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