IASO104 for the Treatment of Patients With Relapsed/Refractory Multiple Myeloma

Exploratory Clinical Study Protocol on the Safety and Efficacy of Fully Human BCMA-Targeted Chimeric Antigen Receptor Autologous T-Cell Injection (IASO104) for the Treatment of Patients With Relapsed/Refractory Multiple Myeloma

This study is a single-center, open-label, dose-exploration trial designed to evaluate the tolerability and safety of different doses of IASO104 in patients with relapsed/refractory plasma cell neoplasms, determine the recommended dose of IASO104, and assess its pharmacokinetic and pharmacodynamic characteristics. Additionally, the study will preliminarily observe the efficacy of the investigational drug in a small sample of subjects with relapsed/refractory multiple myeloma.

This study adopts a "3+3" dose-escalation design, with three predefined dose levels: 0.5×10⁶ CAR-T cells/kg, 1.0×10⁶ CAR-T cells/kg, and 3.0×10⁶ CAR-T cells/kg, administered as a single infusion.For each dose group, the first subject must be observed for at least 2 weeks after infusion before subsequent subjects can be treated. If stable biological activity or clinical benefit is observed at a lower dose level, the study may proceed with 1-2 expanded dose groups at lower levels after discussion between the investigator and sponsor, without requiring MTD determination.During the dose-escalation phase, 2-3 subjects will be enrolled per dose level, with the total number of subjects depending on the escalation progression (estimated 4-6 subjects in this phase). Treatment in the next dose group may only begin after all subjects in the current group have completed DLT assessment post-infusion.

Inclusion Criteria:

1. Age 18-75 years, any gender.

2. Diagnosis of multiple myeloma (MM) per International Myeloma Working Group (IMWG) diagnostic criteria.

3. Prior therapy requirements:

   MM patients: ≥3 prior lines of therapy, including:

   • 1 proteasome inhibitor (PI)
   • 1 immunomodulatory drug (IMiD)
   • 1 anti-CD38 monoclonal antibody Exception: No minimum line requirement for subjects refractory to PIs, IMiDs, and anti-CD38 therapy.

   Primary plasma cell leukemia (pPCL): ≥1 prior line including ≥1 PI and ≥1 IMiD.

4. Documented disease progression during/within 12 months after last anti-myeloma therapy (exemption: No 12-month requirement if last line was CAR-T).

5. Measurable disease at screening (≥1 of the following):

   Serum M-protein:

   IgG ≥10 g/L IgA/IgD/IgE/IgM ≥5 g/L Urine M-protein ≥200 mg/24h Serum free light chains (FLC): Involved FLC ≥100 mg/L with abnormal κ/λ ratio Bone marrow plasma cells ≥30% (if no measurable M-protein/FLC).

6. ECOG performance status 0-1.

7. Life expectancy ≥12 weeks.

8. Adequate organ function (all lab values within 7 days prior to enrollment):

   Hematology:

   Absolute neutrophil count (ANC) ≥1×10⁹/L (allowed: growth factor support, but none within 7 days) Absolute lymphocyte count (ALC) ≥0.3×10⁹/L Platelets ≥50×10⁹/L (no transfusion within 7 days) Hemoglobin ≥60 g/L (no RBC transfusion within 7 days; erythropoietin allowed)

   Liver:

   ALT/AST ≤2.5×ULN Total bilirubin ≤1.5×ULN Renal: Calculated CrCl ≥40 mL/min (Cockcroft-Gault)

   Coagulation:

   Fibrinogen ≥1.0 g/L aPTT/PT ≤1.5×ULN Pulmonary: SpO₂ >91% (room air) Cardiac: LVEF ≥50% (echocardiography).

9. Contraception: Subjects/partners must use effective contraception from consent through 1 year post CAR-T infusion (excluded: calendar method).

10. Signed informed consent approved by the Ethics Committee prior to screening.

Exclusion Criteria:

1. Active graft-versus-host disease (GVHD) or requiring long-term immunosuppressive therapy.

2. Prior hematopoietic stem cell transplantation (HSCT):

   Autologous HSCT (Auto-HSCT) within 12 weeks before apheresis,

   ≥2 prior Auto-HSCTs, Any prior allogeneic HSCT (Allo-HSCT).

3. Prior cell therapy targeting plasma cells within 3 months before apheresis, or detectable residual cellular therapy products in peripheral blood.

4. Recent anti-myeloma therapies (relative to apheresis):

   Monoclonal antibody treatment within 21 days, Cytotoxic chemotherapy or proteasome inhibitors within 14 days, Immunomodulatory drugs within 7 days, Other anti-tumor therapies within 14 days or 5 half-lives (whichever is shorter).

5. Chronic corticosteroid use (>20 mg/day prednisone or equivalent), except for physiologic replacement, topical, or inhaled use.

6. Uncontrolled hypertension despite medication.

7. Severe cardiac disease, including:

   Unstable angina, Myocardial infarction (within 6 months before screening), Congestive heart failure (NYHA Class ≥III), Severe arrhythmias.

8. Unstable systemic illnesses per investigator's judgment (e.g., severe hepatic, renal, or metabolic disorders requiring medication).

9. Other malignancies within 5 years, excluding:

   Carcinoma in situ of the cervix, Basal/squamous cell skin cancer, Localized prostate cancer post-radical resection, Ductal breast carcinoma in situ post-resection.

10. History of solid organ transplantation.

11. Suspected or confirmed CNS involvement by plasma cell neoplasms.

12. Major surgery within 2 weeks before apheresis or planned within 2 weeks post-treatment (allowed: minor procedures under local anesthesia).

13. Investigational drugs within 1 month before apheresis.

14. Uncontrolled active infections:

    Persistent symptoms despite appropriate therapy, Requiring IV antimicrobials at screening.

15. Viral infections:

    HBV: HBsAg(+) or HBcAb(+) with detectable HBV DNA, HCV: HCV Ab(+) with detectable HCV RNA, HIV Ab(+), CMV DNA(+), Syphilis: TRUST(+) and TPPA(+).

16. Pregnancy or lactation.

17. Psychiatric disorders, cognitive impairment, or active CNS diseases.

18. Other conditions deemed ineligible by the investigator.