Nanobody-based Biepitope CAR-T Cells Targeting BCMA in the Treatment of R/RMM

A Multicenter Clinical Study on the Safety and Efficacy of Nanobody-based Biepitope CAR-T Cells Targeting BCMA in the Treatment of Relapsed/Refractory Multiple Myeloma

To explore the safety and efficacy of nanobody-based BCMA-targeting biepitope CAR-T cells in the treatment of relapsed/refractory multiple myeloma，this study will be conducted in multiple study centers, with 60 patients openly enrolled to receive CAR-T cell therapy. Patients participating in clinical trials will be tested and evaluated for treatment safety, efficacy, duration of response, and long-term survival.

This study is a multicenter, open-label, prospective, single-arm clinical study with patients with relapsed/refractory multiple myeloma as the test subjects, in order to evaluate the safety and efficacy of nanobody-based biepitope CAR-T cells targeting BCMA in the treatment of R/RMM, and to collect CAR-T PK/PD indicators. The structure of BCMA target CAR-T is designed to identify two different epitopes of BCMA protein with two recognition domains, in order to killig MM cells without secreting more pro-inflammatory factors and avoiding escape caused by the limitations of single BCMA antigen recognition.

Inclusion Criteria:

• Patient or his or her legal guardian voluntarily participates in and signs an informed consent form.

• Aged ≥ 18 years and ≤ 75 years.

• Diagnosed as Multiple Myeloma (MM) according to the international standard for multiple myeloma (IMWG 2014).

• Diagnosed as relapsed/refractory disease or primary refractory disease; relapse is defined as disease progression within 60 days of the most recent treatment with three or more lines of therapy with different mechanisms of action; refractory is defined as failure to achieve MR or above efficacy with prior treatment and disease progression with recent treatment, or disease progression within 60 days of treatment.

• Flow cytometry or immunohistochemistry showed positive BCMA expression in myeloma cells.

• Have not been treated with antibody-based drugs within 2 weeks prior to cell therapy.

• ECOG score 0-2 points.

• HGB≥70g/L，PLT≥30×10^9/L.

• Liver, kidney and cardiopulmonary functions meet the following requirements:

  1. Serum creatinine ≤ 1.5× ULN or creatinine clearance (Cockcroft-Gault) >30 ml/min；
  2. Left ventricular ejection fraction (LVEF) ≥50%,
  3. Baseline peripheral oxygen saturation > 90%;
  4. Total bilirubin ≤ 1.5×ULN; ALT and AST ≤2.5×ULN.

Exclusion Criteria:

• Previous diagnosis and treatment of other malignancies within 3 years;
• Presence of one of the following cardiac criteria: atrial fibrillation; Myocardial infarction within the last 12 months; Prolonged QT syndrome or secondary QT prolongation, as judged by the investigator. Echocardiogram LVSF <30% or LVEF <50%; Clinically significant pericardial effusion; Cardiac insufficiency NYHA (New York Heart Association) III or IV (absence of this symptom confirmed by echocardiography within 12 months of treatment);
• Patients with active GVHD;
• Patients with a history of severe pulmonary impairment disease;
• Combined with other malignant tumors in the advanced stage;
• Co-infection with severe or persistent infection that cannot be effectively controlled;
• Combined with severe autoimmune disease or congenital immunodeficiency;
• Active hepatitis (hepatitis B virus deoxyribonucleic acid [HBV-DNA ≥ 500 IU/ml and abnormal liver function] or hepatitis C antibody [HCV-Ab] positive, HCV-RNA above the lower limit of detection of the analytical method and abnormal liver function);
• Human immunodeficiency virus (HIV) infection or syphilis infection;
• Patients with a history of severe allergy to biological products (including antibiotics);
• Patients with central nervous system disorders such as uncontrolled epilepsy, cerebrovascular ischemia/hemorrhage, dementia, cerebellar disease, etc;
• Pregnant or Lactating Women; Patients and his or her spouses have a fertility plan within 12 months after CAR-T cell infusion;
• Other conditions considered inappropriate by the researcher.