Anselamimab Misses Overall Primary End Point but Reduces Mortality in Kappa AL Amyloidosis

Anselamimab (CAEL-101) did not significantly improve the hierarchical composite primary end point of all-cause mortality (ACM) and cardiovascular-related hospitalization (CVH) compared with placebo in the overall population of patients with newly diagnosed AL amyloidosis and advanced cardiac involvement; however, a prespecified analysis by light chain isotype showed that the anti-fibril monoclonal antibody led to statistically significant reductions in both ACM and CVH among patients with kappa light chain disease, according to data from the phase 3 CARES CAEL 101-301 (NCT04504825) and CARES CAEL 101-302 (NCT04512235) trials presented at the 2026 Society of Hematologic Oncology (SOHO) Annual Meeting.¹

Findings showed that in the pooled overall population, the ACM-and-CVH win ratio for anselamimab plus anti–plasma cell dyscrasia (anti-PCD) therapy (n = 271) vs placebo plus anti-PCD therapy (n = 135) was 1.11 (95% CI, 0.83-1.50; P = .332).

In the prespecified kappa isotype subgroup (anselamimab, n = 48; placebo, n = 24), anselamimab was associated with a nominally significant 62% reduction in the risk of death via ACM (HR, 0.38; 95% CI, 0.17-0.86; P = .012) and a 71% reduction in the annualized frequency of CVH (incidence risk ratio [RR], 0.29; 95% CI, 0.10-0.87; P = .028). Statistical significance was not reached for patients with the lambda isotype for ACM (HR, 1.02; 95% CI, 0.68-1.52; P = .647) or CVH (incidence RR, 0.87; 95% CI, 0.46-1.65; P = .664).

“[Anselamimab] was well tolerated both in the overall population and in the kappa light chain subgroup, suggesting that this would be a useful tool in terms of improving quality of life, as well as longevity in patients with newly diagnosed amyloidosis with kappa light chain disease,” presenting study author Giada Bianchi, MD, said in a presentation of the data.

Bianchi is a physician-scientist and associate director of the Amyloidosis Program at Brigham and Women’s Hospital/Dana Farber Cancer Institute and an assistant professor at Harvard Medical School in Boston, Massachusetts. She is also an associate physician in the Hematology Division of the Brigham and Women’s Hospital in Boston.

How were the CARES trials designed?

Anselamimab is a first-in-class, kappa light chain–directed chimeric IgG1κ monoclonal antibody that binds insoluble amyloid fibrils and induces their phagocytic clearance from affected organs. Standard first-line treatment for AL amyloidosis targets the underlying plasma cell dyscrasia; in November 2025, the FDA approved daratumumab and hyaluronidase-fihj in combination with cyclophosphamide, bortezomib, and dexamethasone (CyBorD) for patients with newly diagnosed light chain amyloidosis.²

The CARES program comprised two multicenter, double-blind, randomized, placebo-controlled phase 3 studies: CAEL101-301, which enrolled patients with Mayo stage IIIb disease, and CAEL101-302, which enrolled patients with Mayo stage IIIa disease.

Treatment-naïve patients were randomly assigned 2:1 to receive anselamimab at 1000 mg/m² or placebo, each added to first-line anti-PCD therapy. Anselamimab was administered once weekly for 4 weeks and once every 2 weeks thereafter. After 18 months, patients in either arm who completed the primary evaluation period could continue anselamimab plus anti-PCD therapy in an open-label extension.

The CARES primary end point was the hierarchical composite of time to ACM and frequency of CVH, evaluated using the stratified Finkelstein-Schoenfeld test and win ratio estimation 18 months after the last patient was enrolled. Key secondary end points included change from baseline in 6-minute walk test (6MWT) distance, echocardiography-based global longitudinal strain (GLS), NT-proBNP levels, and quality of life; analyses by involved light chain isotype were prespecified.

The pooled analysis included 271 patients treated with anselamimab and 135 who received placebo. In the overall population, the median age was 66 years (range, 36-91) for anselamimab and 69 years (range, 36-90) for placebo. Most patients were male (anselamimab, 67.5%; placebo, 65.2%) and had the lambda isotype (80.8%; 80.7%).

What additional data did the isotype and Mayo stage analyses show?

Within the kappa subgroup, the reduction in ACM was observed across disease severity, including in those with Mayo stage IIIa disease (HR, 0.25; 95% CI, 0.06-0.93; P = .021) and those with Mayo stage IIIb disease (HR, 0.52; 95% CI, 0.17-1.54; P = .238).

Key secondary end points assessed at 50 weeks, including the Kansas City Cardiomyopathy Questionnaire–Overall Summary score, 6MWT distance, and GLS, did not differ significantly between the anselamimab and placebo arms in either the overall or kappa populations.

What did the safety analysis show?

Adverse effects (AEs) of any grade occurred in all patients in both arms, and serious AEs were reported in 75.6% of patients who received anselamimab (n = 271) vs 75.4% of those given placebo (n = 134). AEs leading to death occurred in 27.7% vs 30.6% of patients, respectively, and grade 3 or higher AEs were reported at respective rates of 80.4% and 84.3%. AEs led to discontinuation of study treatment in 13.3% of patients in the anselamimab arm vs 10.4% in the placebo arm.

The most common AEs occurring in at least 25% of patients treated with anselamimab were diarrhea (39.5%), peripheral edema (38.0%), constipation (33.9%), nausea (33.6%), COVID-19 (29.5%), and hypotension (26.9%). Investigators reported that the majority of AEs were consistent with the underlying medical condition and treatment with anti-PCD therapy.

References

1. Wechalekar AD, Dispenzieri A, Sanchorawala V, et al. Phase 3 randomized trial to evaluate the impact of anselamimab on all-cause mortality in kappa light chain amyloidosis. Presented at: 2026 Society of Hematologic Oncology Annual Meeting; September 9-12, 2026; Houston, TX.

2. FDA Approves Daratumumab and Hyaluronidase-fihj in Newly Diagnosed Light Chain Amyloidosis. OncLive. Published November 19, 2025. Accessed September 11, 2026. https://www.onclive.com/view/fda-approves-daratumumab-and-hyaluronidase-fihj-in-newly-diagnosed-light-chain-amyloidosis