Combination Regimens in MM Post Autologous Hematopoietic Cell Transplantation (AHCT) to Eliminate MRD Utilizing Iberdomide (COMMANDER): Results of Dose-Finding Component of a Phase 1b/2 Trial

Background

MRD persistence after upfront treatment for newly diagnosed multiple myeloma (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 results from the part 1, dose-finding component of the COMMANDER trial, testing the ability of Iber + daratumumab (dara) + dexamethasone (Iber-Dd) and Iber-Dd + carfilzomib (Iber-DKd) to upgrade response in MRD positive patients (pts) after AHCT.

Methods

Eligible pts had NDMM, received induction therapy with a proteasome inhibitor and IMiD® +/- anti-CD38 mAb followed by AHCT, had no prior disease progression, obtained ³ PR from induction + AHCT and were 100-180 days from ASCT with MRD ≥10^-5 by next generation sequencing (clonoSEQ®). During part 1 (dose finding) pts in Iber-Dd group 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, consisting of Iber-Dd + carfilzomib 56 mg/m² (20 mg/m² on first dose) on days 1,8,15 of cycles 1-6, followed by iberdomide maintenance. 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). Data cutoff is 01 July 2024.

Results

Median age of participants (N=25) was 67 (range 44-79), 7 were female, 6 were Black, 9 had MM with high-risk chromosome abnormalities, and 11 had received induction containing anti-CD38 mAb. Median follow up is 11.4 months for Iber-Dd, 4.7 months for Iber-DKd, and 11.4 months for the 15 patients enrolled in part 1. 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 (cohort expansion). Overall, 17 pts have been treated with Iber-Dd (9 in part 1, 8 in part 2), and 8 with Iber-DKd (6 in part 1; 2 in part 2). Most common adverse events were neutropenia (8/17; grade≥ 3 in 6/17), thrombocytopenia (5/17, all grades 1-2) and infection (6/17, grade≥ 3 in 2/17) in Iber-Dd and infection (any grade 5/8; grade ≥ 3 in 2/8) in Iber-DKd. Among pts who completed the initial 6 cycles of combination therapy, 7/9 in Iber-Dd and 3/3 in Iber-DKd had quantitative reduction of MRD burden, 4/9 in Iber-Dd and 3/3 in Iber-DKd achieved MRD<10^-5(primary endpoint), and 4/9 and 2/3 respectively also reached 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, able to significantly and rapidly reduce disease burden and lead to MRD negativity after modern induction therapy and AHCT in NDMM. This study is ongoing, complete safety and efficacy results from part 1 and updated results from part 2 will be presented.