The Clinical Pharmacology of Elotuzumab
Novel treatment options are needed to improve long-term outcomes for patients with multiple myeloma (MM). In this article, we comprehensively review the clinical pharmacology of elotuzumab, a first-in-class monoclonal anti-SLAMF7 antibody approved in combination with lenalidomide and dexamethasone (ELd) for the treatment of patients with MM and one to three prior therapies. Elotuzumab has a dual mechanism of action to specifically kill myeloma cells: binding SLAMF7 on myeloma cells facilitates natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC), and direct engagement of SLAMF7 on NK cells further enhances NK cell activity. Elotuzumab administration causes transient elevations of selected cytokines (tumor necrosis factor-α, interferon-γ-induced protein-10 and monocyte chemoattractant protein-1). The temporary nature of these elevations (greatest after the first dose, with a trend to return to baseline by day 7) suggests a low likelihood of facilitating clinically meaningful drug–drug interactions. Elotuzumab exposure increases more than proportionally to dose and >80% SLAMF7 receptor occupancy is achieved with the approved elotuzumab 10 mg/kg regimen. Population pharmacokinetic data from 375 patients demonstrated weight-based dosing is appropriate for elotuzumab, and that ethnicity and hepatic/renal function have minimal effects on exposure. Exposure–response analysis of patients treated with ELd demonstrated that increased elotuzumab exposure does not elevate the risk of grade 3+ adverse events (AEs) or AEs leading to discontinuation/death. Elotuzumab antidrug antibodies occurred in 18.5% of patients treated with ELd or elotuzumab plus bortezomib and dexamethasone, but were generally transient and did not affect elotuzumab efficacy or safety. A monotherapy study indicated elotuzumab does not have clinically relevant effects on QT intervals.
PK and immunogenicity analyses were performed at Covance (formerly Tandem Labs) with oversight by Debbie Hilliard and Tonya Felix, including a significant contribution from Linda Zislin and Pathanjali Kadiyala. NAb assessments were performed at Bristol-Myers Squibb by Marina Juhel and Mike Sank.
Compliance with Ethical Standards
Elotuzumab was developed in a partnership between Bristol-Myers Squibb and AbbVie Biotherapeutics, who funded the studies described in this review. Medical writing assistance was provided by Matthew Thomas, PhD, Caudex, Oxford, UK, and funded by Bristol-Myers Squibb.
Conflict of interest
Chaitali Passey, Jennifer Sheng, Johanna Mora, Amol Tendolkar, Michael Robbins, Robert Dodge, Amit Roy, Akintunde Bello, and Manish Gupta are employees of Bristol-Myers Squibb (Princeton, NJ, USA). Manish Gupta and Chaitali Passey own stocks in Bristol-Myers Squibb; Johanna Mora, Michael Robbins and Amol Tendolkar hold stock options and/or bond holdings in Bristol-Myers Squibb.
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