Paper Details

ABSTRACT

Introduction

While bispecific antibodies are reshaping treatment paradigms for R/R MM, trispecific antibodies that simultaneously target two antigens hold the potential to overcome resistance caused by intra- and inter-tumoral heterogeneity and treatment-induced antigen escape. Substantial unmet clinical needs persist for R/R MM, especially in heavily pretreated and high-risk patients (pts). As previously reported, the GPRC5D×BCMA×CD3 trispecific antibody IBI3003 demonstrated manageable safety profile and promising efficacy in a first-in-human study (Li, et al., 2025 ASH and 2026 IMS). Here, we report updated results of this study with extended follow-up and additional pts from dose expansion.

Methods

The phase 1 study (NCT06083207) enrolled triple-class exposed pts with measurable R/R MM who had failed at least 2 prior lines of therapy that include at least a proteosome inhibitor, an immunomodulator and anti-CD38 antibody. In dose escalation, subcutaneous doses of IBI3003 ranging from 0.1 to 800 μg/kg QW were evaluated. In dose expansion, additional pts were randomized 1:1:1 to 120, 360 and 540 μg/kg QW (with 2 priming doses). For pts treated for ≥6 months who achieved ≥PR for ≥2 months, the regimen could be switched to Q2W maintenance. Anti-tumor activity was assessed by 2016 IMWG criteria.

Results

As of June 30, 2026, 102 pts were treated with IBI3003 (median age: 62.0 years; R-ISS stage III: 16.7%; mSMART high-risk: 52.9%; median lines of prior therapy: 4; extramedullary disease [EMD]: 53.9%; ≥60% plasma cells in bone marrow: 9.8%; triple-class exposed: 100%; penta-class exposed: 55.9%; prior anti-BCMA and/or GPRC5D therapy: 33.3%; refractory to last line of therapy: 88.2%). The median follow-up was 6.7 months (range: 0.8-15.2).

In dose expansion, ORR was 61.9% for 120 μg/kg (N=21), 76.5% for 360 μg/kg (N=17) and 63.2% for 540 μg/kg (N=19). The recommended phase 2 dose was identified as 360 μg/kg QW. In pts treated with 360 μg/kg across dose escalation and expansion (N=26), ORR was 84.6% including 57.7% ≥VGPR and 42.3% ≥CR. In pts with 2-4 prior lines of therapy treated with 360 μg/kg (N=19), ORR was 94.7%. In pts without prior exposure to anti-BCMA and GPRC5D treated with 360 μg/kg (N=22), ORR was 90.9%. Encouraging efficacy was also observed in difficult-to-treat high risk pts. In pts with EMD treated with 360 μg/kg (N=13), ORR was 76.9%. In pts with high tumor burden (defined as baseline sBCMA ≥400 ng/mL) treated with 360 μg/kg (N=4), ORR was 75.0%. In all pts, median DoR and PFS were not reached. Of 11 evaluable pts treated with ≥360 μg/kg, MRD negativity was 100%. In population pharmacokinetic (PopPK) analyses, the elimination half-life of IBI3003 was estimated to be approximately 18 days (cutoff date: January 2, 2026). Profound and durable sBCMA reductions were observed across dose groups, with a median decrease of 98.38% from baseline at 360 μg/kg after 3 cycles.

TEAEs occurred in 99% pts (grade≥3 [G3+]: 88.2%). The most common non-hematologic TEAE (≥50%) was cytokine release syndrome (52.0%, all G1-G2). Infections occurred in 42.2% pts (G3+: 26.5%). GPRC5D oral TEAE occurred in 44.1% pts (all G1-G2). GPRC5D skin and nail TEAEs occurred in 59.8% pts including 2 pts with resolved G3 rash. TRAE led to treatment discontinuation in 5 (4.9%) pts, No TRAE led to death.

Conclusions

The updated data, detailing the dose-expansion part, further validates the ability of IBI3003 to overcome established resistance and provide rapid, deep and durable remissions - specifically in heavily pretreated and high-risk pts with EMD and high-tumor burden, a population that reflects real-world clinical practice. These findings reinforce the therapeutic potential of IBI3003 and support the ongoing phase 3 study of IBI3003 monotherapy in R/R MM and phase 2 study of IBI3003 in combination with an anti-CD38 antibody in newly diagnosed MM.