Study Comparing Therapy for Advanced Relapsed/Refractory Multiple Myeloma With and Without Dexamethasone (FREEDOM)

Free Regimen of Dexamethasone as Initial Therapy for Advanced Relapsed/Refractory Multiple Myeloma: an Open-label Randomized, Non-inferiority, Controlled Trial

Patients with relapsed/refractory symptomatic multiple myeloma who meet all inclusion criteria, will be randomized 1:1 to receive either standard of care chemotherapy (IKEMA or ICARIA) and dexamethasone until disease progression ("dexamethasone arm", arm A) or standard of care chemotherapy (IKEMA or ICARIA) and dexamethasone with dexamethasone discontinuation from the 3rd cycle of treatment (after 8 weeks) ("dexamethasone-free arm", arm B).

In most centers, IKEMA and ICARIA schema can be adapted according to the standard of care in each center Choice between the ICARIA and IKEMA schema is at the discretion of the investigator, in compliance with each drug's SmPC, but must be performed before randomisation for the purpose of stratification.

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma; Relapse Multiple Myeloma
• Intervention / Treatment: Drug: Dexamethasone

Detailed Description

Patients with relapsed/refractory symptomatic multiple myeloma who meet all inclusion criteria, will be randomized 1:1 to receive either standard of care chemotherapy (IKEMA or ICARIA) and dexamethasone until disease progression ("dexamethasone arm", arm A) or standard of care chemotherapy (IKEMA or ICARIA) and dexamethasone with dexamethasone discontinuation from the 3rd cycle of treatment (after 8 weeks) ("dexamethasone-free arm", arm B).

In most centers, IKEMA and ICARIA schema are as follow, but can be adapted according to the standard of care in each center Choice between the ICARIA and IKEMA schema is at the discretion of the investigator, in compliance with each drug's SmPC, but must be performed before randomisation for the purpose of stratification.

1. ICARIA schema:

   • dexamethasone: 40mg (20mg for ≥75yr) on day 1, 8, 15, 22 of each cycle plus
   • isatuximab: 10mg/kg on day 1, 8, 15, 22 in C1 subsequently on day 1, 15; plus
   • pomalidomide: 4mg on days 1-21 of 28-day cycle.

2. IKEMA schema:

   • dexamethasone: 20 mg on day 1-2, day 8-9, day 15-16 and day 22-23 of each cycle;
   • isatuximab: 10 mg/kg on day 1, 8, 15, 22 in C1, then Q2W;
   • carfilzomib: 20 mg/m² on day 1-2; 56 mg/m² day 8-9, day, 15-16 in C1; 56 mg/m² on day 1-2, day 8-9, day 15-16 all subsequent cycles.

In the dexamethasone arm (standard of care):

Dexamethasone: will be given on each cycle

In the dexamethasone-free arm (experimental arm):

Dexamethasone: will be only given on cycle 1 and cycle 2 Supportive care: will be administered according to each participating center's usual practice, in both arms The aim of the current protocol is to investigate whether administration of dexamethasone for a very limited period (2 cycles) combined with standard treatment for relapsed/refractory MM is not inferior to the continuous administration of the combination until disease progression. In this study some patients may have a similar OS while receiving a shorter duration of dexamethasone treatment. This study may allow delivery of a shorter duration of dexamethasone for the treatment of relapsed MM.

The foreseeable risks are those of an earlier relapse in patients receiving a short duration of dexamethasone (8 weeks) compared to the situation where they would have received the dexamethasone until disease progression.

• Study Type: Interventional
• Enrollment (Estimated): 318
• Phase: Phase 3

Contacts and Locations

• Study Contact: Name: Florent MALARD, PU-PH; Phone Number: 01 49 28 34 39; Email: malardf@yahoo.fr
• Study Contact Backup: Name: Mohamad MOHTY, PU-PH; Phone Number: + 33 1 49 28 26 20; Email: mohamad.mohty@inserm.fr

Study Locations

• France
  • Paris, France, 75012
    • Recruiting
    • Service d'hématologie clinique et thérapie cellulaire, Saint-Antoine Hospital
    • Contact: Mohamad MOHTY, PU-PH; Phone Number: 01 49 28 26 20; Email: mohamad.mohty@inserm.fr
    • Contact: Florent MALARD, PU-PH; Phone Number: 01 49 28 34 39; Email: florent.malard@aphp.fr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Adult patients (≥18 years old)
2. Documented MM in relapse according to standard criteria.

3. 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:

     1. ICARIA schema: isatuximab, pomalidomide and dexamethasone.
     2. IKEMA schema: isatuximab, carfilzomib and dexamethasone
4. Subject must have achieved a response (PR or better) to the prior regimen.
5. ECOG Performance Status score of 0, 1, or 2.
6. For subjects experiencing toxicities resulting from previous therapy (including peripheral neuropathy), the toxicities must have been resolved or stabilized.
7. Signed informed consent

Exclusion Criteria:

1. Contraindications to investigational medicinal products or auxiliary medicinal product
2. Evidence of refractoriness or intolerance to anti-CD38 monoclonal antibodies.
3. Previous treatment according to the ICARIA schema with pomalidomide or IKEMA schema with carfilzomib
4. Allogenic hematopoietic cell transplant (HCT, regardless of timing).
5. Planned to undergo an hematopoietic cell transplant prior to progression of disease ie, these patients should not be enrolled in order to reduce disease burden prior to transplant.
6. 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).
7. Known MM meningeal Involvement.
8. 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.
9. 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.
10. Uncontrolled chronic obstructive pulmonary disease (COPD)
11. Clinically significant cardiac disease.
12. Seropositive for hepatitis B with positive PCR
13. Seropositive for human immunodeficiency virus (HIV) or hepatitis C
14. Lactation
15. Participation to another interventional clinical trial
16. Inability to give written informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Dexamethasone-free; Dexamethasone will be stopped after the first 2 cycles (in both ICARIA and IKEMA schemas). ICARIA shemas : dexamethasone isatuximab pomalidomide IKEMA shemas : dexamethasone isatuximab carfilzomib	Drug: Dexamethasone; ICARIA schema : 40mg (20mg for ≥75yr) on day 1, 8, 15, 22 of each cycle plus IKEMA schema : 20 mg on day 1-2, day 8-9, day 15-16 and day 22-23 of each cycle For subjects older than 75 years or underweight (BMI <18.5), the dexamethasone dose may be administered at a total dose of 20 mg weekly. In both schema (ICARIA or IKEMA), dexamethasone will be administrated up to 2 cycle (Arm 1) or until disease progression (Arm2); Other Names: Neofordex
No Intervention: Dexamethasone; Dexamethasone will not be discontinued (in both ICARIA and IKEMA shemas). ICARIA schema : dexamethasone isatuximab pomalidomide IKEMA schema : dexamethasone isatuximab carfilzomib

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall response rate (ORR).	Response rate will be evaluated according to the IMWG criteria, after six 28 days cycles of salvage therapy.	At the end of Cycle 6 of salvage therapy (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
best overall response rate (ORR)	Response rate will be evaluated according to the IMWG criteria, during or after the study treatment at the time of data cutoff. Patients will be followed every 4 weeks (with either a medical visit or only an outpatient blood test) until disease progression and then every 12 weeks until final 2 years.	2 years
Time To Progress (TTP)	Time To Progress defined as the duration from the date of randomization to progressive disease, according to the IMWG criteria	2 years
Progression free survival (PFS)	Progression free survival is defined as the duration from the date of randomization to either progressive disease, according to the IMWG critera or death, at 2 years after randomization.	2 years
Overall survival OS	which is defined as the time between randomization and death due to any cause. Patients, who die, regardless of the cause of death, will be considered to have had an event even if they were lost to follow-up for an extended time	2 years
Quality of Life (QoL)		2 years

Collaborators and Investigators

• Sponsor: Assistance Publique - Hôpitaux de Paris
• Investigators: Principal Investigator: Mohamad MOHTY, PU-PH, Assistance Publique - Hopitaux de Paris

Study record dates

Study Major Dates

• Study Start (Actual): December 12, 2024
• Primary Completion (Estimated): December 1, 2028
• Study Completion (Estimated): December 1, 2028

Study Registration Dates

• First Submitted: August 7, 2024
• First Submitted That Met QC Criteria: August 15, 2024
• First Posted (Actual): August 20, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 13, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Keywords: Multiple myeloma; Pomalidomide; Dexamethasone; Carfilzomib; Isatuximab; Relapse
• Additional Relevant MeSH Terms: Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Neoplasms; Disease Attributes; Immune System Diseases; Neoplasms by Histologic Type; Hematologic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Hemorrhagic Disorders; Recurrence; Multiple Myeloma; Neoplasms, Plasma Cell; Antineoplastic Agents; Physiological Effects of Drugs; Anti-Inflammatory Agents; Antiemetics; Autonomic Agents; Peripheral Nervous System Agents; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Dexamethasone
• Other Study ID Numbers: APHP231089; 2024-510981-18-00 (Ctis)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No