An Uniquely Designed Asymmetric Bispecific Antibody Against GPRC5D and CD3 (LBL-034) in Patients with Relapsed/Refractory Multiple Myeloma: A Phase I/II, First in Human, Open-Label, Multicenter, Dose Escalation/Expansion Study
Authors: Qin Ling , Zhong Yuping , Huang Dongping , Xie Haitang , Du Xin , Liao Aijun , Zhang Hongli , Cai Shengli (Charles) , Lu Jin 
Published: December 2024

Introduction:
LBL-034 is a humanized IgG1 subtype asymmetric bispecific antibody targeting the G protein-coupled receptor class C group 5 member D (GPRC5D) and a cluster of differentiation 3 (CD3). LBL-034 can promote the proliferation and activation of T cells by binding to GPRC5D-expressing tumor target cells and CD3-expressing T cells, thereby inducing the killing of tumor cells. We present preliminary safety and efficacy data for patients with multiple myeloma (MM) who received LBL-034 in a phase Ⅰ/Ⅱ, dose escalation and dose expansion study (NCT06049290). This study is currently in Phase I.
Methods: Relapsed/Refractory (R/R) MM patients who have previously received at least 3 lines of therapy, including one proteasome inhibitor (PI),one immunomodulatory drug (IMiD) and one anti-CD38 monoclonal antibody could be enrolled in this study. But, Patients who are unable to access anti-CD38 monoclonal antibody may be enrolled in phase I if the investigator evaluates that there is a potential benefit for them to participate in the study. In the dose-escalation stage, the drug will be given at a starting dose of 10 μg/kg, followed by 30 μg/kg, 80 μg/kg, 200 μg/kg, 400 μg/kg, 800 μg/kg, and 1,500 μg/kg sequentially via intravenous infusion. The initial dosing schedule for this study will be administered on Days 1 and 15 in each 4-week cycle. Response were investigator assessed per International Myeloma Working Group criteria and adverse events (AEs) by CTCAE v5.0, except for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), which were graded per ASTCT guidelines.
Results: As of July 16, 2024, 15 patients have been enrolled in phase I including 10 patients in dose escalation stage across dose 10 μg/kg to 400 μg/kg and 4 patients in dose expansion stage in dose 80 μg/kg and 200 μg/kg. 15 patients had a median age of 68 years (range 46-80) and a median of 5 prior lines of therapy (range 2-7.5). 13 patients (86.7%) were triple-class exposed and 9 patients (60%) were penta-drug exposed. 7 patients (46.7%) were refractory to last line of therapy. 6 patients (40%) had prior auto stem cell transplantation (ASCT) or BCMA-chimeric antigen receptor (CAR) T-cell immunotherapy. 8 patients (53.5%) had at least 1 extramedullary tumor disease (EMD). 15 patients experienced treatment emergent adverse events (TEAE), Common TEAEs (≥ 20%) included CRS (80%), lymphocyte count decreased and hypokalemia (53.3% each), platelet count decreased (46.7%), dysgeusia, pyrexia and white blood cell (WBC) count decreased (40% each), neutrocytopenia, dysphagia and ecdysis of hands and feet (33.3% each), anemia, diarrhea, vomiting and CRS-related aspartate amino transferase (AST) increased (26.7% each), throat irritation, D-dimer increased (CRS-related), hypocalcemia, hypertriglyceridemia, hyperuricemia (20% each). Most of the adverse events were grade 1 or 2 and manageable. 4 patients had treatment suspension due to TEAE. No patient had dose adjustment. No dose-limiting toxicities (DTLs) have observed and no Grade ≥3 CRS and no ICANS has happened.
13 patients completed at least once tumor assessment. 8 (61.5%) of 13 patients had M protein decrease after one cycle treatment and 3 of 8 patients achieved serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) negative. Clinical Benefit Rate (CBR) is 50% including 2 VGPR (200ug/kg), 2 PR (80 ug/kg and 400ug/kg, respectively), 2 MR (10ug/kg and 80ug/kg, respectively). And 3 patients maintained SD (2 at 80ug/kg, 1 at 400ug/kg) in which 2 patients had ≥1 EMD, disease control rate (DCR) is 69.2%. 5 of 8 evaluable penta-drug refractory patients responded to LBL-034, the CBR is 62.5%.
It has been proved that EMD is independent poor prognostic factors. In our study, 7 of 8 patients with EMD were tumor assessment available. 2 patients had response ≥MR, 1 patient at 400ug/kg achieved PR with M protein undetectable and 62.9% EMD shrinkage after one cycle's treatment, and 1 patient at 80ug/kg achieved MR with M protein undetectable and 33% EMD shrinkage after 4 cycles' treatment. 2 patients maintained SD. The CBR is 28.6%, and the DCR is 57.1%.
Conclusions: LBL-034 has demonstrated good safety profile and promising antitumor effects in patients with RR MM and the preliminary data support to develop monotherapy and combination therapy in this malignancy. Update data will be present on ASH meeting.