Background GC012F/AZD0120 is an autologous CAR-T therapy that targets both B cell maturation antigen (BCMA) and CD19. It is developed using the novel FasTCAR-T platform, which allows for next-day manufacturing. GC012F/AZD0120 has demonstrated deep and durable responses with a manageable safety profile in relapsed/refractory multiple myeloma (RRMM) patients (pts). We conducted two phase 1, open-label, investigator-initiated trials (NCT04935580, NCT05840107) to evaluate safety and efficacy of GC012F/AZD0120 in newly diagnosed multiple myeloma (NDMM) pts, including transplant eligible high risk (TE HR) NDMM and transplant ineligible (TI) NDMM. Here, we report the combined data of these two studies to provide long term follow up data of GC012F/AZD0120 in NDMM pts.

Methods

Eligible NDMM pts received a single infusion of GC012F/AZD0120 following two cycles lenalidomide, bortezomib and dexamethasone (RVd) induction therapy. Leukapheresis was performed before induction therapy, or after 1 or 2 cycles of induction therapy. GC012F/AZD0120 was administered at 4 dose levels: 1x105/kg (n=1), 1.5x105/kg (n=3), 2x105/kg (n=4), or 3x105/kg (n=22) after a standard 3-day lymphodepletion regimen of fludarabine and cyclophosphamide. Lenalidomide maintenance was permitted to be administered post infusion per investigator's discretion.

Results As of June 3, 2025, a total of 30 patients were infused and evaluable. The median age was 64 years (range, 43-78), with 27% aged over 70 years. 19 pts (63%) were male. 25 pts (83%) had R-ISS stage II/III and 14 of 29 pts (48%) had high risk cytogenetics (dep (17p), amp (1q21), t (4;14), t (14;16)). 17 pts (57%) had plasmacytomas, and 3 of them had soft tissue plasmacytomas. 29 pts (97%) received 2 cycles of RVd induction therapy prior to CAR-T infusion. The overall response rate (ORR) was 100%, and the stringent complete response (sCR) rate was 97%. The median time to first response was 28 days and the median time to best response was 68 days. All treated pts (100%) across all dose levels achieved minimal residual disease (MRD) negativity, as assessed by Euroflow (sensitivity of 10-6). Among MRD evaluable pts, MRD negativity reached 100%, 93% and 92% at Month 1, Month 6 and Month 12, respectively. 81.5% (22/27) pts' MRD negativity sustained more than 12 months. With a median follow-up of 30 months (range, 13-47), the median progression-free survival (PFS) and overall response (OS) have not been reached. The 30-month PFS rate was 88% (95% CI 67–96) and 30-month OS rate was 92% (95% CI 71–98). For 3 soft tissue plasmacytomas pts, the median PFS was 17.9 months and the median OS was 20.8 months, significantly shorter than bone related plasmacytomas and non-plasmacytomas pts. No difference was observed between pts with high risk and non-high-risk cytogenetics. GC012F/AZD0120 was well tolerated. Cytokine release syndrome (CRS) occurred in 10 pts (33%), all grade 1–2 (grade 1, n=9; grade 2, n=1); no grade ≥3 CRS was observed. The median time to onset was 8 (range, 6-18), with a median duration of 2 days (range, 1-8). 3 pts were treated with one dose of tocilizumab and 1 pt was treated with one dose of tocilizumab and corticosteroids. No patient developed ICANS of any grade. Robust CAR T-cell expansion was observed in all pts, with a median peak expansion (Cmax) of 62,644 copies /μg DNA and a median Tmax of 10 days. The median Tlast was 29 days. sBCMA level declined sharply post infusion, reaching to nadir with a median time of 2 months. 23 pts (77%) received lenalidomide as maintenance treatment, with a median initiation time of 6 months post infusion.

Conclusion Consistent with findings from the previous relapsed/ refractory MM cohort treated with GC012F/AZD0120, data from these two studies demonstrates that GC012F/AZD0120 induced deep and durable responses in NDMM pts, with a highly favorable safety profile. All patients responded (100% ORR) and all four dose groups achieved MRD negativity. These promising results highlight the potential of GC012F/AZD0120 CAR-T therapy for treating NDMM patients with HR features and transplant ineligible NDMM pts. Further research with a larger patient population and extended follow-up is needed to validate these findings and address this critically unmet medical need.

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2025
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