Preliminary Safety and Efficacy Data Of Daratumumab In Combination With Lenalidomide and Dexamethasone In Relapsed Or Refractory Multiple Myeloma

Daratumumab (HuMax™-CD38) is a human IgG1κ monoclonal antibody with a broad spectrum of killing activity. It directly targets tumor cells and effectively mediates destruction of CD38-expressing tumor cells via antibody-dependent cell-mediated cytotoxicity, antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity and apoptosis. In the first-in-human dose-escalation study GEN501 of Daratumumab (DARA) as monotherapy in patients with relapsed or refractory multiple myeloma (MM) the safety profile was acceptable. In doses ≥4mg/kg 42% of the patients achieved a partial response and 25% achieved a minimal response¹ according to modified IMWG guidelines². Targeting MM cells using a direct and indirect antitumor mechanism has shown to be effective³. Combining DARA with lenalidomide (LEN) enhances NK cell-mediated killing of MM cells and is expected to lead to a synergistically higher efficacy as already proven in an ex-vivo setting⁴. Here, we report the first experience from the GEN503 study combining DARA with LEN and dexamethasone (DEX).

This is a phase I/II open-label multicenter study of DARA in combination with LEN and DEX including a classic 3 + 3 dose-escalation design. DARA is being administered in doses from 2mg/kg to 16mg/kg weekly for 8 weeks, twice a month for 16 weeks and once a month until disease progression, unmanageable toxicity or up to maximum 24 months. LEN is being administered according to the label and 40mg DEX is being administered once weekly.

The primary objective is to establish the safety profile. The secondary objectives are assessment of efficacy and pharmacokinetics.

Data from 6 patients (5 male, 1 female) have been collected to date. The study is ongoing. Median age was 63.5 years (48-71). The median number of prior treatment lines was 2.5 (2-4) and median ECOG status was 0.5 (0-1). Preliminary safety data show a manageable safety profile in line with what has previously been reported for LEN. Six adverse events of grade 3 or more (5 events of neutropenia and 1 event of thrombocytopenia) were reported during the first cycle and assessed as related to the combination of DARA with LEN/DEX. Preliminary efficacy evaluation from the first 6 evaluable patients shows that DARA induced a marked reduction in M-protein, yielding a response rate of PR or better. DARA PK data are currently in process. The results presented are based on data analyzed before database lock.

The safety profile has been manageable. DARA induced a marked reduction in M-protein corresponding to all patients achieving a PR or better with 50% achieving VGPR or better. All available data will be updated and presented at the meeting.

1: Lokhorst et al. EHA 2013 abstract #8512

2: Rajkumar et al Blood 2011;117:4691-5

3: Lonial et al. J Clin Oncol 2010;28(15s)

4: van der Veer et al. Haematologica 2011;96(2):284-90

Plesner:Genmab: Consultancy; Janssen Pharmaceuticals: Membership on an entity’s Board of Directors or advisory committees; Celgene Corporation: Membership on an entity’s Board of Directors or advisory committees. Lokhorst:Johnson-Cilag: Honoraria; Celgene: Honoraria; Genmab A/S: Consultancy, Research Funding; Mudipharma: Honoraria. Minnema:Janssen Cilag: Consultancy, Honoraria. Cakana:Johnson & Johnson Pharmaceuticals: Employment. Brun:Genmab A/S: Employment. Basse:Genmab A/S: Employment. Palumbo:Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Richardson:Millenium: Consultancy; Celgene: Consultancy; Johnson & Johnson: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy.