The investigational antifibril antibody anselamimab was associated with a reduction in all-cause mortality in patients with kappa light-chain amyloidosis but not in the broader trial population, most of whom had lambda light-chain amyloidosis.

The findings come from the Cardiac Amyloid Reaching for Extended Survival (CARES) program, which tested anselamimab added to standard chemotherapy in adults newly diagnosed with advanced, cardiac-stage light-chain amyloidosis. The program missed its primary endpoint of a statistically significant improvement in a hierarchical composite of time to all-cause mortality and adjudicated cardiovascular hospitalizations over placebo.

“While the trial was negative in the overall population, there appears to be a substantial survival and cardiovascular hospitalization advantage in patients with κ light-chain disease,” Giada Bianchi, MD, associate director of the Amyloidosis Program at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, said.

Bianchi, the first author of the study, presented the new findings at the Society of Hematologic Oncology (SOHO) 2026 meeting.

Light-chain amyloidosis begins with a clone of bone marrow plasma cells that, unlike in most other plasma cell disorders, churns out an unstable immunoglobulin light chain, she explained during her talk at the meeting.

“These plasma cells produce a thermodynamically and intrinsically unstable light chain that misfolds in circulation and aggregates into protofibrils,” Bianchi said. These protofibrils eventually become insoluble and lodge in organs, most often the heart.

Daratumumab-based chemotherapy, which consists of daratumumab, cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD), is the standard first-line treatment and is effective at eliminating the plasma cell clone, but it does not remove fibrils already present in the heart or kidneys.

The CARES program consists of two double-blind, placebo-controlled trials (NCT04512235 and NCT04504825) that investigated the efficacy and safety of anselamimab compared with placebo in newly diagnosed patients with European modification of Mayo stage 3A or 3B light-chain amyloidosis.

Patients were randomly assigned in a 2:1 ratio to receive either anselamimab (1000 mg/m² intravenously, weekly for 4 weeks, then every 2 weeks) plus CyBorD (n = 271 patients), or placebo infusions on the same schedule plus CyBorD (n = 135 patients). Daratumumab was added in 79.3% and 83.7% of patients, respectively. Median treatment duration was 21.4 months in the anselamimab arm and 21.1 months in the placebo arm.

In the overall population, for those treated with anselamimab, the hazard ratio (HR) for all-cause mortality was 0.80 (P = .290), and the rate ratio for cardiovascular hospitalization was 0.67 (P = .145).

A prespecified subgroup analysis showed that in the lambda subgroup, anselamimab was associated with a 13% reduction in cardiovascular hospitalization risk, but the difference was not statistically significant (rate ratio, 0.87; P = .664). Anselamimab showed no mortality benefit in this subgroup (HR, 1.02; P = .647).

In the kappa subgroup, anselamimab was associated with a 62% reduction in all-cause mortality (HR, 0.38; P = .012) and a 71% reduction in cardiovascular hospitalization risk (rate ratio, 0.29; P = .028).

“The survival curves start clearly separating after approximately 16-20 weeks from randomization, which means it took approximately 4-5 months for anselamimab to exert a clinically meaningful effect; in Mayo IIIB patients, approximately 35% of patients had died by the time the curves separated,” Bianchi said during an interview with Medscape Medical News.

Early initiation of this drug would be critical to mitigate the early mortality risk in advanced cardiac-stage patients, she concluded.

In an interview, Rahul Banerjee, MD, associate professor of hematology and oncology at the University of Washington and Fred Hutchinson Cancer Center in Seattle, who was not involved in CARES, called the magnitude of benefit potentially significant for a field with few options once fibrils have already deposited.

“Management of light-chain amyloidosis can generally be divided into two categories: shutting off the factory of light-chain-producing cells and mitigating or removing the light chain fibrils that have already deposited in tissues,” he said. “We have made incredible strides with the first category, but the second category remains a challenge. I’ve unfortunately had patients with light-chain amyloidosis die of sudden cardiac death despite being in a hematologic complete response.”

Comparable adverse event frequency and severity were seen across the control and active treatment arms. Treatment-emergent adverse events were common, which Bianchi said reflects the frailty of this population at baseline.

Treatment-emergent adverse events occurred at similar rates in both arms (any-grade adverse events: 100% in both arms; grade 3 adverse events: 80.4% in the anselamimab arm and 84.3% in the placebo arm). The most common treatment-emergent adverse events in the anselamimab arm were diarrhea, peripheral edema, constipation, and nausea.

Bianchi reported financial relationships with Pfizer, AstraZeneca, Prothena, Alexion Pharmaceuticals, and Janssen. Banerjee reported financial relationships with Adaptive Biotechnologies, Bristol Myers Squibb/Celgene, Caribou Biosciences, Genentech, GSK, Janssen, Karyopharm Therapeutics, Legend Biotech, Pfizer, SparkCures, Kite, Poseida Therapeutics, AbbVie, Arcellx, Regeneron, Pack Health/Quest Diagnostics, Prothena, and Sanofi.

Christos Evangelou, PhD, is a freelance medical writer.