IASO104 for the Treatment of Patients 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

• Age 18-75 years, any gender.
• Diagnosis of multiple myeloma (MM) per International Myeloma Working Group (IMWG) diagnostic criteria.
• 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.

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

• ECOG performance status 0-1.
• Life expectancy ≥12 weeks.
• 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).

• Contraception: Subjects/partners must use effective contraception from consent through 1 year post CAR-T infusion (excluded: calendar method).
• Signed informed consent approved by the Ethics Committee prior to screening.

Exclusion criteria

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

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

• Chronic corticosteroid use (>20 mg/day prednisone or equivalent), except for physiologic replacement, topical, or inhaled use.
• Uncontrolled hypertension despite medication.
• Severe cardiac disease, including:

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

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

• History of solid organ transplantation.
• Suspected or confirmed CNS involvement by plasma cell neoplasms.
• Major surgery within 2 weeks before apheresis or planned within 2 weeks post-treatment (allowed: minor procedures under local anesthesia).
• Investigational drugs within 1 month before apheresis.
• Uncontrolled active infections:

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

• 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(+).

• Pregnancy or lactation.
• Psychiatric disorders, cognitive impairment, or active CNS diseases.
• Other conditions deemed ineligible by the investigator.