Iberdomide combined with daratumumab and dexamethasone nearly doubled the rate of minimal residual disease (MRD)-negative complete response compared with daratumumab, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma. Lonial et al reported the primary MRD analysis of the phase III EXCALIBER-RRMM trial in The Lancet Oncology.
The trial has two primary endpoints: MRD-negative complete response and progression-free survival. The current analysis reports the first of these; progression-free survival is still being evaluated in the larger confirmatory cohort.
Iberdomide is an oral drug designed to kill myeloma cells and stimulate the immune system more effectively than conventional immunomodulatory drugs. In August 2026, the U.S. Food and Drug Administration granted accelerated approval to iberdomide in combination with daratumumab and dexamethasone based on the MRD-negative complete response results from EXCALIBER-RRMM.
Study Details
EXCALIBER-RRMM is an ongoing, open-label, randomized phase III trial conducted at 211 hospital and community sites in 31 countries. Eligible adults had relapsed or refractory multiple myeloma after one or two previous lines of therapy and had achieved at least a partial response to prior treatment before experiencing disease progression. Patients with disease refractory to anti-CD38 therapy or bortezomib were excluded.
The trial used a two-stage design. The first stage evaluated several iberdomide doses, with 1 mg selected for further study based on efficacy, safety, and pharmacologic findings. The primary MRD analysis included the first 420 patients assigned to either the 1-mg iberdomide regimen or the control regimen: 207 received iberdomide, daratumumab, and dexamethasone, and 213 received daratumumab, bortezomib, and dexamethasone.
The median age was 68 years, 67% of patients had received one previous line of therapy, and 44% had lenalidomide-refractory disease. Median follow-up was 15.7 months. MRD negativity was defined as fewer than 1 myeloma cell per 100,000 nucleated cells.
Key Findings
MRD-negative complete response was achieved by 41% of patients receiving iberdomide, daratumumab, and dexamethasone compared with 21% receiving daratumumab, bortezomib, and dexamethasone (P < .0001). The odds of achieving an MRD-negative complete response were 2.8 times higher with the iberdomide regimen than with the control regimen. The benefit was also seen across key prespecified subgroups, including patients with prior lenalidomide exposure and lenalidomide-refractory disease.
Overall response rates were 89% with the iberdomide combination and 76% with the control regimen. A complete response or better was achieved by 46% vs 25% of patients, and a very good partial response or better by 74% vs 62%.
MRD-negative complete response sustained for at least 6 months was reported in 16% of all patients assigned to iberdomide, daratumumab, and dexamethasone compared with 8% assigned to the control regimen. The authors noted that longer follow-up will increase the number of patients evaluable for sustained MRD negativity.
Safety
Grade 3 or 4 adverse events occurred in 92% of patients who received iberdomide, daratumumab, and dexamethasone compared with 70% receiving daratumumab, bortezomib, and dexamethasone. The largest differences involved neutropenia, which occurred at grade 3 or 4 in 84% vs 11%, and infections, which occurred at grade 3 or 4 in 39% vs 22%.
Neutropenia occurred predominantly during the first two treatment cycles and was generally managed with granulocyte colony-stimulating factor and dose interruptions or reductions. Despite the high rate of neutropenia, only 2 patients (1%) discontinued iberdomide because of neutropenia.
Peripheral sensory neuropathy was less common with the iberdomide regimen, occurring at any grade in 12% of patients compared with 43% receiving the bortezomib-containing regimen.
Serious adverse events occurred in 58% vs 41% of patients, respectively, with pneumonia the most common. Three treatment-related deaths occurred with the iberdomide regimen and two with the control regimen.
“Overall, the balance between depth of response and the manageable safety profile of iberdomide, daratumumab, and dexamethasone, together with its convenience as an off-the-shelf regimen and oral administration of iberdomide, support its use across a range of clinical settings,” the investigators wrote.
The investigators cautioned that follow-up remains relatively short and that few patients had previous anti-CD38 exposure, limiting the applicability of the findings to patients with anti-CD38–refractory disease. Progression-free survival, the trial’s second primary endpoint, is being assessed in a larger cohort of 800 patients.
Sagar Lonial, MD, of the Winship Cancer Institute of Emory University, is the corresponding author of the study.
DISCLOSURE: The study was funded by Bristol Myers Squibb. For full disclosures of the study authors, visit thelancet.com.
