Results from the Phase 3 ANDROMEDA Study in Patients with Newly Diagnosed Systemic Light Chain Amyloidosis with Cardiac Involvement

In patients with systemic light chain amyloidosis (AL), the deposition of amyloid fibrils within the heart, kidney, and other organs leads to progressive organ dysfunction and ultimately death.

The primary determinant of clinical outcomes is the severity of cardiac involvement experienced by patients, as this significantly impacts overall survival and the degree to which the heart is affected. AL also impairs a range of physical factors, organs, and mental health–related quality-of-life variables. Until recently, there were no approved therapies for AL; however, there have been promising results reported from recent clinical trials that assessed combination therapies. Based on the results of the phase 3 ANDROMEDA trial, daratumumab plus bortezomib/cyclophosphamide/dexamethasone (D-VCd) recently became the first approved treatment for AL.

Grogan and colleagues presented results from the phase 3 ANDROMEDA trial, focusing on the health–related quality-of-life and cardiac function effects of the combination D-VCd in patients with newly diagnosed systemic AL with cardiac involvement.

Daratumumab is a monoclonal antibody that targets CD38; it has been approved for the treatment of multiple myeloma as monotherapy and in combination with other agents.

The focus of the presentation was cardiac organ response and patient-reported outcomes (PROs) in patients with baseline cardiac involvement. In this study, patients (N = 388) with newly diagnosed disease were randomized (1:1) to receive D-VCd or VCd for 6 cycles; cardiac response was assessed in a subset of patients, who were considered evaluable if they had a baseline N-terminal pro b-type natriuretic peptide (NT-proBNP) that was >650 ng/L or New York Heart Association (NYHA) class III or IV heart failure (D-VCd, N = 118; VCd, N = 117). In these patients with cardiac involvement, analyses were performed (mean wall thickness >12 mm, no other cardiac cause, or an elevated NT-proBNP [>332 ng/L] in the absence of renal failure or atrial fibrillation) and included patients with cardiac improvement as shown through evaluation of NYHA and decrease from baseline of NT-proBNP. The percentage of patients with ≥1-point improvement from baseline for single items and a change in the European Organisation for Research and Treatment of Cancer QLQ-C30 global health status (GHS) and fatigue scores were also considered.

The analysis showed that of the total population studied, 140 patients in the D-VCd and 137 patients in the VCd group had cardiac involvement. A total of 41.5% of the D-VCd patients and 22.2% of the VCd patients (P = .0029) demonstrated a cardiac response at 6 months. Among patients who received D-VCd treatment, fatigue and GHS scores remained stable. However, scores worsened with VCd treatment, with the greatest between-group differences occurring at cycles 4 and 5.

In terms of the PRO results, overall compliance with the assessments was high, with more than 80% participation at any given time point and comparable between the treatment groups.

At baseline in both treatment arms, the GHS scores were similar, with the majority of the patients reporting some level of shortness of breath or feeling weak or tired.

The fatigue and GHS scores worsened for patients who were treated with VCd by cycle 4, while it remained stable in patients who were treated with D-VCd. Furthermore, more D-VCd–treated patients experienced a meaningful improvement (>1-point improvement) in the single-item symptom score of shortness of breath, feeling tired, or feeling weak when compared with the D-VCd patients who were treated; scores were 33.3% compared with 26.6% for shortness of breath, 31.1% compared with 12.5% for feeling weak, and 24.4% compared with 10.9% feeling tired.

The investigators concluded that in AL patients with cardiac involvement, treatment with D-VCd resulted in higher rates of cardiac response, with the PRO results suggesting improvement in fatigue-related parameters.

Source: Grogan M, Maurer MS, Witteles R, et al. Effect of daratumumab, bortezomib, cyclophosphamide, and dexamethasone, on cardiac function and health-related quality of life in patients with newly diagnosed AL amyloidosis with cardiac involvement: results from the phase 3 Andromeda study. Presented at: ACC.21, American College of Cardiology 70th Annual Scientific Session & Expo, May 15-17, 2021. Poster 16202.