OA – 61: All oral triplet Iberdomide Ixazomib and Dexamethasone in elderly patients with multiple myeloma patients at first relapse : results of the IFM phase 2 study I2D

Introduction: The triplet combination daratumumab, lenalidomide and dexamethasone (DRd) and bortezomib, lenalidomide and dexamethasone (VRd) are to date the standard of care for patients with transplant ineligible (TI) newly diagnosed multiple myeloma (MM). Most TI patients therefore present with MM refractory to lenalidomide and/or daratumumab at first relapse and represent a difficult-to-treat population. Iberdomide is a novel oral cereblon E3 ligase modulator (CELMoD) that demonstrated promising activity in MM patients refractory to lenalidomide/pomalidomide. Here we report efficacy and safety of the all-oral triplet iberdomide, ixazomib and dexamethasone in elderly patients with MM at first relapse.

Methods: The Intergroupe Francophone du Myélome (IFM) multicenter, open-label, phase 2 study I2D enrolled MM patients aged over 70 years at first relapse (NCT04998786). Patients received iberdomide (oral, 1.6 mg on day 1 to 21), ixazomib (oral, 3 mg on day 1,8,15) and dexamethasone (oral, 20 mg on day 1,8,15,22 on cycle 1-2 and 10 mg on day 1,8,15,22 on cycle 3-6) (28-day cycle) until disease progression or unacceptable toxicity. The primary endpoint was very good partial response (VGPR) rate.

Results: Seventy patients were included from December 2021 to May 2023 in 19 IFM centers. Median age was 76 (range 70-87) years. The International Myeloma Working Group (IMWG) frailty score was >2 in 35 (50%) patients. In evaluable patients (54/70), fluorescence in situ hybridization (FISH) analysis revealed the presence of del(17p) in 10 patients (18.5%) or t(4;14) in 8 (15%) patients. Based on inclusion criteria, all patients had received 1 prior line of treatment, including bortezomib in 31%, lenalidomide in 87% (refractory, 74%) and daratumumab in 40% (refractory, 37%) of patients. At data cut-off, 36 (51%) patients discontinued the study due to disease progression (n=30), adverse event (n=4) or death (n=2). After a median follow-up of 14 months, the overall response rate was 65%, including 36% VGPR. The 12-months progression-free survival (PFS) and duration of response were 52% and 76%, respectively. Patients with MM refractory to both lenalidomide and daratumumab (n=26) had similar PFS compared to the overall population. The 12-month overall survival was 85%. Overall, iberdomide, ixazomib and dexamethasone combination was well tolerated. Most common non-hematologic adverse events were gastro-intestinal disorders (36% of patients), infection (30%), peripheral neuropathy (22%), and were mostly grade 1 or 2. Most common grade 3-4 treatment related adverse events ( >5% of patients) were neutropenia (46%), thrombocytopenia (9%) and infection (8%). Four patients discontinued treatment due to a severe adverse event (cytopenia (n=3), skin rash (n=1).

Conclusions: Overall, the oral triplet iberdomide, ixazomib and dexamethasone demonstrated a favorable efficacy / safety profile in elderly MM patients at first relapse, including patients with lenalidomide and daratumumab refractory disease.