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.

Figure 1

Observed elotuzumab serum concentration versus time curves (mean ± SD). LLOQ indicates lower limit of quantification; and SD, standard deviation.

Figure 2

CS1 saturation of bone marrow CD38⁺ cells at day 56. Symbols indicate observed data from individual patients at each dose level. The vertical line indicates target level of serum elotuzumab concentration (70 μg/mL) based on preclinical studies. BM indicates bone marrow; and Emax, maximum effect.

Figure 3

Transient decrease in lymphocyte counts. N = number of patients at baseline. Changes in cell count (from baseline to 2 hours after first dose, and from 2 hours after first dose to day 56) were significant for both (A) total lymphocyte counts (P = .002 and .004, respectively) and (B) NK cell counts (P = .0025 and .032, respectively). *Postdose. All other assessments were performed predose.

Figure 4

Individual patient serum IP-10 levels (20-mg/kg cohort, n = 6). *Postdose. All other assessments were performed predose.