BCMA/CD19–Targeting CAR T-Cell Therapy Safely Produces Favorable Outcomes in Newly Diagnosed Multiple Myeloma

BCMA/CD19–Targeting CAR T-Cell Therapy Safely Produces Favorable Outcomes in Newly Diagnosed Multiple Myeloma

Targeting both BCMA and CD19 with the CAR T-cell therapy GC012F demonstrated high response rates, favorable safety, and early minimal residual disease (MRD) negativity for the first-line of treatment of transplant-eligible patients with high-risk, newly diagnosed multiple myeloma, according to preliminary findings from a phase 1 cohort study (NCT04935580) published in JAMA Oncology.¹

Results from the preliminary analysis showed that patients in the efficacy-evaluable population (n = 19) achieved an overall response rate (ORR) of 100% (95% CI, 82%-100%) with GC012F across dose levels; all patients achieved stringent complete response (sCR) as their best response. The median duration of response (DOR) was not reached (NR; 95% CI, NR-NR).

Moreover, evaluable patients were MRD negative at 1 month (n = 16), 6 months (n = 15), or 12 months (n = 12) after infusion. The median time to the first sCR was 84 days (range, 26-267); for the first MRD negativity, the median time to first sCR was 28 days (range, 23-135).

Additional subgroup analyses showed that response rates were similar in patients regardless of sex, age, ISS stage, high-risk cytogenetics, high tumor burden, or the presence of plasmacytomas; ORRs across subgroups were also generally comparable with those in the overall cohort. However, 1 patient achieved sCR with MRD negativity during the first assessment but progressed 3 months after infusion. The median progression-free survival (PFS) and overall survival (OS) were NR at the time of analysis.

“In the present study, GC012F resulted in early MRD negativity at 1 month using a more stringent threshold of 10−6. This was sustained at 6 and 12 months, which is favorable in comparison with previous studies,” lead study author Wanting Qiang, MSc, and coauthors, wrote in the paper. “These results suggest that the BCMA/CD19 dual-targeting CAR T-cell therapy GC012F is a safe treatment associated with positive health and survival outcomes for patients with high-risk, newly diagnosed multiple myeloma eligible for transplant following initial induction therapy.”

Qiang serves in the Department of Hematology at the Myeloma & Lymphoma Center as part of Shanghai Changzheng Hospital in China.

Dual-Targeted Approaches May Address Unmet Needs in the Front Line

Patients with high-risk, newly diagnosed multiple myeloma often experience poor outcomes with standard-of-care treatments, indicating the need for more effective regimens in the frontline setting.

“BCMA/CD19 dual-targeting CAR T-cell therapy is a novel approach demonstrating potential efficacy in the treatment of patients with relapsed and refractory multiple myeloma. However, relapses remain frequent, particularly in patients with high-risk disease,” investigators noted. “Hence, the simultaneous targeting of different surface antigens of BCMA and CD19, with CD19 cells having a strong myeloma-propagating capability, is an effective strategy to prevent relapse of multiple myeloma.”

GC012F is an autologous anti-BCMA/CD19 bispecific CAR T-cell therapy developed using the FasTCAR platform that enabled next-day manufacturing. In a prior phase 1 study (NCT04236011; NCT04182581), GC012F showed safety signals, generated durable responses, and produced a high MRD negativity rate in the relapsed/refractory setting.2 However, its use in the front line for transplant-eligible patients with high-risk, newly diagnosed multiple myeloma has not been thoroughly explored.¹

Study Design and Methodology

The single-arm, open-label, phase 1 cohort study was designed to evaluate the safety, pharmacokinetics, and patient health and survival outcomes associated with GC012F in patients with high-risk, newly diagnosed multiple myeloma after induction therapy. All patients were treated at a single center, Shanghai Changzheng Hospital, and those in the efficacy evaluation underwent follow-up for at least 3 months. The data cutoff for this interim analysis was June 1, 2023.

Eligible patients displayed at least 1 high-risk feature, including Revised International Staging System stage (R-ISS) II or III disease at the time of diagnosis; serum lactate dehydrogenase (LDH) levels above the normal institutional limit; high-risk chromosomal abnormalities detected by fluorescence in situ hybridization; plasmacytomas; immunoglobulin D or E subtype; or high-risk disease according to the Mayo Stratification of Myeloma and Risk-Adapted Therapy 3.0 criteria.

Treatment consisted of 2 cycles of induction therapy, followed by GC012F infusion at 1 of 3 dose levels: 1 × 10⁵ cells/kg (dose level 1), 2 × 10⁵ cells/kg (dose level 2), or 3 × 10⁵ cells/kg (dose level 3). Notably, patients who achieved MRD negativity with a complete response (CR) were allowed to maintain treatment with lenalidomide (Revlimid) from month 6 based on investigators’ discretion.

The study’s primary end points were adverse effects (AEs); ORR; CR and sCR rates; MRD negativity rate; DOR; and PFS. OS, time to first response, time to best response, pharmacokinetics, and biomarkers served as key secondary end points.

A total of 26 patients were enrolled onto the study between June 28, 2021, and June 1, 2023.

Of these, 22 patients underwent infusion and were included in the safety analysis, and 19 patients were deemed efficacy evaluable at a median follow-up of 16 months (range, 3.6-23.6). All patients exhibited 2 or more high-risk features and received 2 cycles of induction therapy. Seventeen patients received GC012F at dose level 3, 4 patients were treated at dose level 2, and 1 patient received dose level 1.

The median age of patients in the efficacy population was 59 years (range, 43-69). Most patients were male (63%), had IgG antibodies (42%), displayed any plasmacytomas in multiple myeloma (63%), and had an ECOG performance status of 1 (53%). All patients displayed Durie/Salmon stage III disease; 58%, 74%, and 74% displayed ISS stage II, R-ISS stage II, and R2-ISS stage III disease, respectively. High-risk cytogenetics were observed in 47% of patients, and 26% of patients had high tumor burden. The median time since diagnosis was 3.7 months (range, 2.0-5.4). Prior systemic therapy regimens included 2 cycles of bortezomib (Velcade), lenalidomide, and dexamethasone (VRd; 95%) or bortezomib, doxorubicin, and dexamethasone plus 1 cycle of VRd (5%).

“Only 1 patient, who met all 5 high-risk criteria, progressed after a 3-month follow-up, with rib mass but no measurable disease in blood and urine,” investigators reported. “We postulate that plasmacytoma signals from the tumor microenvironment, tumor antigen escape mechanisms, and systemic inflammatory consequences of infusion might have influenced the efficacy of CAR T-cell therapy.”

Pharmacokinetics and Biomarker Assessment

GC012F expansion was observed in the peripheral blood of 22 patients. The median peak copy number (Cmax) was 60,652 copies/μg of genomic DNA (gDNA; range, 8754-331,159), with a median time to Cmax of 10 days (range, 9-14 days). The median persistence was 29 days (range, 26-196 days). The median area under the curve (AUC0-28) was 289,685 (range, 80,181-3,985,420), with no significant difference across dose levels (P = .77).

Although Cmax and AUC0-28 were not significantly associated with cytokine release syndrome (CRS), Cmax was higher among patients with treated CRS vs untreated CRS (P = .01) and those without CRS (P = .04). GC012F expansion was not significantly associated with DOR, PFS, or OS.

Safety Analysis and Study Limitations

“GC012F also showed a favorable safety profile without dose-limiting toxic effects,” investigators stated.

Within the safety population, the most frequently observed treatment-emergent AEs (TEAEs) were hematologic toxicities, including leukopenia (any-grade, 86%; grade 1/2, 41%), neutropenia (77%; 36%), lymphopenia (77%; 14%), anemia (36%; 32%), and thrombocytopenia (27%; 27%). Nonhematologic TEAEs were primarily grade 1/2, the most common of which were increased LDH levels (any-grade, 41%; grade 1/2, 41%), hypocalcemia (41%; 36%), and hypoalbuminemia (41%; 41%). Grade 3 or higher AEs included lymphopenia (64%), leukopenia (45%), neutropenia (41%), hypocalcemia (5%), and aspartate aminotransferase increase (5%).

“Cytopenia was the most common grade 3 or higher AE exhibiting a rapid recovery, faster than in the cohort of patients with relapsed/refractory multiple myeloma,” investigators noted.

Any-grade CRS was experienced by 27% of patients; all CRS events were grade 1/2, and no other neurotoxicities were observed. The median time to CRS onset was 7 days (range, 6-9) with a median duration of 1 day (range, 1-4).

The study authors added that, “The infrequent occurrence of CRS can be attributed to the reduced tumor burden following induction therapy and the lower levels of key cytokines, in contrast to that observed in published trials for relapsed/refractory multiple myeloma.”

All patients developed B-cell aplasia, and no patients had treatment-related tumor lysis syndrome or replication-competent retrovirus.

“Owing to the small sample size, further studies with larger cohorts and longer follow-up durations are needed,” they concluded.

References

1. Qiang W, Lu J, Jia Y, et al. B-cell maturation antigen/CD19 dual-targeting immunotherapy in newly diagnosed multiple myeloma. JAMA Oncol. Published online July 25, 2024. doi:10.1001/jamaoncol.2024.2172
2. Du J, Fu W, Jiang H, et al. Updated results of a phase I, open-label study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM). Hemasphere. 2023;7(suppl):e84060bf. doi:10.1097/01.HS9.0000970380.84060.bf