Paul G. Richardson, MD
Treatment with elotuzumab in combination with lenalidomide and dexamethasone demonstrated encouraging efficacy as measured by objective response rate (ORR) and progression-free survival (PFS) in patients with relapsed/refractory multiple myeloma, according to findings from a phase Ib/II study presented at the 2014 ASH Annual Meeting.
Elotuzumab is a humanized IgG1 monoclonal antibody targeting Signaling Lymphocytic Activation Molecule F7 (SLAMF7, formerly known as CS1). The novel mechanism of action of elotuzumab and its safety and efficacy observed in this study support the ongoing elotuzumab phase III clinical development program in relapsed/refractory MM and newly diagnosed MM, said lead investigator Paul G. Richardson, MD.
SLAMF7 is a glycoprotein that is expressed on natural killer cells and on >95% myeloma cells, but not on normal tissue. “There is a strong body of evidence to support a dual mechanism of action of this antibody [elotuzumab],” said Richardson, from the Dana-Farber Cancer Institute, Boston. By binding to SLAMF7, elotuzumab activates natural killer cells directly and via a CD16-mediated pathway, which enables selective killing via antibody-dependent cellular cytotoxicity with minimal effects on normal tissue, he explained.
Clinical activity of elotuzumab in relapsed/refractory multiple myeloma had been established in combination with lenalidomide and low-dose dexamethasone in the phase Ib portion of the study (N = 28), with an ORR of 82% (J Clin Oncol
2012;30:1953-1958). No dose-limiting toxicity was observed up to the maximum proposed dosage of 20 mg/kg. The median time to progression (TTP) had not been reached for patients in the 20-mg/kg cohort after a median follow-up of 16.4 months. Updated data revealed a median TTP of 33 months for all treatment groups (5, 10, or 20 mg/kg).
The randomized phase II cohort of the trial randomized 73 patients to receive either 10 or 20 mg/kg of intravenous elotuzumab plus lenalidomide, and dexamethasone. Elotuzumab was administered in 28-day cycles of 10 or 20 mg/kg on days 1, 8, 15, and 22 for cycles 1 and 2, and on days 1 and 15 for subsequent cycles. Patients also received oral lenalidomide, 25 mg/day on days 1 to 21, and oral dexamethasone, 40 mg once weekly. Treatment continued until disease progression or unacceptable toxicity. Patients received a premedication regimen before elotuzumab dosing to reduce the risk of infusion reactions.
Fifty-five percent of patients received either two or three previous therapies. Sixty percent received prior bortezomib and 62% were exposed to thalidomide. One third of patients were refractory to their last MM treatment.
The median number of elotuzumab cycles was 17 (21.5 in the 10-mg/kg group and 16 in the 20-mg/kg group), and the median duration of treatment was 14.8 months (19.1 months in the 10-mg/kg group and 14.5 months in the 20-mg/kg group). At the data cut-off, 13 patients were still on treatment and 60 patients (82%) had discontinued (34 due to disease progression, 12 due to adverse events, and 14 for other reasons). The ORR was 84% (92% with 10 mg/kg; 76% with 20 mg/kg).
“All of us in the trial were very struck by the durability of this treatment approach,” Richardson said. “What was particularly exciting was that we saw a remarkable response rate in this relapsed/refractory population, recognizing that they were lenalidomide-naïve.”
A stringent complete response or complete response was observed in 14% of patients, a very good partial response was seen in 43%, and 27% had a partial response. The median time to first response was 1 month and the median duration of response was 20.8 months. The durability of the response was reflected by a median PFS of 32.5 months with the 10-mg/kg dosage (25.0 months with 20 mg/kg), and an overall median PFS of 28.62 months.
The most common treatment-emergent adverse events were diarrhea (66%), muscle spasms (62%), fatigue (56%), constipation (51%), nausea (48%), and upper respiratory infection (47%), which was similar to the phase I experience. The most common grade 3 or 4 adverse events were neutropenia, thrombocytopenia, lymphopenia and anemia.
“It’s important to judge safety in the context of the duration of treatment; patients were on therapy for a number of years,” advised Richardson.
The premedication regimen successfully mitigated infusion reactions. The overall rate of infusion reactions was 11%. Seven patients had infusion reactions at a flow rate ≤2 mL/min. For patients who tolerated infusion at 2 mL/min, the flow rate was progressively increased to a maximum of 5 mL/min. Of the 3,412 infusions given, 33% were at a rate of 5 mL/min.