Alexander Ratushny: No relevant disclosure to display
Clifton Anderson, n/a: No financial relationships to disclose
Objectives: The phase 2 EMN26 study [1] evaluated Iberdomide (IBER) at doses of 0.75, 1.0, or 1.3 mg on days 1-21 of each 28-day cycle until progression or unacceptable toxicity. The study showed that IBER was an effective post-autologous stem-cell transplantation (ASCT) maintenance strategy for newly diagnosed multiple myeloma (NDMM), with a favorable safety profile and superior response at 6 months and Minimal Residual Disease (MRD) conversion compared to lenalidomide (LEN) maintenance after ASCT [2]. However, anti-myeloma therapies used for induction/consolidation varied between cohorts, and patients on IBER 0.75 mg typically had more intensive regimens. The phase 3 EXCALIBER Maintenance study [3] is evaluating IBER vs. LEN maintenance post-ASCT in a randomized design to determine the optimal maintenance dose by comparing the three IBER dose levels with standard LEN maintenance. Quantitative systems pharmacology (QSP) provides a means to guide the optimal dose of IBER post-ASCT for the EXCALIBER Maintenance study. We leveraged the calibration of immunomodulating drugs (IMiDs) and cereblon E3 ligase modulatory drugs (CELMoDs) from our previously developed QSP model [4] to project dose response in the post-ASCT maintenance phase.
Methods: We developed a QSP model for relapsed/refractory multiple myeloma (RRMM), calibrated with pre-clinical and clinical data, including best and overall response, as well as progression-free survival (PFS) from a range of approved RRMM therapies, including IMiD and CELMoD trial outcomes stratified by dose [4]. To simulate NDMM, we adjusted key baseline characteristics and treatment-related parameters distinguishing NDMM from RRMM, using literature and BMS datasets. NDMM patients were modeled through an abstract ASCT+1L scenario, replicating the baseline characteristics of real patients initiating maintenance therapy in ASCT trials. These patients then received either placebo, LEN, or IBER. Disease control and progression were calibrated to trial data, stratified by cytogenetic risk and MRD status. A stronger 1L scenario was also tested to address uncertainties in the EMN26 study.
Results: The model predicted that the dose response across IBER arms would be minor and emerged after 1 year of maintenance. IBER was projected to lead to deeper responses compared to LEN, with longer PFS and a higher number of patients achieving complete response (CR) and MRD negativity within the first year. Power analysis suggested that a 10% increase in MRD-negative status could be demonstrated with reasonably high power (0.75) for IBER 0.75 mg administered on days 1-21 of a 28-day cycle after 6 months to LEN 10 mg administered on days 1-28 of a 28-day cycle. Increasing the 1L scenario strength delayed disease progression for all drugs. Notably, the stronger 1L + 0.75 mg IBER showed similar disease progression outcomes to the original 1L + 1 or 1.3 mg IBER, providing a mechanistic explanation for the unintuitive dose-response behavior in the EMN26 trial.
Conclusions: The QSP model predicted that IBER would be superior to LEN maintenance, driving deeper responses and longer PFS. It also explained improved outcomes for the 0.75 mg dose compared to higher doses in terms of stronger consolidation regimens.
Citations: [1] NCT04564703. [2] Van de Donk, N. W., Touzeau, C., Terpos, E., Perrot, A., Mina, R. Iberdomide Maintenance after Autologous Stem-Cell Transplantation in Newly Diagnosed MM: First Results of the Phase 2 EMN26 Study. 65th ASH Annual Meeting. Saturday, December 9, 2023 (American Society of Hematology). [3] NCT05827016. [4] Anderson et al. "Optimizing clinical dose and scheduling for multiple myeloma therapies and combinations using a QSP model". ACoP14 November 5-8, 2023, National Harbor, MD.
Keywords: Multiple myeloma, iberdomide, lenalidomide, maintenance therapy, QSP model
