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

A Clinical Study to Evaluate the Safety and Efficacy of BCMA-GPRC5D CAR-T in Patients With R/R MM Who Received Three or More Lines of Therapy

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.

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.