Novel agent iberdomide demonstrated clinically meaningful activity and was generally well tolerated in a multicohort phase 1/2 trial.
Patients with relapsed/refractory multiple myeloma (RRMM) generally have few treatment options remaining in later lines and often experience suboptimal responses and reduced tolerability, especially those with advanced disease. Despite novel treatment advances, there remains a need in RRMM for efficacious, tolerable therapies that allow for the versatility of combination regimens with conventional and novel agents. Iberdomide is a novel cereblon E3 ligase modulator that has demonstrated synergistic effects with dexamethasone, proteasome inhibitors, and CD38 monoclonal antibodies in preclinical models. Recently, Lonial and colleagues published results from a multicohort, open-label, phase 1/2 trial of iberdomide in patients with at least 2 prior lines of therapy. A preplanned dose-expansion cohort at the recommended phase 2 dose was included for patients who had at least 3 prior lines of therapy and triple-class refractory disease.
Ninety patients were enrolled between 2016 and 2020 and treated with iberdomide plus dexamethasone in the dose-escalation cohort. Patients were treated with doses of 0.3 mg, 0.45 mg, 0.6 mg, 0.75 mg, 0.9 mg, 1.0 mg, 1.1 mg, 1.2 mg, 1.3 mg, and 1.6 mg. The median follow-up was 5.8 months, and the overall response rate (ORR) was 32% (95% confidence interval [CI], 23-43) across all doses. Infections at 1.2 mg and 1.3 mg were observed as dose-limiting toxicities, and 1.6 mg was selected as the recommended phase 2 dose. The maximum tolerated dose was not reached. A total of 107 patients were included in the dose-expansion cohort safety and activity analysis and received a dose of iberdomide at 1.6 mg. The ORR was 26% (95% CI, 18-36) in the dose-expansion cohort, and response rates were generally consistent across subgroups, except for patients with extramedullary disease (ORR, 11%). The most common grade ≥3 adverse events were neutropenia (45%), anemia (28%), infection (27%), and thrombocytopenia (22%). A total of 53% of patients experienced serious adverse events. There was 1 treatment-related death due to sepsis, and 5 patients discontinued treatment due to adverse events.
Iberdomide plus dexamethasone showed clinically meaningful activity and was generally well tolerated in heavily pretreated patients with RRMM, including patients who were refractory to immunomodulatory agents. Further research and evaluation of iberdomide is warranted with dexamethasone or other standard combination regimens.
- Lonial S, Popat R, Hulin C, et al. Iberdomide plus dexamethasone in heavily pretreated late-line relapsed or refractory multiple myeloma (CC-220-MM-001): a multicentre, multicohort, open-label, phase 1/2 trial. Lancet Haematol. 2022;9(11):e822-e832.