A validated composite organ and hematologic response model for early assessment of treatment outcomes in light chain amyloidosis

Surbhi Sidana,Shaji K Kumar,Paolo Milani,Francis K Buadi,Martha Q Lacy,Marco Basset,Giampaolo Merlini,Andrea Foli,Prashant Kapoor,Nelson Leung,S Vincent Rajkumar,Moritz Binder,Angela Dispenzieri,Nidhi Tandon,Morie A Gertz,Suzanne R Hayman,Giovanni Palladini

doi:10.1038/s41408-020-0306-5

Abstract

Newly diagnosed AL amyloidosis patients were evaluated to develop a model for early assessment of treatment benefit at 6 months, integrating both hematologic (HR) and organ response (OR) assessment (testing cohort, Mayo: n = 473; validation cohort, Pavia: n = 575). Multiple OR were assessed as follows: All OR (AOR): response in all organs, mixed OR (MOR): response in some organs, no OR (NOR)]. AOR rates at 6 months improved with deepening HR; complete response (CR; 38%, 35%), very good partial response (VGPR; 30%, 26%), and partial response (PR; 16%, 21%), respectively. A composite HR/OR (CHOR) model was developed using incremental scoring based on hazard ratios with scores of 0–3 for HR (0—CR, 1—VGPR, 2—PR, 3—no response) and 0–2 for OR (0—AOR, 1—MOR, 2—NOR). Patients could be divided into two distinct CHOR groups (scores 0–3 and 4–5), with median OS in group 1 and group 2: Not reached vs. 34 months, p < 0.001 [Mayo] and 87 vs. 23 months, p < 0.001 [Pavia]. In conclusion, we developed a model that can assess multiple organs concurrently, and integrate both HR and OR assessments to determine early clinical benefit with treatment, which may be used as a surrogate end-point in trials and to compare outcomes with different therapies.

Highlights

Deposition of misfolded light chains secreted by the plasma cell clone leads to organ dysfunction in patients with light chain (AL) amyloidosis1–3
A composite model that takes into account both hematologic response (HR) and organ response (OR) at a given time point may allow for early assessment and become a useful surrogate endpoint for clinical trials
At present, there is no available model in AL amyloidosis that allows for concurrent analysis of hematologic and organ responses in a group of patients

Summary

Introduction

Deposition of misfolded light chains secreted by the plasma cell clone leads to organ dysfunction in patients with light chain (AL) amyloidosis. No model currently exists to integrate the two assessments for clinical use This makes early assessment of treatment benefit difficult in this disease, preventing relatively rapid evaluation of clinical trial results and precludes design of clinical trials for timely intervention in patients with likely poor outcome with ongoing therapies. A composite model that takes into account both HR and OR at a given time point may allow for early assessment and become a useful surrogate endpoint for clinical trials. It may identify patients who have not achieved a deep HR, but can safely continue first line therapy if they have achieved an OR. Such a surrogate model may be helpful in light of new, emerging therapies that target the amyloid fibril and can potentially lead to earlier OR18,19

Methods

Results

Conclusion