the available treatments for systemic AL amyloidosis and on new drug targets and therapeutic approaches.

Expert opinion: At present, the choice of upfront treatment lies between autologous stem cell transplantation (ASCT) and combination chemotherapy. Chemotherapy agents include dexamethasone, melphalan, cyclophosphamide, thalidomide, bortezomib, lenalidomide, bendamustine in various combinations. Few randomized controlled trials have been performed in AL amyloidosis and treatment has been substantially influenced by clinical practice in myeloma. It has become clear that the best prospects of survival and preservation or improvement in amyloid related organ function require as near complete suppression as possible of the underlying hematological disorder. Future directions include therapies designed to target amyloid deposits directly, in particular anti-amyloid antibodies which are now well advanced in development and are showing great potential.

KEYWORDS:

• Immunoglobulin light-chain amyloidosis
• screening
• treatments
• combination chemotherapy
• stem cell transplantation
• immunotherapeutic targeting
• new frontiers

Article highlights

• Systemic light-chain (AL) amyloidosis is an infiltrative disorder associated with an underlying plasma cells dyscrasia, in which monoclonal immunoglobulin light chains accumulate in an abnormal misfolded form as amyloid fibrils in the extracellular space and disrupt organ function.

• The presenting clinical picture of patients with systemic AL amyloidosis is variable and non-specific. This is associated with a significant delay in the diagnosis, with 30% of patients presenting with a prognosis of less than 12 months. Screening of pre-symptomatic organ damage has the potential to change this.

• The use of autologous stem cell transplantation (ACST) with high dose melphalan is associated with excellent and durable clonal responses, but only 20–25% of patients are currently eligible (low risk patients). Accurate patient selection, based on blood biomarkers, is crucial to reduce treatment related mortality. The intermediate and high risk patients should be considered for combination chemotherapy (melphalan-dexamethasone, bortezomib - cyclophosphamide - dexamethasone, bortezomib - melphalan -dexamethasone). Patients with relapsed or refractory disease should be considered for treatment with agents including bendamustine, lenalidomide and pomalidomide.

• Patients achieving a hematologic complete response/very good partial response have the best chance to achieve organ responses, but stabilization or improvement in amyloidotic organ function occur also in a proportion of patients who achieved only partial hematologic responses. Tracking organ function very closely during chemotherapy is essential. Review after 3 cycles of treatment is suggested with dose increments, additional agents or alternative regimens in patients responding poorly.

• New treatment strategies, directly targeting amyloid deposits and interfering with fibril formation, are currently well advanced in development and have the potential to reshape the treatment of AL amyloidosis.

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Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.