All-oral triplet iberdomide, ixazomib, and dexamethasone in elderly patients with multiple myeloma at first relapse: Results of the IFM phase 2 study I2D.
Authors: Touzeau Cyrille , Leleu Xavier P , Tiab Mourad , Macro Margaret , Perrot Aurore , Gay Julie , Chaleteix Carine , Roussel Murielle , Karlin Lionel , Jacquet Caroline , Manier Salomon , Hulin Cyrille , Decaux Olivier , Richez Valentine , Chalopin Thomas , Mohty Mohamad , Avet-Loiseau Herve , Planche Lucie , Corre Jill , Moreau Philippe ,   Intergroupe Francophone du Myelome
Published: June 2024

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Background: 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 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 results of the oral triplet iberdomide, ixazomib and dexamethasone in elderly patients with MM at first relapse. Methods: The Intergroupe Francophone du Myélome (IFM) prospective, multicenter, phase 2 study I2D enrolled MM patients aged over 70 years at first relapse (NCT04998786).Patients received oral iberdomide (1.6 mg on day 1 to 21), ixazomib (3 mg on day 1,8,15) and dexamethasone (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 Dec 2021 to May 2023 in 19 IFM centers. Median age was 76. The International Myeloma Working Group (IMWG) frailty score was >2 in 35 (50%) patients. In evaluable patients (54/70), cytogenetic analysis revealed del(17p) in 10 patients (18.5%) and t(4;14) in 8 (15%) patients. Based on inclusion criteria, all patients received 1 prior line of treatment, including lenalidomide in 87% (refractory, 74%) and daratumumab in 40% (refractory, 37%) of patients. Median time from MM diagnosis to study enrolment was 28 months. 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 12 months, the overall response rate was 64%, including 33% VGPR. The median progression-free survival (PFS) was 13 months and the 12-month overall survival (OS) was 85% (77-95% 95% CI). In patients with MM refractory to both lenalidomide and daratumumab (n=26), the median PFS was 10 months. Overall, the triplet I2D was well tolerated. Most common non-hematologic adverse events (AE) were infection (30% of patients), peripheral neuropathy (20%), diarrhea (19%), and were mostly grade 1 or 2. Most common grade 3-4 treatment related AEs (>5% of patients) were neutropenia (46%), thrombocytopenia (9%) and infection (8%). Four patients discontinued treatment due to a severe AE (cytopenia (n=3), skin rash (n=1). Conclusions: The oral tripletiberdomide, ixazomib and dexamethasone demonstrated a favorable efficacy / safety profile in elderly MM patients at first relapse, including in patients with lenalidomide and daratumumab refractory disease. Clinical trial information: NCT04998786 .