YTS104 Cell Injection for the Treatment of Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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This is a single-center, single-arm, open-label phase I clinical study to determine the safety and efficacy of relapsed or refractory multiple myeloma subjects

Detailed Description
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This study will recruit LILRB4 positive multiple myeloma subjects,and Subjects should undergo FC chemotherapy before returning the cells, then followed by infusion of YTS104 cells injection. YTS104 cells injection will be intravenously infused with a escalated dose of 1E6#3E6#6E6#1E7 cells/kg.

Official Title
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An Exploratory Clinical Study on the Safety and Efficacy of YTS104 Cell Injection in the Treatment of Relapsed or Refractory Multiple Myeloma

Conditions
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Relapsed or Refractory Multiple Myeloma

Intervention / Treatment
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* Biological: YTS104 Cells injection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 18-70 years, gender is not limited; Patients diagnosed as relapsed/refractory multiple myeloma according to the International Myeloma Working Group (IMWG 2014) criteria for multiple myeloma after at least 3 lines of treatment (including at least one proteasome inhibitor and an immunomodulator based chemotherapy regimen), and at least one complete treatment cycle per line of treatment; Documented disease progression during or within 12 months after the most recent antimyeloma therapy (not limited to 12 months after CAR-T therapy as the last line of therapy); Bone marrow samples were positive for LILRB4; The presence of one or more measurable lesions at screening was defined as any of the following: 1) serum M-protein ≥0.5g/dL (≥5g/L), 2) urinary M-protein level ≥200 mg/24 hours; 3) serum free light chain (sFLC) ≥100 mg/L and serum κ/λ free light chain ratio abnormal (<0.26 or >1.65); Good organ function; ECOG score ≤1; The predicted survival time was ≥12 weeks; Female subjects of childbearing age or male subjects with partners of women of childbearing age agreed to use effective methods of contraception throughout the trial and for 12 months after cell infusion; The subjects voluntarily participated in the study, signed the informed consent form, and complied with the follow-up. Exclusion Criteria: A history of allergy to any component of the cell product; Patients who had used CAR-T cell therapy or any other gene transduction or other therapeutic products within 3 months after signing the informed consent, except those with undetectable CAR-T cells or CAR-T cells below the lower limit of detection; Subjects had plasma cell leukemia, Waldenström's macroglobulinaemia, POEMS syndrome, or primary light chain amyloidosis; Patients with a history of any of the following cardiovascular and cerebrovascular diseases within the preceding 6 months were screened; Congestive heart failure (New York Heart Association [NYHA]≥III), congenital long QT syndrome, left front half block (double bundle block), asymptomatic right bundle branch block allowed; Myocardial infarction, unstable angina pectoris, coronary angioplasty, stent implantation, coronary/peripheral artery bypass grafting; Cerebrovascular accident (CVA) and transient ischemic attack (TIA); Severe arrhythmias requiring treatment (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes, etc.); d: Subjects had uncontrolled hypertension (systolic blood pressure greater than 160 mmHg and/or diastolic blood pressure greater than 100 mmHg), a history of hypertensive crisis, or hypertensive encephalopathy; Had a pulmonary embolism within 6 months prior to screening, or had a history of deep vein thrombosis of the lower extremities, or had active pulmonary disease and/or pneumonia, or had a history of interstitial lung disease; Hepatitis B surface antigen (HBsAg) positive; Hepatitis B core antibody (HBcAb) and HBV DNA in peripheral blood were positive. Hepatitis C virus (HCV) antibody positive and HCV RNA positive; Treponema pallidum antibody was positive; Patients with known systemic lupus erythematosus, co-active or uncontrolled autoimmune diseases (e.g., Crohns disease, rheumatoid arthritis, autoimmune hemolytic anemia, etc.), primary or secondary immunodeficiency (e.g., HIV infection or severe infectious diseases); Patients with previous or concurrent uncured malignant tumors with unstable control, affecting the long-term survival of the subjects, excluding cured cervical carcinoma in situ, non-invasive basal cell or squamous cell skin cancer, or other malignant tumors with local prostate cancer after radical treatment, ductal carcinoma in situ after radical treatment and no recurrence for at least 5 years; Patients with current or previous history of central nervous system disease, such as seizures, stroke, severe brain injury, aphasia, paralysis, dementia, Parkinson's disease, mental illness, etc.; Have central nervous system (CNS) involvement or symptoms of CNS involvement (including cranial neuropathy and extensive lesions or spinal cord compression); Patients had undergone previous solid-organ transplantation or allogeneic hematopoietic stem-cell transplantation (allo-HSCT) 6 months before screening or autologous stem-cell transplantation within 3 months before apheresis; Patients with acute or chronic graft-versus-host disease (GVHD) at screening time; The following anti-MM treatments were used at the indicated times prior to apheresis: Use of any immunosuppressant or radiotherapy within 2 weeks prior to apheresis; Received cytotoxic or proteasome inhibitors or small-molecule targeted therapy within 2 weeks of preapheresis or 3 half-lives, whichever is shorter; Received any macromolecular therapy such as monoclonal antibodies within 4 weeks prior to anapheresis or within 3 half-lives, whichever is shorter; Received immunomodulator within 1 week; The patient had a history of live vaccination within 4 weeks before signing ICF; Subjects had a history of mental illness, or substance abuse; Subjects were pregnant or lactating; If participating in other interventional clinical studies before apheresis, the requirements of drug washout before apheresis should be met; The investigator believes that there are other factors unsuitable for inclusion or affecting participants' participation in or completion of the study.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: YTS104 cells injection<br>Subjects will receive cell infusion, with the initial cell dose of 1E6/kg. 1-6 subjects will be enrolled. The second dose group was 3E6 cells /kg with 1-6 subjects; The third and fourth dose groups were 6E6 cells /kg and 1E7 cells /kg, respectively, with 3-6 subjects. | Biological: YTS104 Cells injection<br>* YTS104 Cell injection is a new STAR-T cell transfected by lentivirus.The study required that lymphocytes were collected from the subjects and cultured for 2-3 weeks to obtain YTS104 cell injection. Subjects were treated with fludarabine and cyclophosphamide chemotherapy prior to reinfusion, followed by a 2-day rest period before cell infusion.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Patients with Dose Limiting Toxicity | Dose-limiting toxicity was defined as adverse events associated with YTS104-cell injection within 28 days of cell transfusion, including grade 4 or 5 CRS and ICANS; grade 4 haematological adverse events did not return to grade 2 or baseline within 28 days of cell transfusion | Within 28 days after cell transfusion | 
| Incidence and severity of adverse events | After YTS104-cell infusion, adverse events will be graded as CTCAE 5.0 | 24 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall response rate (ORR) | Including sCR, CR, VGPR, and PR. | 24 months | 
| Duration OF RESPONSE(DOR) | DOR was defined as the time from the first documentation of response (PR or better) to the first documentation of disease progression or death from any cause after YTS104 infusion in patients with PR or better. | 24 months | 
| Progression-free survival(PFS) | PFS was defined as the time between the subject's YTS104-cell infusion and the occurrence of disease progression or death from any cause. | 24 months | 
| Overall survival(OS) | It was defined as the time between the subject's reinfusion of YTS104 cell injection and death from any cause. | 24 months | 
| Expansion and persistence of YTS104 cell injection in vivo | The proportion of STAR-T in peripheral blood was detected by flow cytometry,The copies of STAR-T DNA in peripheral blood was detected by qPCR method. | 24 months |