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)

Introduction: Daratumumab (DARA) is a human anti-CD38 IgG1κ monoclonal antibody that showed synergistic anti-tumor activity in combination with lenalidomide (LEN) in in vitro preclinical studies (van der Veer M. Haematologica 2011;96(2):284-90). DARA has shown favorable safety and robust efficacy as a single agent in patients with relapsed and refractory (RR) multiple myeloma (MM) (Lokhorst HM. J Clin Oncol 2014;32 Suppl:abstr 8513. Lonial S. J Clin Oncol 2015;33 Suppl:abstr LBA8512) and in combination with LEN/Dexamethasone (DEX) in patients with relapsed or RR MM (Plesner T. Blood 2014;124(21):84). This study assessed the updated safety and efficacy of DARA in combination with LEN/DEX following more than 12 months of exposure in patients with relapsed or RR MM.

Methods: The study design of this ongoing, open-label phase 1/2 study of DARA in combination with LEN/DEX has been presented previously (Plesner T. Blood 2014;124(21):84). Briefly, the study comprised a 3 + 3 design dose escalation study (DARA 2-16 mg/kg + LEN/DEX; Part 1) and a cohort expansion study using the recommended phase 2 dose (DARA 16 mg/kg + LEN/DEX; Part 2). In Part 2, patients refractory to LEN were excluded and patients with ≥1 prior line of therapy were included. In Part 2, DARA 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. LEN 25 mg was administered orally on Days 1 through 21 of each cycle, and DEX 40 mg was given weekly. The primary objective was safety. Efficacy was evaluated per the International Myeloma Working Group criteria. The last patient was enrolled in August 2014.

Results: Updated safety and efficacy results (data cut January 9, 2015) of DARA 16 mg/kg plus LEN/DEX in the expansion cohort (n = 32) are presented. The median (range) number of prior lines of therapy was 2 (1-3) and the median (range) duration of follow up was 7.8 (3.0-10.4) months. Eleven (34%) patients received prior LEN treatment. Six (19%) patients discontinued treatment due to either disease progression (n = 3), treatment-emergent adverse events (TEAE; 1 patient with gastric adenocarcinoma and 1 patient with laryngeal edema that was a grade 3 infusion-related reaction [IRR]), or physician decision (n = 1).

The most common (>25%) TEAEs included neutropenia (81%), muscle spasms (44%), cough (38%), diarrhea (34%), fatigue and hypertension (28% each). Only 1 (3%) patient experienced febrile neutropenia (grade 1). Neutropenia was the most frequently (>25%) reported grade 3 or 4 TEAE (75%). Eighteen (56%) patients had IRRs and these were generally mild to moderate and occurred mostly during the first cycle. IRRs included cough (25%), allergic rhinitis, nausea, and vomiting (9% each), as well as dyspnea, nasal congestion, and hypertension (6% each). Two (6%) patients had grade 3 IRRs (laryngeal edema and hypertension). All patients with IRRs recovered and continued to receive treatment, with the exception of the patient with grade 3 laryngeal edema, who recovered but was discontinued from treatment per protocol.

The overall response rate (Rajkumar SV. Blood. 2011;117:4691-5) 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. The median time to first and best response was 1 (95% confidence interval [CI], 0.9-1.9) month and 4.5 (95% CI, 1.9-5.6) months, respectively. The median duration of response was not reached, as 26 (93%) of 28 responders had not progressed or relapsed at the time of this analysis and remained on treatment at data cutoff. Importantly, responses deepened over time in 17 (61%) of 28 responders. The 12-month duration of response will be updated at the time of ASH.

Conclusions: In the expansion cohort, the combination of DARA and LEN/DEX continues to be associated with a remarkably favorable benefit/risk profile for treatment of relapsed or RR MM. Deep and durable responses were maintained throughout the study. Additional updates on the safety and efficacy results of the expansion cohort with over 12 months of exposure will be presented at the time of the meeting.