P-335: Iberdomide is immune stimulatory and induces deep anti-myeloma activity across doses in combination with daratumumab in patients with TNE NDMM from the CC-220-MM-001 study

Introduction: Daratumumab (DARA) plus lenalidomide (LEN) and dexamethasone (DEX) is a current standard of care for transplant non-eligible (TNE) newly diagnosed multiple myeloma (NDMM). Iberdomide (IBER) is a novel oral CELMoD™ agent that enables more rapid substrate degradation than LEN, inducing greater myeloma cell death and immune stimulation. Preclinically, IBER has shown synergistic activity when paired with DARA, inducing deeper anti-myeloma cell activity than LEN + DARA; however, the activity of IBER + DARA + DEX (IberDd) in TNE NDMM has not been previously reported. Here we report first pharmacodynamic and biomarker results from the phase 1/2 CC-220-MM-001 (NCT02773030) dose-expansion cohort of IberDd in patients (pts) with TNE NDMM to support dose selection of IBER in this setting.

Methods: Eligible pts had NDMM with no autologous stem cell transplant planned or were ineligible due to age or comorbidities. Oral IBER was given at 1.0 mg, 1.3 mg, and 1.6 mg on days (D) 1–21 of each 28-day cycle (C) with subcutaneous DARA (1800 mg) on D1, 8, 15, and 22 in C1–2, on D1 and 15 in C3–6, and on D1 in ≥ C7, plus weekly oral DEX (40 mg; 20 mg of > 75 years of age). Analyses included immunohistochemistry (IHC) of CD138+ bone marrow (BM) samples for cereblon (CRBN), Aiolos, and Ikaros at screening and C2D15, flow cytometry of peripheral blood for changes in immune cell composition at C1D1 and C2D15, changes in involved serum-free light chains (sFLCs), and assessment of minimal residual disease (MRD) by Euroflow assay in pts achieving deep response (≥ very good partial response [VGPR]).

Results: As of December 2023, 75 pts with TNE NDMM received IberDd (25 pts 1.0 mg; 25 pts 1.3 mg; 25 pts 1.6 mg). All pts with available samples showed CRBN expression in BM MM cells by IHC. Across all doses, substrate protein levels were significantly reduced by C2D15, with no dose-dependent trend. In the immune compartment, IberDd led to a > 4-fold increase in proliferating T and NK cells, > 2-fold increase in activated/effector memory T cells, and > 75% decrease in median absolute B cells, CD38+ T cells, and naïve T cells. Immune pharmacodynamics across doses were overlapping. Changes in involved sFLCs as a biomarker for tumor reduction also showed deep and overlapping decreases on treatment across all 3 doses with the nadir observed at around C3D1. In pts attaining ≥ VGPR and with available samples, MRD negativity at 10^-5 was achieved in 10/17 (58.8%) pts at the 1.0-mg dose, 13/22 (59.1%) pts at the 1.3-mg dose, and 7/16 (43.8%) pts at the 1.6-mg dose.

Conclusions: IberDd showed pharmacodynamic response across all 3 doses of IBER tested in pts with TNE NDMM. Notably, data showed significant overlap across doses suggesting all 3 doses of IBER tested are biologically active in combination with DARA + DEX. These data support the use of IBER at doses of 1.0 mg or higher in combination with DARA to achieve maximal pharmacodynamic effects. Previously presented at EHA 2024.