BR101 in Patients With Relapsed/Refractory Multiple Myeloma

An Open-Label, Single-Arm Clinical Study Evaluating the Safety and Efficacy of BR101 Injection in Patients With Relapsed/Refractory Multiple Myeloma

This study is an open-label, single-arm, dose-escalation and dose-expansion clinical trial designed to evaluate the maximum tolerated dose, safety, pharmacokinetic profile following administration of BR101 injection, and preliminary efficacy in subjects with relapsed or refractory multiple myeloma.

This study is a single-center, open-label, single-arm, phase 1 clinical trial consisting of a dose-escalation phase followed by a dose-expansion phase.The primary objectives are to determine the maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), and to characterize the safety and tolerability profile of BR101 injection in subjects with relapsed or refractory multiple myeloma.Secondary objectives include evaluating the pharmacokinetic (PK) characteristics of BR101 after intravenous administration and exploring the preliminary anti-tumor efficacy of the investigational product in this patient population.Throughout the study, adverse events, vital signs, laboratory parameters, and disease status will be closely monitored to comprehensively assess the safety, pharmacokinetics, and preliminary clinical activity of BR101.

Inclusion Criteria:

1. Voluntarily sign the informed consent form and be expected to complete follow-up examinations and treatments as required by the study procedures.
2. Aged 18 to 75 years (inclusive), with no gender restriction.
3. ECOG performance status of 0 or 1, and expected survival time ≥ 12 weeks.
4. Adequate organ function, with laboratory test results within the following criteria within 7 days prior to enrollment:

1) Coagulation function:

• Fibrinogen ≥ 1.0 g/L;

• Activated partial thromboplastin time (APTT) ≤ 1.5 × upper limit of normal (ULN);

• Prothrombin time (PT) ≤ 1.5 × ULN. 2) Hepatic function:

• Aspartate aminotransferase (AST) ≤ 2.5 × ULN;

• Alanine aminotransferase (ALT) ≤ 2.5 × ULN;

• Serum total bilirubin ≤ 1.5 × ULN, unless the subject has a documented diagnosis of Gilbert's syndrome;

• Subjects with Gilbert-Meulengracht syndrome with total bilirubin ≤ 3.0 × ULN and direct bilirubin ≤ 1.5 × ULN may be enrolled.

  3) Renal function:

• Serum creatinine ≤ 1.5 × ULN, or creatinine clearance ≥ 40 mL/min (Cockcroft-Gault formula, see Appendix 16.3).

  4) Hematopoietic function:

• Hemoglobin ≥ 60 g/L (no red blood cell [RBC] transfusion within 7 days prior to laboratory testing; use of recombinant human erythropoietin is permitted); Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L (prior growth factor support is allowed, but no such supportive therapy within 7 days prior to laboratory testing);

• Platelet count ≥ 50 × 10⁹/L (no transfusion support within 7 days prior to laboratory testing);

• Absolute lymphocyte count (ALC) ≥ 0.5 × 10⁹/L;

• T-cell count ≥ 0.15 × 10⁹/L. 5) Cardiopulmonary function:

• Left ventricular ejection fraction (LVEF) ≥ 45%;

• Blood oxygen saturation ≥ 91%. 5. Female subjects of childbearing potential must have a negative pregnancy test during the screening period. All male and female subjects with reproductive potential must agree to use effective contraceptive methods from the signing of the informed consent form until at least 6 months after the completion of BR101 injection infusion, or until CAR-positive cells are undetectable by two consecutive flow cytometry assessments (whichever occurs later). Female subjects considered non-fertile (meeting at least one of the following criteria):

• Status post hysterectomy or bilateral oophorectomy;

• Medically confirmed ovarian failure;

• Medically confirmed postmenopausal status (amenorrhea for at least 12 consecutive months in the absence of pathological or physiological causes).

  6. Meet the following criteria for multiple myeloma (MM):

  1. Subjects with a confirmed diagnosis of multiple myeloma according to the IMWG updated criteria (2016);

  2. BCMA expression positive on the plasma cell membrane surface detected by immunohistochemistry (IHC) or flow cytometry in the subject's tumor specimen (bone marrow);

  3. Meet one of the following laboratory criteria:

     1. Serum M-protein: IgG-type M-protein ≥ 5 g/L; or IgA-type M-protein ≥ 5 g/L; or IgD-type M-protein above the normal reference range;
     2. Urinary M-protein ≥ 200 mg/24 h;
     3. Serum free light chain ≥ 100 mg/L with an abnormal serum κ/λ free light chain ratio;
     4. If the patient has peripheral plasma cells, a plasma cell proportion < 5% is eligible for enrollment.

  4. Relapsed/refractory multiple myeloma, defined as meeting one or more of the following:

     1. Received at least 3 lines of prior therapy (including chemotherapy regimens based on proteasome inhibitors and immunomodulatory drugs);

     2. Documented disease progression during or within 12 months after the most recent anti-multiple myeloma therapy.

        Exclusion Criteria:

        1. History of malignancy within the past 5 years, excluding adequately treated non-melanoma skin cancer (basal cell carcinoma or squamous cell carcinoma), carcinoma in situ of the cervix, or thyroid cancer after radical resection.

        2. Patients who have used or require long-term use of immunosuppressive agents (e.g., cyclosporine or systemic corticosteroids) within 2 weeks prior to enrollment; however, physiological replacement, intermittent, topical, and inhaled corticosteroids are permitted.

        3. Major surgery performed within 2 weeks prior to enrollment, or surgery planned within 2 weeks after study treatment initiation (excluding subjects scheduled for local anesthesia-only procedures).

        4. Subjects with current or past central nervous system (CNS) disorders, such as epilepsy, paralysis, aphasia, stroke, subarachnoid hemorrhage or other CNS hemorrhage, severe brain injury, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, or psychosis.

        5. Patients with suspected or documented central nervous system involvement by plasma cell neoplasm during screening.

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

        7. Unstable systemic diseases judged by the investigator, including but not limited to severe hepatic, renal, or metabolic diseases requiring pharmacologic management.

        8. Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with peripheral blood hepatitis B virus (HBV) DNA titer above the lower limit of detection; positive hepatitis C virus (HCV) antibody with positive peripheral blood HCV RNA; positive human immunodeficiency virus (HIV) antibody; positive cytomegalovirus (CMV) DNA; positive syphilis test.

        9. Subjects with uncontrolled active fungal, viral, bacterial, or other infections (persistent infection-related signs/symptoms without improvement following appropriate antimicrobial therapy) or infections requiring intravenous antimicrobial therapy.

        10. Non-hematologic toxicities from prior therapy that have not resolved to baseline or grade ≤ 1 per NCI-CTCAE version 5.0, excluding alopecia and grade 2 peripheral neuropathy.

        11. Patients who received autologous hematopoietic stem cell transplantation within 12 weeks prior to study drug administration, or who have a history of allogeneic hematopoietic stem cell transplantation.

        12. Prior treatment with in vivo or ex vivo CAR-T therapy or other genetically modified cell therapy prior to enrollment.

        13. Prior BCMA-targeted therapy administered more than 3 years before enrollment, unless BCMA expression >30%.

        14. Administration of a live attenuated vaccine within 1 month prior to study drug dosing.

        15. Prior receipt of any of the following anti-tumor therapies:

     a) Immune/non-immune targeted systemic therapy within 7 days; b) Cytotoxic therapy within 7 days; c) Proteasome inhibitor and immunomodulatory agent therapy within 2 weeks; d) Radiation therapy within 4 weeks (excluding local radiation to myeloma-related bone lesions); e) Targeted therapy, epigenetic therapy, other investigational medicinal products, or therapy involving invasive investigational medical devices within 5 half-lives.

  16. Known severe hypersensitivity to tocilizumab, BR101 Injection, or any of its excipients.

  17. Any other conditions that, in the investigator's judgment, render the subject ineligible for enrollment.