AL Amyloidosis: Current Chemotherapy and Immune Therapy Treatment Strategies

Abstract

Immunoglobulin light chain (AL) amyloidosis is an incurable plasma cell disorder characterized by deposition of fibrils of misfolded immunoglobulin free light chains (FLC) in target organs, leading to failure. Cardiac involvement is common in AL amyloidosis and represents the single most adverse prognostic feature. A high index of clinical suspicion with rapid tissue diagnosis and commencement of combinatorial, highly effective cytoreductive therapy is crucial to arrest the process of amyloid deposition and preserve organ function. The clinical use of molecularly targeted drugs, such as proteasome inhibitors and immunomodulatory agents, monoclonal antibodies such as daratumumab, and risk-adjusted autologous stem cell transplant in eligible patients, has radically changed the natural history of AL amyloidosis. Here, we review the state-of-the-art treatment landscape in AL amyloidosis with an eye toward future therapeutic venues to impact the outcome of this devastating illness.

Perspective Chapter: Lipoprotein (a), Cardiac Amyloidosis, and Aortic Stenosis - Underestimated Associations

“…The "anti-amyloid" strategy is etiology-dependent. The mainstay of the treatment of AL amyloidosis is the cytoreductive, plasma-cells-directed chemotherapy and/or immunetherapy [97]. The standard of care regimen is based on the use of a combination of agents, such as cyclophosphamide, bortezomib, and dexamethasone [98].…”

“…The available therapy does not directly affect amyloid deposition; thus, timing of diagnosis is of paramount importance. Novel agents are being tested in order to obtain amyloid reabsorption [97]. There are three therapeutic strategies for the treatment of ATTR amyloidosis: 1) TTR stabilization; 2) TTR mRNA silencing; and 3) amyloid fibrils disruption and/or extraction (Table 2) [60].…”

Molecular Mechanisms of Cardiac Amyloidosis

“…The basic treatment for AL amyloidosis is to reduce the free LC, which are the source of amyloid, by methods such as chemotherapy and autologous stem cell transplantation [ 5 , 139 , 140 , 141 , 142 ].…”

Red flags for the diagnosis of cardiac amyloidosis: simple suggestions to raise suspicion and achieve earlier diagnosis

“…In 2021, the association of cyclophosphamide, bortezomib, and dexamethasone with the monoclonal antibody daratumumab hyaluronidase (Dara-CyBorD) has been approved by the Food and Drug Administration as a targeted treatment for newly diagnosed AL amyloidosis. 6 In fact, the combination with daratumumab has proven very effective with almost a three-times higher percentage of patients with a hematologic complete response and longer survival free from major organ deterioration or hematologic progression compared with the treatment with the sole association of bortezomib, cyclophosphamide, and dexamethasone. 7 TTR protein is synthesized by the liver and released in the bloodstream where it acts as a thyroxine and holoretinol carrier.…”