CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.

主要终点：Incidence of Treatment-related Adverse Events · Therapy-related adverse events (AE), including severe adverse events (SAE) and laboratory outliers with clinical significance, will be recorded and assessed according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE, Version 5.0). · within 3 years after infusion；Overall response rate (ORR) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM · Disease overall response rate (ORR) will be assessed from CAR-T cell infusion to death or last follow-up (censored). The rates of stringent complete response (sCRs), complete response (CR), very good partial response (VGPR), partial response (PR), minimal response (MR) will be assessed from CAR T cell infusion to death or last follow-up (censored). ORR will be assessed from CAR T cell infusion to death or last follow-up. · within 3 years after infusion；The rates of complete response (CR) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM · CR will be assessed from CAR-T cell infusion to death or last follow-up (censored). · within 3 years after infusion；Very good partial response (VGPR) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM · VGPR will be assessed from CAR-T cell infusion to death or last follow-up (censored). · within 3 years after infusion；Partial response rate (PR) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM · PR will be assessed from CAR-T cell infusion to death or last follow-up (censored). · within 3 years after infusion；Stable diseases (SD) of nanobody-based biepitope CAR-T cells targeting BCMA in R/R MM · SD will be assessed from CAR-T cell infusion to death or last follow-up (censored). · within 3 years after infusion
次要终点：Overall survival (OS) of nanobody-based biepitope CAR-T cells targeting BCMA in Relapsed/Refractory multiple myeloma；Progression-free survival (PFS) of nanobody-based biepitope CAR-T cells targeting BCMA in Relapsed/Refractory multiple myeloma；Event-free survival (EFS) of nanobody-based biepitope CAR-T cells targeting BCMA in Relapsed/Refractory multiple myeloma

• Effective of nanobody-based biepitope BCMA-targeting CAR-T cells · EXPERIMENTAL · The recommended reinfusion dose of biepitope BCMA-targeting CAR-T cells in this trial is: 1 × 10\^6/kg, 2 × 10\^6/kg CAR-T cells.

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.