The 29th Annual Congress of the European Hematology Association (EHA) took place from June 13 to June 16, 2024, in Madrid, Spain. On the afternoon of June 15, local time, Professor Bing Chen From Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School，Nanjing University presented the latest data from the FUMANBA-2 study in an oral report at the main venue of the EHA conference, attracting global medical attention. This study, co-led by Professor Bing Chen and Professor Lijuan Chen from Jiangsu Province People's Hospital, utilizes an all-human BCMA-targeted chimeric antigen receptor T-cell (CAR-T) therapy to bring new hope to high-risk newly diagnosed multiple myeloma (NDMM) patients, heralding a new chapter in multiple myeloma treatment. "Oncology Frontier - Hematology Frontier" invited Professor Bing Chen to provide an in-depth interpretation of the study background, design, and results of the FUMANBA-2 study for our readers.

High-Risk NDMM Patients Still Await Breakthroughs in First-Line Treatment

Professor Bing Chen: Multiple myeloma (MM) is a common hematologic malignancy characterized by high heterogeneity and significant differences in responses to existing treatment regimens. Particularly for high-risk NDMM patients, especially those ineligible for autologous stem cell transplantation (ASCT), current treatment regimens are not ideal and carry substantial side effect risks. This situation urgently calls for new treatment strategies.

Equ-cel is an innovative CAR-T therapy targeting B-cell maturation antigen (BCMA), a protein highly expressed on multiple myeloma cells. As the world’s first all-human BCMA-targeted CAR-T therapy,   Equ-cel has been approved in China for the treatment of relapsed/refractory multiple myeloma (R/R MM) and has demonstrated efficacy in various international conferences. However, for newly diagnosed high-risk MM patients, especially those ineligible for transplantation, current treatment methods remain limited. To address this challenge, Professor Bing Chen and Professor Lijuan Chen initiated the FUMANBA-2 study (NCT05181501), aiming to explore the efficacy and safety of   Equ-cel in high-risk newly diagnosed multiple myeloma patients ineligible for transplantation, thereby providing a new treatment option for these patients.

FUMANBA-2 Study: Design and Key Efficacy Results

The FUMANBA-2 study is a multicenter, single-arm, open-label Phase I clinical trial targeting high-risk NDMM patients. The study enrolled adult patients aged 18 to 70 with newly diagnosed MM, defined as high-risk according to mSMART 3.0 criteria, including RISS stage III, double-hit or triple-hit features, and ineligibility for ASCT. The primary endpoints were the proportion of MRD-negative patients and progression-free survival (PFS), while secondary endpoints included objective response rate (ORR), duration of response, safety, pharmacokinetics, and pharmacodynamics. After enrollment, patients completed four cycles of induction therapy, with transplantation eligibility assessed after the third cycle. Patients ineligible for transplantation underwent apheresis and completed the fourth cycle of induction therapy. Unlike the FUMANBA-1 study, this population had poorer overall tolerance, leading to adjustments in the preconditioning regimen for   Equ-cel infusion. Patients received three consecutive days of cyclophosphamide (300 mg/m²) and fludarabine (30 mg/m²) before receiving a dose of 1.0×10⁶ CAR+ cells/kg.

As of January 25, 2024, 16 patients had received   Equ-cel infusion. With a median follow-up of 13.1 months, the study results showed that all patients achieved MRD negativity, and 71.4% maintained MRD negativity 12 months post-treatment. The median PFS had not been reached, with a 12-month PFS rate of 84.4%. The ORR was 100%, with 93.8% of patients achieving stringent complete remission (sCR). All four EMM patients and all ten double/triple-hit patients achieved sCR, and 83.3% (5/6) of patients with R-ISS stage III also achieved sCR. These results significantly surpass existing treatment methods, bringing a new breakthrough in efficacy for high-risk newly diagnosed MM patients.

Safety and PK/PD Characteristics

In the FUMANBA-2 study, 68.8% of patients experienced grade 1-2 cytokine release syndrome (CRS), with a median onset time of 7 days and a median duration of 3 days. No grade 3 or higher CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), or other neurotoxicity events were observed. The most common ≥grade 3 treatment-related adverse events (TRAEs) were cytopenias. A total of 25.0% (4/16) of patients experienced ≥grade 3 infections. One case of death due to COVID-19 infection was reported, which was deemed unrelated to   Equ-cel.

Pharmacokinetically, the median peak time for   Equ-cel was 10 days (range 7-21), with a median peak level of 79,681.30 copies/μg gDNA. The median duration of   Equ-cel persistence post-infusion was 75 days (range 29-283 days).

Pharmacodynamically, 81.25% (13/16) of patients cleared soluble BCMA (sBCMA) within one month post-  Equ-cel infusion. These pharmacodynamic characteristics are crucial for guiding the clinical application of   Equ-cel, such as dose selection and treatment window determination.

Expert Commentary

The FUMANBA-2 study innovatively reveals the application potential of the novel all-human BCMA CAR-T therapy in high-risk newly diagnosed multiple myeloma patients ineligible for hematopoietic stem cell transplantation, demonstrating outstanding efficacy and safety. Compared to R/R MM patients, this therapy significantly reduced the incidence and severity of CRS in NDMM patients, showcasing superior safety.

CAR-T cell therapy is renowned for its ability to specifically recognize and efficiently kill tumor cells. In multiple myeloma treatment, frontline application of CAR-T therapy can rapidly reduce tumor burden and achieve deep remission. Introducing CAR-T therapy at the early stages of the disease not only improves remission rates and prevents early progression and relapse but also reduces the toxic side effects of traditional treatments, further enhancing patients’ quality of life.

The FUMANBA-2 study not only highlights China’s innovative strength in the field of biomedicine, such as CAR-T cell therapy, but also reflects significant progress in basic research, translational research, clinical trials, and industrialization of cell therapy in China. Looking to the future, we anticipate further exploration of combining CAR-T with traditional immunosuppressants or biological agents to optimize treatment regimens, improve clinical efficacy, and overcome resistance. Additionally, actively developing new indications and leveraging the specific immune response characteristics of CAR-T cells to expand their application beyond hematologic malignancies to fields such as autoimmune diseases, chronic infections, and solid tumors, aims to bring better survival benefits to more patients. Furthermore, as we gain a deeper understanding and control of CAR-T cell therapy mechanisms, future research will continue to optimize CAR design to enhance specificity, potency, and durability. Researchers are also exploring new methods to reduce side effects like CRS, ensuring treatment efficacy while maximizing safety.

In conclusion, through close collaboration among academia, research, industry, and clinical practice, we have reason to believe that China will rapidly rise to the forefront of the world in CAR-T and other cellular immunotherapy research and application, allowing patients globally to benefit from these innovative therapies.

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Professor Bing Chen

• Director of the Department of Hematology and Director of the Hematopoietic Stem Cell Transplantation Center at Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School，Nanjing University
• Chief Physician, Doctoral Supervisor
• Member of the Plasma Cell Disease Group of the Hematology Branch of the Chinese Medical Association
• Member of the Hematologic Oncology Committee of the Chinese Anti-Cancer Association
• Member of the Myeloma Group of the Hematology Branch of the Chinese Geriatrics Society
• Vice Chairman of the Hematology Branch of the Jiangsu Medical Association and Leader of the Plasma Cell Disease Group
• Chairman of the Plasma Cell Disease Committee of the Jiangsu Research Hospital Association
• Vice Chairman of the Hematology Immunology Committee of the Jiangsu Immunology Association
• Vice Chairman of the Hematologic Oncology Committee of the Jiangsu Anti-Cancer Association
• Vice Chairman of the Hematology Branch of the Nanjing Medical Association
• Group Leader at the State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University
• Specializes in the diagnosis and treatment of multiple myeloma and hematopoietic stem cell transplantation. In 2012, She was a visiting scholar at the Memorial Sloan Kettering Cancer Center in the United States, studying hematopoietic stem cell transplantation and CAR-T cell therapy. She has led several research projects, including those funded by the National Natural Science Foundation of China, the Jiangsu Provincial Department of Science and Technology, and the Jiangsu Provincial Health Commission.