Alpha-Emitting Radioimmunotherapy Shows Activity in Daratumumab-Refractory Myeloma

By: Lisa Astor
Posted: Friday, July 24, 2026

A novel alpha-emitting radioimmunotherapy demonstrated tolerability and preliminary activity in patients with daratumumab-refractory multiple myeloma, according to results of a first-in-human trial presented at the 2026 American Association for Cancer Research Annual Meeting (Abstract CT133). The study was led by Scott Ryan Goldsmith, MD, of City of Hope Comprehensive Cancer Center in Duarte, California.

Actinium Ac-225-DOTA-daratumumab (Ac-225-Dara) consisted of an alpha emitter conjugated to daratumumab using a DOTA chelator. The radioimmunotherapy targets CD38, which is of interest as patients retain CD38 expression after becoming refractory to daratumumab.

In the study, nine patients who had benefitted from available therapies and had adequate hematologic and organ function were treated with the novel agent at three dose levels: 20, 40, and 60 kBq/kg. Patients received unlabeled daratumumab intravenously prior to the radioimmunotherapy infusion, then indium-111-DOTA-daratumumab for imaging and a single infusion of Ac-225-Dara.

The maximum tolerated dose was set at 20 kBq/kg. All dose-limiting toxicities were hematologic and occurred in patients with high disease burden or early progression. Nonhematologic adverse events were grade 2 or lower.

Eight of nine evaluable patients achieved a best response of stable disease after a single infusion, and one had progressive disease. Median progression-free survival was 96 days (95% confidence interval = 29–154 days).

Mass cytometry confirmed high baseline CD38 expression on marrow plasma cells. Immune profiling showed early reductions in CD38-positive natural killer cells (−73%), total natural killer cells (−57.5%), and CD38-positive regulatory T cells (−28%) within approximately 24 hours.

In a post hoc exploratory analysis, patients who received bispecific antibody or chimeric antigen receptor T-cell therapy as their next line of treatment had an 80% overall response rate. The median duration of response was 620 days (n = 5).

The investigators concluded that Ac-225-Dara may circumvent immune exhaustion and that translational and clinical observations from the trial support possible synergy with subsequent immunotherapies.

Disclosure: For full disclosures of the study authors, visit abstractsonline.com.

2026 American Association for Cancer Research (AACR) Annual Meeting (Abstract CT133_

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