GT919, a novel IKZF3/1 molecular glue degrader: Phase 1 safety and preliminary efficacy in relapsed or refractory multiple myeloma (R/R MM) Free

Introduction The pathogenesis of multiple myeloma (MM) is critically regulated by IKZF3 and IKZF1, transcription factors involved in plasma cell differentiation. CRBN, the substrate receptor of the CRL4 E3 ubiquitin ligase complex, facilitates the ubiquitination and subsequent degradation of IKZF3/1, and serves as the molecular basis for the therapeutic effects of IMiDs.

GT919 is a novel, oral, highly selective molecular glue degrader that harnesses the CRBN-dependent pathway to induce robust degradation of IKZF3 and IKZF1. Preclinical studies have demonstrated potent IKZF3/1 degradation at low nanomolar concentrations, leading to dual antitumor and immunomodulatory activity in lenalidomide- or pomalidomide-refractory MM cell lines and xenograft models.

Here, we present the result of the first-in-human study (CTR20231255) evaluating the safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary efficacy of GT919 in patients with relapsed/refractory MM (R/R MM).

Methods This is an open-label, multicenter Phase I study designed to evaluate the safety and tolerability of GT919 in R/R MM patients. The study consists of two parts: Part A is a dose escalation phase using a standard 3+3 design, followed by a dose expansion cohort in Part B. GT919 is administered on a 28-day cycle (21 days on, 7 days off) in combination with dexamethasone (40 mg weekly, or 20 mg for pts >75 years old). Treatment continues until disease progression, unacceptable toxicity, or withdrawal of consent. In Part A, eligible pts had R/R MM refractory to ≥1 proteasome inhibitors (PIs) and ≥1 IMiDs. In Part B, patients were refractory to PIs, IMiDs, and anti-CD38 monoclonal antibody therapy.

Results As of July 2025, 29 Chinese pts with R/R MM (median age: 69 years [range, 39-79]; median prior lines of treatment: 3 [range, 1-7]) were enrolled. In Part A, 3 monotherapy dose levels (0.5 mg [n=1], 1 mg [n=1], 2 mg [n=3]) and 4 GT919+dex dose levels (2 mg, 3 mg, 4 mg, and 5 mg [n=3 each]) were evaluated. No dose-limiting toxicities (DLTs) were observed at any monotherapy or GT919 + dex cohorts. Subsequently, 12 pts were enrolled in Part B (3 mg + dex [n=4]; 4 mg + dex [n=8]).

Among all pts, prior therapies included lenalidomide (86%), pomalidomide (61%), PIs (100%), and anti-CD38 therapy (68%), with 100% pts being resistant to PIs and IMiDs, 68% being triple-refractory. Additionally, 10 pts had undergone ASCT, 4 had received anti-BCMA CART therapy, and 7 presented with extramedullary disease (EMD).

Treatment-emergent adverse events (TEAEs) occurred in 100% of pts, with 93% experiencing treatment-related adverse events (TRAEs). Grade ≥3 TEAEs were observed in 50% of pts. Grade ≥3 TRAEs occurred in 46%, including neutropenia 21%, pneumonia 18%, URTI 11% and thrombocytopenia 7%. No cases of grade 3/4 febrile neutropenia or anemia were reported. Of interest, hematologic toxicity was transiently observed during the first two cycles and gradually recovered spontaneously as patients continued treatment, without the need for long-term G-CSF support. No TRAEs led to GT919 discontinuation, dose reduction or death were observed.

PD analysis demonstrated effective degradation of IKZF3 and T-cell activation at doses ≥2 mg. In the 4 mg subgroup, sustained administration of GT919 achieved both IKZF3 and IKZF1 degradation. PK of GT919 exposure increased dose-dependently, with a T_max of 1~2 hours and a moderate T_1/2 of around 20 hours. At doses ≥2 mg, plasma levels exceeded the predicted efficacious threshold based on preclinical models.

Consistent with PK/PD findings, GT919 + dex showed encouraging antimyeloma activity in 22 evaluable pts treated with GT919 ≥2 mg + dex. The ≥VGPR rate was 14% (3/22), overall response rate (ORR) was 36% (8/22), and clinical benefit rate (CBR) was 45% (10/22). Median progression-free survival (mPFS) and duration of response (DOR) were not reached with a median follow-up of 5.2 months [range, 1.1-20.6], the longest ongoing PFS exceeded 20 months. Among 10 evaluable triple-refractory pts that received GT919 at 4 mg dose level, the ORR was 50% and CBR was 60%.

Conclusions:As of data, GT919 in combination with dexamethasone demonstrated a manageable safety profile and encouraging preliminary efficacy in R/R MM pts. Based on the recommendations from the Safety Review Committee (SRC), the recommended Phase II dose (RP2D) for GT919 was established at 4 mg. Phase 2 studies of the drug combination is planned to begin.