Elotuzumab In Combination with Lenalidomide and Dexamethasone In Patients with Relapsed Multiple Myeloma: Interim Results of a Phase 2 Study

Elotuzumab is a humanized monoclonal IgG1 antibody directed against CS1, an antigen highly and uniformly expressed on multiple myeloma (MM) cells but with restricted expression on normal cells. Elotuzumab exhibits significant antimyeloma activity in vitro and against MM xenografts, and its antitumor activity is enhanced independently by both lenalidomide and dexamethasone. In a dose-escalation phase 1 study that evaluated the combination of elotuzumab (5, 10, and 20 mg/kg), lenalidomide, and dexamethasone, the maximum tolerated dose was not reached, and the combination showed encouraging clinical activity (82% response rate) in patients with advanced MM. The most frequent infusion-related adverse events (AEs) were headache (21%), nausea (21%), and dizziness (11%), with 7% (2/28) of patients experiencing 3 serious infusion-related AEs during cycle 1 (1 with a grade 4 hypersensitivity reaction and 1 with 2 grade 3 stridor events). Key objectives of this dose randomized, open-label, multicenter, phase 2 study in patients with relapsed MM were to select the optimum dose of elotuzumab and to evaluate an enhanced premedication regimen to minimize the occurrence of infusion reactions.

Patients with confirmed relapsed and/or refractory MM who had received 1–3 prior therapies were enrolled; prior lenalidomide therapy was excluded. Patients were randomized 1:1 to receive elotuzumab either 10 or 20 mg/kg (IV infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles and then days 1 and 15 of subsequent cycles), along with lenalidomide 25 mg PO daily on days 1 to 21 and dexamethasone 40 mg PO weekly. Patients were treated until disease progression or unacceptable toxicity, if earlier. To control potential infusion reactions, patients received methylprednisolone (50 mg IV), diphenhydramine (25–50 mg PO or IV) or equivalent, ranitidine (50 mg IV) or equivalent, and acetaminophen (650–1000 mg PO) 30 to 60 minutes prior to each elotuzumab infusion. Objective responses (OR) were assessed according to the International Myeloma Working Group (IMWG) criteria.

As of July 8, 2010, a total of 59 patients were randomized (intent to treat population); 47 patients received at least 1 dose of study medication (safety population); and 26 patients completed or progressed prior to completing 2 cycles of treatment (efficacy population). Median age was 64 years; 36 (61%) had received ≥2 prior therapies; 28 (48%) and 31 (53%) had received bortezomib or thalidomide, respectively, and 40 (68%) had undergone transplantation. Among efficacy evaluable patients, 22/26 (85%) had a confirmed or an unconfirmed response (≥ PR) including 31% VGPR/CR. The remaining 4/26 (15%) had stable disease (Table). Treatment-emergent AEs were reported in 36/47 patients (77%); the most common events were fatigue (26%) and nausea (21%). Serious treatment-emergent AEs were reported in 22% of patients; 2 events, nausea and febrile neutropenia with thrombocytopenia, were considered to be related to elotuzumab and lenalidomide. The most common infusion-related AEs within 24 hours of elotuzumab infusion were dizziness (15%), nausea (15%), and headache (9%). These decreased in frequency after the first treatment cycle. There were no severe AEs associated with infusion reactions.

The combination of elotuzumab, lenalidomide, and dexamethasone resulted in a high response rate in patients with advanced MM and was generally well tolerated. These results are consistent with the results previously reported from the phase 1 study. The revised premedication regimen appeared to be more effective in controlling infusion reactions, which were generally mild to moderate with no severe infusion reactions reported to date. Updated response and safety data on all patients by dose level will be presented at the meeting.

Richardson:Millennium, Celgene, Johnson & Johnson, Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Lenalidomide. Moreau:Celgene, Facet, Bristol-Myers Squibb: Honoraria. Jakubowiak:Millennium, Celgene, Bristol-Myers Squibb, Johnson & Johnson Ortho-Centocor: Honoraria; Millennium, Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Millennium, Celgene, Centocor-Ortho Biotech: Speakers Bureau. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium, Takeda Pharm, Janssen: Honoraria. Vij:Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Celgene, Bristol-Myers Squibb: Speakers Bureau. Reece:Celgene: Honoraria, Research Funding. Rossi:Sanofi-Aventis, Celgene: Consultancy, Honoraria. Tsao:Facet Biotech: Employment. Fry:Facet Biotech: Employment. Berman:Bristol-Myers Squibb: Employment. Singhal:Facet Biotech: Employment. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.