P-326: Phase 1b/2 trial of iberdomide in combination with daratumumab, dexamethasone +/- carfilzomib to eliminate MRD after induction therapy and ASCT in NDMM

Introduction: MRD persistence after upfront treatment for NDMM is associated with higher risk of progression. Iberdomide (Iber) is a novel cereblon E3 ligase modulator (CELMoD™) with enhanced immune stimulatory and tumoricidal activity and amenable to combination with other anti-myeloma agents. We report for the first time results of Iber + daratumumab (dara) + dexamethasone (Iber-Dd) and Iber-Dd + carfilzomib (Iber-DKd) consolidation in MRD positive patients (pts) after ASCT.

Methods:
Eligible pts had NDMM, had received induction therapy with a proteasome inhibitor and IMiD +/- anti-CD38 mAb followed by ASCT, had no prior disease progression, obtained ≥PR from induction + ASCT and were 100-180 days from ASCT with MRD ≥ 10^-5 by NGS (clonoSEQ®). On part 1 (dose finding) pts in Iber-Dd received Iber in consecutive cohorts at 1.0, 1.3 and 1.6 mg days 1-21 of 28-day cycles, with dara and dexamethasone. After 6 cycles, pts continued single agent Iber maintenance at 1.0 mg 21/28 days. Upon completion of Iber-Dd, part 1 and demonstration of safety, we enrolled subsequent pts in Iber-DKd, consistent of Iber-Dd + carfilzomib 56 mg/m² (20 mg/m² on first dose) on days 1,8,15 of cycles 1-6. In addition to conventional monitoring for safety and efficacy, pts underwent MRD assessment after 6 cycles and yearly thereafter. Both regimens are being explored in part 2 (dose expansion).

Results:
Median age of participants (N=21) was 66 (range 44-79), 7 had MM with high-risk chromosome abnormalities, and 9 had received induction containing anti-CD38 mAb. Median follow up is 9.5 months for Iber-Dd and 3.2 months for Iber-DKd. None of the pts enrolled in Iber-Dd, part 1 (N=9) developed dose-limiting toxicity (DLT) and all 3 dose levels were considered safe. We completed Iber-DKd, part 1 in the Iber 1.0 and 1.3 cohorts (N=6) with no patient developing DLT. Considering emerging data on Iber PK and PD, we did not explore Iber 1.6 mg dose in Iber-DKd and expanded the 1.0 and 1.3 mg cohorts for both regimens in part 2 (dose expansion). Overall, 14 pts have been treated with Iber-Dd (9 in part 1, 5 in part 2) and 7 with Iber-DKd (6 in part 1, 1 in part 2). Most common adverse events were neutropenia (8/14, grade ³3 in 6/14), thrombocytopenia (4/14, all grades 1-2) and infection (6/14, grade ≥ 3 in 2/14) in Iber-Dd and infection (3/7, grade ≥ 3 in 1/7) in Iber-DKd. Among pts who completed consolidation, 7/9 in Iber-Dd and 2/2 in Iber-DKd had reduction of MRD burden, 4/9 in Iber-Dd and 2/2 in Iber-DKd achieved MRD< 10^-5 (primary endpoint), all also with MRD< 10^-6. One participant with high-risk MM in Iber-Dd discontinued participation due to disease progression after 7 months of treatment. All other pts remain on treatment.

Conclusions:
Iber-Dd and Iber-DKd are safe combinations and able to eliminate MRD persistent after modern induction therapy and ASCT in NDMM. This study is ongoing, complete safety and efficacy results from part 1 and updated results from part 2 will be presented at the meeting.