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The Clinical Pharmacology of Elotuzumab

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Abstract

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.

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Acknowledgements

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.

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Authors and Affiliations

  1. Clinical Pharmacology and Pharmacometrics, Bristol-Myers Squibb, 3551 Lawrenceville Road, Princeton, NJ, 08540, USA

    Chaitali Passey, Jennifer Sheng, Johanna Mora, Amol Tendolkar, Michael Robbins, Robert Dodge, Amit Roy, Akintunde Bello & Manish Gupta

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  1. Chaitali Passey
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  2. Jennifer Sheng
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Correspondence to Manish Gupta.

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Funding

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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Passey, C., Sheng, J., Mora, J. et al. The Clinical Pharmacology of Elotuzumab. Clin Pharmacokinet 57, 297–313 (2018). https://doi.org/10.1007/s40262-017-0585-6

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