Iberdomide, Daratumumab, and Dexamethasone Shows Deep Antimyeloma Activity across Molecular Patient Subsets with Transplant-Ineligible Newly Diagnosed Multiple Myeloma from the CC-220-MM-001 Trial

Introduction: Iberdomide (IBER) is a novel, oral CELMoD™ agent that induces ubiquitination and degradation of the hematopoietic transcription factors Aiolos and Ikaros. IBER binds cereblon (CRBN) with unique interactions and > 20-fold higher affinity, inducing faster and deeper degradation of substrates and more potent immunostimulatory and antimyeloma activity in preclinical models, compared with the immunomodulatory drugs (IMiDs®) lenalidomide (LEN) and pomalidomide. Daratumumab (DARA) in combination with LEN and dexamethasone (DEX) (DRd) is a current standard of care for patients with transplant-ineligible (TNE) newly diagnosed multiple myeloma (NDMM). Preliminary results from the phase 1/2 CC-220-MM-001 trial (NCT02773030) showed impressive activity, including 45% minimal residual disease (MRD) negativity at 10−5, of IBER plus DARA and DEX (IberDd) in patients with TNE NDMM in the cohort as a whole. While IBER has shown synergistic activity when paired with DARA in preclinical models, inducing deeper antimyeloma cell activity than LEN + DARA, the clinical activity of IberDd in patient populations where DRd treatment may be suboptimal has not been reported previously. Here we report results from the CC-220-MM-001 dose-expansion cohort of IberDd in patients with TNE NDMM in biomarker-defined patient populations. Methods: Eligible patients had NDMM with no planned or recommended autologous stem cell transplant 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-D cycle with subcutaneous DARA (1800 mg) on D1, 8, 15, and 22 in cycle (C)1-2, on D1 and 15 in C3-6, and on D1 in ≥ C7, plus weekly oral DEX (40 mg; 20 mg if > 75 years of age). Analyses included immunohistochemistry (IHC), whole genome sequencing (WGS), and RNA sequencing of CD138+ bone marrow (BM) samples at screening, flow cytometry for immunophenotyping in peripheral blood at C1D1, changes in involved serum-free light chains (sFLCs), and assessment of MRD by EuroFlow assay in patients achieving deep response (≥ very good partial response [VGPR]). Results: As of December 2023, 75 patients with TNE NDMM received IberDd (25 patients at each IBER dose level). Changes in involved sFLCs as a dynamic and early biomarker for tumor reduction showed deep decreases (> 90%) on treatment across all 3 doses in the first 4 cycles. In patients attaining ≥ VGPR and with available samples, MRD negativity at 10-5 was achieved in 10/17 (58.8%) patients at the 1.0 mg dose, 13/22 (59.1%) patients at the 1.3 mg dose, and 7/16 (43.8%) patients at the 1.6 mg dose. All patients with available BM samples showed CRBN, Aiolos, and Ikaros expression in BM MM cells by IHC. High expression of Aiolos and Ikaros was generally observed and levels of Aiolos, Ikaros, and CRBN protein were not associated with responses. WGS revealed hypodiploidy (n = 7) as the most common genomic abnormality, and no patients with dysregulated CRBN (including mutations, genomic loss, and COPS mutations) were observed. Several patients with high-risk markers were identified, including TP53 mutations (n = 3), del(17p) (n = 2), 1qAMP (n = 2), and t(4;14) (n = 1), and all patients responded to IberDd in each subgroup, regardless of high-risk markers. Analysis of high-risk gene expression signatures (n = 15) also showed similar progression-free survival between patients with high and low EMC92 (P = 0.17) and UAMS70 (P = 0.99) scores. In the immune compartment, baseline levels and changes in T, B, and NK cells and T-cell subsets, including activated (HLA-DR+, ICOS+), naive, memory, and exhausted (PD1+, LAG3+, TIM3+) CD4 and CD8 T cells, were similar across patient subgroups and did not correlate with depth of response. Conclusions: IberDd showed deep reductions in sFLCs and drove MRD negativity across all 3 doses of IBER tested in patients with TNE NDMM from the CC-220-MM-001 trial. Notably, responses to IberDd were observed across molecular and immune subgroups, including in patients with high-risk markers, providing preliminary evidence of deep and broad activity of IberDd in the TNE NDMM setting.