Evaluation of Functional Cardiac Measures and Response to Treatment Initiation in Patients with Systemic Light-Chain (AL) Amyloidosis: Results from a Single Site Retrospective Study

Light-chain (AL) amyloidosis is a rare, hematologic disorder caused by a plasma cell dyscrasia (PCD) which causes the production of toxic amyloid fibrils resulting in systemic organ dysfunction. Cardiac involvement (increase in serum N-terminal pro-brain natriuretic peptide [NT-proBNP]) ~70% of patients and portends poor prognosis. AL amyloidosis is managed with anti-PCD therapies to decrease amyloidogenic light chain production and to prevent further amyloid fibril formation in organs. Patients treated with cyclophosphamide-bortezomib-dexamethasone + daratumumab (CyBorD-dara) show decreases in serum NT-proBNP levels suggesting cardiac response. However, evidence is sparse on treatment-related change in cardiac function based on imaging. Global longitudinal strain (GLS) is a sensitive, 2-D echocardiogram-based imaging modality to assess change in cardiac systolic function and is an independent predictor of survival in AL amyloidosis.

This study included AL patients aged ≥18 years who were newly initiating a pharmacological treatment regimen (inclusive of bendamustine, bortezomib, carfilzomib, cyclophosphamide, daratumumab, ixazomib, lenalidomide, melphalan, pomalidomide, or venetoclax) at the Cedars Sinai Medical Center 01Jan2021-01Nov2023. For inclusion, patients were required to have a confirmed diagnosis of AL with cardiac involvement and undergone serial echocardiography. Patients were excluded if they had any of the following: treatment with stem cell transplant, diagnosis of familial mediterranean fever or secondary, transthyretin, or hereditary amyloidosis.

To assess changes in cardiac function, we measured GLS during the first 12 months following treatment initiation in patients with AL cardiac amyloidosis. Changes in GLS from baseline included minimal clinically important differences (MCID) defined as a 2% change, and transitions between normal GLS (-16% to -22%) and reduced (> -16%) GLS were assessed at the following timepoints post treatment initiation: 61-90 days, 91-180 days, 181-270 days, and 271-360 days.

A total of 43 patients (mean ± SD age of 62 ± 12 years), the majority of whom were male (n = 30; 70%), were included. The most common treatment regimens were daratumumab monotherapy (n = 12; 30%), bortezomib monotherapy (n = 9; 21%), CyBorD + dara (n = 7; 16%) and CyBorD (n = 5; 12%). Twenty-three (53%) patients initiated treatment with a daratumumab-containing regimen with a mean ± SD GLS of-10.5% ± 4.1 and 20 (87%) were classified as having a reduced GLS at baseline. Twenty (47%) patients initiated on a non-daratumumab regimen with a mean ± SD GLS of -13.0% ± 5.0% and 14 (70%) patients were classified as having a reduced GLS at baseline. Overall, 34 (79%) patients, regardless of treatment, had reduced GLS with a mean ± SD GLS of -11.7% ± 4.7% at baseline.

Follow-up GLS measures for days 61-90, 91-180, 181-270, and 271-360 were available for 4 (9%), 15 (35%), 13 (30%), and 11 (26%) patients, respectively. Eighteen (42%) patients displayed no clinically significant change in GLS from baseline at follow-up. Fifteen (35%) patients had clinically significant absolute improvement in GLS (≥ 2%) at follow-up of whom 10 (67%) remained classified as having a reduced GLS, 3 (10%) remained classified as having normal GLS, and 2 (10%) improved from reduced to normal GLS. Ten (23%) patients had a clinically significant decline in GLS (≥ -2%) at follow-up of whom 7 (70%) remained classified as having a reduced GLS, and 3 (30%) worsened from normal to reduced GLS.

Across all follow-up timepoints, only 3/43 patients moved from a reduced to normal GLS at follow-up (91-180 [non-daratumumab], 181-270 [daratumumab], and 271-360 [daratumumab] days post-index), and 3/43 patients moved from a normal to reduced GLS at follow-up (61-90, 91-180, and 181-270 days post-index; all non-daratumumab).

Current AL treatment regimens aim to induce hematologic response. However, these responses may not be associated with clinically meaningful improvements in cardiac function following treatment initiation. These data underscore the continuing unmet medical need for therapies that are designed to improve organ function by targeting the deposited amyloid fibrils.