Phase 3 Randomized Trial of Daratumumab, Bortezomib, Lenalidomide, Dexamethasone, and Ciltacabtagene Autoleucel in Transplant-Eligible Multiple Myeloma

The primary objective of this Phase 3 randomized study is to compare the **efficacy** of the treatment regimen consisting of daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) followed by ciltacabtagene autoleucel (cilta-cel) and lenalidomide therapy versus DVRd followed by autologous stem cell transplant (ASCT), DVRd consolidation, and lenalidomide therapy. The comparison is based on progression-free survival (PFS) and sustained minimal residual disease (MRD)-negative complete response (CR) in participants with newly diagnosed **Multiple Myeloma** who are eligible for transplant. This objective is clinically relevant as it aims to determine the most effective treatment strategy for improving long-term outcomes in this patient population.

Secondary objectives include:

• Further comparing the efficacy of DVRd followed by cilta-cel and lenalidomide therapy.
• Characterizing the safety of cilta-cel after DVRd therapy followed by lenalidomide therapy versus DVRd followed by ASCT, DVRd consolidation, and lenalidomide therapy.
• Characterizing the pharmacokinetics (PK) and pharmacodynamics of cilta-cel.
• Evaluating the patient-reported outcomes (PRO) associated with DVRd followed by cilta-cel and lenalidomide therapy versus DVRd followed by ASCT, DVRd consolidation, and lenalidomide therapy.
• Determining whether replication-competent lentivirus (RCL) is present in participants receiving cilta-cel.

The clinical trial involves a total of **366 participants** diagnosed with **Multiple Myeloma**. The study population includes both male and female subjects, aged **18 years or older**, who have been diagnosed with newly diagnosed multiple myeloma (NDMM) according to the International Myeloma Working Group (IMWG) diagnostic criteria. Participants are required to have a measurable disease as assessed by a central laboratory at screening. The trial population was selected based on specific inclusion criteria, including an Eastern Cooperative Oncology Group (ECOG) performance status of grade 0 or 1 and clinical laboratory values within a prespecified range. The study does not specify particular lifestyle considerations such as diet or physical activity. The trial includes a vulnerable population, indicating that additional ethical considerations are in place to protect these participants.

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of a treatment regimen in participants with newly diagnosed **multiple myeloma** who are eligible for transplant. The trial will compare the combination of daratumumab, bortezomib, lenalidomide, and dexamethasone (DVRd) followed by ciltacabtagene autoleucel against the same combination followed by autologous stem cell transplant (ASCT). The primary endpoints include progression-free survival (PFS) and sustained minimal residual disease (MRD)-negative complete response (CR). Secondary endpoints encompass overall response rates, time to subsequent antimyeloma therapy, and overall survival (OS), among others.

The trial is expected to span approximately 15 years, with an estimated recruitment start date in September 2022 and an anticipated end date in September 2037. Participants will be involved in the study for a maximum treatment period of 24 months, depending on the treatment arm and individual response. The study will include several key visits: an initial screening visit to confirm eligibility based on criteria such as age, documented diagnosis of multiple myeloma, and measurable disease. Follow-up visits will be scheduled to monitor treatment response, safety, and any adverse events. The end-of-study visit will assess the final outcomes and gather data on long-term effects.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial will adhere to rigorous ethical standards and regulatory requirements to ensure participant safety and data integrity. The study will utilize various pharmaceutical forms, including hard capsules, solutions for injection, and dispersions for infusion, with administration routes such as oral, subcutaneous, and intravenous use. The trial will not include pediatric formulations, and all substances involved are of chemical or protein origin, with one being a structurally diverse cell therapy.

The clinical trial involves the administration of several **experimental medications**. **Lenalidomide Accord** is provided in hard capsule form with dosages of 2.5 mg, 5 mg, 15 mg, 20 mg, and 25 mg. The active substance is **lenalidomide**, a chemical compound, administered orally. The maximum daily dose is 25 mg, with a treatment period extending up to 24 months. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**VELCADE** is administered as a powder for solution for injection, with the active substance **bortezomib**. This chemical compound is delivered subcutaneously at a maximum daily dose of 1.3 mg/m². The treatment period is limited to 6 months. Compliance is monitored through scheduled visits and dosage adjustments as necessary.

**Dexamethason Teva** and **Dexamethasone** tablets, containing the active substance **dexamethasone**, are administered orally. The maximum daily dose for both formulations is 40 mg, with a treatment duration of up to 24 months. Regular monitoring ensures participant adherence to the prescribed regimen.

**CARVYKTI** is a dispersion for infusion containing **ciltacabtagene autoleucel**, a structurally diverse substance used in cell therapy. It is administered intravenously, with a single treatment session. The product is stored in cryo-bags and compliance is ensured through controlled infusion procedures.

**DARZALEX** is provided as a solution for injection, with the active substance **daratumumab**, a protein-based compound. It is administered subcutaneously with a maximum daily dose of 1800 mg, over a treatment period of 24 months. Compliance is monitored through scheduled administration and participant follow-up.

All medications are administered according to the trial protocol, with participant compliance monitored through regular assessments and adherence checks. The trial aims to evaluate the efficacy of these treatments in participants with newly diagnosed **multiple myeloma** who are eligible for transplant. The study compares the efficacy of the DVRd regimen followed by ciltacabtagene autoleucel versus DVRd followed by autologous stem cell transplant (ASCT).

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoints include progression-free survival (PFS) and sustained minimal residual disease (MRD)-negative complete response (CR), defined as MRD-negative CR for a minimum duration of 12 months. MRD status will be determined by next-generation sequencing (NGS) with a sensitivity of at least 10^-5.

Secondary endpoints encompass a range of measures, including overall response status (partial response or better) and CR or better status, overall MRD-negative CR with a sensitivity of at least 10^-5, time to subsequent antimyeloma therapy, PFS on next-line therapy (PFS2), and overall survival (OS). Additionally, the trial will evaluate the incidence, severity, and type of adverse events (AEs), clinical laboratory results, and other safety parameters. Pharmacokinetic and pharmacodynamic markers will be analyzed through protein, DNA, or RNA analyses, including systemic inflammatory cytokine concentrations and markers of CAR-T cell expansion and persistence.

Patient-reported outcomes will be measured using validated instruments such as the EORTC-QLQ-C30, MySIm-Q, and EQ-5D-5L subscale scores, along with the PRO-CTCAE items. The trial will also assess the time to improvement or worsening of symptoms, functioning, and overall well-being, as well as the presence of replication-competent lentivirus (RCL).