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

Overview

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.

MM is a B cells malignancy, and is one of the most frequent primary neoplasms of the bone marrow. The fundamental pathology is an expansion of a single clone of plasma cells that produce monoclonal immunoglobulin (M-proteins) and replace normal bone marrow. Although the etiology of myeloma is not known, several studies have shown that myeloma cells acquire certain genetic changes that allow for uncontrolled growth, migration, and protection from apoptosis. The incidence of MM in Europe is 6.0 cases per 100,000 per year, with a median age at diagnosis between 63 and 70 years; the mortality is 4.1 cases per 100,000 per year. Dara is a human IgG1ĸ monoclonal antibody that binds with high affinity to a unique epitope on CD38, a transmembrane glycoprotein. It is a targeted immunotherapy directed towards tumor cells that express high levels of CD38, such as plasma cells from patients with MM. This target is distinct from those of other approved agents for MM therapy. Darashowed promising efficacy alone and with Len and Den in a phase 1-2 study involving patients with relapsed or refractory MM. Subsequently, a phase 3 trial randomized 569 MM patients to receive Len and Den (Len-Dex; control group) or in combination with Dara (Dara-Len-Dex group) With a median follow-up of 25.4 months, progression-free survival was significantly prolonged in the Dara-Len-Dex group (median not reached versus 17.5 months in the control group; HR, 0.41; 95% CI, 0.31-0.53; P \<0.0001). A significantly higher rate of overall response was observed in the Dara-Len-Dex group than in the control group (93% vs. 76%, P\<0.0001), as was a higher rate of complete response or better (51% vs. 21%, P\<0.0001). Furthermore, the rates of treatment discontinuation owing to adverse events were low and similar in the two groups. 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. 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. Dosage, route of administration and administration schedule of the medications prescribed are in accordance with the FDA and EMEA authorization in MM first relapse. Only the duration of combination is compared. One group of patient will receive the Dara-Len-Dex combination until PD in accordance with the FDA and EMEA authorization in MM first relapse (standard of care). The experimental group will receive the Dara-Len-Dex combination for up to 24 months. This shorter duration of treatment (24 months) 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 aim of the current protocol is to investigate whether a fixed duration of treatment (24 months) with the Dara-Len-Dex combination is not inferior to the continuous administration of the combination until PD. In this study some patients may have a similar OS while receiving a shorter duration of treatment. This study may allow to deliver a shorter duration of therapy for the treatment of MM at first relapse. The foreseeable risks are those of an earlier relapse in patients receiving a fixed duration of Dara-Len-Dex combination compare to the situation where they would have received the treatment until PD.