A Phase 2 Study of Elotuzumab in Combination with Lenalidomide and Low-Dose Dexamethasone in Patients with Relapsed/Refractory Multiple Myeloma

Elotuzumab is a humanized monoclonal IgG1 antibody directed against the cell surface glycoprotein CS1, which is highly expressed on tumor cells from >95% of multiple myeloma (MM) patients. The mechanism of action of elotuzumab is primarily natural killer cell-mediated antibody-dependent cellular cytotoxicity against myeloma cells. A Phase 1 study of elotuzumab (at doses of 5, 10, and 20 mg/kg) in combination with lenalidomide and low-dose dexamethasone (N=28) in relapsed/refractory MM patients demonstrated an 82% objective response rate (ORR). Median PFS was not yet reached after a median of 16.4 months follow-up in patients who were treated until progression (only the 20 mg/kg cohort). Of the 13 Phase 1 patients without premedication, 12 (92%) experienced infusion reactions (IR), including 2 with Grade 3/4 IR adverse events (AE). Phase 3 trials of lenalidomide/dexamethasone with or without elotuzumab are ongoing.

In the ongoing Phase 2 study, patients with relapsed/refractory MM and 1 to 3 prior therapies were randomized to elotuzumab 10 or 20 mg/kg IV (days 1, 8, 15, and 22 every 28 days in the first 2 cycles and days 1 and 15 of subsequent cycles), lenalidomide 25 mg PO (days 1–21) and dexamethasone 40 mg PO weekly or 28 mg PO plus 8 mg IV on elotuzumab dosing days. Patients treated with prior lenalidomide were excluded. All patients received a premedication regimen, which consisted of either methylprednisolone (50 mg IV) or in a later amendment dexamethasone (8 mg IV), diphenhydramine (25–50 mg PO or IV) or equivalent, ranitidine (50 mg IV) or equivalent, and acetaminophen (650–1000 mg PO). Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess efficacy (ORR; 'partial response [PR]) according to the International Myeloma Working Group criteria. The incidence of IRs were analyzed by 1) AEs, regardless of investigator attribution, and that potentially could be an IR by virtue of their onset on the day of, or day after, elotuzumab infusion, and 2) investigator attribution of an AE as an IR.

Among 73 enrolled and treated patients (median age 63 years; range 39–82), 55% had ≥2 prior therapies, 62% received prior thalidomide, 60% received prior bortezomib, and 47% had β2 microglobulin ≥3.5 mg/L at screening (N=71). ORR was 82% in the combined treatment group (10 mg/kg, n=36; 20 mg/kg, n=37), including 44% ≥ very good PR (VGPR). Of these patients, 12% had a stringent complete response (CR) or a CR, and 32% had a VGPR. In the 10 mg/kg group (Phase 3 dose), the ORR was 92%. ORRs for patients who received 10 mg/kg by subgroup were: 1 prior therapy (n=16), 100%; ≥2 prior therapies (n=20), 85%; prior thalidomide (n=21), 91%; prior bortezomib (n=22), 86%. Median time to objective response was 1.0 months (range, 0.7–4.3). After a median follow-up of 11.4 months, 22% of patients had progressed in the 10 mg/kg group and 30% of patients in the 20 mg/kg group. For all treated patients, the most common Grade 3/4 treatment-emergent AEs were lymphopenia (16%), thrombocytopenia (16%), neutropenia (15%), and anemia (11%). Forty-six patients (63%) experienced a study sponsor-defined IR (all grades).The most common IR AEs (mostly Grade 1/2; 1 Grade 3 nausea) were nausea (18%), headache (14%), pyrexia (14%), and dizziness (12%). Among the pre-specified IR AEs, Grade 3 rash and Grade 3 nausea were identified in 2 patients, respectively. However, the incidence of investigator-identified IR AEs was 16% (all grades) including the Grade 3 rash. No Grade 4 or 5 IR AEs were reported. Of the 73 patients, 40 patients are still on treatment.

Elotuzumab 10 mg/kg in combination with lenalidomide and low-dose dexamethasone was generally well tolerated and exhibited a 92% ORR in relapsed/refractory MM patients; 10 mg/kg is the Phase 3 dose. Twenty-two percent of patients progressed after a median of 11.4 months follow-up. Elotuzumab-associated AEs were primarily Grade 1 and 2 infusion-related reactions, with the incidence and severity mitigated by the defined premedication regimen. Phase 3 clinical trials of this combination are ongoing in relapsed/refractory MM (ELOQUENT2; CA204-004) and front-line MM (ELOQUENT1; CA204-006); the latter is based on the Phase 2 study ORR of 100% in patients who had received only 1 prior therapy. Updated results will be presented at the meeting.

Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Off Label Use: Elotuzumab. Jakubowiak:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millennium: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Facon:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vij:Washington University School of Medicine: Honoraria, Research Funding, Speakers Bureau; Multiple Myeloma Consortium: Membership on an entity's Board of Directors or advisory committees. Reece:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Princess Margaret Hospital: Honoraria, Research Funding; Johnson&Johnson: Research Funding. White:Celgene: Consultancy, Honoraria, Research Funding. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Rossi:Pierre Fabre Medicaments: Consultancy; LFB: Consultancy. Tsao:Abbott Biotherapeutics Corp.: Employment. Parli:Abbott Biotherapeutics: Employment. Kroog:Bristol-Myers Squibb: Employment. Singhal:Abbott: Employment. Richardson:Millennium 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; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees.