Novel CAR T-Cell Therapy Achieves 100% MRD Negativity in Patients With Newly-Diagnosed Myeloma

BCMA/CD19 dual-targeting FasTCAR-T cells showed a high objective response rate in a study of patients with newly diagnosed high-risk multiple myeloma.

GC012F, a novel BCMA/CD19 dual-targeting therapy from the FasTCAR-T Cells program, achieved an overall response rate (ORR) of 100%, with all treated patients evaluable for minimal residual disease (MRD) showing MRD negativity to 12 months in patients with newly diagnosed high-risk multiple myeloma.1

Findings from the open-label phase 1 study of 16 transplant-eligible patients demonstrated that all 13 patients with an MRD assessment with Euroflow at month 1 were MRD-negative, as were all 8 patients followed to month 6 and all 3 followed to month 12, reported Juan Du, MD, at the 2022 ASH Annual Meeting in New Orleans. Fourteen of the 16 (88%) patients had a stringent complete response at a median follow-up of 8 months.1 The median duration of response was not reached at data cut-off (October 14, 2022).

In the ongoing study, 16 transplant-eligible patients with newly diagnosed multiple myeloma had received GC012F infusion. All patients had multiple high-risk features. After receiving a conditioning lymphodepletion regimen of cyclophosphamide and fludarabine, patients were treated with GC012F as a single infusion at 1 of 3 dose levels: 1x105 cells/kg, 2x105 cells/kg, and 3x105 cells/kg. All patients showed robust CAR T-cell expansion with long persistence at all dose levels, and safety data demonstrated that only 4 patients (25%) experienced grade 1 or 2 cytokine release syndrome (CRS), all of which resolved within 4 days. There were no cases of grade 4 or 5 CRS.

“GC012F BCMA/CD19 dual-targeting CAR T-cell therapy shows very encouraging antitumor activity in transplant-eligible, high-risk, newly diagnosed multiple myeloma patients,” said Du, from Shanghai Changzheng Hospital, The Second Military Medical University, China.

GC012F is an autologous dual CAR T-cell therapy that targets BCMA and CD19. Manufacturing time for CAR T cells developed on the proprietary FasTCAR-T is 22 to 36 hours compared with the standard of 1 to 6 weeks, as it combines activation and transduction steps and eliminates the need for ex vivo expansion, Du said. In addition to being faster, T-cell quality is enhanced in this first-line setting.

Eligible patients had one or more high-risk features. High-risk features included Revised International Staging System stage II or III disease in 94% of patients, extramedullary disease in 69%, 47% with high-risk cytogenetics, 94% with high-risk features per SMART3.0, and 19% with a lactate dehydrogenase (LDH) level above the upper limit of normal. The type of myeloma was IgG in 7 patients (44%), IgA in 4 (25%), IgD in 2 (12%), and light chain in 3 (19%).

Fifteen (94%) patients received 2 cycles of induction therapy with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd), and one patient received 1 cycle of bortezomib, epirubicin, and dexamethasone and 1 cycle of VRd prior to the CAR T-cell infusion.

All 16 patients achieved a very good partial response or better. Patients continue to be followed for deepening and durable response. The median Tmax of CAR T cells occurred on day 10 (range, 9-14). The median peak copy number was 63,086 copies/µg genomic DNA (range, 20,097-331,159).

The median time to onset of CRS in the 4 patients with grade 1 or 2 CRS was 6 days (range, 6-7), and the duration was a median of 2 days (range, 1-4). No cases of immune effector cell-associated neurotoxicity syndrome or neurotoxicity were observed. The most common hematologic 3 or greater treatment-emergent grade adverse effects (TEAEs) were lymphopenia (81%), leukopenia (50%), neutropenia (44%), and anemia (6%). Nonhematologic TEAEs of any grade were an increase in LDH in 7 (44%) patients and hypoalbuminemia in 6 (38%).

On November 19, 2021, the FDA granted an orphan drug designation to GC012F for the treatment of patients with multiple myeloma.2

References

1. Du J, Fu W, Qiang W, et al. Phase I open-label single-arm study of BCMA/CD19 dual-targeting FasTCAR-T cells (GC012F) as first-line therapy for transplant-eligible newly diagnosed high-risk multiple myeloma. Blood. 2022;140(suppl 1):889-890. doi:10.1182/blood-2022-162295

2. Gracell Biotechnologies granted FDA orphan drug designation for FasTCAR-enabled BCMA/CD19 dual-targeting CAR-T cell therapy candidate GC012F for the treatment of multiple myeloma. News release. Gracell. November 19, 2021. Accessed December 13, 2022. https://bit.ly/3FMuiBx