Study Comparing Continuous Versus Fixed Duration Therapy With Daratumumab, Lenalidomide, and Dexamethasone for Relapsed Multiple Myeloma

NCT03836014 | Active Not Recruiting Phase 3

• 2 other identifiers: D201801382016-002129-12
• Study Type: interventional
• Target: 436
• Locations: 1 country
• Sites: 1

Brief Summary

The incorporation of proteasome inhibitors and immunomodulatory drugs into the standard of care has improved the outcome for patients with multiple myeloma (MM) over the past 10 years. However, most patients (\>85%) still eventually relapse around 3-4 years after diagnosis, and ultimately die of their disease, despite salvage therapies. Relapse can occur even when complete remission is achieved after first-line therapy. Currently, daratumumab (Dara) is approved by the american FDA and EMA in combination with lenalidomide (Len) and dexamethasone (Dex) or bortezomib and Dex for the treatment of MM patients who have received at least one prior therapy. Therefore, the Dara-Len-Dex combination is likely to become the most widely used standard of care regimen for MM at the time of first relapse. However, although approval of the latter combination is meant for until disease progression (PD) ("continuous therapy") (CT), the actual optimal duration of relapse treatment is still unknown. Of note, many experts advocate that a "fixed duration" of therapy should be favored, especially if one can show that CT does not translate into a significant overall survival (OS) benefit. As a matter of fact, given the extremely high cost of such novel agents (\>100 KEuros/year/patient), the pharmacoeconomic consequences of a "continuous" versus "fixed" duration therapy are also of utmost importance. Based on this background, the investigator propose to conduct a non-inferiority phase III randomized, multicenter, open label trial for treatment of MM at first relapse, comparing the Dara-Len-Dex combination administered continuously until PD, versus a fixed duration of 24 months. The choice of this duration is justified by the currently available evidence with respect to achievement of a plateau in terms of deep disease response, patients' compliance, and physicians' preference according to different surveys. The primary objective of this study is to estimate the OS rate at 4 years after diagnosis of relapse and initiation of salvage therapy. The primary endpoint is OS at 4 years after randomization. The analysis will be performed on both per-protocol and intent-to-treat sets of patients.

Conditions

Multiple Myeloma in Relapse

Keywords

Multiple myeloma; Relapse; daratumumab,; lenalidomide; dexamethasone

Outcome Measures

Primary Outcomes (1)

• overall survival

  Overall survival (OS) 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. All subjects who are lost to follow-up prior to the end of the trial or who are withdrawn from the trial will be censored at the last available date the subject is known to be alive

  4 years after randomization

Secondary Outcomes (7)

• Response rate

  Within the 4 years after randomization

• overall response rate (ORR)

  assessed monthly from Randomization until PD, (approximately up to 3 years).

• Progression free survival (PFS)

  at 4 years after randomization and initiation of salvage therapy

• Incidence of adverse events.

  within the 4 years after randomization

• Quality of Life (QoL)

  within the 4 years after randomization

Study Arms (2)

Fixed duration therapy for 24 months.

EXPERIMENTAL

Daratumumab, Lenalidomide, Dexamethasone

Combination Product: Daratumumab/Lenalidomide/Dexamethasone for 24 months

Continuous therapy

ACTIVE COMPARATOR

Daratumumab, Lenalidomide, Dexamethasone

Combination Product: Daratumumab/Lenalidomide/Dexamethasone until progression

Interventions

Daratumumab/Lenalidomide/Dexamethasone for 24 months COMBINATION_PRODUCT

Conditioning regimen: 16 mg/kg IV : * Weekly (Cycles 1 and C2) * Every two weeks (C3 to C6) * Monthly from C7 up to 24 months in total (Arm 1) Infusion reaction prophylaxis : * Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 hour or less prior to infusion * An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of promethazine) approximately 1hour prior to infusion; after Cycle 6, if a subject has not developed an infusion-related reaction and is intolerant to antihistamines, modifications are acceptable as per investigator discretion * Dexamethasone 40 mg IV (preferred) or PO, approximately 1 hour or less prior infusion. Lenalidomide: Conditioning regimen: 25 mg per os. From day 1 to day 21 of each cycle up to 24 months in total (Arm 1) Dexamethasone: Conditioning regimen: 40 mg at day 1 (preinfusion medication IV preferred), day 8, day 15 and day 22 per os of each cycle up to 24 months in total (Arm 1)

Fixed duration therapy for 24 months.

Daratumumab/Lenalidomide/Dexamethasone until progression COMBINATION_PRODUCT

Conditioning regimen: 16 mg/kg IV : * Weekly (Cycles 1 and C2) * Every two weeks (C3 to C6) * Monthly from C7 until disease progression (Arm 2). Infusion reaction prophylaxis : * Acetaminophen (paracetamol) 650-1000 mg IV or orally (PO) approximately 1 hour or less prior to infusion * An antihistamine (diphenhydramine 25-50 mg IV or PO, or equivalent but avoid IV use of promethazine) approximately 1hour prior to infusion; after Cycle 6, if a subject has not developed an infusion-related reaction and is intolerant to antihistamines, modifications are acceptable as per investigator discretion * Dexamethasone 40 mg IV (preferred) or PO, approximately 1 hour or less prior infusion. Lenalidomide: Conditioning regimen: 25 mg per os. From day 1 to day 21 of each cycle until disease progression (Arm 2). Dexamethasone: Conditioning regimen: 40 mg at day 1 (preinfusion medication IV preferred), day 8, day 15 and day 22 per os of each cycle until disease progression (Arm 2).

Continuous therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Adult patients (≥ 18 years old)
• Documented MM in relapse according to standard criteria and requiring initiation of a first line salvage therapy.
• Subject must have received one prior line of therapy for MM.
• Subject must have achieved a response (PR or better) to the prior regimen.
• Subject must have an 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
• Affiliation to a social security system or equivalent (recipient or assign)
• Effective method of contraception for the duration of treatment and 3 months after the last dose for women of childbearing age and men with a partner of childbearing age:
• Progestin-only pill associated with inhibition of ovulation
• Hormonal methods of contraception, including oral contraceptive pills containing a combination of estrogen + progesterone, vaginal ring, injectables, implants and intrauterine devices (IUDs)
• non-hormonal IUD
• Bilateral tubal occlusion
• Vasectomized partner with documented azoospermia 90 days after procedure and who received a medical assessment of surgical success
• Intrauterine hormone release system (IUS)

You may not qualify if:

• Evidence of refractoriness or intolerance to lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). If previously treated with a lenalidomide or daratumumab-containing regimen, the subject is excluded if he or she:
• Discontinued due to any severe adverse event related to prior lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) treatment, or
• If, at any time point, the subject was refractory to any dose of lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). Refractoriness to lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) is defined either as:
• Subjects whose disease progressed within 60 days of lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody) administration; or
• Subjects whose disease is nonresponsive while on lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody). Nonresponsive disease is defined as either failure to achieve at least a minimal response or development of progressive disease while on lenalidomide and/or daratumumab (or another anti CD38 monoclonal antibody).
• Subject has received an allogenic stem cell transplant (regardless of timing).
• Subjects planning to undergo a stem cell transplant prior to progression of disease on this study, ie, these subjects should not be enrolled in order to reduce disease burden prior to transplant.
• Subject has a 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).
• Subject has known MM meningeal involvement.
• Subject has 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.
• Subject has any concurrent medical condition or disease (eg, 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 for participating in this study.
• Subject has known uncontrolled chronic obstructive pulmonary disease (COPD)
• Subject has clinically significant cardiac disease.
• Subject is known to be seropositive for human immunodeficiency virus (HIV), hepatitis B or hepatitis C.
• Creatinine clearance ≤30 mL/min (MDRD method) (lenalidomide dose adjustment will be considered for subjects with creatinine clearance 30-60 mL/min).

Sponsors & Collaborators

• Assistance Publique - Hôpitaux de Paris: lead

Study Sites (1)

Saint Antoine Hospital - Hematology Department

Paris, 75012, France

Location

MeSH Terms

Conditions

Multiple Myeloma; Recurrence

Interventions

daratumumab; Lenalidomide; Dexamethasone

Condition Hierarchy (Ancestors)

Neoplasms, Plasma Cell; Neoplasms by Histologic Type; Neoplasms; Hemostatic Disorders; Vascular Diseases; Cardiovascular Diseases; Paraproteinemias; Blood Protein Disorders; Hematologic Diseases; Hemic and Lymphatic Diseases; Hemorrhagic Disorders; Lymphoproliferative Disorders; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Phthalimides; Phthalic Acids; Acids, Carbocyclic; Carboxylic Acids; Organic Chemicals; Piperidones; Piperidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Isoindoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Steroids, Fluorinated

Study Officials

• Mohamad Mohty, PU-PH

  Assistance Publique - Hôpitaux de Paris

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 20, 2018
• First Posted: February 11, 2019
• Study Start: July 25, 2019
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): July 1, 2026
• Last Updated: December 6, 2024

Record last verified: 2024-12

Locations

FR (1)