The novel agent elotuzumab, when administered with lenalidomide (Revlimid) and dexamethasone, produced responses in 81% of previously treated myeloma patients, according to interim phase II study data presented at ASH 2010. Paul G. Richardson, MD, of Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, reported the findings.
Elotuzumab is a humanized monoclonal immunoglobin G1 antibody that targets CS1, a glycoprotein heavily expressed on the surface of multiple myeloma cells but with limited expression on normal cells. Phase I studies had demonstrated a high rate of response in patients with advanced disease, providing the rationale for the current phase II study. The primary objective of the open-label, multicenter trial is to select the maximum-tolerated dose.
The study included 63 patients whose disease had relapsed after or was refractory to 1 to 3 prior therapies; patients previously treated with lenalidomide were ineligible for the study. Richardson said 61% of patients had received ≥2 prior therapies, usually including bortezomib (Velcade) and/ or thalidomide, and more than three-quarters had undergone autologous transplantation.
Investigators randomized the patients to 28-day cycles of elotuzumab at a 10-mg/kg or 20-mg/kg dose, administered intravenously on days 1, 8, 15, and 22 of a 28-day cycle for the first 2 cycles Elotuzumab Highly Active in Patients With Advanced Myeloma and then on days 1 and 15 for subsequent cycles. Patients given both doses of elotuzumab received 25 mg of oral lenalidomide daily on days 1-21 and 40 mg of oral dexamethasone weekly. Treatment continued until disease progression or unacceptable toxicity. To mitigate possible infusion reactions, patients were pretreated with methylprednisolone, diphenhydramine or its equivalent; ranitidine or its equivalent; and acetaminophen. This regimen was administered 30 to 60 minutes prior to an elotuzumab infusion.
Among the 63 patients, a partial response or greater was observed in 51 (81%) patients, including 90% of those taking the lower, 10-mg dose. As a result of the response trend favoring the 10-mg dose, Richardson said the investigators selected this as the therapeutic dose for future evaluations. Overall, 5% of patients experienced complete response, which included 7% of patients in the 10-mg dosing arm. Nearly one-third (29%) of patients in the study had a very good partial response, and this increased to 32% of patients taking the 10-mg dose. In addition, 16% of patients study-wide achieved stable disease.
Prior treatment with thalidomide or bortezomib was not associated with weaker responses. In the 10-mg/kg dosing arm, the overall response rate was 90% for patients treated previously with thalidomide compared with an 83% overall response rate for patients who had taken bortezomib.
“The quality of the responses was very impressive as well,” said Richardson. “We saw a consistent signal in patients with prior thalidomide or bortezomib [use].” At a median follow-up of 4.9 months, the median progressionfree survival has not yet been reached.
Grade 3/4 toxicities were observed in 56% of patients, consisting primarily of muscle spasms, constipation, fatigue, pyrexia, and nausea. Richardson said toxicities were easily managed for most patients. Grade 3/4 hematologic toxicities were rare; 14% of patients developed neutropenia, another 14% experienced lymphopenia, and 13% experienced thrombocytopenia.
While 49% of patients had infusion reactions, only 1 patient had a grade 3 reaction. Richardson credited this to the effectiveness of the premedication regimen.
Richardson concluded that elotuzumab produced “robust and durable responses” in a population of patients who were highly refractory to existing therapies. He said the investigative drug will be further evaluated in a phase II trial expected to start in 2011.
_________________________________________________________________________Richardson PG, Moreau P, Jakubowiak J, et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: interim results of a phase 2 study. Presented at: 52nd ASH Annual Meeting and Exposition; December 4-7, 2010; Orlando, Florida.