Abstract
Introduction: Despite significant therapeutic advances, patients with triple-class-exposed and triple-class-refractory multiple myeloma continue to face poor clinical outcomes. TQB2934 is an innovative 2+1 BCMA × CD3 bispecific antibody featuring bivalent BCMA binding domains and a monovalent CD3 domain. This unique design enables simultaneous targeting of BCMA-expressing myeloma cells and CD3-expressing T cells, resulting in T cell activation and subsequent myeloma cell death. We present updated results from an ongoing phase I study (NCT05646758) evaluating TQB2934 monotherapy in patients with relapsed/refractory multiple myeloma (RRMM).
Methods: This study is an open-label, phase I trial comprising dose escalation and expansion phases. Eligible patients were aged 18-75 years with RRMM who had received ≥1 prior lines of therapy, including a proteasome inhibitor, immunomodulatory drug, and anti-CD38 antibody. Patients with prior BCMA-targeted therapies were excluded from the dose escalation cohort. Dose escalation followed a Bayesian Optimal Interval design. TQB2934 was administered intravenously with weekly (QW) dosing in cycles 1-3, biweekly (Q2W) in cycles 4-6, and monthly (Q4W) from cycle 7 onward for patients achieving partial response or better (28-day cycles). The regimen included two step-up doses administered one week before target doses of 3mg, 10mg, 20mg, and 40mg. Primary objectives included safety assessment, determination of maximum tolerated dose (MTD), and recommended phase 2 dose (RP2D) based on dose-limiting toxicities (DLTs). Secondary objectives encompassed evaluation of preliminary anti-myeloma activity, pharmacokinetics (PK), pharmacodynamics (PD), and immunogenicity.
Results: As of July 20, 2025, 60 RRMM patients have been treated with TQB2934. The median age was 67 years (range 39-75), with 56.7% female patients. IgG and IgA myeloma subtypes accounted for 53.3% and 21.7% of cases, respectively. According to the Revised International Staging System (R-ISS), 63.3% of patients had stage II/III disease, while 45% harbored high-risk cytogenetic abnormalities and 13.3% presented with extramedullary disease. Patients had received a median of 3 prior lines of therapy (range 1-6), with all patients being refractory to their last line of treatment.TQB2934 was tested across dose levels ranging from 0.09 to 40mg, with the MTD not yet reached. A single DLT event (grade 4 ICANS) occurred at the 3mg dose level without step-up dose. 40mg was determined as the RP2D, which includes two step-up doses of 1mg and 6mg. Treatment-emergent adverse events (TEAEs) were observed in 93.3% (56/60) of patients. The most frequent TEAEs (occurring in ≥30% of patients) included lymphopenia (63.3%), CRS (58.3%), neutropenia (56.7%), leukopenia (55%), anemia (55%), thrombocytopenia (51.7%), hypokalemia (46.7%), hypocalcemia (40%), diarrhea (40%), and fever (31.7%). Grade ≥3 TEAEs were reported in 75% (45/60) of patients, with the most common being lymphopenia (40%), neutropenia (33.3%), anemia (25%), pneumonia (25%), thrombocytopenia (21.7%), and leukopenia (20%). CRS events were predominantly grade 1-2, with only two grade 3 cases reported. CRS typically occurred following the first target dose and resolved within 3 days. One patient experienced fatal grade 4 ICANS. Among 52 efficacy-evaluable patients across all dose levels, 32 patients achieved partial response or better, the overall response rate (ORR) was 61.54%. No responses were observed at doses below 3mg. At doses ≥20mg, the ORR was 70%, with ≥very good partial response (VGPR) and ≥complete response (CR) rates of 52.5% and 22.5%, respectively. Specifically, at the 20mg dose level, these rates were 61.5%, 53.8%, and 30.8%, while at 40mg they were 74.1%, 51.9%, and 18.5%, respectively. Pharmacokinetic analysis demonstrated dose-proportional increases in plasma peak concentrations and AUC, with no evidence of drug accumulation. Notably, changes in serum soluble BCMA levels at cycle 2 day 1 showed significant correlation with clinical response.
Conclusions: TQB2934, a novel 2+1 BCMA bispecific antibody, has demonstrated a manageable safety profile and encouraging clinical activity at doses ≥20mg in heavily pretreated RRMM patients. These results position TQB2934 as a promising new therapeutic option for this challenging patient population.
