FDA Grants FTD to GPRC5D Bispecific LBL-034 for R/R Multiple Myeloma

The FDA has granted fast track designation (FTD) to LBL-034, an investigational GPRC5D/CD3 bispecific T-cell engager (BiTE), for patients with relapsed/refractory multiple myeloma (R/R MM).

The FTD follows promising data from an ongoing phase 1/2 clinical trial (NCT06049290) conducted in China. Key findings, which were featured as an oral presentation at the 2025 American Society of Hematology Annual Meeting, suggest that LBL-034 offers favorable tolerability and robust efficacy. The FTD enables faster communication on the further development of trials for this agent.

Mechanism of Action: The 2:1 Structure

LBL-034 is engineered using the proprietary LeadsBody platform. Unlike traditional bispecific antibodies, LBL-034 utilizes a unique 2:1 molecular format with 2 binding sites for GPRC5D on tumor cells and 1 binding site for CD3 on T cells. This asymmetric design facilitates high-avidity binding to myeloma cells while maintaining controlled activation of T cells to maximize antitumor efficacy while mitigating common immunotherapy complications, such as cytokine release syndrome (CRS) and T-cell exhaustion. By selectively targeting cells with high GPRC5D expression, LBL-034 aims to provide a more favorable safety profile than first-generation BiTEs.

The phase 1 dose escalation trial enrolled patients with at least 3 prior lines of therapy including a proteasome inhibitor and immunomodulatory drug. Treatment was given intravenously on days 1 and 15 of each 4-week cycle, with escalating dose levels of 10, 30, 80, 200, 400, 800, and 1200 μg/kg. A step-up dosing strategy of 10 to 80 μg/kg was used starting from the 80 μg/kg dose.

Clinical Efficacy

Preliminary results from the monotherapy dose-escalation phase included an objective response rate (ORR) of 70.9% among 55 evaluable patients, with dose dependent responses in those receiving 800 μg/kg or higher. Minimal residual disease negativity at the 10-5 threshold was achieved in 16 of 19 patients (84.2%) who had a complete response or better.

Outcomes were favorable in patients in difficult-to-treat subgroups, including an ORR of 75.0% in those with extramedullary disease, 78.1% in those who were penta-drug exposed, and 85.8% in those who had prior B-cell maturation antigen–targeted therapy.

Across the 400 to 1200 μg/kg dose levels (n = 40), the 12-month progression-free survival (PFS) rate was 61.2% at a median follow-up of 9.6 months. In the 400 μg/kg group, (n = 11), the 12-month PFS rate was 56.8% at a longer median follow-up of 13.1 months.

Safety and Tolerability

There was no dose-limiting toxicity or maximum tolerated dose reached with dose escalation up to 1200 μg/kg. CRS occurred in 73.2% of patients, but most CRS events reported were low-grade and manageable within the first days of cycle 1, with only 1 patient reporting a grade 3 CRS.

Grade 3 treatment-emergent adverse events (TEAEs) were reported in 83.9%, including lymphopenia, neutropenia, leukopenia, thrombocytopenia, and anemia. GPRC5D-associated TEAEs including dysgeusia, nail disorder, skin disorder, and decreased appetite were reported but were all low-grade and manageable.

Significance of Fast Track Designation

This milestone follows the previous orphan drug designation granted in 2024.⁴ The FTD is reserved for drugs that treat serious conditions and fill an unmet medical need and provides the sponsor with increased access to FDA guidance regarding clinical trial design and data requirements and eligibility for priority review.

LBL-034’s structure and conditional activation targeting GPRC5D offers an approach to bispecific design that may balance efficacy and tolerability and provide another option for heavily pretreated patients with less favorable outcomes.

REFERENCES

1. Leads Biolabs’ GPRC5D/CD3 bispecific T-Cell engager LBL-034 earns FDA fast track designation—accelerating launch of potential best-in-class therapy for relapsed/refractory multiple myeloma. News release. Leads Biolabs. January 28, 2026. Accessed January 29, 2026. https://tinyurl.com/yjcd8j4c

2. Median PFS trending beyond one year: Leads Biolabs’ LBL-034 showcases breakthrough clinical data in oral presentation at the 2025 ASH Annual Meeting. News release. Leads Biolabs. December 7, 2025. Accessed January 29, 2026. https://tinyurl.com/ydt9mpzw

3. A first-in-human, phase I/II, open-label, multicenter, dose escalation and expansion study of LBL-034, a conditionally activated bispecific antibody targeting GPRC5D and CD3 with a 2:1 format, in patients with relapsed/refractory multiple myeloma. Blood. 2025;146(suppl 1):91. doi:10.1182/blood-2025-91

4. Leads Biolabs receives orphan drug designation from the US FDA for LBL-034, a uniquely designed, highly differentiated anti-GPRC5D/CD3 bispecific antibody, for the treatment of multiple myeloma. News release. Leads Biolabs. November 6, 2024. Accessed January 29, 2026. https://tinyurl.com/2fjezyah