Overview
This is an open-label, single-arm, Phase 2 study to evaluate the efficacy and safety of IL-15-armored chimeric antigen receptor T-cell (CAR-T) therapy in subjects with relapsed or refractory multiple myeloma and plasma cell leukemia.
Description
This is an open-label, single-arm, Phase 2 study to evaluate the efficacy and safety of IL-15-armored CAR-T therapy in subjects with relapsed or refractory (R/R) multiple myeloma (MM) and plasma cell leukemia (PCL). Subjects with persistent measurable residual disease (MRD) positivity or conversion from MRD-negative to MRD-positive status are also eligible.
IL-15-armored CAR-T cells are autologous T lymphocytes genetically engineered to express a chimeric antigen receptor along with IL-15. The co-expression of IL-15 is intended to enhance in vivo expansion, persistence, and anti-tumor activity.
Subjects will undergo leukapheresis for CAR-T cell manufacturing, followed by lymphodepletion prior to infusion. Bridging therapy is permitted at the investigator's discretion, and radiotherapy is allowed before infusion for subjects with extramedullary disease.
After infusion, the efficacy and safety will be evaluated by the investigators.
Exploratory Objectives and Correlative Studies:
In addition to the primary efficacy and safety evaluations, exploratory analyses will be conducted to investigate clinical, biological, and treatment-related factors associated with treatment response and severe toxicity, with the aim of developing predictive models.
Multi-omics approaches, including single-cell sequencing, bulk RNA sequencing, and spatial transcriptomics, will be employed to characterize the dynamics of the tumor microenvironment.
Circulating tumor DNA (ctDNA) will be longitudinally collected from baseline through post-infusion follow-up. The associations between ctDNA dynamics and clinical outcomes will be assessed.
The clinical efficacy and biological mechanisms of radiotherapy (including site-directed radiotherapy and low-dose intestinal irradiation) in combination with CAR-T cell therapy will also be explored.
Eligibility
Inclusion Criteria:
- Able and willing to provide written informed consent and comply with the scheduled visits, study treatment, laboratory assessments, and other study procedures.
- Clinically diagnosed relapsed or refractory multiple myeloma or plasma cell leukemia (PCL). Patients with persistent minimal residual disease (MRD) positivity or conversion from MRD-negative to MRD-positive status following induction and consolidation therapy are also eligible for enrollment.
- Age 18 to 80 years, inclusive.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.
- Estimated life expectancy \> 3 months from the date of signing the informed consent form.
- Hemoglobin ≥ 60 g/L (transfusion permitted).
- Adequate organ function as defined below:
- Creatinine clearance (CrCl) ≥ 40 mL/min, calculated using the Cockcroft-Gault formula;
- Left ventricular ejection fraction (LVEF) ≥ 50%;
- Oxygen saturation \> 90% on room air;
- Total bilirubin ≤ 1.5 × upper limit of normal (ULN); alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 × ULN.
- Participants of childbearing potential must agree to use effective contraception prior to study enrollment and for at least 6 months after completion of study treatment. Participants who become pregnant or suspect pregnancy must notify the investigator immediately.
Exclusion Criteria:
- History within 1 year prior to signing the informed consent form of any of the following:
- New York Heart Association (NYHA) Class III or IV heart failure;
- Myocardial infarction;
- Cardiac angioplasty or stent placement;
- Unstable angina;
- Other clinically significant symptomatic cardiac disease;
- Active graft-versus-host disease (GVHD) or requirement for systemic immunosuppressive therapy.
- History of other malignancies within 5 years prior to screening, except for adequately treated carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of the skin, localized prostate cancer after radical surgery, or ductal carcinoma in situ of the breast after curative surgery.
- Active infection requiring systemic therapy or uncontrolled infection within 7 days prior to screening (excluding mild genitourinary or upper respiratory tract infections).
- Evidence of active viral or infectious disease as follows:
- Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood hepatitis B virus (HBV) DNA above the lower limit of detection;
- Positive hepatitis C virus (HCV) antibody with detectable HCV RNA;
- Positive human immunodeficiency virus (HIV) antibody;
- Positive Treponema pallidum particle agglutination assay (TPPA).
- Participation in another clinical trial within 4 weeks prior to signing the informed consent form, or if the time from the last dose of an investigational drug to informed consent is less than 5 half-lives of that drug (whichever is longer).
- History of severe allergic reactions to biologic products.
- Any unstable systemic disease, as judged by the investigator, including but not limited to severe hepatic, renal, or metabolic disorders requiring medical treatment.
- Pregnant or breastfeeding women; women planning to become pregnant within 2 years after cell infusion; or male participants whose partners plan to become pregnant within 2 years after cell infusion.
- Any condition that, in the opinion of the investigator, may increase the participant's risk or interfere with study participation or interpretation of study results.
