Novel targeted therapies for immunoglobulin light chain amyloidosis: latest updates from the 2024 ASH annual meeting

Abstract

Immunoglobulin light chain (AL) amyloidosis is an incurable disease caused by the accumulation and sedimentation of unstable free light chains produced by monoclonal plasma cells. The key to treatment is to achieve a deep hematologic remission in order to improve organ function or reverse organ dysfunction. Conventional treatment has not been able to fully meet the treatment needs of patients with AL, while therapies targeting malignant plasma cells or amyloid have potentially improved treatment outcomes. This study provides an overview of the latest reports on targeted therapies for AL amyloidosis from the 2024 ASH Annual Meeting.

To the editor,

Immunoglobulin light chain (AL) amyloidosis is a rare plasma cell neoplasm, characterized by the excessive production of misfolded light chains from abnormal plasma cell clones, leading to multi-organ dysfunction and failure. Compared with conventional treatment, targeted therapies led to more promising clinical outcomes, changing the treatment landscape for AL amyloidosis. This review highlights the latest advances in the targeted therapies of AL presented at the 2024 ASH annual meeting.

CD38-targeted treatment

Daratumumab in combination with bortezomib, cyclophosphamide and dexamethasone (Dara-VCd) received the first and only FDA accelerated approval as a therapy specifically for AL amyloidosis, based on the excellent response rates observed in the ANDROMEDA study [1]. Kastritis et al. [2] reported the final analysis for major organ deterioration progression-free survival (MOD-PFS) and overall survival (OS) from the ANDROMEDA study, with a median follow-up of 61.4 months. Compared to newly diagnosed (ND) AL amyloidosis patients treated with VCd, the Dara-VCd arm demonstrated a significantly better survival outcomes (median MOD-PFS: not yet reached vs. 30.2 months, P < 0.0001; 5-year survival rate: 76.1% vs. 64.7%, P = 0.0121).

The ongoing EMN22 trial investigated the daratumumab monotherapy in patients with stage IIIB ND AL amyloidosis [3]. The results indicated daratumumab has the potential to benefit the population experiencing serve cardiac dysfunction, achieving a 77.5% hematologic overall response rate (hemORR), including both a hematologic very good partial response (hemVGPR) and a hematologic complete response (hemCR) of 27.5%. Additionally, a cardiac response was observed in 50% among the 40 patients. However, the study also raised concerns regarding a 27.5% early mortality rate and 42.5% incidence of fatal serious adverse events (SAEs) in these ultra-high-risk patients.

The SWOG S1702 study evaluated another anti-CD38 monoclonal antibody isatuximab, as monotherapy in relapsed or refractory (R/R) AL amyloidosis and achieved a 77.1% hemORR, with a hemVGPR or better in 57%, a cardiac response in 56% (14/25) and a renal response in 50% (7/14) of patients [4]. In the ISAYP study, when isatuximab was combined with pomalidomide and dexamethasone for relapsed AL amyloidosis, 80% (33/41) of patients achieved a hemVGPR or better after 6 cycles, including 51.0% of hemCR [5]. Cytopenia and infections were the most common AEs. It is worth noting that the study protocol specified a dose of 4 mg/day for pomalidomide, however, 35% of patients required dose adjustments to 3 mg/day due to neutropenia or skin rash.

BCMA-targeted treatment

In the EMN27 study, the anti-BCMA antibody-drug conjugate belantamab mafodotin (belamaf) was administered as monotherapy in R/RAL [6]. A total of 35 patients received 130 doses of belamaf, resulting in a hemORR of 51.4%, including a hemVGPR or better of 31.4%. Additionally, one patient achieved a hematologic complete response (hemCR). The median OS and MOD-PFS were 21.54 and 9.99 months respectively, with ocular AEs being the most frequent grade ≥ 3 safety findings.

In a phase 1a/b study, Lebel et al. [7] enrolled 16 R/R AL amyloidosis patients with a median of 4 prior lines of therapy, to evaluate an academic anti-BCMA chimeric antigen receptor T-cell (CART), HBI0101. Although 14/16 (88%) patients were triple-refractory and 6/16 (38%) were belamaf-refractory, a hemORR of 15/16 (94%) and a hemCR rate of 12/16 (75%) were achieved. 9/14 evaluable patients achieved minimal residual disease (MRD) negativity at 10^-5, indicating a deep hematologic response. Although no treatment-related deaths were reported, 7 patients died during follow-up, 3 of whom were in hematologic response.

Bcl-2 targeted treatment

A phase 2 study was conducted to evaluate the role of venetoclax in AL amyloidosis with t(11;14) as a front-line treatment [8]. Among the 29 patients evaluable for response, hemVGPR or better was observed in 62.9% at any time, with a hemCR rate of 37.1%. At 6 months, 35.0% of patients had a cardiac response, while 90.9% had a renal response.

Lisaftoclax, a novel selective Bcl-2 inhibitor administered orally at doses ranging from 400 to 1000 mg daily, was attempted in combination with pomalidomide and dexamethasone for R/R AL amyloidosis in a phase 1b/2 study [9]. The results showed a hemORR of 85.7%, with 71.4% of the evaluable patients achieving a hemVGPR or better, and two patients exhibiting a cardiac response.

Amyloid-targeted treatment

CD34⁺ hematopoietic stem cell-derived 11-1F4-CAR macrophages have shown promising amyloid targeting and phagocytic efficacy both in vitro and in a humanized AL amyoidoma mouse model [10]. AT-02 is an investigational humanized IgG1 peptide fusion containing the pan-amyloid binding peptide p5R [11]. The monoclonal antibody could bind to amyloid through peptide interactions, activate macrophage phagocytosis, and induce complement activation, showing promise in clearing the deposited amyloid and reversing organ dysfunction. Additionally, another preclinical study investigated small molecule kinetic stabilizers designed to mitigate toxicity by enhancing the kinetic and thermodynamic stability of amyloidogenic proteins [12]. Further clinical evidence is required to assess the viability of these amyloid-targeting therapies in human patients.

In summary, the ASH 2024 Annual Meeting highlighted promising progress in therapies targeting plasma cells and amyloid for AL amyloidosis, as illustrated in Tables 1 and 2. Moreover, although data were not presented at this conference, several therapies targeting amyloid are currently being explored in clinical trials, such as CEAL-101 and birtamimab, and they have yielded some promising preliminary results. Additional large-scale prospective studies are needed to provide further clinical evidence for these novel target treatment regimens.

Table 1 Updates on therapies targeting plasma cell clones in AL amyloidosis

Table 2 Updates on therapies targeting amyloid in AL amyloidosis