A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma

Abstract

This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 ؉ 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow-derived plasma cells was reliably saturated (> 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens. (Blood. 2012;120(3):552-559) IntroductionMultiple myeloma (MM) is an incurable malignancy arising from postgerminal mature B cells, characterized by an excess of monotypic plasma cells in the bone marrow and elevated levels of monoclonal immunoglobulins in the serum and/or urine. 1 Common clinical sequelae include lytic bone lesions, fractures, myelosuppression, and renal failure. In the United States, the estimated annual diagnosed incidence is 20 000, with a prevalence of approximately 62 000 as of 2007. 2,3 MM accounts for 15% of all hematologic malignancies and 2% of all malignancies. 4 Advances in high-dose chemotherapy and stem cell transplantation have improved overall survival (OS) and event-free disease periods in MM, 5-7 although relapses are inevitable. Newer therapeutic agents, such as bortezomib, thalidomide, and lenalidomide, have demonstrated clinical benefit in patients with newly diagnosed [8][9][10][11][12][13] and relapsed or refractory disease. 5,14,15 Despite these therapeutic advances, longterm control of relapsed/refractory MM remains elusive for most patients. Progressive disease that is resistant to both immunomodulatory drugs and bortezomib is associated with a particularly poor prognosis. 16 As such, there remains an important need for additional novel therapies to augment existing first-generation agents and continue to improve patient outcome.Elotuzumab is a humanized monoclonal IgG1 antibody directed against human CS1 (also known as CD2 subset-1, SLAMF7, CRACC, and CD319), a cell surface antigen glycoprotein that is highly expressed on MM cells and normal plasma cells. CS1 is expressed at a lower ...

Preclinical and clinical evaluation of elotuzumab, a SLAMF7-targeted humanized monoclonal antibody in development for multiple myeloma

“…Infusion-related events were observed in 20 (59%) patients although these were mitigated after the protocol was amended to include premedication before the first elotuzumab dose. Although no objective responses were observed, 9/35 (26%) heavily-pretreated patients had stable disease according to the European Group for Blood and Marrow Transplantation myeloma response criteria [44].…”

“…Pretreatment for infusion reactions originally included an antihistamine and acetaminophen, which was optional for patients who experienced any infusion reaction [46]; during the course of the study, the pretreatment regimen evolved considerably, reducing the severity and incidence of infusion reactions [66]. Several other elotuzumab-based trials are currently ongoing or recruiting patients (Table 3) [44,45,47,[67][68][69][70][71][72], the results of which will further enhance the understanding of elotuzumab in multiple myeloma. The Phase 3 ELOQUENT-2 trial (NCT01239797) further investigates elotuzumab in combination with lenalidomide and dexamethasone in relapsed and refractory patients, using a randomized, controlled study design.…”

“…Elotuzumab was generally well tolerated. Most treatment-related AEs were grade 1 or 2 in severity, with the most common (>10% of patients) including chills, pyrexia and flushing (Table 2) [44][45][46][47][48]. The maximum tolerated dose was not reached.…”

“…Patients with relapsed or refractory multiple myeloma were treated with intravenous elotuzumab at one of six dose levels (0.5 to 20 mg/kg) once every 14 days for 8 weeks, with the option of a second course of treatment in patients without relapse [44].…”

“…On the basis of promising preclinical results, elotuzumab was evaluated as monotherapy in a phase I, dose-escalation trial (Table 1) [44][45][46][47]. Patients with relapsed or refractory multiple myeloma were treated with intravenous elotuzumab at one of six dose levels (0.5 to 20 mg/kg) once every 14 days for 8 weeks, with the option of a second course of treatment in patients without relapse [44].…”