Editor’s Note: At the 65th American Society of Hematology Annual Meeting in 2023 (ASH), Professor Du Juan and her team from Shanghai Changzheng Hospital presented preliminary findings from a Phase I study (abstract 1022) assessing the efficacy and safety of BCMA/CD19 dual-target FasTCAR-T cells (GC012F) in treating high-risk, newly diagnosed multiple myeloma (HR-NDMM) patients. The study was selected for oral presentation at the conference. In this article, “Tumor Insight” has compiled the abstract content and invited Professor Du Juan to provide commentary for readers’ reference.

Background:

High-risk (HR) newly-diagnosed multiple myeloma (NDMM) has poor outcomes with standard first-line therapies, even in transplant-eligible (TE) patients (pts). A CAR-T therapy with high efficacy and manageable safety profile would be a potential solution to this significant unmet need. GC012F is an autologous B cell maturation antigen (BCMA) and CD19 dual-targeting CAR-T cells therapy developed on the novel FasTCAR-T enabling next-day manufacturing platform [J Clin Oncol 41, 2023 (suppl; abstr 8005)]. The phase I single-arm study has been conducted in frontline setting for TE high-risk NDMM pts to characterize the safety and feasibility of GC012F CAR-T cell therapy (NCT04935580). The data was presented at ASH 2022 for initial 13 pts (Blood (2022) 140 (Supplement 1): 889–890.). Here we present updated data with longer follow up and 9 additional pts treated (total N=22) in this study.

Methods:

This is a single arm, open-label phase I investigator-initiated study (NCT04935580). TE NDMM pts, aged between 18-70, and with one or more of the following features were considered eligible for the study: R-ISS-II or-III; del17p, t (4;14), t (14;16), or 1q21amp ≥ 4 copies; extramedullary disease (EM); IgD or IgE subtype; LDH > the upper limit of normal; or any of the high-risk definition of mSMART3.0.

As of the data cutoff date, 22 evaluable pts (median age 59, range 43-69) are reported here. The median time from diagnosis to infusion was 100 days (range 63-152). All patients had one or more high-risk features including 91% R-ISS stage II or III, 55% with EM, 32% 1q21≥4 copies, and 9% IgD type. Of the 22 pts, 21 pts received 2 cycles induction therapy of bortezomib, lenalidomide and dexamethasone (VRd), and one patient received 1 cycle bortezomib, epirubicin, and dexamethasone (PAD) and 1 cycle VRd prior to the infusion. GC012F was administered as a single infusion at 3 doses levels (DL) of 1×105/kg (n=1), 2×105/kg (n=4), or 3×105/kg (n=17), after a standard 3-day lymphodepletion consisting of cyclophosphamide and fludarabine.

Results:

As of June 9th, 2023 data cutoff, 22 patients were enrolled and evaluable for safety and efficacy. Median follow-up was 13.6 months (range 2.1-23.9 months). Overall response rate (ORR) was 100% and stringent complete response (sCR) rate was 95.5%. All treated pts (100%) across all dose levels achieved minimal residual disease (MRD) negativity assessed by Euroflow (sensitivity of 10-6). All evaluable pts achieved MRD negativity at Month 1, and maintained MRD- at landmark analysis of Month 6 and Month 12. Median duration of response (DOR) and progression-free survival (PFS) were not reached. Only 6 pts (27%) experience low-grade cytokine release syndrome (CRS), including 23% grade 1 (n=5) and 4% grade 2 (n=1). No treatment-related grade ≥3 CRS, nor ICANS of any grade, and nor deaths occurred in the study. Robust CAR T-cell expansion was observed in all pts; the median peak expansion (Cmax) was 62,131 (range: 8,754-331,159) copies /μg DNA with a median Tmax of 10 days (range 9-14 d).

Conclusion:

Consistent with the previous RRMM cohort treated with GC012F, initial data from this phase I study demonstrated that BCMA-CD19 dual-targeting FasTCAR-T GC012F resulted in deep and durable response in transplant-eligible newly-diagnosed high-risk pts with a very favorable safety profile. All three dose groups achieved 100% MRD negativity and 100% ORR and sCR. The promising preliminary results achieved with GC012F demonstrate potential of CAR-T therapy in newly-diagnosed MM pts. Further research with larger patient population and longer follow-up shall bring the hope to this unmet medical need.

Expert Commentary:

Professor Du Juan: Patients with high-risk (HR) newly diagnosed multiple myeloma (NDMM) face a challenging prognosis under standard first-line treatment, with a median survival of around three years for R2-ISS IV patients. Therefore, there is a pressing need for more effective treatments to prolong progression-free survival (PFS) and overall survival (OS) in high-risk patients. Our center initiated a Phase I study evaluating “BCMA/CD19 dual-target FasTCAR-T cells (GC012F) for HR-NDMM patients” two years ago. The results, reported at the ASH annual meetings over two years, have shown an overall response rate (ORR) of 100%, a stringent complete response (sCR) as high as 95%, and a 100% rate of minimal residual disease (MRD) negativity, indicating deep and durable remission. The safety profile is excellent, with only 27% of patients experiencing low-grade CRS, of which 23% were grade 1 and 4% were grade 2, and no cases of grade 3 CRS or ICANS. In summary, BCMA/CD19 dual-target FasTCAR-T cells (GC012F) demonstrate high safety and efficacy in the treatment of HR-NDMM, and whether they will enter standard first-line treatment requires longer follow-up and larger clinical studies.

Department of Hematology, Shanghai Changzheng Hospital

Director, Center for Multiple Myeloma and Lymphoma Diseases, PLA General Hospital

Chief Physician, Professor, Doctoral Supervisor

Selected for Shanghai “Pujiang Talent” Plan in 2009

Recipient of the 8th Shanghai Youth Science and Technology Elite Award in 2016

People’s Good Doctor (Hematologic Oncology) Youth Model in 2021

People’s Good Doctor (Hematologic Oncology) Special Contribution Award in 2022

Honorary title of “Shanghai Good Doctor” in 2023

Member of the International Myeloma Working Group (IMWG) Committee

Member of the Asian Myeloma Network (AMN)

Committee Member, Multiple Myeloma Professional Committee, Chinese Physicians Association Hematology Branch

Committee Member, Deputy Director, Hematology Branch, Shanghai Medical Association