Evaluation of [68Ga]Ga-PentixaFor PET for Initial Staging and Therapeutic Assessment in Symptomatic Multiple Myeloma Patients at Diagnosis or Relapse

The primary objective of this exploratory study is to determine the **sensitivity** of [68Ga]Ga-PentixaFor-PET in detecting lesions associated with **Multiple Myeloma** (MM), including bone marrow lesions and extra-medullary disease, at the time of initial diagnosis or at relapse. This is clinically relevant as accurate detection of MM lesions is crucial for effective staging and management of the disease.

Secondary objectives include:

• Determining the specificity, positive predictive value (PPV), and negative predictive value (NPV) of [68Ga]Ga-PentixaFor-PET at initial diagnosis or relapse.
• Assessing the discrepancies rate between FDG-PET and [68Ga]Ga-PentixaFor-PET at initial diagnosis, relapse, and therapeutic evaluation.
• Evaluating the prognostic impact of FDG-PET and [68Ga]Ga-PentixaFor-PET based on uptake positivity, number, and intensity at initial diagnosis, relapse, and therapeutic evaluation.
• Identifying factors associated with discrepancies between FDG-PET and [68Ga]Ga-PentixaFor-PET.
• Exploring the correlation between PET uptakes evaluated by SUV and cytogenetic data from the myelogram, particularly the expression of the gene coding for hexokinases.
• Assessing the tolerance of [68Ga]Ga-PentixaFor-PET at initial diagnosis, relapse, and therapeutic evaluation.
• Investigating the link between PET results and minimal residual disease evaluated by flow cytometry during therapeutic evaluation.

The clinical trial involves participants diagnosed with **Multiple myeloma**, focusing on both male and female subjects. The study population includes adults aged 18 years and older, who are symptomatic and require first-line treatment or are experiencing a relapse. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of less than 2, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not specify the total number of participants, as this information was not provided by the sponsor. The selection criteria include individuals affiliated with or beneficiaries of the National Health Service, ensuring access to healthcare resources. The trial population is characterized by a vulnerable group, necessitating careful ethical considerations. Lifestyle factors such as diet, physical activity, or habits are not detailed in the available data.

The clinical trial is designed to evaluate the relevance of **[68Ga]Ga-PentixaFor** for initial staging and therapeutic evaluation in patients with symptomatic **multiple myeloma**. This is a Phase IV, exploratory study employing a randomized, double-blind, controlled trial design. The trial is expected to span approximately ten years, with an estimated recruitment start date of September 21, 2021, and an anticipated end date of September 21, 2031. Participants will be involved in the study for a maximum treatment period of two months, with the possibility of early termination if specific conditions arise, such as adverse reactions or withdrawal of consent.

The study will include several key visits: an initial screening visit, follow-up visits, and an end-of-study visit. During the **screening visit**, eligibility will be assessed based on criteria such as age (≥18 years), symptomatic multiple myeloma requiring treatment, and an ECOG performance status of less than 2. Informed consent will be obtained at this stage. Follow-up visits will involve the administration of the investigational product, **[68Ga]Ga-PentixaFor**, via intravenous injection, with a maximum daily dose of 200 MBq and a total dose not exceeding 400 MBq. The primary endpoint will assess the sensitivity of **[68Ga]Ga-PentixaFor-PET** in detecting multiple myeloma lesions, confirmed by other imaging methods or histology. Secondary endpoints will evaluate specificity, prognostic impact, and tolerance of the investigational product.

Participants will be monitored for clinical data, including heart rate, oxygen saturation, and blood pressure, before and after the injection of **[68Ga]Ga-PentixaFor**. The end-of-study visit will conclude the participant's involvement, with a final assessment of the investigational product's impact on progression-free survival (PFS) and overall survival (OS). Conditions for early termination include adverse events, non-compliance with the study protocol, or voluntary withdrawal by the participant. The trial aims to provide valuable insights into the diagnostic and therapeutic potential of **[68Ga]Ga-PentixaFor** in managing multiple myeloma.

The clinical trial involves the administration of the experimental medication **[68Ga]Ga-PentixaFor**, which is a **solution for injection**. The active substance in this medication is **pentixafor gallium Ga-68**, a chemical compound. The pharmaceutical form is specifically designed for **intravenous use**. The dosing regimen for this trial specifies a maximum daily dose of 200 MBq (megabecquerels) and a maximum total dose of 400 MBq over a treatment period of up to 2 days. The administration of the medication is conducted under controlled conditions to ensure participant safety and adherence to the protocol.

In this study, there are no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments being utilized. The focus is solely on evaluating the efficacy and safety of the experimental medication **[68Ga]Ga-PentixaFor**. Participant compliance with the dosing schedule is monitored closely to ensure accurate assessment of the medication's effects. The trial aims to determine the sensitivity of **[68Ga]Ga-PentixaFor-PET** in detecting lesions associated with **multiple myeloma**, both in bone marrow and extra-medullary disease, at the time of initial diagnosis or relapse.

The efficacy of the investigational product, **[68Ga]Ga-PentixaFor**, will be assessed in a clinical trial focusing on patients with symptomatic multiple myeloma. The primary endpoint involves evaluating the sensitivity of **[68Ga]Ga-PentixaFor-PET** in detecting multiple myeloma lesions, including bone marrow lesions and extra-medullary disease, at initial diagnosis or relapse. Sensitivity will be determined through patient and lesion analysis, categorizing lesions as true positive (TP) if confirmed by another imaging method such as FDG-PET/CT, CT scan, MRI, or histology, and as false negative (FN) if not detected by **[68Ga]Ga-PentixaFor-PET** but confirmed by other methods.

Secondary endpoints include assessing the specificity, prognostic impact, and tolerance of **[68Ga]Ga-PentixaFor-PET**. Specificity will be evaluated using positive predictive value (PPV) and negative predictive value (NPV) at initial diagnosis or relapse. The prognostic impact will be determined by analyzing the number and intensity of lesions detected by **[68Ga]Ga-PentixaFor-PET** and FDG-PET, and their effect on progression-free survival (PFS) and overall survival (OS). Tolerance will be monitored through clinical data collection, including heart rate, oxygen saturation, and blood pressure, before and after **[68Ga]Ga-PentixaFor** injection.

Additional analyses will consider discordant lesions between **[68Ga]Ga-PentixaFor-PET** and FDG-PET, as well as the uptake of **[68Ga]Ga-PentixaFor** and FDG assessed by standardized uptake value (SUV) and the expression of biological markers on myelogram. The trial will also evaluate the impact of **[68Ga]Ga-PentixaFor-PET** on therapeutic evaluation, including the assessment of minimal residual disease by flow cytometry and the prognostic impact of imaging changes on PFS and OS.