evaluate cart-bcma in patients with relapsed and/or refractory multiple myeloma

Conditions: Multiple Myeloma

Summary: this is a phase 1, multicenter, open-label study o evaluate the safety and efficacy of cart-bcma in subjects with relapsed/refractory multiple myeloma.

the study will consist of 2 parts: dose-escalation (part a) and dose-expansion (part b). the dose-escalation part (part a) of the study is to evaluate the safety and tolerability of increasing dose levels of cart-bcma to establish a recommended dose (rd); and the dose-expansion part (part b) of the study is to further evaluate the safety, pharmacokinetics/pharmacodynamics, and efficacy of cart-bcma at the rd.

Eligibility criteria:
inclusion criteria: * at least 18 years old (inclusive), gender is not limited; * multiple myeloma patients who have received at least 3-line previous multiple myeloma therapy and have failed at least through proteasome inhibitors and immunomodulators; each line of treatment has at least 1 complete treatment cycle, unless the best remission for the treatment is recorded as disease progression (pd) (according to the imwg efficacy evaluation criterialpublished in 2016, appendix 4); pd must be recorded during or within 12 months after the last treatment; * bone marrow specimens were confirmed by immunohistochemistry or flow cytometry as positive bcma expression in plasma cells and myeloma cells (\>5%); * the presence of measurable lesions during screening was defined as any of the following: serum m protein ≥1 g/dl (≥10 g/l); urinary m protein level ≥200 mg/24 h; serum light chain (flc) : abnormal serum flc ratio (\ 1.65), and affected flc≥10 mg/dl (100mg/l); * ecog score (appendix 1) 0\~1; * expected survival time ≥3 months; * the mononuclear cells meet the following standards within 3 days before collection: hematology:≥0.5×109/l\[the use of past granulocyte colony stimulating factor (g-csf) is allowed, but patients shall not receive this supportive treatment within 7 days prior to the screening phase of laboratory examination\];≥1.0 ×109 /l\[ex-granulocyte colony-stimulating factor (g-csf) is allowed, but subjects shall not receive this supportive treatment within 7 days prior to the screening laboratory examination\];subjects' platelet count ≥50×109/l (subjects shall not receive blood transfusion support within 7 days before the screening laboratory examination);≥8.0 g/dl (recombinant human erythropoietin is allowed) \[subjects have not received a red blood cell infusion (rbc) within 7 days prior to the screening phase laboratory examination\]; heart:left ventricular ejection fraction (lvef) ≥ 50%; lung:blood oxygen saturation ≥91% under non-inhaled oxygen condition; kidney:creatinine clearance (crcl) or glomerular filtration rate (gfr) (cockcroft-gault formula) ≥30 ml/min; liver:total bilirubin (serum) ≤1.5 × uln;gilbert's disease patients with \>1.5 × uln could be enrolled with the consent of the sponsor; blood coagulation:plasma prothrombin time (pt) ≤1.5 × uln, international standardized ratio (inr) ≤1.5 × uln, partial prothrombin time (aptt) ≤1.5 × uln; * peripheral venous access can meet the needs of single collection and intravenous drip; * the subject agrees to use reliable contraceptive methods for contraception within 1 year after signing the informed consent form to the infusion. including but not limited to: abstinence, men undergoing vasectomy, implantable progesterone contraceptives that can inhibit ovulation; intrauterine contraceptive devices; hormone-releasing intrauterine devices; sexual partner sterilization methods; copper intrauterine devices, correct use of proven compound hormonal contraceptives that can inhibit ovulation; progesterone contraceptives that can inhibit ovulation. at the same time, female subjects should promise not to donate eggs (egg cells, oocytes) for assisted reproduction within 1 year after the infusion; * volunteer to participate in clinical trials and sign informed consent form; exclusion criteria: * subjects who are known to have allergic reactions, hypersensitivity, intolerance, or contraindications to any component of cart-bcma or any drugs that may be used in the study (including fludarabine, cyclophosphaamide, or tozumab), or who are allergic to β-lactam antibiotics, or who have had severe allergic reactions in the past; * prior to any car-t therapy or bcma-targeted therapy; * have received the following anti-mm treatment within the prescribed time range before single calyzer: has received small molecule targeted therapy within 4 weeks or 5 half-lives, whichever is longer; treatment with a large molecule within 4 weeks or 2 half-lives, whichever is longer; received cytotoxic therapy, proteasome inhibitor, or modern chinese medicine preparation with anti-tumor effect within 2 weeks; received immunomodulatory drug therapy within 1 week; received radiotherapy within 1 week * participated in a clinical trial within 4 weeks before the single collection; * patients who received autologous hematopoietic stem cell transplantation (asct) or previous allogeneic stem cell transplantation within 12 weeks before a single collection (no time limit); * people who received live vaccine or attenuated vaccine within 4 weeks before the cart-bcma harvest; note: inactivated viral vaccines for seasonal influenza are allowed for injection; intranasally administered live attenuated influenza vaccines are not allowed; * received any of the following treatments within 7 days prior to the single collection or as determined by the investigator to require long-term treatment during the study period: systemic steroid therapy (except inhalation or topical use), immunosuppressive therapy, graft versus host therapy, preventive treatment of central nervous system * incomplete recovery or stabilization to grade 1 (nci-ctcae v5.0) of toxicity (including peripheral neuropathy) caused by previous treatment; * mm is suspected to be involved in the central nervous system or meninges and confirmed by mri or ct, or to have other active central nervous system diseases; * patients with plasma cell leukemia or waldenstrom macroglobulinemia or poems syndrome (polyneuropathy, organ enlargement, endocrine disorder, monoclonal protein, and cutaneous disease) or amyloidosis at the time of screening; * heart disease: existing heart failure (nyha classification ≥ii, appendix 2), unstable angina pectoris, or severe heart disease as determined by the investigator; myocardial infarction had occurred no more than 6 months before single arthroplasty. had an episode of unstable angina pectoris, severe arrhythmia as determined by the researchers, or had undergone coronary artery bypass grafting (cabg) no more than 3 months before the single harvest; * poor control of hypertension (systolic blood pressure \> 160 mmhg and/or diastolic blood pressure \> 100 mmhg) or with hypertensive crisis or hypertensive encephalopathy; * patients who had undergone major surgery or plasma separation other than diagnosis or biopsy within 4 weeks prior to the study alone, or who were expected to undergo major surgery during the study period; note: patients who plan to undergo surgery under local anesthesia may participate in the study. kyphoplasty or vertebra osteoplasty are not considered major surgery; * receiving thrombolytic, anticoagulant or antiplatelet therapy; * infections require intravenous antibiotics or hospitalization; * patients with active hepatitis b; hepatitis c virus (hcv) antibody positive; hiv-positive persons; syphilis primary screening antibody positive; a) inactive/asymptomatic patients with carryable, chronic, or active hbv who meet the following criteria are eligible for inclusion: hbv dna \<500 iu/ml (or 2500 copies /ml) at the time of screening. * women who are pregnant or lactating; * the investigator considers that the subject is unsuitable to participate in this clinical study due to any abnormal clinical or laboratory examination or other reasons.