Background
Randomized, placebo-controlled, phase 3 program (the CARES trials) in newly diagnosed European-modification Mayo 2004 stage IIIa/IIIb (advanced cardiac) immunoglobulin light chain (AL) amyloidosis. N=406. Evaluated the amyloid-fibril–directed monoclonal antibody anselamimab added to standard plasma cell–directed therapy.
Results
Interventions and follow up: Arm A: Anselamimab + cyclophosphamide–bortezomib–dexamethasone (CyBorD), with or without daratumumab
Arm B: Placebo + CyBorD, with or without daratumumab
Primary endpoint: Hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVH), by Finkelstein–Schoenfeld test / win ratio
mFollow up: NR
Results: Primary composite (overall, win ratio): 1.11 (95% CI 0.83–1.50); P=.332 — not met
All-cause mortality (overall): HR 0.80 (95% CI 0.57–1.13); P=.290
Cardiovascular hospitalization rate: 0.59 (anselamimab) vs 0.89 (placebo); P=.145
Kappa subgroup (n=72), win ratio: 2.06 (95% CI 0.98–4.31); P=.100; ACM HR 0.38 (95% CI 0.17–0.86; nominal P=.012); CVH IRR 0.29 (95% CI 0.10–0.87; nominal P=.028)
Lambda subgroup: no clinical benefit
Arm B: Placebo + CyBorD, with or without daratumumab
Primary endpoint: Hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVH), by Finkelstein–Schoenfeld test / win ratio
mFollow up: NR
Results: Primary composite (overall, win ratio): 1.11 (95% CI 0.83–1.50); P=.332 — not met
All-cause mortality (overall): HR 0.80 (95% CI 0.57–1.13); P=.290
Cardiovascular hospitalization rate: 0.59 (anselamimab) vs 0.89 (placebo); P=.145
Kappa subgroup (n=72), win ratio: 2.06 (95% CI 0.98–4.31); P=.100; ACM HR 0.38 (95% CI 0.17–0.86; nominal P=.012); CVH IRR 0.29 (95% CI 0.10–0.87; nominal P=.028)
Lambda subgroup: no clinical benefit
Adverse events
Overall tolerability: generally well-tolerated; safety comparable between anselamimab and placebo arms
Grade ≥3 / event-level rates: NR in abstract
Grade ≥3 / event-level rates: NR in abstract
Conclusions
Anselamimab added to standard plasma cell–directed therapy did not meet its primary composite endpoint of mortality and cardiovascular hospitalization in the overall stage III AL amyloidosis population. A prespecified analysis suggested benefit in the kappa light-chain subgroup (reduced mortality and hospitalizations), but these findings are exploratory and hypothesis-generating.
Key Limitations
Negative trial for the primary endpoint; the kappa-subgroup benefit (n=72) is exploratory, nominal, and not corrected for multiplicity; composite mortality/hospitalization endpoint analyzed by win ratio; heterogeneous backbone therapy (with or without daratumumab); follow-up duration not reported in the abstract.
Clinical Context
First-line standard for AL amyloidosis is daratumumab plus CyBorD (ANDROMEDA). Anselamimab (formerly CAEL-101) is an amyloid-fibril–directed antibody intended to clear deposited amyloid—a mechanism distinct from suppressing the plasma cell clone. CARES is the phase 3 read-out for this approach and is not approved; the overall negative result with a kappa-restricted signal will inform whether fibril-depleting antibodies have a role and in which patients.