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Elotuzumab Receives ‘Breakthrough Therapy’ Designation for Multiple Myeloma

Monoclonal antibody is used in combination with lenalidomide and dexamethasone

The FDA has granted a “breakthrough therapy” designation to elotuzumab (Bristol-Myers Squibb/AbbVie), an investigational humanized monoclonal antibody, for use in combination with lenalidomide and dexamethasone for the treatment of multiple myeloma in patients who have received one or more prior therapies.

According to the FDA, a “breakthrough therapy” designation is intended to expedite the development and review of drugs for serious or life-threatening conditions. The criteria for the designation require preliminary clinical evidence demonstrating that the drug may provide substantial improvement on at least one clinically significant endpoint compared with available therapy.

The FDA’s decision was based on findings from a randomized phase II, open-label study that evaluated two dose levels of elotuzumab — including the 10-mg/kg dose that is being studied in phase III trials — in combination with lenalidomide and low-dose dexamethasone in previously treated patients.

In this phase II study, patients with relapsed or refractory multiple myeloma were randomly assigned to receive elotuzumab 10 or 20 mg/kg (intravenous infusion on days 1, 8, 15, and 22 of a 28-day cycle in the first two cycles and then days 1 and 15 of subsequent cycles) in combination with oral lenalidomide 25 mg daily on days 1 to 21 and oral dexamethasone 40 mg weekly. The patients were treated until disease progression or unacceptable toxicity occurred. The study’s primary endpoint was the objective response rate (ORR). Secondary endpoints include progression-free survival (PFS) and safety.

In patients treated with elotuzumab 10-mg/kg (n = 36), median PFS was 33 months after a median follow-up period of 20.8 months, and the ORR was 92%. The median PFS was 18 months in the 20-mg/kg arm (n = 37) after a median follow-up period of 17.1 months, and the ORR was 76%.

In patients receiving elotuzumab 10 or 20 mg/kg, most treatment-emergent adverse events (AEs) occurred within 18 months after the initiation of therapy. The most common grade-3 or grade-4 AEs for the 10-mg/kg and 20-mg/kg arms, respectively, were lymphopenia (26% and 9%), neutropenia (21% and 22%), thrombocytopenia (21% and 17%), anemia (13% and 12%), leukopenia (8% and 7%), hyperglycemia (5% and 12%), pneumonia (8% and 5%), diarrhea (10% and 5%), fatigue (8% and 9%), and hypokalemia (8% and 5%).

The data from this phase II study were presented in June 2013 at the 18th annual congress of the European Hematology Association (EHA), held in Stockholm, Sweden.

Elotuzumab is a humanized immunoglobulin G1 (IgG1) monoclonal antibody targeted against signaling lymphocyte activation molecule 7 (SLAMF7), a glycoprotein expressed on myeloma and natural killer cells but not detectable in normal tissue. An ongoing study is investigating whether, through both direct activation and engagement of natural killer cells, elotuzumab may selectively target and kill SLAMF7-expressing myeloma cells.

Elotuzumab is also being studied as monotherapy in patients with smoldering myeloma and in combination with other therapies in first-line and relapsed or refractory multiple myeloma. A clinical development program for the agent is underway, including phase III trials in first-line multiple myeloma (ELOQUENT-1) and relapsed or refractory multiple myeloma (ELOQUENT-2). Moreover, elotuzumab is being investigated in a randomized phase II study along with bortezomib and dexamethasone in relapsed or refractory multiple myeloma.

Multiple myeloma is a progressive hematologic cancer that originates in the bone marrow. It is the second most common blood cancer and remains incurable, with a 5-year survival rate of 45%. It is estimated that approximately 24,050 new cases will be diagnosed in the U.S. in 2014 and that more than 11,000 Americans will die from the disease. Globally, an estimated 750,000 people have myeloma.

Sources: Bristol-Myers Squibb; May 19, 2014; and BMS; June 15, 2013.

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