An oral triplet deepens responses in relapsed myeloma

Design

Open-label, randomised, controlled phase 3 trial (surrogate endpoint reported)

Population

420 patients with relapsed or refractory myeloma after 1-2 prior lines

Primary outcome

MRD-negative complete response (co-primary; PFS pending)

Effect

41% vs 21% MRD-negative CR; difference 20.1 points (95% CI 11.5-28.6); odds ratio 2.8 (1.8-4.3)

EXCALIBER-RRMM, an open-label phase 3 trial, compared iberdomide (an oral cereblon modulator) plus daratumumab and dexamethasone with daratumumab, bortezomib and dexamethasone in 420 patients with relapsed or refractory myeloma after one or two prior lines, excluding anti-CD38- or bortezomib-refractory disease.

At a median 15.7 months, MRD-negative complete response was reached in 41% of the iberdomide group versus 21% with the bortezomib-based triplet (difference 20.1 percentage points; odds ratio 2.8). This came with more toxicity: grade 3-4 events in 92% versus 70%, driven by neutropenia (84% vs 11%) and infection, and more serious pneumonia (18% vs 6%).

The appeal is a deep response from an all-oral-and-subcutaneous regimen deliverable outside major centres, which matters for access, including in India. But MRD-negative complete response is a surrogate; the co-primary progression-free survival endpoint is still maturing, and the infection burden demands active prophylaxis and monitoring.

• Iberdomide, daratumumab and dexamethasone doubled MRD-negative complete response (41% vs 21%).
• The odds ratio for MRD-negative complete response was 2.8 over the bortezomib-based triplet.
• Grade 3-4 neutropenia (84% vs 11%) and infection were markedly higher with iberdomide.
• The regimen is oral and subcutaneous, deliverable outside major centres.
• Progression-free survival, the co-primary endpoint, is not yet reported.

Why it matters

It offers a deep-response, mostly outpatient alternative to a bortezomib-based triplet in early relapse.

Don't overread it

Open-label trial reporting a surrogate endpoint; progression-free survival is not yet available and toxicity is higher, so it is not yet a settled standard.

The statistics, in plain English

MRD-negative complete response is a deep but surrogate marker; a doubling (odds ratio 2.8) is substantial, yet whether it translates into longer progression-free or overall survival awaits the maturing co-primary endpoint.

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