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GC012F/AZD0120 produced responses in high-risk, transplant-eligible multiple myeloma, as well as transplant-ineligible, newly diagnosed disease.
The BCMA- and CD19-targeted CAR T-cell therapy GC012F/AZD0120 yielded a 100% overall response rate (ORR) and displayed tolerable safety in patients with newly diagnosed multiple myeloma, including those with high-risk, transplant-eligible disease and patients ineligible for transplant, according to data from a pair of phase 1 trials (NCT04935580; NCT05840107) presented at the 2025 ASH Annual Meeting and Exposition.1
Findings demonstrated that at a median follow-up since diagnosis of 36.5 months (range, 19.6-53.9) for all evaluable patients (n = 30), 97% achieved a stringent complete response (sCR), and 3% had a very good partial response (VGPR). In the transplant-eligible, high-risk cohort (n = 22), the sCR and VGPR rates were 95% and 5%, respectively. In the transplant-ineligible group (n = 8), all patients achieved a sCR. In the overall population, the median time to first response was 28 days, and the median time to best response was 68 days.
Regarding safety, grade 1 cytokine release syndrome (CRS) occurred in 30% of patients. Three percent experienced grade 2 CRS, and no grade 3 or higher CRS was reported. The median onset and duration of CRS was 8 days (range, 6-18) and 2 days (range, 1-8), respectively. Four patients received tocilizumab (Actemra) for CRS. Notably, no instances of immune effector cell–associated neurotoxicity syndrome, immune effector cell–associated hemophagocytic syndrome, immune effector cell–associated encephalopathy, delayed neurotoxicities, or secondary primary malignancies were reported.
“In the largest autologous stem cell transplant–naive, CAR T-cell therapy–treated newly diagnosed multiple myeloma cohort to date, GC012F/AZD0120 demonstrated a favorable efficacy profile,” lead study author Juan Du, MD, PhD, said in a presentation of the data. “With the longest follow-up of CAR T-cell therapy in newly diagnosed multiple myeloma, GC012F/AZD0120 demonstrated a well-tolerated safety profile and [could] broaden therapeutic options for [patients with] newly diagnosed multiple myeloma.”
Du is director of the Department of Hematology at Shanghai Changzheng Hospital of the Naval Medical University in China.
The autologous CAR T-cell therapy GC012F/AZD0120 is manufactured using the next-generation FAST CAR platform, allowing the therapy to be manufactured in less than 3 days and enhancing T-cell fitness.
The first phase 1 study (NCT04935580) included patients 18 to 70 years of age with newly diagnosed, transplant-eligible multiple myeloma that was classified as high risk if they had Revised International Staging System (R-ISS) stage II or III disease; a lactate dehydrogenase (LDH) level above the upper limit of normal; had extramedullary disease; had IgD or IgE subtypes; or met 1 or more high-risk definition per mSMART3.0 criteria.2 Patients were also classified as high risk if they harbored at least 1 of the following high-risk cytogenetic factors: deletion 17p, t(4:14), or t(14:16); had 1q21 gain with at least 4 copies.
The other phase 1 study (NCT05840107) included patients at least 18 years of age with newly diagnosed multiple myeloma who were ineligible for transplant.3
In both trials, patients needed to have an ECOG performance status no higher than 3 and measurable disease.1
Enrolled patients underwent leukapheresis and were allowed to receive 2 cycles of induction therapy with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd). On days –5 to –3 ahead of CAR T-cell therapy infusion, patients received lymphodepleting chemotherapy in the form of fludarabine at 30 mg/m2 per day and cyclophosphamide at 300 mg/m2 per day. GC012F/AZD0120 was given on day 0 at dose levels of less than 2 x 105 cells/kg (n = 4), 2 x 105 cells/kg (n = 4), or 3 x 105 cells/kg (n = 22). Maintenance lenalidomide was permitted at investigator's discretion following CAR T-cell therapy infusion.
Safety served as the primary end point in both trials. Secondary end points included ORR per 2016 International Myeloma Working Group criteria, CR rate, minimal residual disease (MRD)–negativity rate, duration of response, overall survival (OS), and progression-free survival (PFS).
The median age of patients from both trials (n = 30) was 64 years (range, 43-78), and 63% of patients were male. Ninety-seven percent of patients received 2 cycles of RVd induction, and the ORR was 93.3% following induction. Apheresis occurred prior to induction therapy in 13% of patients, after 1 cycle of induction therapy in 53% of patients, and after 2 cycles of induction therapy in 33% of patients.
R-ISS stage II or III disease was reported in 83% of patients, and 48% had high-risk cytogenetics. Any plasmacytomas were observed in 57% of patients at baseline, including 10% with soft tissue–related plasmacytomas. Seventy-three percent of patients had an ECOG performance status of 0 or 1. The median time from diagnosis to infusion of GC012F/AZD0120 was 3 months (range, 2-5).
Findings also showed that all 30 patients experienced MRD negativity at a sensitivity of 10–6 during at least 1 post-treatment measurement. All patients were MRD negative prior to the start of lenalidomide maintenance therapy, and 83% sustained MRD negativity for at least 12 months after infusion. All MRD-evaluable patients (n = 27) achieved MRD negativity 1 month after CAR T-cell therapy infusion; the MRD-negativity rates in this population were 96% at month 6 and 93% at month 12.
The 12- and 36-month PFS rates in the overall population were 96.7% (95% CI, 78.7%-99.5%) and 89.2% (95% CI, 70.1%-96.4%), respectively. All patients were alive 12 months following CAR T-cell therapy infusion, and the 36-month OS rate was 89.2% (95% CI, 70.2%-96.4%).
Lenalidomide maintenance therapy was administered to 77% of patients at a median time to initiation of 6 months following GC012F/AZD0120. Two patients treated with lenalidomide post–CAR T-cell therapy experienced disease progression and subsequently died. In the 7 patients who did not receive lenalidomide maintenance, 5 remained disease-free as of the data cutoff. One patient experienced progressive disease and later died, and the other patient died without documented disease progression.
No patients who achieved MRD negativity for at least 12 months (n = 25) experienced disease progression or died. In patients without sustained MRD negativity (n = 5), the median PFS and OS were 21.7 months and 23.5 months, respectively.
The most common treatment-emergent adverse effects in the overall population included neutropenia (any-grade, 80%; grade ≥3, 50%), leukopenia (80%; 43%), lymphopenia (63%; 53%), increased LDH levels (40%; 0%), thrombocytopenia (37%; 0%), hypoalbuminemia (33%; 0%), anemia (33%; 0%), infection (33%; 20%), CRS (33%; 0%), and hypocalcemia (23%; 0%).
Disclosures: Du did not report any financial conflicts of interest.
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