At the 2026 Annual Congress of the European Hematology Association (EHA) held in Stockholm, Sweden, new clinical data on OL-101, a dual-target BCMA/GPRC5D CAR-T cell therapy, were presented as an oral abstract, drawing significant attention from the global hematology community.
The presentation was featured among high-impact early-phase cellular therapy studies, highlighting the growing role of dual-antigen targeting strategies in overcoming relapse after prior CAR-T or bispecific therapies. Experts at the meeting noted that antigen escape remains one of the most critical barriers in multiple myeloma. treatment.
The study, conducted by a team from the First Affiliated Hospital, Zhejiang University School of Medicine, evaluated OL-101 in heavily pretreated patients with relapsed/refractory multiple myeloma (R/R MM), including those with prior exposure to BCMA- or GPRC5D-targeted therapies and patients with extramedullary disease (EMD), a population known for poor prognosis and limited treatment options.
OL-101 is an autologous CAR-T cell therapy designed with optimized tandem nanobody (VHH) constructs targeting both B-cell maturation antigen (BCMA) and G protein-coupled receptor class C group 5 member D (GPRC5D), aiming to overcome antigen escape and improve durability of response. The dual-target design is intended to reduce tumor immune evasion by simultaneously engaging two independent myeloma-associated antigens.
Study Design
This first-in-human Phase I study (NCT06644118) is an open-label, dose-escalation and dose-expansion trial. The primary objective was to evaluate safety and determine the recommended Phase II dose (RP2D), while secondary objectives focused on preliminary efficacy and CAR-T cell kinetics.
Eligible patients had received at least three prior lines of therapy, including a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 monoclonal antibody. Many patients were considered triple-class refractory, reflecting a highly resistant disease population with limited standard treatment options.
Following standard lymphodepletion with fludarabine and cyclophosphamide (FC), patients received OL-101 infusion. The use of FC conditioning was consistent across all dose levels to ensure uniform immune suppression prior to CAR-T expansion.
Three dose levels were evaluated:
- DL1: 1.0 × 10⁶ CAR+ T/kg
- DL2: 2.0 × 10⁶ CAR+ T/kg
- DL3: 1.5 × 10⁶ CAR+ T/kg
The study followed a modified 3+3 design. One dose-limiting toxicity (DLT) occurred in DL2, prompting evaluation of the intermediate DL3 dose, which is being considered as the recommended Phase II dose (RP2D). This adaptive adjustment reflects the effort to balance efficacy and safety in high-burden disease settings.
Endpoints included safety (DLT, AE, CRS, ICANS), efficacy (ORR, VGPR, sCR, DOR, PFS, OS), pharmacokinetics (PK), pharmacodynamics (PD), anti-drug antibodies (ADA), and replication-competent lentivirus (RCL), providing a comprehensive assessment of both clinical activity and biological behavior.
Patient Characteristics
As of May 26, 2026, 16 patients with R/R MM had been enrolled:
- Median age: 57 years
- Median prior therapies: 5 lines
- 43.8% had high-risk cytogenetics
- 43.8% had extramedullary disease (EMD)
- 43.8% had prior BCMA CAR-T therapy
- Some patients had previously received BCMA/GPRC5D dual CAR-T or GPRC5D-targeted bispecific T-cell engager (TCE)
This population represents a particularly challenging clinical cohort, as most had exhausted multiple advanced treatment modalities. A significant proportion had already relapsed after CAR-T therapy, highlighting the unmet need for novel dual-target strategies.
All patients were triple-class exposed and heavily pretreated, with a median of five prior lines of therapy, underscoring the refractory nature of the disease.
Efficacy Results (All Patients)
After a median follow-up of 8.6 months, OL-101 demonstrated profound anti-myeloma activity across all dose levels. Responses were observed early after infusion and continued to deepen over time in most patients.
- Overall response rate (ORR): 100%
- ≥VGPR rate: 93.8%
- Stringent complete response (sCR): 75%
- Minimal residual disease (MRD) negativity: 100%
The median time to first response was 28 days, indicating rapid disease control after CAR-T infusion. In several patients, responses continued to deepen beyond the initial assessment, suggesting ongoing immune-mediated tumor clearance.
Only three patients experienced disease progression, including one patient previously treated with a dual-target CAR-T therapy. These cases primarily involved patients with aggressive disease biology or extremely high baseline tumor burden.
One death occurred at day 138 post-infusion due to severe COVID-19 pneumonia, considered unrelated to treatment.
Efficacy in BCMA/GPRC5D-Exposed Patients
A particularly challenging subgroup included 9 patients previously treated with BCMA and/or GPRC5D-targeted therapies. This population is clinically important because prior antigen-targeted therapy often leads to partial antigen loss or immune resistance.
- 77.8% had ≥5 prior lines of therapy
- 55.6% had EMD
Results remained highly encouraging:
- ORR: 100%
- ≥VGPR: 88.9%
- sCR: 66.7%
Most patients maintained ongoing or deepening responses, with only one relapse observed. Importantly, prior exposure to CAR-T therapy did not appear to significantly diminish OL-101 activity, suggesting effective overcoming of antigen escape mechanisms.
Extramedullary Disease (EMD) Subgroup
Among 7 patients with EMD:
- 85.7% achieved ≥VGPR
- sCR rate: 71.4%
Tumor burden reduction was rapid and sustained, including in patients with large or multi-site extramedullary lesions. EMD is typically associated with poor CAR-T penetration and inferior outcomes, making these results particularly notable.
By week 12, nearly all measurable lesions showed dramatic reduction, and in several patients, imaging suggested near-complete metabolic remission.
These findings suggest that dual-antigen targeting may enhance CAR-T activity in sanctuary sites where single-target therapies often fail.
Safety Profile
OL-101 demonstrated a manageable and predictable safety profile consistent with CAR-T class effects.
- CRS occurred in 100% of patients, mostly Grade 1–2 (75%)
- Median onset: Day 2
- Median duration: 6.5 days
- Only one case of Grade 4 CRS (DL2), successfully managed with intensive intervention
- Only one case of Grade 1 ICANS (1-day duration)
Other adverse events:
- Hematologic toxicity consistent with CAR-T therapy
- Transient liver enzyme elevation without Hy’s law cases
- Infection rate: 37.5% (all Grade 1–2)
- GPRC5D-related effects (low incidence, all Grade 1): taste alteration, rash, nail changes
Importantly, after protocol optimization following the DL2 toxicity event, no further high-grade CRS was observed in DL3, suggesting improved risk control with dose refinement.
A single late death (COVID-19 pneumonia at day 138) was deemed unrelated to OL-101.
Pharmacokinetics
CAR-T cell expansion peaked between Day 7–14 post-infusion, consistent with expected in vivo expansion kinetics for autologous CAR-T products.
- Peak concentration (Cmax): ~1000 cells/μL (DL2 and DL3)
- Higher and more sustained expansion observed in DL2 and DL3 compared to DL1
- Similar PK profiles observed regardless of prior BCMA/GPRC5D exposure
These results suggest that prior antigen-directed therapy does not significantly impair CAR-T expansion capacity in this regimen.
Clinical Significance
OL-101, a dual-target BCMA×GPRC5D CAR-T therapy, demonstrates several important advances in the treatment of relapsed/refractory multiple myeloma.
The most notable finding is the ability to achieve deep and universal responses in a heavily pretreated population, including patients previously exposed to CAR-T and bispecific therapies. This suggests a potential strategy to overcome one of the key limitations in current myeloma treatment: antigen escape and relapse after single-target therapy.
In addition, the strong activity observed in extramedullary disease highlights its potential role in high-risk biological subtypes that are typically resistant to conventional CAR-T approaches.
Taken together, these early results support further clinical development of OL-101 and its progression into Phase II studies to confirm durability, survival benefit, and optimal dosing strategies in larger patient cohorts.
