Evaluation of Dexamethasone as Initial Therapy in Advanced Relapsed/Refractory Multiple Myeloma: A Randomized, Open-Label, Non-Inferiority Trial

Trial ID: 2024-510981-18-00
Protocol: APHP231089
Sponsor: Assistance Publique Hopitaux De Paris

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Diseases & Conditions

Plasma cell myeloma

Objectives

The primary objective of this study is to determine the **overall response rate (ORR)** after six cycles of salvage therapy in patients with advanced relapsed/refractory **multiple myeloma**. This is assessed using the International Myeloma Working Group (IMWG) criteria. The clinical relevance of this objective lies in evaluating the efficacy of the treatment regimen, which is crucial for improving therapeutic strategies for this patient population.

Secondary objectives include:

Best ORR, defined as the proportion of subjects achieving complete response (CR) or partial response (PR) according to the IMWG criteria, at any time point following salvage therapy.
Time to progression (TTP).
Progression-free survival (PFS), defined as the duration from the date of randomization to either progressive disease, according to the IMWG criteria, or death, at 2 years after randomization.
Overall survival (OS), defined as the duration from the date of randomization to death, at 2 years after randomization.
Incidence of adverse events (AE) within the 2 years after randomization.
Quality of Life (QoL) within the 2 years after randomization.

Participants

The clinical trial focuses on **Multiple Myeloma**, a B cell malignancy and a common primary neoplasm of the bone marrow. The study population includes both male and female adult patients aged 18 years and older. Participants are required to have documented relapsed Multiple Myeloma and must have undergone between one to three prior therapies. The trial does not involve a vulnerable population. Participants are expected to have an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0, 1, or 2, indicating they are in relatively good health. The trial population was selected based on their eligibility for specific antibody-based approved combinations, such as the ICARIA or IKEMA schema. The sponsor has not provided information regarding the total number of participants. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **randomized**, open-label, non-inferiority, controlled study to evaluate the efficacy of **dexamethasone** as an initial therapy for advanced relapsed/refractory **multiple myeloma**. The primary objective is to determine the overall response rate (ORR) after six cycles of salvage therapy, assessed using the International Myeloma Working Group (IMWG) criteria. The trial is expected to commence recruitment on December 11, 2024, and conclude by October 11, 2028. Participants will be involved in the study for a maximum treatment period of 96 weeks, with a maximum daily dose of 40 mg of dexamethasone, administered either orally or via intramuscular and intravenous routes.

The trial will include several study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age (≥18 years), documented relapse of multiple myeloma, and prior therapy history. Participants must have received between one to three prior therapies and achieved a response to the prior regimen. Follow-up visits will occur throughout the treatment cycles to monitor response and manage any adverse effects. The end-of-study visit will assess the final response to the treatment and gather data for the primary endpoint analysis.

Participants may be withdrawn from the study if they experience unresolved or unstable toxicities from previous therapies, fail to comply with the study protocol, or withdraw consent. The trial's design ensures rigorous monitoring and adherence to ethical standards, with informed consent obtained from all participants. The study's findings will contribute to understanding the role of dexamethasone in treating advanced relapsed/refractory multiple myeloma, potentially influencing future therapeutic strategies.

Treatment

The clinical trial involves the administration of **dexamethasone** in three different pharmaceutical forms, each with specific administration routes and dosing schedules. The first form is a **tablet** containing the active substance **dexamethasone**, administered orally. The maximum daily dose for this form is 40 mg, with a total maximum dose of 3840 mg over a treatment period of 96 days. Participants are required to adhere to the prescribed dosing schedule, and compliance will be monitored throughout the trial.

The second form of **dexamethasone** is a **solution for injection**, which can be administered either intramuscularly or intravenously. Similar to the tablet form, the maximum daily dose is 40 mg, with a total maximum dose of 3840 mg over the same treatment period of 96 days. The administration of this form will be conducted by qualified healthcare professionals to ensure proper dosing and participant safety.

The third form is an **oral solution** of **dexamethasone**, also administered orally. This form shares the same dosing parameters as the tablet and injectable forms, with a maximum daily dose of 40 mg and a total maximum dose of 3840 mg over 96 days. Participants will be instructed on the correct method of administration to ensure accurate dosing and compliance.

Throughout the trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The trial is designed to evaluate the efficacy of **dexamethasone** as a standalone treatment for advanced relapsed/refractory multiple myeloma. Participant compliance with the dosing schedule will be closely monitored to ensure the integrity of the trial data.

Efficacy

Efficacy in the clinical trial titled "Free regimen of Dexamethasone as initial therapy for advanced relapsed/refractory multiple myeloma: an open-label randomized, non-inferiority, controlled trial (FREEDOM)" will be assessed primarily through the **Overall Response Rate (ORR)** after six cycles of salvage therapy. The ORR is defined as the proportion of subjects who achieve a complete response (CR) or partial response (PR) according to the International Myeloma Working Group (IMWG) criteria. This primary endpoint will be measured following the completion of the salvage therapy cycles.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Adult patients (≥18 years old) • Documented MM in relapse according to standard criteria. • All patients must have received between 1 to 3 prior therapies for MM (a prior therapy is defined as 2 or more cycles of therapy given as a MM treatment plan • Eligible for one of the following antibody-based approved combinations (see 2.6 for details on EMEA authorization): (1) ICARIA schema: isatuximab, pomalidomide and dexamethasone. (2) IKEMA schema: isatuximab, carfilzomib and dexamethasone • Subject must have achieved a response (PR or better) to the prior regimen. • ECOG Performance Status score of 0, 1, or 2. • For subjects experiencing toxicities resulting from previous therapy (including peripheral neuropathy), the toxicities must have been resolved or stabilized. • Signed informed consent

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Exclusion Criteria

Contraindications to investigational medicinal products or auxiliary medicinal product • Evidence of refractoriness or intolerance to anti-CD38 monoclonal antibodies or if the patient received an anti-CD38 within the last 6 months. • Previous treatment according to the ICARIA schema with pomalidomide orIKEMA schema with carfilzomib • Allogenic hematopoietic cell transplant (HCT, regardless of timing). • Planned to undergo an HCT prior to progression of disease ie, these patients should not be enrolled in order to reduce disease burden prior to transplant. • History of malignancy (other than MM) within 3 years before the date of randomization (exceptions are squamous and basal cell carcinomas of the skin, carcinoma in situ of the cervix, or malignancy that in the opinion of the Investigator is considered cured with minimal risk of recurrence within 3 years). • Known MM meningeal Involvement. • Plasma cell leukemia (>2.0 × 109/L circulating plasma cells by standard differential) or Waldenström’s macroglobulinemia or POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) or amyloidosis. • Any concurrent medical condition or disease (e.g., active systemic infection) that is likely to interfere with study procedures or results, or that, in the opinion, of the Investigator would constitute a hazard by participating in this study. • Uncontrolled chronic obstructive pulmonary disease (COPD) • Clinically significant cardiac disease. • Seropositive for hepatitis B with positive PCR • Seropositive for human immunodeficiency virus (HIV) or hepatitis C. • Creatinine clearance ≤30 mL/min • Pregnancy or absence of effective contraceptive method for women of childbearing potential • Lactation • Participation to another interventional clinical trial except with the agreement of the coordinating investigator.• Inability to give written informed consent