JY232(JY232) Injection in Relapsed/Refractory Multiple Myeloma

A Clinical Study to Evaluate the Safety, Tolerability and Preliminary Efficacy of JY232 Injection in Patients With Relapsed/Refractory Multiple Myeloma

This study is an investigator-initiated single center, single arm clinical study with a target population of patients with relapsed/refractory multiple myeloma. It is an early exploratory clinical study of the safety, tolerability and initial efficacy of JY232 injection in the treatment of relapsed/refractory multiple myeloma.

This open-label, single-arm study is designed to evaluate the efficacy and safety of in vivo CAR-T cell therapy (JY232 Injection) in patients with relapsed/refractory multiple myeloma. Following screening, eligible subjects will provide informed consent and be enrolled in the study. They will then receive JY232 Injection via intravenous infusion. Subsequently, subjects will undergo safety and efficacy assessments for up to 24 months to evaluate disease control.

Inclusion Criteria:

1. The subject voluntarily signs the informed consent form, is willing and able to comply with all study requirements.

2. Age 18-75 years, male or female.

3. Diagnosis of active MM according to the diagnostic criteria established by the International Myeloma Working Group (IMWG).

4. Must have undergone stem cell transplantation (SCT) or be transplant-ineligible.

5. Must have received at least 2 prior lines of anti-MM therapy (including immunomodulatory drugs, proteasome inhibitors, and anti-Cluster of Differentiation 38 (CD38) therapy, as single agents or in combination. Patients who are intolerant or have contraindications to these therapies are eligible for enrollment if they meet other inclusion/exclusion criteria). Each line of therapy must have included at least one complete cycle, and there must be documented evidence of disease progression on or relapse after the last line of therapy, or permanent discontinuation of therapy due to treatment-related toxicities (the reason for permanent discontinuation due to toxicity must be documented in the CRF). Furthermore, the patient must be refractory or intolerant to any established standard-of-care regimen that, in the investigator's assessment, is of significant clinical benefit to the patient.

6. The subject's tumor sample (bone marrow) tests positive for B-Cell Maturation Antigen (BCMA) expression on the plasma cell membrane via immunohistochemistry (IHC) or flow cytometry.

7. Presence of measurable disease at screening determined by any one of the following criteria:

   • Proportion of clonal plasma cells in bone marrow cytology, bone marrow biopsy histology, or flow cytometry ≥ 5%;
   • Serum monoclonal protein (M-protein) level: Immunoglobulin G (IgG) type M-protein ≥10 g/L; or Immunoglobulin A (IgA), Immunoglobulin D (IgD), Immunoglobulin E (IgE), Immunoglobulin M (IgM) type M-protein ≥5 g/L;
   • Urine M-protein level ≥200 mg/24 hours;
   • For MM without measurable serum or urine M-protein: involved serum free light chain ≥100 mg/L (10 mg/dL) and abnormal serum κ/λ free light chain ratio (<0.26 or >1.65);
   • Or clinical relapse: a. New bone lesions or soft tissue plasmacytomas (excluding osteoporotic fractures); b. Confirmed increase in Sum of the Product of Diameters (SPD) of existing plasmacytomas or bone lesions (≥50% increase in SPD of measurable lesions, absolute increase ≥1 cm).

8. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-2 (see Appendix 1 for ECOG scale).

9. Expected survival time ≥12 weeks.

10. The subject must have adequate organ function, meeting all the following laboratory results prior to enrollment:

    • Hematology: Absolute neutrophil count (ANC) ≥ 1×10^9 /L (growth factor support is allowed, but must not have been administered within 7 days prior to the laboratory test); Absolute lymphocyte count (ALC) ≥0.3×10^9 /L; Platelets ≥50×10^9 /L (must not have received transfusion support within 7 days prior to the laboratory test); Hemoglobin ≥60 g/L (no red blood cell (RBC) transfusion within 7 days prior to the laboratory test; recombinant human erythropoietin is allowed);
    • Liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 × upper limit of normal (ULN); Serum total bilirubin ≤1.5 × ULN;
    • Renal function: If available, measured CrCl from 24-hour urine collection; otherwise, calculated creatinine clearance (CrCl) via Cockcroft-Gault formula ≥ 40 ml/min;
    • Coagulation: Fibrinogen ≥1.0 g/L; Activated partial thromboplastin time (aPTT) ≤1.5 × ULN; Prothrombin time (PT) ≤1.5 × ULN;
    • Oxygen saturation >91% (on room air);
    • Left ventricular ejection fraction (LVEF) ≥ 50 %;
    • No clinically significant pericardial effusion detected.

11. The subject and their spouse agree to use effective barrier or pharmacological contraception from signing the informed consent until one year after CAR-T cell infusion (excluding the rhythm method).

Exclusion Criteria:

1. History of graft-versus-host disease (GvHD), or presence of autoimmune disease, immunodeficiency, or any condition requiring long-term immunosuppressive therapy.

2. Allogeneic hematopoietic stem cell transplantation within 6 months prior to infusion, or autologous hematopoietic stem cell transplantation within 3 months prior to infusion.

3. Prior anti-tumor therapy as follows:

   • Monoclonal antibody therapy for multiple myeloma (MM) within 21 days prior to dosing or within at least 5 half-lives (whichever is longer), or
   • Cytotoxic chemotherapy within 14 days prior to dosing or within at least 5 half-lives (whichever is longer), or
   • Proteasome inhibitor or immunomodulatory agent therapy within 14 days prior to dosing or within at least 5 half-lives (whichever is longer), or
   • Treatment with investigational drugs within 30 days prior to screening or within 5 half-lives (whichever is longer), or still within the washout period; or treatment involving invasive investigational medical devices, or
   • Radiotherapy within 4 weeks prior to dosing, or
   • Other anti-tumor therapies not listed above within 14 days prior to dosing or within at least 5 half-lives (whichever is longer).

4. Use of therapeutic doses of corticosteroids (defined as prednisone or equivalent > 20mg/day) within 7 days prior to screening, except for physiological replacement, topical, and inhaled steroids.

5. Hypertension uncontrolled by two or more antihypertensive medications to the following range (systolic BP <160 mmHg, diastolic BP <90 mmHg); or hypotension below normal range despite treatment (systolic BP <90 mmHg or diastolic BP <60 mmHg).

6. Severe cardiac disease: including but not limited to unstable angina, myocardial infarction (within 6 months prior to screening), congestive heart failure New York Heart Association (NYHA) class ≥III, severe arrhythmia.

7. Unstable systemic diseases as judged by the investigator: including but not limited to severe hepatic, renal, respiratory, or metabolic diseases requiring medication.

8. Diagnosis of malignancy other than MM within 5 years prior to screening, except for adequately treated carcinoma in situ of the cervix, basal cell or squamous cell skin cancer, localized prostate cancer treated with radical surgery, ductal carcinoma in situ of the breast treated with radical surgery.

9. History of solid organ transplantation.

10. Presence of central nervous system (CNS) involvement, symptoms of CNS involvement (including cranial nerve lesions and extensive lesions or spinal cord compression), or CNS metastasis.

11. MM patients with extramedullary disease (except for those with a single para-medullary lesion with a maximum transverse diameter ≤3cm).

12. MM patients with concomitant plasma cell leukemia (peripheral blood plasma cell proportion ≥5%).

13. Major surgery within 2 weeks prior to dosing, or planned surgery within 2 weeks after study treatment (subjects scheduled for local anesthesia surgery may participate).

14. Treatment with other interventional investigational drugs within 1 month prior to signing the informed consent form (ICF).

15. Uncontrolled active infection within 7 days prior to dosing, e.g., positive blood culture ≤72 hours prior to infusion (except for <CTCAE Grade 2 genitourinary tract and upper respiratory tract infections), or infection requiring medication.

16. Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with detectable Hepatitis B Virus (HBV) DNA ≥1×10^3 copies/mL in peripheral blood; positive for hepatitis C virus (HCV) antibody with detectable HCV RNA in peripheral blood; positive for human immunodeficiency virus (HIV) antibody; positive for cytomegalovirus (CMV) DNA; positive for syphilis.

17. Pregnant or breastfeeding women.

18. Psychiatric illness, impaired consciousness, or central nervous system disorders.

19. Non-hematological toxicities from prior therapy have not recovered to baseline or ≤ Grade 1 (per NCI-CTCAE v5.0, except for alopecia and Grade 2 peripheral neuropathy).

20. Any other condition considered by the investigator to be unsuitable for enrollment.