Patients with relapsed or refractory multiple myeloma (R/R MM) have a poor prognosis after failing standard treatments, including proteasome inhibitors (PI), immunomodulatory drugs (IMiD), and anti-CD38 therapies (i.e., triple-class exposure). Significant unmet needs persist, particularly for high-risk R/R MM patients with high-risk features, such as extramedullary disease (EMD) or prior anti-BCMA/GPRC5D therapies. IBI3003, a novel trispecific antibody targeting GPRC5D, BCMA and CD3, was designed to overcome single tumor antigen escape and has demonstrated superior in vivo antitumor activity to marketed benchmark bispecific antibodies, especially in MM with low BCMA and GPRC5D expression. Herein, we report the initial results of an ongoing first-in-human phase 1 study evaluating safety and efficacy of IBI3003 in patients with R/R MM (NCT06083207).

The phase 1 study enrolled eligible patients with R/R MM who have failed at least 2 lines of prior treatments, including at least a PI, an IMiD and an anti-CD38-based therapy. IBI3003 was administered subcutaneously once weekly (QW). Dose escalation was conducted from 0.1 to 1500 μg/kg, and 1-3 priming doses incorporated to mitigate cytokine release syndrome (CRS). Adverse events were graded per CTCAE v5.0. CRS and immune effector cell-associated neurotoxicity syndrome (ICANS) were graded per ASTCT guidelines. Anti-tumor activity was assessed by 2016 IMWG criteria.

As of July 28, 2025, 28 patients were enrolled from 0.1 μg/kg to 540 μg/kg in China and Australia (median age: 61.5 years; females: 53.6%; ECOG PS 1: 85.7%; R-ISS stage III: 32.1%; mSMART high-risk: 75.0%; median lines of prior treatments: 5; EMD: 50.0%; ≥60% plasma cells in bone marrow: 17.9%; triple-class exposed (defined as previous treatment with at least one PI, at least one IMiD, and at least one antiCD38 antibody): 100%; penta-class exposed (defined as previous treatment with at least two PIs, at least two IMiDs, and at least one antiCD38 antibody): 53.6%; prior anti-BCMA and/or anti-GPRC5D therapy: 50.0%; refractory to last line of therapy: 85.7%) with median follow-up of 2.4 months (range: 0.8-7.0). Dose-limiting toxicity occurred in 1 patient (transient grade 4 platelet count decreased at 40 μg/kg without priming dose). Treatment-emergent adverse events (TEAEs) occurred in 100% patients (grade≥3 [G3+]: 78.6%), most commonly being CRS (71.4%, all G1-G2), anemia (64.3%, G3+: 25.0%), platelet count decreased (57.1%, G3+: 28.6%), lymphocyte count decreased (53.6%, G3+: 50.0%) and neutrophil count decreased (53.6%, G3+: 39.3%). Infections occurred in 11 (46.4%, G3+: 14.3%) patients. ICANS occurred in 2 (7.1%) patients (all G1-2). patients treated with 40 μg/kg (n=6, all had EMD), 50% ORR. In patients treated with ≥120 μg/kg (n=13), 84.6% ORR including 4 VGPR and 7 PR. In patients treated with ≥360 μg/kg (n=5), 100% ORR including 2 VGPR and 3 PR. In patients with prior anti-BCMA and/or anti-GPRC5D therapy and treated with ≥120 μg/kg (n=7), 85.7% ORR including 3 VGPR and 3 PR. In patients with EMD and treated with ≥120 μg/kg (n=6), 83.3% ORR including 1 VGPR and 4 PR. The median baseline soluble BCMA (sBCMA) level was 205 ng/mL (range: 10 to 3010 ng/mL). A reduction of 72.15% in sBCMA after Cycle 1 (28 days) was observed in 120 μg/kg cohort, while deeper reductions of 88.75% after Cycle 1 and 95.12% after Cycle 2 were observed in 360 μg/kg cohort.

IBI3003 demonstrated a manageable safety profile in patients with R/R MM. Encouraging efficacy signals were observed across 40-540 μg/kg, including 100% ORR in patients receiving ≥ 360 μg/kg. Responses were observed in high-risk patients with EMD or those who had received prior anti-BCMA/GPRC5D therapies. The current follow-up period is relatively short, and the anti-tumor response is anticipated to be more profound following continuous treatment. The dose escalation and expansion of IBI3003 is ongoing in the phase 1 study.

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2025
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