a clinical study to evaluate the safety and efficacy of bcma-gprc5d car-t in patients with relapsed/refractory multiple myeloma who received three or more lines of therapy

Conditions: Multiple Myeloma

Summary: this is a single-center, open-label, single-arm study to evaluate the safety and efficacy of bispecific bcma-gprc5d chimeric antigen receptor (car) t-cells in patients with relapsed or refractory multiple myeloma who received three or more lines of therapy.

b-cell maturation antigen (bcma)-targeted chimeric antigen receptor (car) t-cell therapy has yielded satisfactory clinical outcomes in patients with relapsed or refractory (r/r) multiple myeloma (mm). however, bcma-targeted car-t cells cannot achieve a favorable response in patients with dim or negative bcma expression on the tumor surface at baseline or relapse. g protein-coupled receptor, class c, group 5, member d (gprc5d) is highly distributed on mm cells and proves to be a promising target for mm. in normal tissues, it is restrictedly expressed in hair follicle, rendering it a safe target for car-t cell therapy as well. to construct a bispecific bcma-gprc5d car structure would help mitigate the antigen escape and elevates the clinical efficacy. this is an investigational study. the objectives are to evaluate the safety and efficacy of bcma-gprc5d car-t cells in adult patients with relapsed or refractory mm disease.

Eligibility criteria:
inclusion criteria: 1. patient or his or her legal guardian voluntarily participates in and signs an informed consent form; 2. aged ≥ 18 years and ≤ 75 years; 3. diagnosed as multiple myeloma (mm) according to the international standard for multiple myeloma (imwg); 4. the presence of measurable disease at screening meets one of the following criteria:serum m-protein ≥ 1.0 g/dl or urine m-protein ≥ 200 mg/24h or diagnosed as light-chain mm without measurable disease in serum and urine; serum free light chain ≥ 10 mg/dl with an abnormal κ/λ ratio; 5. patients must relapse or be refractory after three or more lines of therapy, which at least include: one proteasome inhibitor (pi), one immunomodulatory drug (imid), and one anti-cd38 monoclonal antibody; 6. diagnosed as relapsed/refractory disease or primary refractory disease; 7. the last treatment is ineffective, or the disease progresses within 60 days after the end of the last therapy; 8. patients must recover from the toxicity of the last therapy (\< grade 2 by ctcae criteria); 9. ecog score 1-2 points and the expected survival period ≥ 3 months; 10. liver, kidney and cardiopulmonary functions meet the following requirements: 1. total bilirubin ≤ 1.5×uln, alanine aminotransferase (alt) ≤ 3 × uln and aspartate aminotransferase (ast) ≤ 3 × uln; 2. serum creatinine ≤ 1.5×uln, or creatinine clearance ≥ 60 ml/min; 3. hemoglobin (hb) ≥ 50 g/l without prior blood transfusion within 7 days; 4. baseline peripheral oxygen saturation \> 92%; 5. corrected serum calcium ≤ 12.5 mg/dl (≤ 3.1 mmol/l) or free (ionized, ionic) calcium ≤ 6.5 mg/dl (≤ 1.6 mmol/l); 6. left ventricular ejection fraction (lvef) \> 45%, without confirmed pericardiac effusion and abnormal electrocardiography with clinical significance; 7. without clinically significant pleural effusion; 11. venous access could be established; without contraindications of apheresis. exclusion criteria: 1. previous diagnosis and treatment of other malignancies within 3 years; 2. patients received previous anti-tumor therapies before apheresis including following therapies: targeted therapies, epigenetics modulation drugs, other drugs or medical devices (invasive) of clinical trials, monoclonal antibodies, cytotoxic agents, pis, imids, radiotherapy; 3. central nervous system (cns) involvement; 4. patients with fahrenheit macroglobulinemia, poems syndrome, or primary al, amyloidosis; 5. subjects with positive hbsag or hbcab positive and peripheral blood hbv dna titer is higher than the lower limit of detection of the research institution; hcv antibody positive; hiv antibody positive; cmv dna titer is higher than the lower limit of detection of the research institution; ebv dna titer is higher than the lower limit of detection of the research institution; 6. patients have a severe allergic history; 7. patiens have severe systemic diseases or poor cardiovascular, liver, kidney functions; 8. acute or chronic graft versus host disease (gvhd) occurs within 6 months before the screening or needs be treated with immunosuppressive agents; 9. active autoimmune or inflammatory diseases of the nervous system; 10. patients develop oncology emergencies and need to be treated before screening or infusion; 11. uncontrolled infections that need antibiotics treatment; 12. exposure to hematopoietic growth factor of cells within 1-2 weeks before apheresis; 13. exposure to corticosteriods or immunosuppressive agents within 2 weeks before apheresis; 14. patients receive a major surgical operation within 4 weeks before lymphodepletion or do not recover completely before the enrollment; or plan to receive a major surgical operation during the study period; 15. live attenuated vaccine within 4 weeks before screening; 16. patients with severe mental illness; 17. patients are addcited to alcohol or drugs; 18. pregnant or lactating women; patients and his or her spouse have a fertility plan within two years after car-t cell infusion; 19. other conditions considered inappropriate by the researcher.