Iberdomide combination doubled MRD-negative response in relapsed myeloma, with more infections

Design

Phase 3, randomised, open-label, two-stage trial

Population

420 adults with relapsed or refractory myeloma after 1–2 prior lines (primary MRD analysis)

Primary outcome

MRD-negative complete response (dual primary with PFS)

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 in adults with relapsed or refractory multiple myeloma after one or two prior lines, excluding those refractory to anti-CD38 antibodies or bortezomib. Patients received iberdomide, an oral cereblon modulator, with daratumumab and dexamethasone, or daratumumab, bortezomib and dexamethasone.

In the first 420 patients, at a median 15.7 months, MRD-negative complete response was 41% with the iberdomide regimen and 21% with the bortezomib regimen (difference 20.1 points, 95% CI 11.5–28.6). Grade 3–4 adverse events occurred in 92% vs 70%, driven by neutropenia (84% vs 11%) and infections (39% vs 22%); pneumonia was the commonest serious event (18% vs 6%). Treatment-related deaths were 1% in each arm.

MRD negativity is a strong prognostic marker, but progression-free survival — the second primary endpoint — has not yet been reported. Until it is, this is a promising signal with a clear infection cost, not a new standard.

• MRD-negative complete response doubled with the iberdomide regimen, but progression-free survival is still awaited.
• Expect high rates of grade 3–4 neutropenia; plan growth factor support and infection monitoring.
• Pneumonia was three times more common with iberdomide — counsel patients and consider prophylaxis per local practice.
• Patients refractory to anti-CD38 antibodies or bortezomib were excluded.
• Iberdomide is not yet approved; this is trial evidence only.

Why it matters

It is the first phase 3 evidence for a newer cereblon modulator, and the infection signal will shape who can receive it.

Don't overread it

MRD negativity is a surrogate; whether it translates into longer progression-free or overall survival here is not yet known.

The statistics, in plain English

A proportion difference of 20.1 points means about one extra MRD-negative complete response for every five patients treated. The interval of 11.5 to 28.6 points is clearly above zero.

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