Anti-BCMA CAR-NK Cell Therapy for the Relapsed or Refractory Multiple Myeloma

Study Overview
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Brief Summary
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The purpose of this study is to infuse BCMA CAR-NK cells（Umbilical & Cord Blood (CB) Derived CAR-Engineered NK Cells） to the patients with relapsed and refractory multiple myeloma (MM), to assess the safety and feasibility of this strategy. The CAR enables the NK cells to recognize and kill the MM cells by targeting of BCMA, a protein expressed of the surface of the malignant plasma cells in MM patients.

Official Title
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Phase I Study to Evaluate the Safety and Effectiveness of Anti-BCMA CAR-NK Therapy in Relapsed or Refractory Multiple Myeloma

Conditions
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Multiple Myeloma, Refractory

Intervention / Treatment
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* Biological: Anti-BCMA CAR-NK Cells
* Drug: Fludarabine
* Drug: Cytoxan


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Signed written informed consent; According to the international standard for multiple myeloma，have information on medical examination proving the diagnosis of multiple myeloma. Received at least 2 prior lines of treatment, including proteasome inhibitor and immunomodulator, no efficacy more than PD; disease progression or relapsed after disease remission and refractory or no remission after treated in the last time. Measurable disease at screening as defined by any of the following: Serum monoclonal paraprotein (M-protein) level ≥1.0 g/dL or urine M-protein level veing as defined ；or light chain MM without measurable disease in the serum or the urine；serum immunoglobulin free light chain isease dL and abnormal serum immunoglobulin kappa/lambda free light chain ratio ； ECOG Scores: 0 2（See Annex 3），the estimated survival time was more than 3 months; During the screening period, the clinical laboratory values met the following criteria： Hemoglobins70g/L (did not receive red blood cell transfusion ≤7 days prior to laboratory tests，recombinant human erythropoietin is allowed); Platelet count >50×10^9/L (did not receive blood transfusion ≤7 days prior to laboratory tests); Neutrophil absolute count oietin is (did not receive supportive treatment lowed); Platelet count >50×10^9/L，allowed to use over growth factor support); ALT and AST ≤3×ULN；Total bilirubin ≤2.0× UNL；Creatinine clearance×40mL/min；corrected serum calcium L/minctordL (3.1 mmol/L), or free calcium ion or freedL(L( ommol/L); Prothrombin time and activated partial thromboplastin time ≤1.5×ULN. The urine pregnancy test of female subjects of childbearing age should be negative and not in lactation; Females of childbearing potential and males must use efficient contraception（form signing the ICF to the end of the trial） Exclusion Criteria: Have received CAR-NK therapy； Have a history of allergy to any component of cell products; Previous history of other malignancy; Any unstable cardiovascular disease happened the informed consent form by themselves or their legal guardian;boratory tests); be infused using the 3 + 3 dos grade), severe arrhythmia that require drug interference, cardiac angioplasty/coronary stent implantation/cardiac bypass surgery ≤6 months prior to enrollment; Have received allogeneic hematopoietic stem cell transplantation in 3 months for the treatment of multiple myeloma; who has suffered from brain injury, consciousness disorder, epilepsy, more serious cerebral ischemia or cerebral hemorrhage disease; There were live vaccinations within 4 weeks before admission; Active hepatitis (positive for HBVDNA or HCVRNA), syphilis and other acquired and congenital immunodeficiency diseases, including but not limited to those with HIV infection; Oxygen is needed to maintain adequate oxygen saturation; Contraindications for fludarabine or cyclophosphamide treatment. There was uncontrolled active infection;Patients with autoimmune diseases, immunodeficiency or other diseases requiring immunosuppressive （excluding glucocorticoid）therapy; Pregnant or breasting-feeding women; Subjects had a history of alcohol, drug or mental illness; Any other condition that researcher think it is inappropriate for the subject to anticipate the trial.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Anti-BCMA CAR-NK Cells
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Anti-BCMA CAR-NK Cells<br>After preconditioning with chemotherapy, the Anti-BCMA CAR-NK Cells will be evaluated | Biological: Anti-BCMA CAR-NK Cells<br>* 1-3×10^6 /KG, 3-6×10^6 /KG, 0.6-1.2×10^7/KG Treatment follows a lymphodepletion<br>Drug: Fludarabine<br>* recommendation: 30mg/m2 (D-5 D-3),determined by tumor burden at baseline.<br>Drug: Cytoxan<br>* recommendation: 300-500mg/m2 (D-5 D-3),determined by tumor burden at baseline.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Remission Rate (ORR) | Response assessment per International Myeloma Working Group (IMWG) criteria | 2 monthes after infusion | 
| Incidence of dose limiting toxicity (DLTs) | To characterize the safety, tolerability of Anti-BCMA CAR-NK Cells | within 2 monthes after infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Progression-free survival (PFS) | Response assessment per International Myeloma Working Group (IMWG) criteria | up to 24 months | 
| Duration of Response (DOR) | Response assessment per International Myeloma Working Group (IMWG) criteria | up to 24 months |