Long-Term Follow-up from the Phase 2 ICON Study of Iberdomide Combined with Low-Dose Cyclophosphamide and Dexamethasone in Relapsed/Refractory Multiple Myeloma (IberCd)

Introduction: Patients with triple-class exposed multiple myeloma (MM) who received 2-4 prior lines of therapy have a poor outcome with a median progression free survival (PFS) of only 4.4 months with standard treatment regimens. This indicates that there is still an unmet need for new treatment options. Iberdomide, a novel potent cereblon E3 ligase modulator (CELMoD™), binds with higher affinity to cereblon, which explains the improved direct anti-MM activity and immune-stimulatory effects, compared to immunomodulatory drugs (IMiDs) in preclinical experiments. In addition, iberdomide demonstrated promising clinical activity and a favorable safety profile in heavily pretreated MM patients refractory to both lenalidomide and pomalidomide. Continuous low-dose cyclophosphamide has immunomodulatory effects and potentiates the activity of IMiDs. We designed the phase 2 ICON study of iberdomide plus low-dose cyclophosphamide and dexamethasone (IberCd), an all oral combination, to further improve clinical outcome of relapsed/refractory (RR) MM patients who received 2-4 prior lines of therapy. Aims: This phase 2 study evaluates the safety and efficacy of IberCd in RRMM patients. Here we present an updated analysis with longer follow-up. Methods: The ICON study is an investigator-initiated, prospective, phase 2, multicenter study conducted in 8 hospitals in the Netherlands. Patients were included if they had lenalidomide-refractory MM, relapsed from or refractory to 2-4 prior lines of treatment. All patients were treated with 28-day cycles of iberdomide (1.6 mg orally, days 1-21), cyclophosphamide (50 mg orally, days 1-28) and dexamethasone (40 mg QW orally [20 mg in patients age > 75 years]) until progression. The primary endpoint is progression-free survival (PFS) and secondary endpoints include safety, overall response rate (ORR), overall survival (OS), and second PFS. All patients provided written informed consent. This trial is registered at ClinicalTrials.gov (NCT04392037). Results: Between February 2021 and July 2023, 61 patients were enrolled and received IberCd treatment. Median age of patients was 67 years (range 46 - 81). Patients received a median of 3 prior lines of therapy (range 2-5), 100% were lenalidomide refractory, 98% proteasome inhibitor (PI) exposed (52% refractory), 85% anti-CD38 antibody exposed (77% refractory), and 44% were triple-class refractory. Thirty % had at least one high-risk cytogenetic abnormality (defined as del(17p), t(4;14) and/or t(14;16)). At a median follow-up of 21.9 months (IQR 16.3 -27.7), 18 patients (30%) remained on treatment. Median PFS was 17.8 months (95% CI, 14 - 22) and was comparable across subgroups, including patients who had received 2 or >3 prior lines (median PFS 17.6 vs 17.8 months) and standard-risk or high-risk patients (median PFS 19.7 vs 16.6 months). Overall response rate (ORR) was 82% with a very good partial response (VGPR) or better in 49% of patients and complete response in 14.8%. Median time to response was 28 days (IQR 28-62). Responses deepened over time. Median duration of response was 18.8 months (95% CI, 15.8 - 24.7). The median overall survival (OS) was not yet reached at the time of the analysis (18-month OS: 75.3% (95% CI, 64.7 - 87.7). Overall, IberCd was well tolerated. The most common grade ≥3 adverse events (AEs) were neutropenia (n=35, 57%) and infections (n= 21; 34%). We also evaluated the efficacy of therapy administered directly after IberCd treatment. Thirty-five of the 61 patients (57%) received next-line treatment. T-cell redirecting antibodies were the most common next-line therapy (14 of 35 patients; 40%), followed by carfilzomib-based therapy (11 of 35 patients, 31%). Median PFS on next line of treatment was 5.9 months (95% CI, 2.9 - 7.8); 8.3 months (95% CI, 3.5 - NR) for those receiving T-cell redirecting antibodies immediately after relapse, and 3.7 months (95% CI, 2.8 - 6.5) for those receiving an alternative treatment (including IMiDs, PIs, or anti-CD38 antibodies). Conclusion: Iberdomide combined with low-dose cyclophosphamide and dexamethasone demonstrated substantial clinical activity that compares favorably with standard treatment regimens for RRMM patients. With longer follow-up, patients continued to demonstrate durable responses and a greater depth of response. This fully oral, well tolerated, and active combination warrants further evaluation in RRMM.