Paper Details

ABSTRACT

Introduction: SIM0500 is a novel trispecific antibody with bivalent GPRC5D and monovalent BCMA binding domains. The binding affinity for GRPC5D and BCMA is high, while the binding affinity for CD3 is low. This strong avidity-based dual targeting is expected to deliver robust efficacy, with the low CD3 affinity enabling a favorable safety profile. SIM0500 demonstrates superior anti-tumor effects versus bispecific/trispecific antibody analogs in vivo, with reduced off-tumor toxicities compared to GPRC5D-monotargeted agents. Here, we report first clinical data from an ongoing international phase 1 study evaluating SIM0500 monotherapy in RRMM (NCT06375044).

Methods: Dose escalation cohorts enrolled patients (pts) with RRMM who had received ≥3 prior lines of therapy, including exposure to PI, IMiD and anti-CD38-based therapy. Prior BCMA or GPRC5D exposure (CAR-T, ADC, and TCE), but not both, was allowed. Antimicrobial (antibiotic, antiviral, antifungal) prophylaxis and intravenous immunoglobulin were given per institutional/IMWG guidelines. Subcutaneous dose escalation included dose levels (DL) 1-12 at frequent and extended dosing schedules. In some dose levels, a priming dose was introduced to mitigate cytokine release syndrome (CRS). Pts received steroid prophylaxis for CRS.

Results: As of June 22, 2026, 38 pts had received SIM0500 (DL1-12) in China and the US. The median follow-up was 7.53 months. Median age was 63 years (42.1% ≥ 65 years); 39.5% had high risk cytogenetics, 42.1% had extramedullary disease, and 23.7% had International Staging System (ISS) stage III disease. The median prior line of therapy was 5 (range, 3-13). 71.1% were triple-class refractory, 89.5% were CD38-refractory, 36.8% had prior anti-BCMA/GPRC5D therapy, and 81.6% were refractory to their last line of therapy.

No DLTs occurred. ≥ Grade (G) 3 treatment-emergent adverse events (TEAEs) occurred in 63.2% of pts. CRS occurred in 44.7% of pts (G1: 36.8%; G2: 7.9%; ≥G3: 0%), and no pts had ICANS. CRS was predictable with most events (82.4%) occurring after the first dose. Median time to onset was 17.8 hours after the priming dose, and median time to resolution was 12.0 hours. Infection occurred in 39.5% pts (G3 13.2%; no G4/5). Non-rash skin disorder occurred in 57.9% pts (G1: 39.5%; G2: 18.4%; ≥ G3: 0%), taste-related disorder in 34.2% pts (G1: 28.9%; G2: 5.3%) and nail disorder in 31.6% pts (all G1). No treatment discontinuations occurred due to toxicity.

In response-evaluable pts treated at DL8-12 (n=16), ORR was 81.3% (≥VGPR 75%; ≥CR 37.5%). Among 3 pts with prior BCMA- or GPRC5D-targeted therapy, 2 (66.7%) achieved VGPR. In pts treated at DL10-12 (n=7), ORR was 85.7% (≥VGPR 71.4%; ≥CR 28.6%). MRD negative (10?5) was achieved in 100% (9/9) of evaluable pts. Median time to response was 4.7 weeks. Median free sBCMA reduction on C2D1 was 93.2% at DL8-12. Early T-cell proliferation and activation correlated with clinical response.

Emerging clinical data, along with the estimated half-life of ~10 days, support extended dosing schedule. Based on available preliminary data, the anti-drug antibody incidence was 9.7% (3/31) with no incidence at doses over DL5.

Conclusions: This early data on SIM0500 shows highly promising efficacy in heavily pretreated and difficult-to-treat patients with ORR >80% at therapeutic doses. The safety profile is favorable, with predictable and low-grade CRS, low infection rates, and low incidence and severity of GPRC5D-associated AEs. Emerging pharmacokinetics and efficacy data support extended dosing frequency. These findings support further evaluation of SIM0500 in MM, including in outpatient treatment settings.