Daratumumab in Combination with Lenalidomide and Dexamethasone in Patients with Relapsed or Relapsed and Refractory Multiple Myeloma: Updated Results of a Phase 1/2 Study (GEN503)

Conference Correspondent - TON - ASH 2015 - Multiple Myeloma

Daratumumab, a human anti-CD38 IgG1κ monoclonal antibody, has shown synergistic antitumor activity in combination with lenalidomide inin vitropreclinical studies (van der Veer MS, et al. Haematologica. 2011;96[2]:284-290) and in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma (Plesner T, et al.Blood.2014;124[21]:84). This study assessed the updated safety and efficacy of daratumumab in combination with lenalidomide and dexamethasone following more than 12 months of exposure in patients with relapsed or relapsed/refractory multiple myeloma.

The study design included a dose-escalation component (daratumumab 2-16 mg/kg + lenalidomide/dexamethasone; part 1) and a cohort expansion component using the recommended phase 2 dose (daratumumab 16 mg/kg + lenalidomide/dexamethasone; part 2). In part 2, daratumumab 16 mg/kg was administered weekly during the first two 28-day cycles, every other week during cycles 3 through 6, and monthly in cycle 7 and beyond until disease progression or unacceptable toxicity. Lenalidomide 25 mg was administered orally on days 1 through 21 of each cycle, and dexamethasone 40 mg was given weekly. The primary objective was safety. Six (19%) patients discontinued treatment due to either disease progression (n = 3), treatment-emergent adverse events (n = 2), or physician decision (n = 1).

The most common (>25%) treatment-emergent adverse events (TEAEs) included neutropenia (81%), muscle spasms (44%), cough (38%), diarrhea (34%), fatigue and hypertension (28% each). One (3%) patient experienced grade 1 febrile neutropenia. Neutropenia was the most frequently (>25%) reported grade 3 or 4 TEAE (75%). Eighteen (56%) patients had infusion-related reactions (IRRs); most were mild to moderate in severity and occurred primarily during the first cycle of treatment. Two (6%) patients had grade 3 IRRs (laryngeal edema and hypertension). The patient with grade 3 laryngeal edema recovered but was discontinued from treatment per the study protocol. All other patients who experienced IRRs recovered and continued to receive treatment. 

In terms of efficacy, the overall response rate (Rajkumar SV, et al.Blood. 2011;117:4691-4695) was 88%, with 11 (34%) partial responses and 17 (53%) ≥very good partial responses (VGPRs) that included 7 (22%) stringent complete responses, 1 (3%) complete response, and 9 (28%) VGPRs. All but 2 (93%) responders had not progressed or relapsed at the time of this analysis and remained on treatment; therefore, the median duration of response was not reached. Importantly, responses deepened over time in 17 (61%) of 28 responders.

Researchers concluded that daratumumab in combination with lenalidomide and dexamethasone continues to be associated with a favorable benefit/risk profile for treatment of relapsed or relapsed/refractory multiple myeloma. For many patients, deep and durable responses were maintained throughout the study.

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Last modified: December 8, 2015