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

Condition(s) studied

Investigational drug(s) / intervention(s)

Daratumumab/Lenalidomide/Dexamethasone for 24 months: 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)

Daratumumab/Lenalidomide/Dexamethasone until progression: 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).

Study 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.

Eligibility

Primary outcome measure(s)

• overall survival — 4 years after randomization
  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

Trial sites (1)

More Assistance Publique - Hôpitaux de Paris trials in France

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