Longitudinal analysis of MRD negativity and immune dynamics in patients with transplant-ineligible newly diagnosed multiple myeloma treated with iberdomide, daratumumab, and dexamethasone from the CC-220-MM-001 trial Free

Introduction: Iberdomide (IBER) is an oral CELMoD™ agent with optimized cereblon binding leading to improved direct antitumor and immunostimulatory effects versus immunomodulatory drug (IMiD®) agents. Preliminary findings from the phase 1/2 CC-220-MM-001 trial (NCT02773030) demonstrated promising efficacy of IBER plus daratumumab (DARA) and dexamethasone (DEX) (IberDd), including high rates of minimal residual disease (MRD) negativity in the transplant-ineligible newly diagnosed multiple myeloma (TNE NDMM) cohort. With the recent acceptance of MRD-negative complete response (CR) as an intermediate endpoint by the FDA Oncologic Drugs Advisory Committee (ODAC), here we focused on MRD negativity rate, sustainability, and kinetics of IberDd treatment in patients with TNE NDMM from the CC-220-MM-001 trial. In addition, given the immunostimulatory effects of IBER, we investigated how immune changes driven by IberDd impact MRD negativity rate.

Methods: Eligible patients had NDMM with no planned or recommended autologous stem cell transplant due to age or comorbidities. Patients received oral IBER at doses of 1.0 mg, 1.3 mg, or 1.6 mg on days (D) 1–21 of each 28-day cycle (C). Subcutaneous DARA (1800 mg) was administered weekly on D1, 8, 15, and 22 during C1–2; every 2 weeks on D1 and 15 during C3–6; and monthly on D1 from C7 onward. Oral DEX was given weekly at 40 mg (or 20 mg for patients >75 years of age). Peripheral blood immunophenotyping was performed by flow cytometry on C1D1 and C2D15. Additional assessments included changes in involved serum free light chains (sFLCs) and MRD evaluation using the EuroFlow assay in patients achieving at least a very good partial response (VGPR). MRD data analysis was performed similar to the EVIDENCE meta-analysis, with a sensitivity threshold of 10^–5 (Landgren O, et al. Blood 2024;144:359–367).

Results: As of March 3, 2025, 75 patients with TNE NDMM received IberDd (25 patients at each IBER dose level) with a median (range) follow-up of 22.3 (0.4–28.5) months. MRD-negative CR at any time was achieved by 44% of patients, with a median (range) time to MRD negativity of 12.0 (2.3–22.5) months. Among patients achieving MRD-negative CR, 63.6% were MRD-negative CR at landmark 12 months. In addition, 57.3% of patients achieved MRD-negative VGPR at any time, with a median 6.7-month time to MRD negativity. In those achieving MRD-negative VGPR, 72.1% were MRD-negative VGPR at landmark 12 months. At 6 months, sustained MRD-negative CR was observed in 48.5% of patients who had previously achieved MRD-negative CR, and sustained MRD-negative VGPR was observed in 53.5% of patients who had previously achieved MRD-negative VGPR. Progression-free survival (PFS) did not significantly differ by MRD-negative CR status (log-rank test at 0.05 level of significance), likely due to the limited number of PFS events and substantial censoring.

Consistent with the expected antitumor activity of IBER, data indicate a strong drop in sFLCs at C1D15 across all doses. Reduction in sFLCs deepened by C2D1 and was sustained through C6D1. No significant differences were observed among IBER doses.

In the peripheral immune compartment, higher baseline CD3⁺, CD8⁺, activated CD8⁺ T cells (CD38⁺ as well as ICOS⁺), proliferating CD8⁺ T cells (Ki67⁺),CD8⁺ effector memory T cells (CD3⁺CD8⁺CD45RA^-CD45RO⁺CCR7^-), central memory CD8⁺ T cells (CD3⁺CD8⁺CD45RA^-CD45RO⁺CCR7⁺), and CD19⁺ B cells were each significantly associated with MRD-negative CR status (P<0.05). Notably, at C2D15, patients with MRD-negative CR had a reduced regulatory T cell (Treg) population (CD3⁺CD4⁺CD25⁺CD127^-/loFoxP3) compared with those with MRD-positive CR (3-fold higher Tregs in MRD-positive CR), highlighting the impact of IBER-mediated immune changes on MRD negativity.

Conclusions: IberDd demonstrated robust activity that deepened over time and high rates of MRD negativity at the 12-month follow-up landmark. MRD-negative CR correlated with immune changes driven by IberDd, supporting the potential of IberDd as a broadly effective treatment option in patients with TNE NDMM.