A Study of Fully Human BCMA CAR-T (CT103A) in Patients With Newly Diagnosed High-risk Multiple Myeloma (FUMANBA-2)

This study is a multi-center, single-arm clinical study to evaluate the efficacy, safety, pharmacokinetics and pharmacodynamic characteristics of CT103A as the first-line treatment in newly diagnosed high-risk multiple myeloma subjects with induction chemotherapy as bridging therapy.

Before enrollment, subjects will receive chemotherapy regimen of either Bortezomib-Lenalidomide-Dexamethasone (VRD), Bortezomib-Cyclophosphamide-Dexamethasone (PCD) or Bortezomib-Adriamycin-Dexamethasone (PAD) as induction therapy for 3 cycles. Evaluation will be made after 2 cycles of chemotherapy. If the subject is not intended to have stem cell transplantation or unsuitable for autologous hematopoietic stem cell transplantation (ASCT) as judged by the investigator, he/she will receive the 3rd cycle of chemotherapy. If the subject meets the inclusion criteria, he/she will be enrolled in the study.

Peripheral blood mononuclear cell (PBMC) will be collected to manufacture CT103A. After PBMC collection, the subject will receive another cycle of chemotherapy and evaluated. Lymphodepletion with fludarabine and cyclophosphamide will be performed for three consecutive days. After 1-day rest, subjects will receive a single infusion of CT103A at 1.0 ×10\^6 /kg. Subjects will be followed in the study for a minimum of 2 years after CT103A infusion. Long-term follow-up for lentiviral vector safety will be followed for up to 15 years after CT103A infusion.

Eligibility Criteria:
Inclusion Criteria:

1. 18 to 70 years old, male or female;
2. Newly diagnosed as high-risk multiple myeloma:

   * Revised Multiple Myeloma International Staging System (R-ISS) stage 3;
   * Double-hit or triple-hit according to FISH test.
3. Presence of measurable lesions during screening according to any of the following criteria:

   * The proportion of primitive naive or monoclonal plasma cells ≥ 5% by bone marrow cytology, bone marrow biopsy histology or flow cytometry;
   * Serum monoclonal protein (M-protein) level: M protein ≥10 g/L for IgG type, M protein ≥5g/L for IgA, IgD, IgM, and IgE type;
   * Urine M protein level ≥200 mg/24 hours;
   * Light chain multiple myeloma without measurable lesions in serum or urine: the affected serum free light chain ≥100 mg/L with abnormal serum κ/λ free light chain ratio;
4. ECOG score of 0 or 1;
5. Expected survival time ≥ 12 weeks;
6. Subjects must have appropriate organ functions and meet all the following laboratory test requirements before enrollment:

   * Hematology: Absolute neutrophil count (ANC) ≥ 1×10\^9/L (prior growth factor support is allowed, but supportive treatment within 7 days before laboratory test is not allowed); Absolute lymphocyte count (ALC) )≥0.3×10\^9/L; platelets≥75×10\^9/L (blood transfusion support within 7 days before laboratory test is not allowed); hemoglobin ≥60 g/L (without red blood cell \[RBC\] transfusion within 7 days before laboratory test; recombinant human erythropoietin is allowed);
   * Liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5×upper limit of normal (ULN); serum total bilirubin≤1.5×ULN;
   * Renal function: creatinine clearance calculated according to Cockcroft-Gault formula≥ 40 ml/min.
   * Coagulation function: fibrinogen ≥1.0 g/L; activated partial thromboplastin time≤1.5×ULN, prothrombin time (PT)≤1.5×ULN;
   * Blood oxygen saturation\>91%;
   * Left ventricular ejection fraction (LVEF) ≥50%;
7. Subjects and their spouses agree to take effective tools or contraceptive measures (safe period contraception is not included) from the time the subject signs the informed consent form until one year after the CAR-T cell infusion.

Exclusion Criteria:

1. Patient who needs chronic use of immunosuppressive agents;
2. Patient with hypertension that cannot be controlled by medication;
3. Severe heart disease: including but not limited to unstable angina, myocardial infarction (within 6 months before screening), congestive heart failure (New York Heart Association \[NYHA\] classification ≥ grade III), severe arrhythmia;
4. Unstable systemic diseases judged by the investigator: including but not limited to severe liver, kidney or metabolic diseases that require drug treatment;
5. Patients with malignant tumors other than multiple myeloma within 5 years before screening, excluding fully treated cervical carcinoma in situ, basal cell or squamous cell skin cancer, local prostate cancer after radical resection, and those after radical resection Ductal carcinoma in situ of breast;
6. Patient with a history of solid organ transplantation;
7. Patient who is suspected with or with symptoms of central nervous system invasion by plasma cell tumors;
8. Multiple myeloma patients with plasma cell leukemia;
9. Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) and detectable hepatitis B virus (HBV) DNA in peripheral blood; hepatitis C virus (HCV) antibody positive and peripheral blood hepatitis C virus ( HCV) RNA positive; human immunodeficiency virus (HIV) antibody positive; cytomegalovirus (CMV) DNA test positive; syphilis test positive;
10. Women who are pregnant or breastfeeding;
11. Patient with mental illness or disturbance of consciousness or central nervous system disease;
12. Major surgery history within 2 weeks before entering the study, or scheduled surgery during the study period or within 2 weeks after the study treatment;
13. Other situations considered unsuitable by the investigator.