Elotuzumab In Combination with Lenalidomide and Low-Dose Dexamethasone In Patients with Relapsed/Refractory Multiple Myeloma: Interim Results of a Phase 1 Study

Elotuzumab is a humanized monoclonal IgG1 antibody targeting CS1, which is highly and uniformly expressed on multiple myeloma (MM) cells, and important to myeloma cell survival. Elotuzumab exerts significant antitumor activity against primary myeloma cells via NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC), regardless of sensitivity or resistance to conventional therapies. In preclinical studies, the activity of elotuzumab is independently enhanced by lenalidomide and dexamethasone. We present the results of an ongoing phase 1 study evaluating the maximum tolerated dose (MTD), safety, clinical response, and pharmacokinetics of elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed/refractory MM.

Entry criteria included patients who had measurable disease, had experienced at least 1 relapse, and had not received lenalidomide for at least 6 weeks before the first dose of elotuzumab. The study enrolled 3 escalating dose cohorts of elotuzumab (5, 10, and 20 mg/kg IV), administered on days 1, 8, 15, and 22 of a 28-day cycle in the first 2 cycles, and then days 1 and 15 of each subsequent cycle, along with lenalidomide 25 mg PO daily on days 1 to 21 and dexamethasone 40 mg PO weekly. At each dose level, dose-limiting toxicities (DLTs) were assessed during cycle 1 and clinical responses were evaluated with International Myeloma Working Group (IMWG) criteria during each cycle. The first 5 patients received up to 6 cycles of therapy before a protocol amendment allowed subsequent patients to be treated until disease progression.

Twenty-nine patients with advanced MM (median stage III) who had received a median of 3 prior MM therapies, including bortezomib (69%), thalidomide (59%), or lenalidomide (21%), were enrolled. Of these, 28 received elotuzumab; 3 patients each were treated with 5 and 10 mg/kg and 22 with 20 mg/kg. Patients received a median of 8.5 treatment cycles and 20.5 doses of elotuzumab. Sixteen patients have permanently discontinued study treatment. No DLTs were observed up to 20 mg/kg during the escalation phase and hence no MTD was established. The most frequent grade 3/4 toxicities were neutropenia (36%) and thrombocytopenia (21%); 2 patients experienced 3 serious infusion-related reactions (1 patient with a grade 4 hypersensitivity reaction and 1 with 2 grade 3 stridor events) during the first treatment cycle. Objective responses (partial response or better) were obtained in 82% (23/28) of treated patients and 96% (21/22) of lenalidomide-naïve patients. ORRs were also high in patients who had received prior thalidomide 94% (15/16) or whose disease was refractory to the most recent therapy 82% (9/11). The median time to response was 7 weeks. The proportion of patients without disease progression (Kaplan-Meier estimate) at 16 months is 53% for total patients and 66% for patients in the 20 mg/kg elotuzumab cohort, who are being treated until disease progression. The median time to progression was not reached.

The combination of elotuzumab, lenalidomide, and low-dose dexamethasone was generally well tolerated and showed encouraging overall response rates in patients with relapsed/refractory MM who had received multiple prior therapies. A larger phase 2 study is ongoing to confirm the rate and durability of the responses observed in this phase 1 trial.

Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding. Vij:Bristol-Myers Squibb: Honoraria; Celgene: Research Funding; Celgene, Bristol-Myers Squibb: Speakers Bureau. Harousseau:Bristol-Myers Squibb, Celgene, Janssen-Cilag, Novartis, Onyx: Honoraria; Celgene, Janssen-Cilag: Speakers Bureau. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Moreau:Celgene, Facet Biotech, Bristol-Myers Squibb: Honoraria. Leleu:Janssen-Cilag, Celgene, Chugai Pharmaceutical, Roche, Amgen, Novartis, Leo Pharma: Consultancy, Honoraria, Research Funding. Kaufman:Celgene, Millennium: Consultancy; Celgene, Merck: Research Funding. Westland:Facet Biotech: Employment. Tsao:Facet Biotech: Employment. Singhal:Facet Biotech: Employment. Jagannath:Millennium, Takeda Pharmaceutical Company, Janssen-Cilag: Honoraria.