Long-term Follow-up Study on Delayed Adverse Events and Safety Profile of Ciltacabtagene Autoleucel in Patients with Multiple Myeloma

The primary objective of this study is to collect long-term follow-up data on **delayed adverse events** following the administration of **ciltacabtagene autoleucel** in patients with **Multiple Myeloma**. This objective is clinically relevant as it aims to characterize and understand the long-term safety profile of ciltacabtagene autoleucel, which is crucial for assessing the risk-benefit ratio of this treatment in a chronic and often relapsing condition like Multiple Myeloma.

Secondary objectives include collecting additional long-term data on replication competent lentivirus (RCL), cilta-cel persistence, efficacy, and overall survival. These objectives are important for evaluating the sustained effectiveness and safety of the treatment, as well as understanding the potential for long-term viral replication and its implications for patient health.

The clinical trial involves a total of **300 participants** diagnosed with **Multiple Myeloma**. The study population includes both male and female subjects, with an age range that corresponds to categories 3 and 4, indicating adult and elderly participants. The trial population was selected from individuals who have previously received at least one dose of cilta-cel in a company-sponsored clinical study and have provided informed consent for participation in Study MMY4002. The participants are considered a vulnerable population, which necessitates careful monitoring and ethical considerations. The trial does not specify particular lifestyle considerations such as diet or physical activity. The primary objective is to collect long-term follow-up data on delayed adverse events and to understand the long-term safety profile of cilta-cel.

The clinical trial is designed as a **long-term follow-up study** for participants previously treated with **ciltacabtagene autoleucel** for **multiple myeloma**. This study aims to collect data on delayed adverse events and to characterize the long-term safety profile of the treatment. The trial is structured as a **randomized, double-blind, controlled** study, with an estimated duration extending until May 31, 2042. Participants who have received at least one dose of ciltacabtagene autoleucel in a company-sponsored clinical study and have provided informed consent are eligible for inclusion. There are no specific exclusion criteria listed for this study.

The sequence of study visits includes an initial inclusion (screening) visit, followed by regular follow-up visits, and concludes with an end-of-study visit. The primary endpoints focus on the number of subjects experiencing delayed adverse events, such as new malignancies, neurologic disorders, rheumatologic or autoimmune disorders, hematologic disorders, and infections. Secondary endpoints include the number of subjects with measurable replication-competent lentivirus (RCL) in peripheral blood, CAR transgene levels, and overall survival. The study also assesses the pattern of lentiviral vector integration sites and the long-term efficacy of CAR-T therapy.

Participant involvement is expected to last up to 15 years, with conditions for early termination including the occurrence of serious adverse events or the initiation of subsequent antimyeloma therapy. The study is not classified as low intervention and is categorized as a Phase 4 trial, focusing on the long-term safety of the treatment. The trial is conducted under the authorization of the European Union, with the product being a dispersion for infusion, specifically designed for intravenous use. The study is sponsored by Janssen-Cilag International NV, and the product is identified as CARVYKTI, containing the active substance ciltacabtagene autoleucel.

The clinical trial involves the administration of **CARVYKTI**, a dispersion for infusion containing **ciltacabtagene autoleucel** as the active substance. This investigational product is a genetically modified autologous T-cell immunotherapy designed to target B-cell maturation antigen (BCMA). The pharmaceutical form is a dispersion for infusion, and it is administered via the **intravenous route**. The dosage range for this product is between 3.2 × 10^6 and 1.0 × 10^8 cells. The treatment is administered once, with no specified maximum daily or total dose amount, and the maximum treatment period is one day. The product is not formulated for pediatric use and is classified as an orphan drug.

**Ciltacabtagene autoleucel** is a structurally diverse substance used in cell therapy. It is an autologous human T-cell product that has been genetically modified ex-vivo with a lentiviral vector encoding a chimeric antigen receptor (CAR) specific for BCMA. This modification allows the T-cells to recognize and bind to BCMA-expressing cells, facilitating targeted immunotherapy. The product is stored in cryo-bags, specifically OriGen CryoStore CS50 and CS250, which are used to maintain the integrity of the cell product until infusion. These cryo-bags are CE marked and are intended for intravenous use.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in this study. Participant compliance with the treatment regimen is monitored through standard clinical trial procedures, ensuring adherence to the dosing schedule and proper administration of the investigational product. The trial aims to collect long-term follow-up data on delayed adverse events and to characterize the long-term safety profile of ciltacabtagene autoleucel.

Efficacy in the clinical trial will be assessed through several secondary endpoints. These include the number of subjects with measurable replication-competent lentivirus (RCL) in peripheral blood and the number of subjects with **CAR transgene** levels above the lower limit of quantitation (LLOQ) in peripheral blood cells. Additionally, the pattern of lentiviral vector integration sites will be evaluated if at least 1% of cells in the blood sample or new malignancy are positive for vector sequences. Long-term follow-up on CAR-T therapy efficacy will be conducted if the subject does not have confirmed disease progression or does not initiate subsequent antimyeloma therapy at the entry of the study and at any time during the study. Overall Survival (OS) will also be monitored as a key measure of efficacy.