Study to Evaluate the Safety of UF-KURE-BCMA CAR T-Cells in Advanced Myeloma

Inclusion Criteria:

Subjects must meet ALL of the following criteria to be eligible for study enrollment:

1. Age: ≥18 years at time of signing informed consent

2. Diagnosis: Documented multiple myeloma meeting one of the following:

   • Relapsed disease: Progression after achieving at least minimal response (MR) to prior therapy
   • Refractory disease: Non-responsive or progressive disease while on therapy or within 60 days of last treatment (in subjects who achieved ≥MR on prior therapy)

3. Prior Therapy:

   • Received ≥3 prior lines of anti-myeloma therapy
   • Prior therapy must include:

   At least one proteasome inhibitor At least one immunomodulatory drug (e.g., lenalidomide, pomalidomide, thalidomide) At least one anti-CD38 monoclonal antibody (e.g., daratumumab, isatuximab) o Prior anti-BCMA CAR-T therapy is permitted if subject achieved PFS ≥6 months post-infusion

4. Measurable Disease: At least one of the following at screening (for response assessment eligibility):

   • Serum M-protein ≥0.5 g/dL by protein electrophoresis (SPEP)
   • Urine M-protein ≥200 mg/24 hours by protein electrophoresis (UPEP)
   • Serum free light chain (FLC) difference ≥10 mg/dL with abnormal FLC ratio Note: Subjects with non-measurable disease may enroll for safety assessment
5. Performance Status: ECOG Performance Status 0-2 (see Appendix A)

6. Organ Function: Adequate organ function as defined by:

   Hepatic:

   o Total bilirubin ≤2× institutional upper limit of normal (ULN), except subjects with Gilbert's syndrome

   • AST and ALT ≤2.5× institutional ULN

   Renal:

   o Calculated creatinine clearance ≥30 mL/min (Cockcroft-Gault formula)

   Cardiac:

   o Left ventricular ejection fraction (LVEF) ≥45% by echocardiogram or MUGA

   Pulmonary:

   o ≤Grade 1 dyspnea

   o Oxygen saturation ≥92% on room air

   o If PFTs performed: FEV₁ ≥50% predicted and DLCO ≥40% predicted (corrected for hemoglobin)

7. Prior Therapy Washout:

   o ≥2 weeks since last radiation or systemic anti-myeloma therapy (standard agents)

   o ≥4 weeks since last investigational therapy

   o ≥6 weeks since autologous stem cell transplant

8. Informed Consent: Ability to understand and willingness to provide written informed consent
9. Contraception Requirements (for subjects of reproductive potential):

Female subjects:

o Women of childbearing potential must: Have negative serum pregnancy test at screening Agree to use highly effective contraception (failure rate <1% per year) from enrollment through 6 months post-CAR-T infusion

• Acceptable methods: bilateral tubal ligation, male partner sterilization, hormonal contraceptives that inhibit ovulation, hormone-releasing IUD, copper IUD
• Sexual abstinence is acceptable if consistent with subject's preferred lifestyle

Male subjects:

• Must agree to use condom plus effective contraception if partner is of childbearing potential
• Must refrain from sperm donation from enrollment through 6 months post-CAR-T infusion

Exclusion Criteria:

Subjects meeting ANY of the following criteria will be excluded:

1. Disease-Specific Exclusions:

   • Active CNS involvement by multiple myeloma
   • Plasma cell leukemia
   • History of allogeneic hematopoietic stem cell transplantation

2. Malignancy Exclusions:

   o Second active malignancy, except: Non-melanoma skin cancer Carcinoma in situ (cervix, bladder, breast) Stage 1 uterine cancer Localized prostate cancer

3. Cardiovascular Exclusions:

   • New York Heart Association (NYHA) Class IV congestive heart failure
   • Unstable angina pectoris
   • Clinically significant cardiac arrhythmias
   • Myocardial infarction, stroke, or TIA within 6 months of enrollment

4. Infectious Disease Exclusions:

   • Known HIV infection or AIDS-related illness
   • Active hepatitis B or C infection:

Positive HBsAg, or Positive anti-HBc or anti-HCV with detectable viral nucleic acid by PCR

• Active infection requiring systemic therapy 5. Neurological Exclusions:
• History of clinically relevant CNS pathology including:

Epilepsy or seizure disorders Paresis, aphasia Uncontrolled cerebrovascular disease Severe brain injury Dementia Parkinson's disease 6. Autoimmune Disease:

• Active autoimmune disease requiring systemic immunosuppression >15 mg/day prednisone equivalent within past 6 months
• Examples: rheumatoid arthritis, lupus