TOPLINE

Combining iberdomide with daratumumab and dexamethasone significantly improved minimal residual disease (MRD)-negative complete response rates compared with daratumumab, bortezomib, and dexamethasone in patients with relapsed or refractory multiple myeloma in a phase 3 trial, with the benefit seen across key subgroups, including patients who had previously received lenalidomide. However, the iberdomide regimen was linked to higher rates of severe neutropenia and infection.

METHODOLOGY

• Multiple myeloma follows a relapsing course, with treatment efficacy decreasing with later lines of therapy. Most patients entering first relapse already have lenalidomide-exposed or lenalidomide-refractory disease, further narrowing available treatment options. Iberdomide, an oral cereblon E3 ligase modulator, has shown synergistic activity with daratumumab in preclinical studies and promising efficacy in a phase 1/2 trial. This early evidence prompted further evaluation using MRD-negative complete response, an early indicator of long-term clinical benefit that has led the FDA to endorse it as a valid endpoint for accelerated drug approval.
• Building on this rationale, researchers conducted an ongoing two-stage, open-label, randomized, controlled phase 3 trial in adults with relapsed or refractory multiple myeloma who had received one to two previous lines of therapy and achieved at least a partial response to prior treatment before experiencing disease progression.
• The intention-to-treat population for the primary MRD analysis included the first 420 patients (median age, 68 years) enrolled between July 2022 and July 2024 who were randomly assigned to receive iberdomide, daratumumab, and dexamethasone (n = 207) or daratumumab, bortezomib, and dexamethasone (n = 213). 
• Patients in the iberdomide group received oral iberdomide 1.0 mg daily on days 1-21 of each 28-day cycle plus subcutaneous daratumumab 1800 mg and oral dexamethasone 40 mg; the comparator group received subcutaneous daratumumab 1800 mg, subcutaneous bortezomib 1.3 mg/m², and oral dexamethasone 20 mg. Bortezomib and dexamethasone were given for eight 21-day cycles, and daratumumab continued every 4 weeks in 28-day cycles from cycle 9.
• The two co-primary endpoints were the rate of MRD-negative complete response at any time and progression-free survival; this analysis reported the MRD-negative complete response findings at a median follow-up of 15.7 months, with progression-free survival still being assessed in a larger 800-patient confirmatory cohort.

TAKEAWAY

• Overall, MRD-negative complete response was seen in 85 of 207 patients (41%) in the iberdomide group and in 44 of 213 patients (21%) in the daratumumab/bortezomib/dexamethasone group, a stratified proportion difference of 20.1% (odds ratio [OR], 2.8; P  < .0001). The benefit was also seen in prespecified subgroups, including patients with lenalidomide-exposed or lenalidomide-refractory disease.
• Sustained MRD-negative complete response lasting 6 months or more occurred in 16% of patients receiving iberdomide/daratumumab/dexamethasone vs 8% receiving daratumumab/bortezomib/dexamethasone (proportion difference, 8.7%; P = .0040).
• Overall response rate was also higher with the iberdomide/daratumumab/dexamethasone regimen (proportion difference, 12.5%; P = .0008).
• Among patients evaluated for safety (n = 204 in each group), grade 3 or 4 adverse events were more frequent in the iberdomide/daratumumab/dexamethasone group than in the daratumumab/bortezomib/dexamethasone group (92% vs 70%), driven largely by neutropenia (84% vs 11%) and infection (39% vs 22%). Serious adverse events were also more frequent in the iberdomide/daratumumab/dexamethasone group (58%) than in the daratumumab/bortezomib/dexamethasone group (41%), with pneumonia being the most common serious event in both arms (18% vs 6%, respectively).

IN PRACTICE

"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," the study authors wrote.

SOURCE

The study, led by Sagar Lonial, MD, of Winship Cancer Institute at Emory University in Atlanta, was published online in The Lancet Oncology.

LIMITATIONS

Restricting MRD testing to patients with complete response or better may have underestimated true MRD negativity, and the 15.7-month median follow-up limited assessment of sustained response durability. The trial excluded patients with anti-CD38-refractory disease and capped enrollment of those with prior non-refractory anti-CD38 exposure, so the findings may not generalize to patients with anti-CD38 antibody-refractory disease. 

DISCLOSURES

The study was supported by Celgene, a Bristol Myers Squibb company. Nine authors reported being employed by or owning stock in Bristol Myers Squibb. Full disclosures are reported in the original article.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.