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
Mené sur 197 patients atteints d'un myélome multiple réfractaire ou récidivant, cet essai multicentrique de phase I/II évalue la dose maximale tolérée de l'iberdomide (un immunomodulateur du complexe cereblon E3 ligase) en combinaison avec la dexaméthasone et l'efficacité, du point de vue du taux de réponse globale, de cette combinaison, après l'échec de plusieurs lignes thérapeutiques (nombre médian de thérapies antérieures : 5)
Résumé en anglais
Background : Iberdomide is a novel cereblon E3 ligase modulator with enhanced tumouricidal andimmune-stimulatory effects compared with immunomodulatory drugs. In preclinical myelomamodels, iberdomide has shown synergy with dexamethasone, proteasome inhibitors, andCD38 monoclonal antibodies. We aimed to evaluate the safety and clinical activity of iberdomide plus dexamethasone in patients with heavily pretreated relapsed or refractory multiple myeloma.
Methods : We conducted a multicohort, open-label, phase 1/2 trial (CC-220-MM-001) at 42 treatment centres in Europe, Canada, and the USA. Patients aged 18 years or older with multiplemyeloma who had received at least two previous lines of therapy, including lenalidomideor pomalidomide and a proteasome inhibitor, were enrolled into the dose-escalationcohort. Patients received escalating doses of oral iberdomide (0·3–1·6 mg on days1–21 of each 28-day cycle) plus oral dexamethasone (40 mg [20 mg if age >75 years]once per week). A dose-expansion cohort at the recommended phase 2 dose was plannedfor patients who had received at least three previous lines of therapy and had triple-classrefractory disease (refractory to immunomodulatory drugs, proteasome inhibitors, andCD38 antibodies). Treatment continued until progressive disease or unacceptable toxicity.The primary outcomes were the recommended phase 2 dose (in the dose-escalation cohort,phase 1) and overall response rate (defined as complete response or partial response;in the dose-expansion cohort, phase 2) in the full analysis set. This trial is ongoingand is registered with ClinicalTrials.gov, NCT02773030.
Findings : Between Dec 5, 2016, and Dec 16, 2020, 460 patients were assessed for eligibility across all cohorts and 197 were enrolled and treated with iberdomide plus dexamethasone(90 patients in the dose-escalation cohort and 107 in the dose-expansion cohort).In the dose-escalation cohort, 47 (52%) patients were female and 43 (48%) were male,70 (78%) were White, and the median number of previous lines of therapy was 5 (IQR4–8). In the dose-expansion cohort, 47 (44%) were female and 60 (56%) were male, 84(79%) were White, and the median number of previous lines of therapy was 6 (IQR 5–8).At data cutoff (June 2, 2021), median follow-up was 5·8 months (IQR 3·0–13·7) in thedose-escalation cohort and 7·7 months (5·3–11·4) in the dose-expansion cohort. Twodose-limiting toxicities (both infections, at 1·2 mg and 1·3 mg) were observed inthe dose-escalation cohort, and 1·6 mg was selected as the recommended phase 2 dose.In the dose-escalation cohort, the overall response rate was 32% (95% CI 23–43; 29of 90 patients) across all doses, and the maximum tolerated dose was not reached.In the dose-expansion cohort, the overall response rate was 26% (95% CI 18–36; 28of 107 patients). The most common grade 3 or worse adverse events were neutropenia(48 [45%] of 107 patients), anaemia (30 [28%]), infection (29 [27%]), and thrombocytopenia(23 [22%]). Serious adverse events occurred in 57 (53%) patients. There was one (1%)treatment-related death (sepsis) and five (5%) patients discontinued iberdomide dueto adverse events.
Interpretation : Iberdomide plus dexamethasone was generally safe and showed meaningful clinical activity in heavily pretreated patients with multiple myeloma, including in disease that was refractory to immunomodulatory drugs. These data suggest that further evaluation ofiberdomide plus dexamethasone or other standard antimyeloma therapies is warranted.
