CS1-Targeted CAR-T Cells for Relapsed/Refractory Multiple Myeloma

This investigator-initiated Phase 1 clinical study is designed to evaluate the feasibility, safety, tolerability, and preliminary antitumor activity of autologous CS1-targeted chimeric antigen receptor T (CAR-T) cells in adults with relapsed or refractory multiple myeloma (MM).

Multiple myeloma is a hematologic malignancy characterized by the clonal proliferation of plasma cells. Although treatment options for multiple myeloma have expanded, patients with relapsed or refractory disease may develop resistance to available therapies and have limited treatment options. Cellular immunotherapies directed against antigens expressed on malignant plasma cells represent a potential therapeutic approach for this patient population.

CS1, also known as signaling lymphocytic activation molecule family member 7 (SLAMF7; CD319), is a cell-surface antigen that is highly expressed on plasma cells and multiple myeloma cells. The expression of CS1 on malignant plasma cells provides a rationale for investigating CS1-directed CAR-T cell therapy. Autologous CS1-targeted CAR-T cells are genetically modified T lymphocytes designed to recognize CS1-expressing cells and mediate an immune response against target cells.

This is a single-center, single-group, open-label, non-randomized Phase 1 study without a control arm. The study uses a dose-escalation design to evaluate different dose levels of autologous CS1-targeted CAR-T cells. Participants receive the investigational treatment according to the protocol-defined dose-escalation scheme. The investigational treatment consists of a single infusion of autologous CS1-targeted CAR-T cells.

Participants undergo collection of autologous T cells for manufacture of the investigational CAR-T cell product. Once the CAR-T-cell product is ready, participants receive a single infusion of CS1-targeted CAR-T cells at the assigned dose level. Participants are subsequently monitored according to the study protocol for treatment-related adverse events, tolerability, and clinical and laboratory findings.

The primary purpose of the dose-escalation portion of the study is to characterize the safety and tolerability of CS1-targeted CAR-T cell therapy across the planned dose levels. The study will also provide preliminary information regarding the antitumor activity of the investigational treatment. Disease assessments and safety evaluations will be conducted according to protocol-defined procedures and criteria.

The study is intended to generate preliminary clinical evidence regarding the feasibility, safety, tolerability, and potential antitumor activity of autologous CS1-targeted CAR-T cell therapy in patients with relapsed or refractory multiple myeloma. The findings may provide information to support further clinical investigation of CS1-targeted CAR-T cell therapy in this patient population.

Inclusion criteria

• Subjects fully understand the trial purpose, study design, procedures, and potential adverse reactions, voluntarily agree to participate, and sign written informed consent before any study-related procedures are performed.
• Subjects have no contraindications to leukapheresis.
• Subjects are aged ≥ 18 years at screening.
• Subjects have a confirmed diagnosis of relapsed or refractory multiple myeloma (RRMM) consistent with the International Myeloma Working Group (IMWG) diagnostic criteria.
• Subjects have documented disease progression after receiving at least two lines of prior systemic therapy. Autologous or allogeneic hematopoietic stem cell transplantation (SCT) with corresponding supportive care is defined as one line of therapy. Subjects must have progressed after at least one proteasome inhibitor and one immunomodulatory agent. Subjects must have previously received CD38 monoclonal antibody therapy or be unsuitable for CD38 monoclonal antibody administration. All subjects must be currently ineligible for or decline autologous or allogeneic SCT.
• Subjects have evaluable disease and meet at least one of the following conditions:

• Serum M-protein ≥ 10 g/L; for subjects with IgA, IgD, IgE, or IgM multiple myeloma, serum M-protein ≥ 5 g/L.
• 24-hour urinary M-protein ≥ 200 mg.
• For light-chain multiple myeloma without measurable serum or urine M-protein: abnormal serum κ/λ free light chain (FLC) ratio and involved FLC ≥ 100 mg/L;
• Presence of evaluable plasmacytoma on imaging examination, or bone marrow plasma cell proportion ≥ 10%, with reserved bone marrow fluid or tissue for CS1 expression detection.
• Subjects have adequate organ function within the screening period and within 10 days prior to treatment initiation, as defined below:

a. Renal function: i. Serum creatinine ≤ 2.5 × upper limit of normal (ULN); OR ii. 24-hour creatinine clearance ≥ 30 mL/min (calculated via the Cockcroft-Gault formula).

b. Hepatic function: i. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 × ULN; ii. Total bilirubin (TBil) ≤ 2.0 × ULN. c. Hematological function: i. Absolute neutrophil count ≥ 0.5 × 109/L; ii. Absolute lymphocyte count ≥ 0.7 × 109/L; iii. Platelet count ≥ 25 × 109/L; iv. Hemoglobin ≥ 60 g/L. d. Biochemical and other baseline indicators: i. Corrected serum calcium ≤ 14 mg/dL (≤ 3.5 mmol/L) or ionized calcium ≤ 6.5 mg/dL (≤ 1.6 mmol/L); ii. Prothrombin time (PT) ≤ ULN + 3 seconds; iii. Oxygen saturation ≥ 92% while breathing ambient air.

• Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to treatment initiation. Post-menopausal status (minimum 2 years of amenorrhea), prior total hysterectomy, bilateral tubal ligation, bilateral oophorectomy, or congenital infertility confirms non-childbearing potential.
• Subjects of childbearing potential, and male subjects with sexually active female partners of childbearing potential, must agree to use highly effective contraceptive methods (failure rate < 1%) throughout the treatment period and for 12 months after the last study drug administration, including tubal ligation, male sterilization, hormonal implants, combined oral/injectable hormonal contraceptives, and approved intrauterine devices.

Exclusion criteria

• Female subjects who are pregnant or breastfeeding.
• Subjects unable to tolerate venous puncture required for leukapheresis and screening laboratory assessments.
• Subjects with any of the following prior treatment histories:

• Prior hematopoietic stem cell transplantation within 12 weeks before leukapheresis.
• Administration of any live vaccine within 4 weeks before leukapheresis or planned live vaccine administration during study participation.
• Use of immunosuppressive agents for the prophylaxis or treatment of graft-versus-host disease (GVHD) within 4 weeks before leukapheresis, or a confirmed diagnosis of acute or chronic GVHD at screening.
• Receipt of any investigational product within 4 weeks prior to signing the informed consent form.
• Concurrent enrollment in any other interventional clinical trial at screening.
• Subjects presenting with any of the following medical conditions at screening:

• Confirmed active central nervous system involvement, or clinical manifestations suggestive of multiple myeloma meningeal infiltration.
• Poorly controlled hypertension despite stable medical therapy, defined as systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg at screening.
• Left ventricular ejection fraction (LVEF) <50% measured via screening Doppler echocardiography.
• Any arrhythmia graded Grade 2 or higher per NCI CTCAE Version 5.0.
• Prolonged QTc interval corrected by Fridericia formula (QTcF), defined as QTcF >450 ms in male subjects or QTcF >470 ms in female subjects. The correction formula is QTcF = QT / RR0.33. Subjects with such QTcF prolongation and concomitant use of QT-prolonging medications (including Class Ia and Class III antiarrhythmic agents) are excluded.
• Documented personal history of torsades de pointes or congenital long QT syndrome.
• Occurrence of any of the following cardiovascular adverse events within 6 months prior to signing informed consent:

i. Myocardial infarction; ii. Severe or unstable angina pectoris; iii. Coronary artery bypass graft or peripheral arterial bypass surgery; iv. Congestive heart failure. h. Medical history of severe craniocerebral trauma, altered mental status, epilepsy, severe cerebral ischemia, or intracerebral hemorrhage.

i. Any congenital or acquired neurological, vascular, or systemic disorder that may interfere with study safety monitoring or efficacy evaluation (examples include Parkinson's disease, cerebral palsy, diabetic neuropathy).

j. Uncontrolled active infectious disease identified by investigator assessment during screening.

k. Confirmed human immunodeficiency virus (HIV) infection. l. Positive hepatitis B surface antigen (HBsAg) and positive hepatitis B core antibody with active hepatitis B viremia (HBV DNA level exceeding the upper limit of normal).

m. Positive anti-hepatitis C virus antibody (Anti-HCV) with detectable active HCV viremia, defined as HCV RNA ≥ 1.00×102 copies/mL.

n. Well-documented severe hypersensitivity or anaphylactic reaction to human, humanized, or murine monoclonal antibodies.

o. Prior history of solid organ transplantation. p. History of alcohol or illicit drug abuse within 52 weeks before screening visit, or ongoing alcohol abuse judged by the investigator.

q. Unremitted psychotropic substance abuse history or clinically significant psychiatric disorders.

r. Severe, inadequately controlled concomitant diseases (including but not limited to neurological, renal, hepatic, endocrine, and gastrointestinal disorders) that would prevent safe study participation per investigator judgment.

s. Any clinically significant abnormal findings across nervous, cardiovascular, hematologic/lymphatic, immune, renal, hepatic, gastrointestinal, respiratory, metabolic, or skeletal systems that warrant exclusion from study enrollment.

• Any other clinical condition determined by the investigator to render the subject unsuitable for participation in this trial.