Iberdomide plus daratumumab and dexamethasone versus daratumumab, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma (EXCALIBER-RRMM): an open-label, randomised, controlled, phase 3 trial

Why clinicians should know about it

• Picked for Family Practice (top studies of the week, 27 September 2026): Not directly relevant to primary care
• Picked for Oncology and Radiation Oncology (top studies of the week, 27 September 2026): EXCALIBER‑RRMM phase 3 trial of iberdomide vs VRd
• Picked for Pulmonary and Respiratory Medicine (top studies of the week, 27 September 2026): Phase III RCT comparing iberdomide‑daratumumab vs bortezomib
• Picked for Radiation Oncology (top studies of the week, 27 September 2026): Not relevant to radiation oncology
• Picked for Surgical Oncology (top studies of the week, 27 September 2026): Multiple myeloma drug trial, no surgery

Abstract

BACKGROUND: Iberdomide, a cereblon E3 ligase modulator with enhanced antimyeloma and immunostimulatory activity compared with immunomodulatory drugs, has shown clinical activity in relapsed or refractory multiple myeloma and synergy with anti-CD38 antibodies. EXCALIBER-RRMM, comparing iberdomide, daratumumab, and dexamethasone with daratumumab, bortezomib, and dexamethasone, uses minimal residual disease (MRD)-negative complete response and progression-free survival as dual primary endpoints. Here, we report the results of the primary analysis of MRD-negative complete response. METHODS: EXCALIBER-RRMM is an ongoing, two-stage, open-label, randomised, controlled, phase 3 trial done at 211 hospital and community-based sites in 31 countries. Eligible participants were adults (aged ≥18 years) with relapsed or refractory multiple myeloma, who had undergone one to two previous lines of therapy, had an Eastern Cooperative Oncology Group performance-status score of 0-2, achieved at least a partial response to previous treatment, and subsequently experienced disease progression. Patients with anti-CD38-refractory disease or bortezomib-refractory disease were excluded from both stages, whereas stage 2 permitted enrolment of up to 10% of patients with previous anti-CD38 exposure. Patients were randomly assigned (1:1:1:1 in stage 1 and 1:1 in stage 2) using interactive response technology to iberdomide, daratumumab, and dexamethasone or daratumumab, bortezomib, and dexamethasone. In stage 1, patients received iberdomide, daratumumab, and dexamethasone (oral iberdomide [1·0 mg, 1·3 mg, or 1·6 mg]; subcutaneous daratumumab [1800 mg]; and oral dexamethasone [40 mg or 20 mg for patients older than 75 years]) or daratumumab, bortezomib, and dexamethasone (subcutaneous daratumumab [1800 mg]; subcutaneous bortezomib [1·3 mg/m2]; and oral dexamethasone [20 mg]). In stage 2, patients received iberdomide (1·0 mg), daratumumab, and dexamethasone or daratumumab, bortezomib, and dexamethasone, all at the same doses and schedules as in stage 1. Treatment was received until confirmed disease progression, unacceptable toxicity, discontinuation, or withdrawal of consent. Dual primary endpoints were MRD-negative complete response at any time and progression-free survival. MRD was assessed in patients with suspected complete response or better. The primary analysis of MRD-negative complete response, reported here, was performed once the first 420 patients (intention-to-treat [ITT] population) had at least 12 months of follow-up (or discontinued early). Progression-free survival assessment is ongoing in a larger confirmatory cohort of 800 patients. Safety was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04975997, and is ongoing (active, not recruiting). FINDINGS: 1163 patients were screened for eligibility of whom 939 patients were randomised, 279 in stage 1 and 660 in stage 2. 800 patients were randomised to the 1·0-mg dose of iberdomide, daratumumab, and dexamethasone or to daratumumab, bortezomib, and dexamethasone. The primary MRD analysis ITT population comprised the first 420 patients enrolled between July 14, 2022, and July 3, 2024: 207 in the iberdomide, daratumumab, and dexamethasone group and 213 in the daratumumab, bortezomib, and dexamethasone group. Of these 420 patients, 244 [58%] were male, 176 [42%] were female, median age was 68 years [IQR 60-73], and 257 [61%] were White. At a median follow-up of 15·7 months (IQR 12·8-23·2), MRD-negative complete response was achieved in 85 (41%) of 207 patients receiving iberdomide, daratumumab, and dexamethasone and 44 (21%) of 213 receiving daratumumab, bortezomib, and dexamethasone (stratified proportion difference 20·1% [95% CI 11·5-28·6, p<0·0001]; odds ratio 2·8 [95% CI 1·8-4·3]). Grade 3 or grade 4 adverse events occurred in 187 (92%) of 204 patients with iberdomide, daratumumab, and dexamethasone and 143 (70%) of 204 patients with daratumumab, bortezomib, and dexamethasone, including neutropenia (172 [84%] vs 23 [11%]) and infection (80 [39%] vs 44 [22%]). Serious adverse events occurred in 119 (58%) patients in the iberdomide, daratumumab, and dexamethasone group and in 83 (41%) patients in the daratumumab, bortezomib, and dexamethasone group; the most common was pneumonia (36 [18%] vs 13 [6%]). Three (1%) deaths (sepsis, listeria encephalitis, and unknown cause) in the iberdomide, daratumumab, and dexamethasone group and two (1%) deaths (one due to sepsis and pneumonia and one due to sepsis) in the daratumumab, bortezomib, and dexamethasone group were considered related to any study treatment by the investigator. INTERPRETATION: Iberdomide, daratumumab, and dexamethasone significantly improved MRD-negative complete response compared with daratumumab, bortezomib, and dexamethasone. The most common grade 3 or grade 4 adverse events were haematological events and infections, which were mostly manageable with standard supportive care. These findings support iberdomide, daratumumab, and dexamethasone as an efficacious treatment option for patients with relapsed or refractory multiple myeloma with the potential to be administered across diverse care settings. Assessment of progression-free survival, the second dual primary endpoint, is ongoing. FUNDING: Bristol Myers Squibb.

Abstract as published, via PubMed.