Iberdomide doubled MRD-negative responses in relapsed myeloma, at a cost in infections

Design

Open-label randomised phase 3 trial, primary MRD analysis

Population

420 adults with relapsed or refractory myeloma after 1–2 prior lines

Primary outcome

MRD-negative complete response (co-primary with progression-free survival)

Effect

41% vs 21%; difference 20.1 points (95% CI 11.5–28.6); OR 2.8

EXCALIBER-RRMM is an open-label phase 3 trial at 211 sites in 31 countries in relapsed or refractory myeloma after one or two prior lines, excluding anti-CD38- or bortezomib-refractory disease. This primary analysis, published on 25 September, covers the first 420 patients randomised to iberdomide, daratumumab and dexamethasone or daratumumab, bortezomib and dexamethasone. Median age was 68.

At a median 15.7 months, MRD-negative complete response was achieved by 41% with iberdomide against 21% with the bortezomib regimen (OR 2.8). Grade 3–4 adverse events were more frequent (92% vs 70%), driven by neutropenia (84% vs 11%) and infection (39% vs 22%); pneumonia was the commonest serious event (18% vs 6%).

Iberdomide is an oral cereblon modulator, more potent than lenalidomide or pomalidomide. An all-oral partner for daratumumab, without bortezomib's neuropathy, is attractive.

MRD negativity is a surrogate. Progression-free survival, the co-primary end point, is still being assessed in the full 800-patient cohort. Until it reads out, the infection burden weighs heavily against a deeper but unproven response.

• Keep current daratumumab-based regimens as standard until progression-free survival data are reported.
• Expect high rates of neutropenia with iberdomide combinations and plan growth factor and infection prophylaxis.
• Counsel patients that deeper responses have not yet been shown to delay progression.
• Monitor closely for pneumonia in older patients on cereblon modulators with anti-CD38 antibodies.

Why it matters

An all-oral partner for daratumumab could simplify relapsed myeloma care if survival follows.

Don't overread it

MRD negativity is a surrogate; progression-free survival has not yet been reported.

The statistics, in plain English

A 20-point difference in MRD-negative complete response (95% CI 11.5 to 28.6) is large and clearly beyond chance. But MRD negativity is a surrogate: it predicts better outcomes in general, yet a regimen that deepens response does not always lengthen survival.

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