A Study of KIV-318 Injection in Patients With BCMA-Positive Relapsed/Refractory Multiple Myeloma

This was a single-arm, open-label, multicenter, dose-escalation study designed to assess the safety, tolerability, and preliminary antitumor activity of KIV-318 Injection in relapsed/refractory multiple myeloma.

Primary endpoints:

To assess the safety and tolerability of KIV-318 Injection administered via intravenous infusion in patients with relapsed/refractory multiple myeloma, and to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D).

Secondary endpoints:

To evaluate the preliminary efficacy of KIV-318 Injection in relapsed/refractory multiple myeloma; To characterize the pharmacokinetic (PK), pharmacodynamic (PD), and replication-competent lentivirus (RCL) profiles of KIV-318 Injection in humans.

Inclusion criteria

• Subjects are eligible for inclusion only if they meet all of the following criteria:

• Age between 18 and 70 years (inclusive), regardless of gender;
• Diagnosis of multiple myeloma (MM) confirmed per the IMWG diagnostic criteria. and presenting with relapsed/refractory (r/r) MM following at least ≥3 prior lines of therapy. Prior therapies must have included proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and/or CD38 monoclonal antibodies. While prior exposure to all three therapeutic classes is preferred, subjects must have received at least two of these treatment categories (PIs, IMiDs, and/or anti-CD38) during their prior therapy;
• Subjects with r/r MM at screening, with documented disease progression, or who are considered refractory, either during or within 12 months after the most recent anti-myeloma treatment.
• The following cohort-specific criteria must be satisfied:

For Cohort A: No previous exposure to T-cell engager (TCE) agents and/or CAR-T cell therapy; For Cohort B: Prior treatment with TCEs and/or CAR-T therapy, and positive for BCMA target expression. Prior TCE therapy is defined as completion of at least the full initial step-dose regimen, or cumulative administration of at least 2 therapeutic doses. Prior CAR-T therapy is defined as having received at least one infusion of CAR-T cells targeting any antigen; For Cohort B (additional): In patients whose most recent anti-tumor therapy was a TCE, enrollment will be considered only if the TCE was discontinued due to intolerance or for reasons other than disease progression, with a disease status of stable disease (SD) or better at the time of discontinuation, and with no evidence of rapid disease progression prior to screening.

• Measurable disease at screening, meeting at least one of the following criteria:

Serum M-protein level ≥0.5 g/dL; or urine M-protein level ≥200 mg/24h; or for light-chain multiple myeloma in which disease is not measurable in serum or urine: involved serum immunoglobulin free light chain (sFLC) ≥10 mg/dL with an abnormal serum immunoglobulin κ/λ free light chain ratio.

• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 , and an estimated life expectancy of ≥3 months.
• Bone marrow function test results meeting the following requirements:

Hemoglobin ≥60 g/L (with no red blood cell transfusion within 1 week prior to screening), and the use of recombinant human erythropoietin is permitted; Absolute neutrophil count (ANC) ≥0.75×10⁹/L (with no granulocyte colony-stimulating factor [G-CSF] use within 1 week prior to screening, or no pegylated G-CSF use within 2 weeks prior to screening); Platelet count (PLT) ≥50×10⁹/L; Absolute lymphocyte count (ALC) ≥0.5×10⁹/L; CD3-positive T-cell absolute count ≥0.15×10⁹/L.

• Adequate organ function, defined as:

Left ventricular ejection fraction (LVEF) ≥45% assessed by echocardiography, with no clinically significant abnormalities on electrocardiogram (ECG); Creatinine clearance (CrCl) ≥30 mL/min, calculated using the Cockcroft-Gault formula ; Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤3.0 × upper limit of normal (ULN); Total bilirubin (TBIL) and alkaline phosphatase (AKP/ALP) ≤2.0 × ULN (≤3.0 × ULN for patients with Gilbert's syndrome); Prothrombin time (PT) ≤1.5 × ULN, activated partial thromboplastin time (APTT) <1.5 × ULN, and international normalized ratio (INR) <1.5 × ULN.

• Male subjects with reproductive potential and female subjects of childbearing potential must agree to use effective contraceptive measures from the time of signing the informed consent form (ICF) through 1 year after administration of the study drug. Female subjects of childbearing potential must have a negative serum pregnancy test at screening and prior to drug infusion, and must not be lactating.
• Subjects or their legally authorized representatives must agree to participate in this clinical trial and sign the informed consent form (ICF), indicating their understanding of the purpose and procedures of the trial and their willingness to participate in the study.

Exclusion criteria

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

• Receipt of any type of T-cell engager (TCE) therapy within 8 weeks or 5 half-lives (whichever is shorter) prior to the first dose of the investigational drug.
• Receipt of any of the following within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose of the investigational drug:

Participation in other interventional clinical trials; Receipt of any anti-tumor chemotherapy, hormonal therapy, targeted therapy, epigenetic therapy, or treatment using invasive investigational medical devices.

• Receipt of proteasome inhibitors, immunomodulatory agents, radiotherapy, or traditional Chinese medicine preparations approved for anti-tumor indications within 2 weeks or 5 half-lives (whichever is shorter) prior to the first dose of the investigational drug.
• Presence of meningeal, brainstem, or spinal cord metastasis and/or compression, or active central nervous system (CNS) metastasis.
• Receipt of allogeneic hematopoietic stem cell transplantation (allo-HSCT) within 6 months prior to infusion, or autologous hematopoietic stem cell transplantation (auto-HSCT) within 3 months prior to infusion.
• Presence of active second primary malignancies, with the following exceptions: malignancies that have received curative treatment with no known active disease for ≥2 years prior to enrollment; or adequately treated non-melanoma skin cancer with no current evidence of disease.
• Prior treatment with any agent pseudotyped with vesicular stomatitis virus G (VSVG).
• Presence of severe, uncontrolled active infection (bacterial, viral, fungal, etc.) at screening.
• Within 6 months prior to infusion:

Positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) with a detectable peripheral blood HBV DNA titer above the normal range; Positive for hepatitis C virus (HCV) antibody with a detectable peripheral blood HCV RNA titer above the normal range; Positive for human immunodeficiency virus (HIV) antibody; Positive for syphilis screening test.

• Presence of symptomatic heart failure or severe cardiac arrhythmias, including:

New York Heart Association (NYHA) Class III or IV congestive heart failure; Myocardial infarction or coronary artery bypass grafting (CABG) or coronary stent implantation within ≤6 months prior to signing the ICF; Clinically significant ventricular arrhythmias, or history of syncope of unknown cause (except for cases due to vasovagal or dehydration); History of severe non-ischemic cardiomyopathy.

• Clinically significant comorbidities, including:

Primary immunodeficiency; Stroke or seizure within 6 months prior to screening; Significant clinical evidence of dementia or altered mental status; Parkinson's disease or parkinsonian movement disorder or history thereof.

• Major surgery within 2 weeks prior to study drug administration, or planned major surgery within 2 weeks after study drug administration, excluding surgeries performed under local anesthesia.
• Uncontrolled hypertension, hypercalcemia, or diabetes mellitus.
• Administration of live attenuated vaccines within 1 month prior to study drug administration.
• Known severe hypersensitivity reaction to KIV-318 or its formulation components (e.g., protein components).
• Known severe hypersensitivity reaction to tocilizumab.
• Any other condition that, in the investigator's judgment, makes the subject unsuitable for participation in this study.