Background: BCMA- or GPRC5D-targeting agents are becoming the mainstay for treating R/R MM. However, resistance eventually develops, leaving patients with limited subsequent options. OL-101 is a CAR-T designed with VHH binders that target both BCMA and GPRC5D to overcome antigen escape through mutation or downregulation of either target, providing a new treatment option, especially for BCMA- and/or GPRC5D-exposed patients. We report preliminary data from an ongoing phase I, first-in-human, dose-escalation and dose-expansion study (NCT06644118).

Methods: Patients with R/R MM who had received ≥3 prior lines of therapies underwent standard lymphodepletion (fludarabine/cyclophosphamide) followed by a single OL-101 infusion at 3 dose levels (DL1: 1.0×106, DL2: 2.0×106, DL3: 1.5×106 cells/kg). Dose levels were explored in a modified “3+3” design, after a dose-limiting toxicity (DLT) at DL2, an intermediate DL3 was evaluated. The primary objective was to evaluate the safety, including DLT. Secondary objectives included overall response rate (ORR), duration of response (DOR), progression-free survival (PFS), and cellular kinetics assessment of OL-101.

Results: As of Jul 30th, 2025, 10 patients were dosed (DL1: n=3, DL2: n=6, DL3: n=1) with a median follow-up of 3.3 months (range: 0.9-8.0). All patients had prior exposure to at least a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and anti-CD38 monoclonal antibody (mAb), with a median of 5 prior lines of therapy (range: 3-8). Five (50%) had high-risk cytogenetics and 4 (40%) had extramedullary plasmacytomas (EMD). Three (30%) patients had prior exposure to BCMA and/or GPRC5D targeted therapies, including 1 each with BCMA/GPRC5D dual CAR-T, BCMA CAR-T and GPRC5D T-cell engager.

Cytokine release syndrome (CRS) occurred in all patients (grade 1-2: 60%, grade ≥3: 40%, no grade 5), with median onset at Day 2 and duration of 6.5 days. At the 2.0×106 cells/kg dose level, 1 of 6 patients experienced a DLT, manifested as grade 4 CRS with onset on Day 3 post-infusion, which resolved by Day 17 following treatment with tocilizumab, steroids, plasma exchange and other supportive care. A CRS management algorithm was implemented to mitigate CRS severity and no further grade 4 CRS was observed. No immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. Other grade ≥3 toxicities included neutropenia (90%), thrombocytopenia (80%), and anemia (30%), with no grade ≥3 infections reported.

The ORR was 100% (70% ≥VGPR, 40% ≥CR), with deeper response at higher dose (DL1: 66.7% ≥VGPR, 33.3% ≥CR vs. DL2: 83.3% ≥VGPR, 50% ≥CR). Among 4 patients with EMD, 3 (75%) achieved ≥VGPR and 2 (50%) achieved ≥CR. Of the 3 patients previously treated with BCMA- and/or GPRC5D-targeted therapy, 1 (33.3%) achieved sCR and 2 (66.7%) achieved PR. Median time to response was 28 days post-infusion. Deeper responses were achieved over time with extended follow-up. All patients had ongoing responses at the data cut-off. MRD negativity (at 10-5sensitivity) was achieved by all 10 patients at D28 and maintained through the cut-off date. All patients had positive BCMA and GPRC5D expression at baseline and expression levels were not associated with responses. The peak cell expansion occurred between Day 10-21 post-infusion with a median of 1.29×105 copies/μg DNA (range: 1.05×105to 3.08×106 copies/μg DNA). CAR-T cells persisted for at least 12 weeks post-injection in patients with longer follow-up at the time of data cut-off.

Conclusion: OL-101, a novel bispecific BCMA/GPRC5D VHH CAR-T, demonstrates promising efficacy (100% ORR, 100% MRD negativity) and manageable safety (CRS manageable, no ICANS) in heavily pretreated, triple-class exposed R/R MM patients, with no new safety signals identified than those with previously reported BCMA or GPRC5D targeting CAR-T cells. Notably, responses were observed in patients relapsed after prior BCMA- and/or GPRC5D-targeted therapies and in EMD population. These early results support the potential of dual-targeting to overcome antigen escape. The study is currently ongoing to further characterize the safety and efficacy profile of OL-101 in patients previously exposed to BCMA- or GPRC5D-directed therapy.

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2025
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