A Phase 1b clinical trial to evaluate the safety and efficacy of BCMA-targeted CAR T-cell therapy in Thai patients with relapsed or refractory multiple myeloma.

The investigational product used in this study is a chimeric antigen receptor T-cell, also known as "CAR T-cell," engineered to specifically target B-cell maturation antigen (BCMA) protein. The patient's own T-lymphocytes are genetically modified ex vivo to express receptors capable of binding to BCMA protein expressed on the surface of malignant cells. These CAR T-cells are then expanded and infused back into each patient for the treatment of relapsed or refractory multiple myeloma.

Previous clinical research has demonstrated promising outcomes in the treatment of multiple myeloma with CAR T-cell therapy. For example, a clinical trial conducted by Bluebird Bio in 128 patients reported an overall response rate of 73% and a complete response rate of 33%, leading to approval by the United States Food and Drug Administration (FDA) in March 2021. Additionally, a clinical trial by Nanjing Legend Biotech in China, evaluating the investigational CAR T-cell product LCAR-B38M in 97 patients, demonstrated an overall response rate of 97.9% and a complete response rate of 80.4%.

The investigational product used in the current study has previously undergone a Phase 1 clinical trial in 15 patients with relapsed or refractory multiple myeloma, evaluating three dose levels: low (0.25 × 10⁷ cells/kg body weight), intermediate (0.5 × 10⁷ cells/kg body weight), and high (0.75 × 10⁷ cells/kg body weight). The study demonstrated an overall response rate of 100% and a complete response rate of 66.7%. Furthermore, patients who had previously received anti-CD38 monoclonal antibody immunotherapy and/or those with extramedullary disease also achieved an overall response rate of 100%.

Regarding safety, the most notable adverse event associated with BCMA-directed CAR T-cell gene therapy was cytokine release syndrome (CRS), which was observed in all patients and tended to be more severe in the high-dose cohort. However, all adverse events were manageable and clinically controllable. No treatment-related study discontinuations or deaths were reported.

Based on the efficacy and safety data, the high dose level (0.75 × 10⁷ cells/kg) was found to be associated with dose-limiting toxicity. Therefore, the intermediate dose (0.5 × 10⁷ cells/kg) - which demonstrated favorable therapeutic efficacy with an acceptable safety profile - was selected for the Phase 1b clinical trial in Thailand, in order to maximize benefit while minimizing risk to participants.

For the aforementioned reasons, this research project aims to further evaluate the safety and efficacy of BCMA-targeted CAR T-cell therapy in Thai patients with relapsed or refractory multiple myeloma. This Phase 1b study represents the first-in-Thai-patient clinical investigation of this approach. The research team anticipates that this therapy will demonstrate a high safety profile and effective disease control in patients with relapsed or refractory multiple myeloma.

Inclusion Criteria:

1. Age above 18 years old (inclusive), regardless of gender.

2. Patients with multiple myeloma who have received at least three lines of treatment for multiple myeloma and have failed at least after treatment with proteasome inhibitors and immunomodulators; At least one complete cycle of each line of therapy, unless the best response to that therapy was documented as progressive disease (PD) (according to the 2016 published IMWG criteria for efficacy evaluation, Appendix 4); Patients must have PD records during or within 12 months after the last treatment or no response (no MR or better response) within 60 days after the last treatment.

3. The presence of measurable lesions at screening was defined as any of the following:

   • Serum M protein ≥ 1 g/dL (≥ 10 g/L)
   • Urinary M-protein level ≥ 200 mg/24 hours
   • Serum free light chains (FLC): abnormal serum FLC ratio (< 0.26 or > 1.65) with involved FLC ≥ 10 mg/dL (100 mg/L)

4. ECOG Performance Status (Appendix 1) of 0-1.

5. Expected survival time ≥ 3 months.

6. Meets the following criteria prior to mononuclear cell apheresis:

   Hematology

   • Absolute count of lymphoid cells ≥ 0.5×109/L [Granulocyte colony-stimulating factor (G-CSF) is allowed, but this supportive treatment shall not be received by the test subjects within 7 days before laboratory tests during the screening period];
   • Absolute neutrophil count ≥ 1.0 ×109/L [Granulocyte colony-stimulating factor (G-CSF) is allowed, but the subjects shall not receive this supportive treatment within 7 days before laboratory tests during the screening period];
   • Platelet count ≥ 50×109/L (subjects must not receive blood transfusion support within 7 days before the screening laboratory test);
   • Hemoglobin ≥ 8.0 g/dL (recombinant human erythropoietin is allowed) [subjects have not received red blood cells (RBCS) within 7 days prior to screening laboratory testing]; Heart
   • Ejection function: Left ventricular ejection fraction (LVEF) ≥ 50% Lungs
   • Oxygen saturation: A blood oxygen saturation of ≥ 91% on non-oxygen therapy Kidneys
   • Creatinine clearance (CrCl) or glomerular filtration rate (GFR) (Cockcroft-Gault formula) ≥ 30 mL/min Liver
   • Total bilirubin (serum) ≤ 1.5 × ULN Patients with Gilbert's disease and a serum bilirubin level of more than 1.5 × ULN could be enrolled after approval from the sponsor
   • AST and ALT ≤ 3× ULN Clotting
   • PT ≤ 1.5× ULN, APTT ≤ 1.5×ULN, INR ≤ 1.5×ULN

7. Peripheral venous access can meet the requirements of apheresis and intravenous infusion.

8. Subjects agreed to use a reliable contraceptive method for contraception from the time they signed the informed consent form until 1 year after infusion. These include, but are not limited to: abstinence, vasectomy in men, and an implantable progestin-based contraceptive that suppresses ovulation; Intrauterine contraceptive devices; Hormone-releasing intrauterine devices; Sexual partner sterilization; Copper intrauterine devices, proper use of combined hormonal contraceptives that have been shown to inhibit ovulation; Progestin-based contraceptives that inhibit ovulation. Female subjects should be at the same time commitment to lose after 1 year not to donate eggs (eggs, oocyte) used for assisted reproduction.

9. They should voluntarily participate in the clinical trial and sign the informed consent.

Exclusion Criteria:

1. Subjects with a known history of allergy, hypersensitivity, intolerance, or contraindication to any component of CART-BCMA or drugs that may be used in the study (including fludarabine, cyclophosphamide, tocilizumab); or subjects allergic to beta-lactam antibiotics; or subjects with a history of severe allergic reactions.

2. Subjects who have previously received any CAR-T therapy or BCMA-targeted therapy.

3. Subjects who have received the following anti-multiple myeloma (anti-MM) treatments within the specified time frame before apheresis:

   • Small-molecule targeted therapy within 4 weeks or five half-lives, whichever was longer
   • Macromolecular drug therapy within 4 weeks or 2 half-lives (whichever is longer)
   • Cytotoxic therapy or proteasome inhibitor within 2 weeks
   • Immunomodulatory drug therapy within 1 week
   • Radiotherapy within 1 week

4. Subjects who have received any investigational drug within 4 weeks prior to apheresis or are concurrently participating in another clinical study (except for the following: subjects participating in observational, non-interventional clinical studies, or those in the follow-up period of an interventional clinical study).

5. Patients who have received autologous hematopoietic stem cell transplantation (ASCT) within 12 weeks prior to apheresis or have previously received allogeneic stem cell transplantation (with no time limit).

6. Subjects who have received live vaccines or attenuated vaccines within 4 weeks prior to CART-BCMA apheresis.

   Note: Administration of inactivated viral vaccines for seasonal influenza via injection is permitted; however, intranasal attenuated live influenza vaccines are not permitted.

7. Subjects who have received any of the following treatments within 7 days prior to apheresis, or are judged by the investigator to require long-term receipt of such treatments during the study:

   • Cumulative corticosteroids use equivalent to ≥ 70 mg prednisone within 7 days prior to apheresis, or long-term receipt of therapeutic-dose corticosteroids during the study as judged by the investigator
   • Immunosuppressive therapy
   • Graft-versus-host disease therapy
   • Central nervous system (CNS) prophylactic therapy

8. Toxicities resulting from previous treatments (including peripheral neuropathy) have not fully resolved or stabilized to Grade 1 (per NCI-CTCAE v5.0), except for those judged by the investigator to not affect the patient's safe receipt of treatment (e.g., alopecia).

9. Any clinically significant past or current history of CNS disorders, such as altered mental status, psychosis, dementia, neurocognitive, neurodegenerative, or neuroinflammatory diseases (e.g., Alzheimer's disease, Parkinson's disease, multiple sclerosis), epilepsy, seizures, hemiplegia, aphasia, stroke, subarachnoid hemorrhage or other CNS hemorrhage, and severe traumatic brain injury. For subjects with history of such CNS alterations, they must have fully recovered at least 1 year before administration.

10. Presence of meningeal, brainstem, spinal cord metastasis and/or compression, or active CNS metastasis; or suspected involvement of the CNS or meninges by multiple myeloma (MM), confirmed by magnetic resonance imaging (MRI) or computed tomography (CT).

11. Suspected involvement of the CNS or meninges by MM (confirmed by MRI or CT), or presence of other active CNS diseases.

12. Patients with plasma cell leukemia, Waldenstrom's macroglobulinemia, POEMS syndrome (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal protein, Skin changes), or amyloidosis at screening.

13. Cardiac diseases: Current heart failure (New York Heart Association [NYHA] classification ≥ Class II, Appendix 2); severe cardiac diseases as determined by the investigator; myocardial infarction occurring ≤ 6 months before apheresis; unstable angina pectoris, severe arrhythmia (as judged by the investigator), or coronary artery bypass grafting (CABG) performed ≤ 3 months before apheresis.

14. Poorly controlled hypertension (systolic blood pressure > 160 mmHg and/or diastolic blood pressure > 100 mmHg), or a history of hypertensive crisis or hypertensive encephalopathy.

15. Patients who have undergone major surgery (other than diagnostic procedures or biopsies) or plasmapheresis within 4 weeks before apheresis or are expected to undergo major surgery during the study. Note: Patients scheduled for surgical procedures under local anesthesia may participate in the study. Kyphoplasty or vertebroplasty is not considered major surgery.

16. Subjects currently receiving thrombolytic, anticoagulant, or antiplatelet therapy.

17. Subjects with infections requiring intravenous antibiotic administration or hospitalization.

18. Subjects with active hepatitis B; subjects positive for hepatitis C virus (HCV) antibody and positive for HCV RNA; subjects positive for human immunodeficiency virus (HIV) antibody; subjects positive for syphilis screening antibody;

    a) Non-active/asymptomatic carrier, chronic, or active HBV-infected subjects may be enrolled if they meet the following criteria: HBV deoxyribonucleic acid (DNA) < 500 IU/mL (or 2500 copies/mL) at screening.

19. Pregnant or lactating women.

20. Subjects diagnosed with or treated for other invasive malignant tumors except multiple myeloma, except for the following cases: non-melanoma skin cancer that has been surgically removed, cured cervical carcinoma in situ, localized prostate cancer, low-stage bladder cancer, ductal carcinoma in situ of the breast, or malignant tumors with no recurrence and no treatment within 2 years before enrollment.

21. Subjects deemed by the investigator to be unsuitable for participation in this clinical study due to any clinical or laboratory abnormalities or other reasons.