Abstract: Multiple myeloma (MM) poses significant therapeutic challenges due to its heterogeneous nature. Bispecific chimeric antigen receptor T (CAR-T) cell therapy targeting CS1 and BCMA antigens offers a novel approach. We report findings from a phase I/IIa clinical trial assessing the safety and efficacy of this therapy in patients with relapsed or refractory MM (RRMM). Sixteen patients received CAR-T cell infusion, demonstrating manageable adverse events and promising response rates. Further research is warranted to optimize therapy and understand resistance mechanisms.Introduction:
Multiple myeloma (MM) is a hematologic malignancy characterized by heterogeneity, necessitating innovative therapeutic approaches. Bispecific chimeric antigen receptor T (CAR-T) cell therapy targeting CS1 and BCMA antigens presents a promising avenue. Here, we present the findings of a phase I clinical trial assessing the safety and efficacy of this novel therapy in patients with relapsed or refractory MM (RRMM).
Study Design:
The design of this phase I/IIa clinical trial (registered as NCT04662099) was meticulously crafted to assess the safety and efficacy of bispecific CS1-BCMA CAR-T cell therapy in patients with relapsed or refractory multiple myeloma (RRMM). The study was conducted with stringent adherence to ethical principles and in accordance with regulatory requirements, ensuring the protection of patients’ rights and well-being.
- Patient Selection: Patients eligible for enrollment in this trial were those diagnosed with RRMM who had received at least two prior lines of therapy, including BCMA or CS1-targeted treatments, and had experienced disease progression or relapse. Eligibility criteria also included adequate organ function, performance status, and measurable disease as per standard criteria. Patients with active infections or significant comorbidities were excluded from participation.
- Intervention: The investigational intervention in this trial involved the administration of bispecific CS1-BCMA CAR-T cells to enrolled patients. Prior to CAR-T cell infusion, patients underwent lymphodepleting regimens to optimize the host environment for CAR-T cell expansion and persistence. The CAR-T cells used in this study were engineered to express receptors targeting both CS1 and BCMA antigens, thereby enabling dual-targeted recognition and destruction of MM cells.
- Dosing and Administration: The dosage regimen for CAR-T cell infusion was predetermined based on preclinical studies and early-phase trials to ensure safety and efficacy. Infusions were administered in a carefully monitored clinical setting, with close observation for any signs of infusion-related reactions or adverse events. Patients were followed up regularly post-infusion to assess treatment response, safety profile, and disease progression.
- Study Endpoints: The primary objectives of this trial were to evaluate the occurrence and severity of adverse events associated with bispecific CS1-BCMA CAR-T cell therapy. Secondary objectives included assessing the overall response rate (ORR), including complete response (CR), stringent complete response (sCR), partial response (PR), and minimal residual disease (MRD) negativity, as well as overall survival (OS) and progression-free survival (PFS). Exploratory endpoints included biomarker analyses to identify predictors of response and resistance.
Results:
- Patient Demographics and Baseline Characteristics: Sixteen patients with relapsed or refractory multiple myeloma (RRMM) were enrolled in the trial, with a median follow-up duration of 246 days. The baseline demographics and disease characteristics of the study population were reflective of a typical RRMM cohort, with a median age of XX years (range XX-XX) and a predominance of advanced disease stages. The majority of patients had received multiple lines of prior therapy, including proteasome inhibitors, immunomodulatory drugs, and monoclonal antibodies targeting BCMA.
- Safety Profile: The safety profile of bispecific CS1-BCMA CAR-T cell therapy was evaluated based on the occurrence and severity of adverse events following treatment. Cytokine release syndrome (CRS), the most commonly observed adverse event associated with CAR-T cell therapy, occurred in 38% of patients. CRS events were predominantly of grade 1-2 severity and were effectively managed with supportive care measures, including tocilizumab and corticosteroids. Notably, no instances of severe neurological toxicity, such as immune effector cell-associated neurotoxicity syndrome (ICANS), were documented in the study cohort.
- Hematological Adverse Events: Hematological adverse events were frequently observed following CAR-T cell infusion, reflecting the expected myelosuppressive effects of lymphodepleting regimens and CAR-T cell activity. Leukopenia was reported in all patients, with varying degrees of severity, and neutropenia was observed in 94% of patients. Thrombocytopenia and anemia were also common, albeit generally manageable with supportive transfusion therapy and growth factor support.
- Treatment Response: The efficacy of bispecific CS1-BCMA CAR-T cell therapy was assessed based on treatment response rates, including overall response rate (ORR), stringent complete response (sCR), and duration of response. The overall response rate was 81%, with 38% of patients achieving stringent complete response (sCR), indicating deep and durable responses to therapy. Notably, one patient demonstrated a remarkable response despite prior failure of BCMA-targeted CAR-T cell therapy, suggesting the potential for overcoming resistance mechanisms with bispecific targeting strategies.
- Survival Outcomes: Survival outcomes following bispecific CS1-BCMA CAR-T cell therapy were encouraging, with one-year survival rates for overall survival (OS) and progression-free survival (PFS) of 72.73% and 56.26%, respectively. The median duration of response in patients achieving stringent complete response (sCR) was 17 months, highlighting the durability of responses observed with this therapeutic approach. These survival outcomes compare favorably with historical data for patients with RRMM receiving standard salvage therapies, underscoring the potential clinical benefit of bispecific CAR-T cell therapy in this setting.
- Exploratory Biomarker Analysis: Exploratory analyses were conducted to evaluate the utility of soluble BCMA as a potential biomarker predictive of treatment response and outcomes. Preliminary findings suggested a correlation between baseline levels of soluble BCMA and treatment response, warranting further investigation in larger patient cohorts. Additionally, ongoing research efforts are focused on identifying additional biomarkers associated with response and resistance to inform patient selection and treatment optimization strategies.
Conclusion: The results of this phase I/IIa clinical trial demonstrate the safety, efficacy, and clinical activity of bispecific CS1-BCMA CAR-T cell therapy in patients with relapsed or refractory multiple myeloma (RRMM). Despite the expected myelosuppressive effects and cytokine release syndrome associated with CAR-T cell therapy, adverse events were generally manageable, with no instances of severe neurological toxicity observed. Treatment responses were robust, with a high overall response rate and durable stringent complete responses observed in a significant proportion of patients. These promising results support the continued development and investigation of bispecific CAR-T cell therapy for RRMM and underscore its potential to improve outcomes for patients with this challenging hematologic malignancy.
Authors contribution: The study on bispecific CS1-BCMA CAR-T cells for relapsed or refractory multiple myeloma was led by Drs. Heng Mei and Yu Hu from the Institute of Hematology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. Dr. Wei Xiong supervised CAR-T cell production at Wuhan Sian Medical Technology Co., Ltd. The research was published in Leukemia, a prestigious journal specializing in hematological malignancies, although the specific impact factor isn’t provided.
