Relapsed/refractory multiple myeloma (RRMM) is particularly difficult to treat in later lines, especially in patients who are refractory to immunomodulatory drugs, proteasome inhibitors (PIs), and CD38 monoclonal antibodies. Few treatment options remain for patients in later-line RRMM, and patients often experience suboptimal responses and reduced tolerability, especially those with advanced disease. 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, PIs, 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 ≥2 previous lines of therapy. A preplanned dose-expansion cohort at the recommended phase 2 dose was included for patients who had ≥3 previous lines of therapy and triple-class refractory disease.
In total, 90 patients were enrolled between 2016 and 2020 and treated with iberdomide plus dexamethasone in the dose-escalation cohort. Patients were treated with an escalating range of doses: 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 in the dose-escalation cohort, 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.
From 2019 to 2020, 107 patients were included in the dose-expansion cohort and received a dose of 1.6 mg of iberdomide. All 107 patients were included in the safety and activity analysis. 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%). In all, 53% of patients experienced serious adverse events, and 1 treatment-related death occurred due to sepsis.
Iberdomide in combination with dexamethasone showed clinically meaningful activity in heavily pretreated patients with RRMM, with a recommended phase 2 dose of 1.6 mg. Further research and evaluation of this combination warrants further investigation and larger studies.
Source: 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.