A Clinical Study on Minimal Residual Disease in Patients With Systemic Light Chain Amyloidosis

Light chain amyloidosis (AL amyloidosis), as a plasma cell disorder, is caused by a typically small and slowly proliferating clone of plasma cells in the bone marrow. The light chains produced by this clone misfold, forming amyloid fibrils that deposit in various tissues and organs, leading to progressive organ dysfunction. Prior to effective treatment, the prognosis for AL amyloidosis patients is very poor, with a median survival of approximately 12 months. In recent decades, with continuous improvements in patient selection criteria for autologous hematopoietic stem cell transplantation (ASCT) and the development of novel drugs such as proteasome inhibitors, the treatment landscape for AL amyloidosis has changed significantly, resulting in a marked improvement in patient prognosis.

Hematologic response assessment is a primary focus during treatment, with achieving very good partial response (VGPR) or even complete response (CR) leading to higher rates of organ response and longer survival. However, not all patients who achieve ≥VGPR reach organ response. This may be due to the presence of minimal residual plasma cell clones, which continue to produce monoclonal light chains that deposit in tissues and organs, causing ongoing damage, making organ response difficult. With the continuous development of novel drugs, the rate of hematologic CR has improved, and recent advancements in minimal residual disease (MRD) detection techniques, have increasingly drawn attention in AL amyloidosis research. Therefore, in an era of continuous drug development, achieving MRD negativity may become an important clinical treatment goal for AL amyloidosis, further improving long-term patient prognosis.

A favorable result from the 2021 randomized clinical trial (NCT03201965) led to the Dara-CyBorD regimen becoming the first FDA-approved first-line treatment in Europe and the U.S., which has sparked some debate about the role of ASCT. Dara can lead to early and deep hematologic remission, with a CR rate comparable to ASCT. Some studies have shown that patients receiving ASCT as first-line treatment have higher MRD-negative rates compared to those undergoing chemotherapy alone. MRD negativity is associated with better organ response and longer survival. However, there is currently no data comparing the MRD-negative rates between Dara and ASCT. ASCT can provide early and deep hematologic remission, and more importantly, long-lasting deep remission. Studies show that the median duration of hematologic CR in ASCT patients is 12.3 years, with 45% of patients remaining relapse-free 15 years after transplantation. In contrast, there is no data available on the duration of deep remission with Dara. In conclusion, for patients with AL amyloidosis who meet the ASCT criteria, ASCT may still be the preferred treatment.

Based on the favorable results of MRD in AL amyloidosis research and the continued advantages of ASCT (autologous stem cell transplantation) in the era of Dara, our department plans to conduct a single-center, prospective clinical study. The main objective of the study is to explore the MRD status in patients who achieve hematologic CR (complete response) after first-line induction chemotherapy (Dara-CyBorD). Additionally, the study will investigate whether ASCT in MRD-positive CR patients who meet transplantation criteria can further improve organ response, progression-free survival, and overall survival. Through MRD detection, this study aims to achieve deeper hematologic remission in the era of novel drugs, ultimately improving the long-term prognosis of AL amyloidosis patients.