This is a single arm, open-label, dose escalation, phase 1 study to evaluate the safety, tolerability, preliminary efficacy, pharmacokinetics, pharmacodynamics and immunogenicity of RN9101 injection for patients with relapsed/refractory multiple myeloma.

This investigator-initiated clinical study aims to evaluate RN9101, the third-generation self-inactivating lentiviral vector that carries a CD19/BCMA-targeted CAR, in patients with relapsed refractory multiple myeloma (MM). Eligible patients with multiple myeloma, who failed prior lines of therapy or show persistent minimal residual disease (MRD), will be enrolled. Participants will receive a single intravenous infusion of RN9101. Primary endpoints include treatment-emergent adverse events (TEAEs) and dose-limiting toxicities (DLTs). Secondary endpoints include objective response rate (ORR), disease control rate (DCR), pharmacokinetics, and pharmacodynamics of in vivo CAR-T. This study aims to provide initial evidence for the safety and anti-tumor activity of in vivo CAR-T in multiple myeloma.

Inclusion Criteria:

• Subjects must meet all of the following criteria to be enrolled in this study:

  1. Age ≥18 years, either sex;

  2. Diagnosis of multiple myeloma (MM) according to IMWG response criteria, with BCMA target antigen expression on MM cells confirmed by flow cytometry or bone marrow pathology and immunohistochemistry;

  3. Received at least 2 prior lines of anti-multiple myeloma therapy, with each line containing at least one complete treatment cycle, and documented disease progression during or after the most recent anti-myeloma therapy based on assessment data;

  4. Measurable disease at screening, defined as meeting at least one of the following criteria:

     1. Serum M-protein ≥ 0.5 g/dL;
     2. Urine M-protein level ≥ 200 mg/24 h;
     3. Involved serum free light chain ≥ 10 mg/dL with abnormal serum free light chain κ/λ ratio;
     4. Clinical relapse: a. New bone lesions or soft tissue plasmacytomas (excluding osteoporotic fractures); b. Definite increase in existing plasmacytomas or bone lesions (sum of the products of perpendicular diameters [SPD] of measurable lesions increased by ≥50% with an absolute increase of ≥1 cm);

  5. ECOG performance status of 0-2, with an estimated life expectancy of ≥3 months;

  6. Bone marrow function test results (at screening or within 2 months prior to screening) meeting the following conditions:

     1. Hemoglobin ≥ 6 g/dL (no red blood cell transfusion within 1 week prior to screening), with recombinant human erythropoietin permitted; for patients meeting the hemoglobin ≥ 6 g/dL enrollment criterion, red blood cell transfusions may be allowed to maintain hemoglobin ≥ 6 g/dL;
     2. Absolute neutrophil count (ANC) ≥ 600/μL (no granulocyte colony-stimulating factor [G-CSF] used within 1 week prior to screening, or no pegylated G-CSF used within 2 weeks prior to screening);
     3. Platelet count ≥ 50,000/μL;
     4. Lymphocyte count ≥ 500/μL;
     5. Absolute CD3-positive T-cell count ≥ 150/μL;

  7. Normal renal function during screening or within 2 months prior to screening: creatinine clearance (CrCl) (calculated by the Cockcroft-Gault formula) ≥ 45 mL/min;

  8. Hepatic function during screening or within 2 months prior to screening meeting the following conditions:

     1. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3.0 × upper limit of normal (ULN);
     2. Total bilirubin (TBIL) and alkaline phosphatase (AKP or ALP) ≤ 2.0 × ULN (except for congenital hyperbilirubinemia, such as Gilbert's syndrome, where direct bilirubin may be ≤ 1.5 × ULN);
     3. Albumin ≥ 3 g/dL;

  9. Cardiac function during screening or within 2 months prior to screening meeting the following conditions:

     1. Left ventricular ejection fraction (LVEF) ≥ 40% (assessed by echocardiography or MUGA scan);
     2. No clinically significant pericardial effusion;
     3. No clinically significant electrocardiogram abnormalities;

  10. Pulmonary function during screening or within 2 months prior to screening meeting the following conditions:

      1. Oxygen saturation ≥ 90%;
      2. No clinically significant pleural effusion;

  11. For females of childbearing potential, a negative pregnancy test at screening and prior to dosing, and not currently breastfeeding;

  12. Males and females of childbearing potential must agree to use effective contraception from the date of informed consent signing until 1 year after the end of study treatment;

  13. Males and females of childbearing potential must agree not to donate gametes (including sperm or ova) from the date of informed consent signing until 1 year after the end of study treatment;

  14. The subject or their legally authorized representative has signed the Informed Consent Form (ICF), indicating understanding of the study objectives and procedures, and voluntary participation in this study.

Exclusion Criteria:

• Subjects meeting any of the following criteria will be excluded from the study:

  1. Received other anti-tumor therapy during the screening period (as determined primarily by the investigator):

     1. Received targeted therapy, epigenetic therapy, other investigational drug therapy, or treatment involving invasive investigational medical devices within 5 half-lives;
     2. Received systemic immunologic or non-immunologic therapy within 1 week;
     3. Received cytotoxic therapy within 1 week;
     4. Received proteasome inhibitor and immunomodulatory therapy within 2 weeks;
     5. Received radiotherapy within 4 weeks (except if the radiation field involves ≤5% of bone marrow reserve, in which case there is no restriction on the time since completion of radiotherapy, and the subject may still be enrolled);

  2. Received allogeneic hematopoietic stem cell transplantation within 6 months prior to dosing, or autologous hematopoietic stem cell transplantation within 3 months prior to dosing;

  3. History of malignancy other than multiple myeloma prior to screening, except for the following: malignancies treated with curative intent and with no known active disease for ≥2 years prior to enrollment; adequately treated non-melanoma skin cancer with no current evidence of disease;

  4. Previously received any therapy utilizing vesicular stomatitis virus glycoprotein (VSV-G) pseudotyped virus;

  5. Presence of severe and uncontrolled infection during screening (including bacterial, viral, fungal, etc.);

  6. Positive hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb), with peripheral blood hepatitis B virus (HBV) DNA titer above the normal range detected within 6 months prior to infusion; positive hepatitis C virus (HCV) antibody with peripheral blood HCV RNA titer above the normal range; positive human immunodeficiency virus (HIV) antibody; positive syphilis test;

  7. Symptomatic heart failure or other cardiac diseases, such as severe arrhythmias:

     1. New York Heart Association (NYHA) Class III or IV congestive heart failure;
     2. Myocardial infarction within 6 months prior to informed consent signing, or prior coronary artery bypass grafting (CABG) or coronary artery stent implantation;
     3. Clinically significant ventricular arrhythmias or history of unexplained syncope (excluding vasovagal or dehydration-induced syncope);
     4. History of severe non-ischemic cardiomyopathy;

  8. Other clinically significant diseases, including:

     1. Primary immunodeficiency;
     2. Stroke or seizure within 6 months prior to screening;
     3. Definite clinical evidence of dementia or altered mental status;
     4. Parkinson's disease, parkinsonian movement disorders, or relevant history;

  9. Received surgery within 2 weeks prior to dosing, or planned surgery within 2 weeks after dosing (except for local anesthesia procedures);

  10. Received live attenuated vaccines within 1 month prior to dosing;

  11. Known severe allergic reaction to RN9101 or any of its formulation components;

  12. Known severe allergic reaction to tocilizumab;

  13. Patients unsuitable for intravenous infusion;

  14. Other conditions deemed by the investigator as rendering the subject unsuitable for participation in this study.