Clinical Study on Evaluating the Safety and Effectiveness of BCMA-GPRC5D CAR-T in Patients With Relapsed/Refractory Multiple Myeloma Who Have Received Third-line or Above Treatment

Prior treatment

• Diagnosed or treated with other aggressive malignant tumors other than multiple myeloma within 3 years;
• Previously received anti-tumor treatment (before blood collected for CAR-T preparation): received targeted therapy, epigenetic therapy or experimental drug treatment within 14 days or at least 5 half-life (whichever is shorter) or used for invasive experimental medical devices; treated with monoclonal antibodies within 21 days; received cytotoxic treatment within 14 days; received proteasome inhibitors within 14 days; received immunomodulatory agents within 7 days; received radiotherapy within 14 days (except for 5% bone marrow reserves);
• Suffering from severe heart disease, including but not limited to severe arrhythmia, unstable angina, large-area myocardial insufficiency, New York Heart Association Grade III or IV cardiac insufficiency, myocardial infarction ≤6 months before screening or receiving Coronary artery bypass bypass (CABG), a history of syncope with unknown causes and non-vasovagal or dehydration, a history of severe non-ischemic cardiomyopathy, and refractory hypertension (refractory hypertension is defined as: a sufficient amount of ≥3 antihypertensive drugs (including diuretics) that are reasonably tolerated on the basis of improving lifestyle > 1 month of blood pressure still not meet the standards or taking ≥4 antihypertensive drugs to effectively control blood pressure);
• The screening time has used short-acting hematopoietic cytokine drugs that have an effect on the patient's blood sign within 1 week after the planned blood collection for CAR-T preparation, or long-acting hematopoietic cytokine drugs within 2 weeks, and the researchers have determined that it has an effect on cell preparation.
• During the screening period, hormone or immunosuppressant drugs are being received within 2 weeks of blood collection planned to prepare CAR-T, and the researchers judged that it has an impact on cell preparation:
  • Hormones: Subjects who were receiving systemic steroids within 2 weeks of the planned blood collection for CAR-T preparation and who were deemed to require long-term use of systemic steroids during treatment (except inhaled or topical use); and subjects who were using systemic steroids within 72 hours before cell reentering (except inhaled or topical use);
  • Immunization Inhibitors: Those who are undergoing immunosuppressors within 2 weeks of the planned blood collection for the preparation of CAR-T during screening;
• Those who have undergone major surgical operations (except diagnostic surgery and biopsy) or major surgery during the study period within 4 weeks before the study period, or those who have not fully healed before the enrollment;
• Those who have received (attenuated) live virus vaccine within 4 weeks before the screening;

Other illness

• Suspected that MM has been involved in the central nervous system or meninges and has been confirmed by magnetic or CT, or has other active central nervous system diseases;
• Suffered from Fahrenheit macroglobulinemia, POEMS syndrome (multiple neuropathy, enlarged organs, endocrine lesions, monoclonal protein diseases and skin changes) or primary AL amyloidosis during screening;
• Hepatitis B surface antigen (HBsAg) positive, or hepatitis B core antibody (HBcAb) positive and peripheral blood HBV DNA quantitative test; hepatitis C virus (HCV) antibody positive; human immunodeficiency virus (HIV) antibody positive; cytomegalovirus (CMV) DNA test; EB virus DNA test; syphilis test positive;
• People with a history of severe allergic allergies [the history of severe allergies is defined as a secondary or above all allergic reaction, and any of the following clinical manifestations appear when an allergic reaction occurs: airway obstruction (running nose, cough, Stirrhage, dyspnea), tachycardia, hypotension, arrhythmia, gastrointestinal symptoms (nausea, vomiting), incontinence, laryngeal edema, bronchospasm, cyanosis, shock, respiratory, cardiac arrest] or known to be allergic to any drug active ingredients, excipients or mouse-derived products or xenoproteins contained in this trial (including the clearing regimen);
• Systemic diseases that are unstable by the researchers: including but not limited to severe liver, kidney or metabolic diseases that require drug treatment;
• Before screening Patients with acute/chronic graft-versus-host disease (GVHD) within 6 months or need to receive immunosuppressants for GVHD;
• Patients with active nervous system autoimmunity or inflammatory diseases (such as: Guillin-Barre syndrome (GBS), amyotrophic lateral sclerosis (ALS)) and clinically significant active cerebrovascular diseases (such as cerebral edema, posterior reversible encephalopathy syndrome (PRES));
• There are uncontrollable bacteria, fungi, viruses or other infections that require antibiotic treatment;
• Those who have severe mental illness;
• Those who have alcoholics or have a history of drug abuse;
• Subjects who have contraindications to any research procedure or who have other medical conditions that may put them at unacceptable risks according to the investigator's judgment and/or clinical standards.

Lab values

• Patients with emergency tumor emergencies (such as spinal cord compression, intestinal obstruction, leukocyte stasis, tumor lysis syndrome, etc.) that require emergency treatment;

Other

• Women who are pregnant or breastfeeding, and female subjects who are planning to pregnancy within 2 years after cell rebirth or male subjects who are planning to pregnancy within 2 years after cell rebirth;

• The patient or his/her guardian understands and voluntarily signs informed consent form, and is expected to complete the follow-up examination and treatment of the research procedure;
• Ages 18-75 years old (including the threshold), gender is not limited;
• Patients diagnosed with multiple myeloma according to the IMWG diagnostic criteria;
• Determine that there are measurable lesions during screening according to any of the following criteria: serum single cloned paraprotein (M-protein) level ≥1.0g/dL or urine M-protein level ≥200mg/24 hours; or light chain multiple myeloma diagnosed with serum or urine: serum immunoglobulin free light chain ≥10mg/dL and serum immunoglobulin κ/γ free light chain ratio ;
• Previously received treatment with at least three-line multiple myeloma;
• Materials have proved that the patient's multiple myeloma disease is relapse-refractory or primary-refractory, defined as:
  • relapse-refractory: non-responsive to rescue treatment (no response is defined as the inability to obtain a slight remission [MR] or disease progression in treatment), or disease progression within 60 days of the last treatment, or MR or above remission has occurred;
  • primary-refractory: patients who have never obtained MR or above treatment, including patients who have never obtained MR or above remission, but have little change in M protein, have no evidence of clinical progress, and are subject to the definition of progress.
• The patient has recovered from the toxicity of the previous treatment, that is, the CTCAE toxicity grade is < 2 (unless the abnormality is related to the tumor or is judged by the researcher to be in a stable state, and has little impact on safety or efficacy);
• ECOG physical fitness status score 0 to 1 point and the estimated survival period is greater than 3 months;
• Have appropriate organ functions:
  • Alanine aminotransferase (ALT) ≤3 times the upper limit of normal value (ULN);
  • Alanine aminotransferase (AST) ≤3 times the ULN;
  • Total bilirubin ≤1.5 times the ULN;
  • Serum creatinine ≤1.5 times the ULN, or creatinine clearance ≥60mL/min;
  • Hemoglobin ≥50g/L (no blood transfusion support must be received within 7 days before laboratory examination );
  • Indoor oxygen saturation ≥92%;
  • Correction of serum calcium ≤12.5 mg/dL (≤3.1 mmol/L) or free ionic calcium ≤6.5 mg/dL (≤1.6 mmol/L);
  • Left ventricular ejaculation fraction (LVEF) ≥45%, echocardiography confirms that no pericardial effusion is seen, and no clinically significant electrocardiogram discovery is found;
  • There is no clinically significant pleural effusion;
• The venous pathway required for collection can be established, and there are no contraindications for white blood cell collection.