Evaluation of Minimal Residual Disease Techniques in Untreated Multiple Myeloma with Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone Therapy

The primary objective of this study is to compare **minimal residual disease (MRD)** measurements using next-generation sequencing (NGS) in bone marrow (BM) and mass spectrometry (MS) for M-protein measurement in peripheral blood (PB) at specified timepoints. This comparison is conducted across two cohorts: Cohort 1, which involves transplant-eligible newly diagnosed multiple myeloma (NDMM) participants treated with daratumumab, bortezomib, lenalidomide, and dexamethasone (D-VRd) prior to and after autologous stem cell transplantation (ASCT), and Cohort 2, which involves participants treated with D-VRd followed by TEC-TAL therapy. The clinical relevance of this objective lies in its potential to enhance the precision of MRD assessment, which is crucial for evaluating treatment efficacy and guiding therapeutic decisions in multiple myeloma.

Secondary objectives include: • Comparing MRD measurements by NGS (BM) and MS (M-protein measurement in PB) at various timepoints, including post-induction, following 6 cycles of D-VRd, and following 12 cycles of TEC-TAL therapy in Cohort 2. • Comparing MRD measurements by next-generation flow (NGF) and MS at specified timepoints, including post-induction and post-consolidation or following 3 cycles of TEC-TAL therapy, combined across cohorts. • Comparing MRD measurements by NGF and NGS at specified timepoints, including post-induction and post-consolidation or following 3 cycles of TEC-TAL therapy, combined across cohorts. • Evaluating the MRD negativity rate achieved up to the end of consolidation or up to the end of 12 cycles of TEC-TAL therapy using BM-based MRD techniques and the MS-MRD technique. • Evaluating the depth of response at specified timepoints for both cohorts. • Assessing the impact of cytogenetic abnormalities, the Revised International Staging System (R-ISS), and circulating tumor cells (CTCs) on the likelihood of developing MRD-negative disease and the agreement between different techniques. • Evaluating the safety and tolerability of TEC-TAL therapy.

The clinical trial involves participants diagnosed with **Multiple Myeloma**, specifically those who are newly diagnosed and treatment-naïve, with high-dose therapy and autologous stem cell transplantation as part of their intended treatment plan. The study population includes both male and female subjects, aged between 18 to 70 years. Participants are required to have adequate bone marrow, liver, and renal function, as well as a measurable disease as defined by specific laboratory criteria. The trial includes a vulnerable population, and the selection criteria ensure that participants have an Eastern Cooperative Oncology Group (ECOG) performance status score of 0, 1, or 2. The sponsor has not provided information regarding the total number of participants in the study. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy of a treatment regimen for **multiple myeloma** using a randomized, double-blind, controlled methodology. The trial will involve participants who are newly diagnosed and treatment-naïve, with the study duration estimated to conclude by September 2027. The trial will commence with a screening visit to assess eligibility based on specific inclusion criteria, such as age between 18 to 70 years and adequate organ function. Participants will be randomly assigned to receive either the investigational treatment or a control, with the investigational treatment comprising a combination of **daratumumab**, **bortezomib**, **lenalidomide**, and **dexamethasone** (D-VRd), followed by either an autologous stem cell transplantation (ASCT) and D-VRd consolidation or D-VRd followed by **teclistamab** in combination with **talquetamab**.

The trial will include multiple study visits to monitor the participants' response to treatment and assess the primary endpoint, which is the proportion of agreement and disagreement in minimal residual disease (MRD) measurements in bone marrow and peripheral blood. Secondary endpoints will evaluate the overall response rate and the incidence of adverse events. Follow-up visits will occur at specified intervals to ensure comprehensive data collection and participant safety. The end-of-study visit will mark the conclusion of the participant's involvement, which is expected to last up to 12 months, depending on the treatment arm and response.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, disease progression, or if they withdraw consent. The trial's design ensures that all data collected will contribute to understanding the treatment's efficacy and safety profile, with the ultimate goal of improving therapeutic strategies for multiple myeloma.

The clinical trial involves the administration of several experimental and non-experimental treatments. **Lenalidomide Accord** is provided in various dosages, including 5 mg, 10 mg, 15 mg, 20 mg, and 25 mg hard capsules. The active substance is **lenalidomide**, a chemical compound, administered orally. The maximum daily dose is 25 mg, with a total dose limit of 3150 mg over a 12-month period. Compliance with the dosing schedule is monitored throughout the trial.

**Daratumumab**, marketed as **DARZALEX**, is administered as a solution for injection. The active substance is a protein of other origin, delivered via subcutaneous injection. The maximum daily dose is 1800 mg, with a total dose limit of 28800 mg over the course of the study. This medication is used in conjunction with other treatments to assess its efficacy in the trial.

**Bortezomib**, known commercially as **VELCADE**, is provided as a powder for solution for injection. The active substance is a chemical compound, administered through subcutaneous injection. The maximum daily dose is 1.3 mg/m², with a total dose limit of 31.2 mg/m² over 12 months. This treatment is part of the experimental regimen for participants.

**Teclistamab** is administered as a solution for injection, with the active substance being a protein of other origin. It is delivered via subcutaneous injection, with a maximum daily dose of 0.3 mg/kg and a total dose limit of 0.36 mg/kg. The treatment period extends up to 12 months, with compliance monitored throughout the trial.

**Talquetamab** is also provided as a solution for injection, with the active substance being a protein of other origin. It is administered subcutaneously, with a maximum daily dose of 0.8 mg/kg and a total dose limit of 9.6 mg/kg over the study period. This medication is used in combination with other treatments to evaluate its effectiveness.

**Dexamethasone** is available in tablet form, with the active substance being a chemical compound. It is administered orally, with a maximum daily dose of 20 mg and a total dose limit of 960 mg over 12 months. This treatment serves as a standard-of-care therapy in the trial.

**Paracetamol** is provided as a hard capsule, with the active substance being a chemical compound. It is administered orally, with a maximum daily dose of 1000 mg and a total dose limit of 16000 mg over the study duration. This medication is used as an auxiliary treatment to manage symptoms.

**Diphenhydramine** is administered in capsule form, with the active substance being a chemical compound. It is taken orally, with a maximum daily dose of 50 mg and a total dose limit of 800 mg over the course of the trial. This treatment is used to manage side effects associated with other medications.

Efficacy in this clinical trial will be assessed through the evaluation of **Minimal Residual Disease (MRD)** using innovative techniques. The primary endpoint involves measuring the proportion of agreement and disagreement in MRD measurements in bone marrow (BM) using Next-Generation Sequencing (NGS-MRD) and in peripheral blood using Mass Spectrometry (MS-MRD) at specific timepoints. These timepoints include post-consolidation for Cohort 1 and following three cycles of TEC-TAL therapy for Cohort 2, with data combined across cohorts.

Secondary endpoints will further explore the proportion of agreement and disagreement in MRD measurements at various stages, including post-induction, following six cycles of D-VRd therapy, and following twelve cycles of TEC-TAL therapy. Additionally, the study will assess MRD negativity achieved at any time up to the end of consolidation for Cohort 1 or up to the end of twelve cycles of TEC-TAL therapy for Cohort 2, using both BM-based and peripheral blood-based techniques. The overall response rate (ORR), very good partial response (VGPR) or better, complete response (CR) or better, and stringent CR (sCR) will also be evaluated at multiple stages, including post-induction and post-transplant.

The study will utilize both NGS and Next-Generation Flow (NGF) for BM-based MRD assessments, while MS-MRD will be employed for peripheral blood evaluations. These assessments will be conducted at specified intervals to ensure comprehensive data collection and analysis. The trial aims to provide insights into the efficacy of the treatment regimen in achieving MRD negativity and overall response in participants with previously untreated Multiple Myeloma.