CAR-T 细胞治疗多发性骨髓瘤、白血病：I 期临床试验（Peking University）

Inclusion Criteria:

1. Age 18 to 75 years old, male or female;
2. Diagnosed as Multiple Myeloma (MM) according to the international standard for multiple myeloma (IMWG), or diagnosed as primary plasma cell leukemia;
3. Subjects have had at least 3 prior lines of therapy including at least one proteasome inhibitor (PI), one immunomodulatory agent (IMiD), and one anti-CD38 monoclonal antibody, or subjects who were refractory to the above treatments.
4. Disease progression must be documented during or within 12 months following the most recent anti-tumor treatment (the progression for subjects whose last line treatment was CAR-T therapy was not limited to 12 months post-treatment);
5. Presence of measurable lesion at screening as determined by any of the following criteria for subjects with MM:

   * Serum M protein level: IgG type M protein ≥ 10 g/L, or IgA, IgD, IgE, IgM type M protein ≥ 5 g/L;
   * Urine M protein level ≥ 200 mg/24h;
   * Light chain multiple myeloma without measurable M protein in serum or urine: Involved serum free light chain (sFLC) ≥ 100 mg/L and abnormal serum κ/λ free light chain ratio；
   * Serum M- protein, urine M- protein, or involved sFLC not meeting above criteria but bone marrow plasma cell percentage ≥30%;
6. Subjects with primary plasma cell leukemia: peripheral blood plasma cell percentage≥5%at screening;
7. ECOG score of 0 or 1;
8. Estimated life expectancy ≥12 weeks;
9. Subjects must have adequate organ function and meet all of the following laboratory test results prior to enrollment:

   1. Blood routine: absolute neutrophil count (ANC) ≥ 1×10\^9/L (support with growth factor is allowed, but must not have received support treatment within 7 days before the laboratory test); Absolutely lymphocyte count (ALC) ≥0.3×10\^9/L; Platelets ≥50×10\^9/L (must not have received platelet transfusion support within 7 days before the laboratory test); Hemoglobin ≥60 g/L(must not have received red blood cell \[RBC\] transfusion within 7 days before the laboratory test);
   2. Liver function: alanine aminotransferase (ALT) and aspartate aminotransferase (AST)≤2.5× Upper limit of normal value (ULN); Serum total bilirubin ≤1.5 ×ULN;
   3. Renal function: creatinine clearance (CrCl) calculated by Cockcroft-Gault formula ≥ 40 ml/min;
   4. Coagulation function: fibrinogen ≥ 1.0g /L; Activated partial thromboplastin time (aPTT) ≤1.5× ULN, Pro thrombin time (PT) ≤1.5× ULN;
   5. Blood oxygen saturation(SaO2) \>91%;
   6. Left ventricular ejection fraction (LVEF) ≥ 50%;
10. Subjects agree to take effective measures or drug contraceptive measures (excluding safe period contraception) after signing the ICF and within one year after CAR-T cell infusion;
11. Subjects must sign an informed consent approved by the Ethics Committee before starting any screening procedures.

Exclusion Criteria:

1. Subjects who are known to have Graft-Versus-host disease (GVHD) or need long-term immunosuppressive therapy;
2. Subjects have received an autologous hematopoietic stem cell transplantation (auto-HSCT) within 12 weeks before leukapheresis or have a previous history of two times of auto-HSCT or previous history of an allogeneic hematopoietic stem cell transplantation (allo-HSCT);
3. Received targeted plasma cell therapy within 3 months before leukapheresis, or previous cell therapy products can still be detected in peripheral blood.
4. Subjects have received any anti-tumor treatment as follows, prior to leukapheresis:

   * Monoclonal antibody for multiple myeloma or plasma cell leukemia within 21 days, or;
   * Cytotoxic chemotherapy or proteasome inhibitors within 14 days, or;
   * Immunomodulators within 7 days, or;
   * Received other anti-cancer therapy within 14 days or at least 5 half-lives
5. Subjects require long-term use of glucocorticoids (defined as prednisone or equivalent \> 20 mg/day) at a therapeutic dose during the study, physiologic replacement, topical, and inhaled steroids are permitted, nevertheless.
6. Subjects with hypertension that cannot be controlled by medication;
7. Sever cardiac disease including but not limited to unstable angina pectoris, myocardial infarction (within 6 months prior to screening), cardiac failure congestive (New York Heart Association \[NYHA\] class ≥ III), severe arrhythmia;
8. Unstable systemic disease as judged by the investigator: including but not limited to severe liver, renal, or metabolic disease requiring drug therapy ;
9. Subjects has prior history of malignancies, other than MM and plasma cell leukemia within 5 years before screening, with the exception of radical carcinoma in situ of the cervix, basal cell carcinoma or squamous cell carcinoma of skin, localized cancer of prostate after radical prostatectomy, ductal carcinoma in situ of breast after radical mastectomy, or papillary thyroid carcinoma after radical thyroidectomy;
10. Subjects with a history of organ transplantation;
11. Subjects with suspected or known central nervous system (CNS) involvement with myeloma;
12. Subjects with history of major surgery within 2 weeks prior to leukapheresis or planned to have surgery within 2 weeks after study treatment (except for subjects who were planned to have local anesthesia);
13. Treated with other investigational products within 1 month prior to leukapheresis;
14. Subjects have uncontrolled systemic fungal, bacterial, viral or other infection (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antimicrobial treatment) or requiring IV antimicrobials for management;
15. Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with detectable hepatitis B virus (HBV) DNA in peripheral blood; positive hepatitis C virus (HCV) antibody with positive HCV RNA in peripheral blood; positive human immunodeficiency virus (HIV) antibody; positive cytomegalovirus (CMV) DNA; Syphilis toluidine red unheated serum test (TRUST) and treponemal particle agglutination test (TPPA) were positive;
16. Pregnant or breastfeeding women;
17. Subjects have psychiatric disorders, conscious disorders, or central nervous system diseases;
18. Any condition for which, at the discretion of investigators, participation would not be in the best interest of the subject.

主要终点：Adverse Events · Type and incidence of adverse events (AEs) · 2 years after CAR-T cell infusion
次要终点：Overall response rate (ORR)；Duration of Response (DOR)；Progression-free Survival (PFS)；Overall Survival (OS)；Time to Response (TTR)；Time to Complete Response (TTCR)；Minimal Residual Disease (MRD)；Duration of MRD negativity

• RD140 injection · EXPERIMENTAL · subjects will receive a single infusion of Fully Human Anti-BCMA/GPRC5D Chimeric Antigen Receptor T Cells with does of 1-6×10\^5 CAR T cells/kg.

This is a single-center, open clinical study, divided into two phases of dose escalation and dose expansion, to observe the safety and efficacy of RD140 injection at different doses in patients with relapsed/refractory multiple myeloma or plasmacytic leukemia.