Key Information
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.
Keywords: Immunoglobulin light chain amyloidosis, Targeted therapies, Clinical trials
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 [1external link, opens in a new tab]. Kastritis et al. [2external link, opens in a new tab] 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 [3external link, opens in a new tab]. 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.