Iberdomide–daratumumab–dexamethasone doubled MRD-negative complete response in relapsed myeloma

Design

Open-label, randomised, phase 3 (EXCALIBER-RRMM), primary MRD analysis

Population

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

Primary outcome

MRD-negative complete response (co-primary with PFS)

Effect

41% vs 21%, difference 20.1% (95% CI 11.5–28.6); OR 2.8 (1.8–4.3)

EXCALIBER-RRMM is an open-label phase 3 trial at 211 sites in 31 countries in adults with relapsed or refractory myeloma after one or two prior lines, excluding anti-CD38- or bortezomib-refractory disease. Iberdomide, an oral cereblon E3 ligase modulator more potent than lenalidomide or pomalidomide, was given with daratumumab and dexamethasone (IberDd) and compared with daratumumab, bortezomib and dexamethasone (DVd).

In the first 420 patients (median age 68) with at least 12 months' follow-up, MRD-negative complete response occurred in 41% with IberDd versus 21% with DVd (difference 20.1 points, 95% CI 11.5–28.6; OR 2.8). Grade 3–4 adverse events were 92% versus 70%, driven by neutropenia (84% vs 11%) and infection (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 and an accepted early endpoint, but the trial's other primary endpoint — progression-free survival — is still being analysed in 800 patients. Until it reports, IberDd is a promising option rather than a new standard. The infection burden calls for proactive prophylaxis and growth factor support.

• Iberdomide is investigational; do not substitute for approved regimens outside trials.
• If used, plan for neutropenia in most patients — growth factor support and dose modification.
• Give antimicrobial prophylaxis and vaccinations, and educate patients to report fever promptly.
• Await progression-free survival data before treating MRD response as practice-changing.
• Excluded: anti-CD38- or bortezomib-refractory disease.

Why it matters

It is the first phase 3 evidence for a next-generation cereblon modulator, which could replace bortezomib in early-relapse combinations.

Don't overread it

MRD-negative complete response is a surrogate endpoint; progression-free survival has not yet been reported.

The statistics, in plain English

A 20-point difference in MRD-negative CR (95% CI 11.5–28.6) is large and precise, but deeper responses do not always translate into longer survival, which is why PFS is a co-primary endpoint.

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