Immune Therapies in AL Amyloidosis—A Glimpse to the Future

Published: Apr 22, 2024
Category
Scientific Articles
Key Information
Source
National Library of Medicine
Year
2024
summary/abstract

Simple Summary

Light-chain (AL) amyloidosis is a rare disease similar to the more common disease, multiple myeloma (MM). Both are caused by proliferation of malignant plasma cells. In AL amyloidosis, disease is a result of the deposition of aggregates of proteins, namely immunoglobulin light chains, secreted by the malignant plasma cells, in target organs such as the heart or kidneys. Historically, treatment of AL amyloidosis has followed that of MM. A wide range of novel immunotherapies, i.e., therapies which utilize or activate immune mechanisms to eliminate the disease, are already established in MM and are gradually being adopted in AL amyloidosis as well. Although promising, the increased frailty of typical AL amyloidosis compared to MM patients is a concern in the administration of these therapies, which may be associated with severe side effects. We review both the promise and the challenges with the expansion of MM immunotherapies to AL amyloidosis.

Abstract

Light-chain (AL) amyloidosis is a rare plasma cell disorder characterized by the deposition of misfolded immunoglobulin light chains in target organs, leading to multi-organ dysfunction. Treatment approaches have historically mirrored but lagged behind those of multiple myeloma (MM). Recent advancements in MM immunotherapy are gradually being evaluated and adopted in AL amyloidosis. This review explores the current state of immunotherapeutic strategies in AL amyloidosis, including monoclonal antibodies, antibody–drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell therapy. We discuss the unique challenges and prospects of these therapies in AL amyloidosis, including the exposure of frail AL amyloidosis patients to immune-mediated toxicities such as cytokine release syndrome (CRS) and immune effector-cell-associated neurotoxicity syndrome (ICANS), as well as their efficacy in promoting rapid and deep hematologic responses. Furthermore, we highlight the need for international initiatives and compassionate programs to provide access to these promising therapies and address critical unmet needs in AL amyloidosis management. Finally, we discuss future directions, including optimizing treatment sequencing and mitigating toxicities, to improve outcomes for AL amyloidosis patients.

Keywords: plasma cell dyscrasia, amyloidosis, light chain, immunotherapy, bispecific antibodies, chimeric antigen receptor T cells

1. Introduction

Light-chain (AL) amyloidosis is a rare plasma cell dyscrasia characterized by multi-organ damage due to misfolded immunoglobulin light chains (LC) secreted by clonal abnormal plasma cells (PC). In line with their common origin in clonal malignant PCs in the bone marrow, treatment of AL amyloidosis has traditionally followed that of multiple myeloma (MM), utilizing a combination of PC-targeted agents [,,]. Recent development of therapies unique to AL amyloidosis, which aim to promote the clearance of the amyloidogenic LC from affected organs rather than targeting the abnormal PCs secreting the amyloidogenic LC, show great promise, yet are an adjunct to systemic anti-PC therapy []. Notwithstanding recently uncovered differences in underlying disease biology [,], treatment approaches successful in MM have effectively translated to treatment of AL amyloidosis. Thus, mirroring improvements in MM survival over the last decades with the introduction of novel therapeutic agents [,,,,], progress has also been made in the treatment of AL amyloidosis []. Nevertheless, the prognosis of many patients, especially frail patients who are less able to tolerate the toxicity of effective therapies, remains dismal [,]. Although the concept of frailty in AL amyloidosis is not rigorously defined nor accompanied by disease-specific frailty scores, it is agreed that the main determinants of frailty and increased short-term mortality in these patients are older age and the extent of cardiac involvement at diagnosis. To a lesser degree, other organ involvement as well as pre-existing comorbidities also play a role in determining frailty []. Because improvement in organ function usually lags behind the cessation of further secretion of the toxic amyloidogenic LC [], patients with advanced cardiac disease are not only less able to tolerate the side effects of treatment but also may succumb to pre-existing organ damage before gaining any benefit from therapy, as evinced by high rates of early mortality (within 3–6 months of diagnosis) in this patient population [,,].

The aforementioned improvements in survival in both MM and AL amyloidosis in the last decades have largely been the result of widespread adoption of so-called novel agents, including proteasome inhibitors, immunomodulatory agents [,], and the anti-CD38 monoclonal antibody daratumumab, the first immunotherapy to gain the approval of the Food and Drug Administration (FDA) for treatment of MM [] and subsequently AL amyloidosis []. More recently, the spectrum of immunotherapeutic agents (i.e., therapies that stimulate the host immune system to target cancerous cells) in MM has widened to include antibody–drug conjugates (ADCs), bispecific antibodies (BSAs), and chimeric antigen receptor T cells (CART). These are rapidly being integrated into the therapeutic armamentarium in MM, primarily in the context of relapsed/refractory disease [], and are gradually being evaluated in AL amyloidosis as well.

Malignant PCs in MM and AL amyloidosis share several key features which are of relevance to immunotherapeutic approaches, including the surface expression of CD38 [], B-cell maturation antigen (BCMA) [], and G-protein-coupled receptor, class C group 5 member D (GPRC5D) []. These three proteins (Figure 1external link, opens in a new tab) are the targets of most immunotherapeutic agents developed to date [] and, as referred to above, daratumumab, targeted against CD38, is already part of the current standard-of-care first-line treatment of AL amyloidosis, in combination with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) [].

Authors
Department of Hematology, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel; li.gro.hassadah@nonra (A.H.); li.gro.hassadah@ghsomr (M.E.G.)