Emerging drugs for the treatment of light chain amyloidosis

ABSTRACT

Introduction

Systemic AL amyloidosis is a protein-misfolding disorder that is characterized by the deposition of insoluble amyloid fibrils derived from kinetically unstable light chains. Achieving a rapid and deep hematologic response is critical for long-term survival.

Areas covered

This review covers the existing and emerging treatment options for systemic AL, divided into anti-plasma cell and fibril-directed therapies. The anti-CD38 monoclonal antibody daratumumab has demonstrated an unprecedented hematologic response rate and will become the new standard-of-care in newly diagnosed patients in combination with CyBorD/VCD. Other plasma cell-directed drugs that have prospective data on safety and efficacy in AL include proteasome inhibitors [bortezomib and ixazomib], immunomodulatory drugs [lenalidomide and pomalidomide], and alkylating agents [melphalan and bendamustine]. A major unmet need is the development of fibril-directed therapies with the goal of eliminating amyloid fibrils that are already deposited in vital organs.

Expert opinion

The treatment of newly diagnosed AL in the future will likely include daratumumab-based therapy in conjunction with fibril-directed therapy. The most promising second line drugs are venetoclax [for t(11;14)] and pomalidomide, with several others in the pipeline, including antibody-drug conjugates. Minimal residual disease will emerge as a new endpoint for drug development and will potentially guide treatment duration.

KEYWORDS:

• Amyloidosis
• al amyloidosis
• daratumumab
• venetoclax
• cael-101

Declaration of interest

S Lentzsch is a Consultant/Advisor at Caelum Bioscience, Sorrento, Celularity, Janssen; has stock ownership at Caelum Bioscience; Research grant from Kyropharm and Sanofi; and has Royalties/Patents with Caelum Bioscience. The authors have no other 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 apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.