AL Amyloidosis: Current Chemotherapy and Immune Therapy Treatment Strategies: JACC: CardioOncology State-of-the-Art Review

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.

Keywords: AL amyloidosis; AL, immunoglobulin light chain; ASCT, autologous stem cell transplant; FLC, free light chains; Ig, immunoglobulin; MM, multiple myeloma; PC, plasma cell; cardiomyopathy; chemotherapy; fibrils; immunotherapy; organ failure; plasma cell disorders.

Graphical abstract

Figure 1

Evolution of Treatment in AL Amyloidosis The timeline outlines in chronological order the clinical use of distinct treatments in immunoglobulin light chain (AL) amyloidosis. Commonly used agents/regimens are in red boxes, less commonly used agents/regimens are in green boxes. The top of the figure outlines some of the most impactful technological/clinical advances in AL amyloidosis. ASCT = autologous stem cell transplant; CyBorD = cyclophosphamide-bortezomib-dexamethasone; Dara = daratumumab; Dex = dexamethasone; FLC = free light chain; LC-MS = liquid chromatography-mass spectrometry; MALDI-TOF = matrix-assisted laser desorption ionization time-of-flight; Mel = melphalan; MM = multiple myeloma; MRD = minimal residual disease; NSG = next generation sequencing; Pred = prednisone.

Figure 2

Algorithm for Treatment Approach to Newly Diagnosed AL Amyloidosis Patients The schema outlines an algorithm for therapeutic decisions in newly diagnosed AL amyloidosis patients with the goal of achieving a deep hematologic response. An early branching point is eligibility for high dose chemotherapy and ASCT. We recommend induction chemotherapy for all patients for 4-6 cycles with monthly assessment of disease response and change of therapy after 2 months if an optimal response is not achieved. ASCT and/or distinct chemotherapy regimens can be used to intensify treatment to achieve a hematologic CR. #Number of cycles is arbitrary and dependent on kinetic of response, tolerability, and indication for ASCT. ∗Monthly monitoring of hematologic and organ response is mandatory. If a VGPR is not achieved after 2 cycles, we recommend changing chemotherapy. ^Stem cells should be harvested even if ASCT is deferred to second remission. MRD assessment may be useful to aid in discussion regarding intensification of treatment. CR = complete response; other abbreviations as in Figure 1.

Central Illustration

Therapeutic Strategies in Immunoglobulin Light Chain Amyloidosis: Current Use and Clinical Development The Figure outlines the target and/or mechanisms of action of the most frequently used drugs in immunoglobulin light chain amyloidosis and agents in advanced clinical development. Proteasome inhibitors block the function of the proteasome, inducing polyubiquitinated protein accumulation. IMiDs induce Ikaros and Aiolos (IKZF1 and IKZF2, respectively) proteasome-mediated degradation and enhance T-cell and NK-T-cell function. MoAbs DARA and ISA cause complement-dependent cytotoxicity (CDC), antibody-dependent cell cytotoxicity (ADCC), and direct cytotoxicity from crosslinking. ELO triggers ADCC, and the antibody drug conjugated (ADC) targeting BCMA, belantamab mafodotin, induces DNA damage via MMAF. Alkylating agents similarly induce DNA damage and selinexor blocks XPO1. Venetoclax binds BCL2, releasing BAX and triggering cytochrome C release and caspase 9-mediated apoptosis. Antifibrillary antibodies facilitating macrophage-mediated amyloid reabsorption are depicted in the top left corner. U.S. Food and Drug Administration–approved drugs in MM therapy are green, whereas investigational agents are in red. DARA = daratumumab; ELO = elotuzumab; IL = interleukin; ISA = isatuximab; MMAF = monomethyl auristatin F; TNFα = tumor necrosis factor alpha; MDSC = myeloid derived suppressor cell; pDC = plasmacytoid dendritic cell; TH17 = T helper 17; Treg = regulatory T cells; Ub = ubiquitin; XPO1 = exportin 1.