Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress 2023 EHA Congress 2023 ASCO Annual Meeting
Clinical Collections
Advances in Alzheimer’s

At a glance: The ONWARDS insulin icodec trials

A round-up of the ONWARDS phase 3 clinical trials evaluating the novel weekly insulin icodec in people with diabetes.
ADVANCED SEARCH
Log in
Top
Clinical Pharmacokinetics
Published in: Clinical Pharmacokinetics 4/2018

Open Access 01-04-2018 | Original Research Article

Influence of Disease and Patient Characteristics on Daratumumab Exposure and Clinical Outcomes in Relapsed or Refractory Multiple Myeloma

Authors: Xiaoyu Yan, Pamela L. Clemens, Thomas Puchalski, Sagar Lonial, Henk Lokhorst, Peter M. Voorhees, Saad Usmani, Paul G. Richardson, Torben Plesner, Kevin Liu, Robert Z. Orlowski, Nedjad Losic, Richard Jansson, Tahamtan Ahmadi, Kristen Lantz, Juan Jose Perez Ruixo, Honghui Zhou, Xu Steven Xu

Published in: Clinical Pharmacokinetics | Issue 4/2018

Login to get access

Abstract

Objective

The aim of this study was to understand the influence of disease and patient characteristics on exposure to daratumumab, an immunoglobulin Gκ (IgGκ) monoclonal antibody, and clinical outcomes in relapsed or refractory multiple myeloma (MM).

Patients and Methods

Baseline myeloma type, albumin levels, renal/hepatic function, age, sex, race, weight, Eastern Cooperative Oncology Group (ECOG) status, refractory status, and number of prior therapies were evaluated using data from two clinical studies—GEN501 (N = 104) and SIRIUS (N = 124).

Results

Daratumumab clearance was approximately 110% higher in IgG myeloma patients than non-IgG myeloma patients, leading to significantly lower exposure in IgG myeloma patients based on maximum trough serum concentrations (p < 0.0001). However, the overall response rate was similar for IgG and non-IgG myeloma patients (odds ratio 1.08, 95% confidence interval 0.54–2.17, p = 0.82). For a given exposure, the drug effect was significantly higher (approximately two times) in IgG versus non-IgG patients (p = 0.03). The influence of other patient and disease characteristics on daratumumab exposure was minimal and no significant effect on efficacy was observed (p ≥ 0.1). The incidences of infections and overall grade 3 or higher adverse events in subpopulations were generally consistent with that of the overall population.

Conclusion

Due to competition with the MM-produced IgG M-protein for neonatal Fc receptor protection from clearance, IgG-based monoclonal antibodies in general may have significantly higher clearance and lower concentrations in IgG MM patients compared with non-IgG MM patients. Careful evaluation of the impact of exposure and patient and disease characteristics on safety and efficacy is warranted for all IgG-based monoclonal antibodies used in MM.
Appendix
Available only for authorised users
Literature
1.
Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121:482–8.CrossRefPubMed
2.
Santonocito AM, Consoli U, Bagnato S, Milone G, Palumbo GA, Di Raimondo F, et al. Flow cytometric detection of aneuploid CD38(++) plasmacells and CD19(+) B-lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients. Leuk Res. 2004;28:469–77.CrossRefPubMed
3.
de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DC, et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J Immunol. 2011;186:1840–8.CrossRefPubMed
4.
Lammerts van Bueren J, Jakobs D, Kaldenhoven N, Roza M, Hiddingh S, Meesters J, et al. Direct in vitro comparison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood. 2014;124:3474.
5.
Overdijk MB, Verploegen S, Bogels M, van Egmond M, Lammerts van Bueren JJ, Mutis T, et al. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7:311–21.CrossRefPubMedPubMedCentral
6.
Overdijk MB, Jansen JH, Nederend M, Lammerts van Bueren JJ, Groen RW, Parren PW, et al. The therapeutic CD38 monoclonal antibody daratumumab induces programmed cell death via Fcγ receptor-mediated cross-linking. J Immunol. 2016;197:807–13.CrossRefPubMed
7.
Krejcik J, Casneuf T, Nijhof IS, Verbist B, Bald J, Plesner T, et al. Daratumumab depletes CD38+ immune-regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128:384–94.CrossRefPubMedPubMedCentral
8.
Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375:754–66.CrossRefPubMed
9.
Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis N, Usmani S, et al. Daratumumab, lenalidomide, and dexamethasone for mulitple myeloma. N Engl J Med. 2016;375:1319–31.CrossRefPubMed
10.
McKeage K, Lyseng-Williamson KA. Daratumumab in multiple myeloma: a guide to its use as monotherapy in the EU. Drugs Ther Perspect. 2016;32:463–9.CrossRef
11.
12.
DARZALEX™ (daratumumab) injection, for intravenous use [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2016.
13.
14.
Roopenian DC, Akilesh S. FcRn: the neonatal Fc receptor comes of age. Nat Rev Immunol. 2007;7:715–25.CrossRefPubMed
15.
Dirks NL, Meibohm B. Population pharmacokinetics of therapeutic monoclonal antibodies. Clin Pharmacokinet. 2010;49:633–59.CrossRefPubMed
16.
Knudsen LM, Hippe E, Hjorth M, Holmberg E, Westin J. Renal function in newly diagnosed multiple myeloma—a demographic study of 1353 patients. The Nordic Myeloma Study Group. Eur J Haematol. 1994;53:207–12.CrossRefPubMed
17.
Lokhorst HM, Plesner T, Laubach JP, Nahi H, Gimsing P, Hansson M, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207–19.CrossRefPubMed
18.
Lonial S, Weiss BM, Usmani S, Singhal S, Chari A, Bahlis N, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet. 2016;387:1551–60.CrossRefPubMed
19.
20.
Yan X, Clemens PL, Puchalski T, Lonial S, Lokhorst HM, Orlowski RZ, et al. Target-mediated drug disposition of daratumumab following intravenous infusion in relapsed or refractory multiple myeloma after prior proteasome inhibitors and immunomodulatory drugs: a population pharmacokinetic analysis. Blood. 2015;126:4222.
21.
Tabrizi M, Bornstein GG, Suria H. Biodistribution mechanisms of the therapeutic monoclonal antibodies in health and disease. AAPS J. 2010;12:33–43.CrossRefPubMed
22.
Leveque D, Wisniewski S, Jehl F. Pharmacokinetics of therapeutic monoclonal antibodies used in oncology. Anticancer Res. 2005;25:2327–43.PubMed
23.
Tabrizi MA, Tseng CM, Roskos LK. Elimination mechanisms of therapeutic monoclonal antibodies. Drug Discov Today. 2006;11:81–8.CrossRefPubMed
24.
Gibiansky L, Passey C, Roy A, Bello A, Gupta M. Model-based pharmacokinetic analysis of elotuzumab in patients with relapsed/refractory multiple myeloma. J Pharmacokinet Pharmacodyn. 2016;43:243–57.CrossRefPubMed
25.
Xu XS, Yan X, Puchalski T, Lonial S, Lokhorst HM, Voorhees PM, et al. Clinical implications of complex pharmacokinetics for daratumumab dose regimen in patients with relapsed/refractory multiple myeloma. Clin Pharmacol Ther. 2017;101:721–4.CrossRefPubMedPubMedCentral
26.
Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128:37–44.CrossRefPubMedPubMedCentral
27.
Dosani T, Carlsten M, Maric I, Landgren O. The cellular immune system in myelomagenesis: NK cells and T cells in the development of MM and their uses in immunotherapies. Blood Cancer J. 2015;5:e306.CrossRefPubMedPubMedCentral
28.
Casneuf T, Xu XS, Adams H III, Axel A, Verbist B, Liu K, et al. Pharmacodynamic relationship between natural killer cells and daratumumab exposure in relapsed/refractory multiple myeloma. In: Presented at the 21st Congress of the European Hematology Association (EHA); 9–12 June 2016; Copenhagen.
Metadata
Title
Influence of Disease and Patient Characteristics on Daratumumab Exposure and Clinical Outcomes in Relapsed or Refractory Multiple Myeloma
Authors
Xiaoyu Yan
Pamela L. Clemens
Thomas Puchalski
Sagar Lonial
Henk Lokhorst
Peter M. Voorhees
Saad Usmani
Paul G. Richardson
Torben Plesner
Kevin Liu
Robert Z. Orlowski
Nedjad Losic
Richard Jansson
Tahamtan Ahmadi
Kristen Lantz
Juan Jose Perez Ruixo
Honghui Zhou
Xu Steven Xu
Publication date
01-04-2018
Publisher
Springer International Publishing
Published in
Clinical Pharmacokinetics / Issue 4/2018
Print ISSN: 0312-5963
Electronic ISSN: 1179-1926
DOI
https://doi.org/10.1007/s40262-017-0598-1

Other articles of this Issue 4/2018

Clinical Pharmacokinetics 4/2018 Go to the issue

Original Research Article

Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis

Review Article

Clinical Pharmacokinetics and Pharmacodynamics of the Epidermal Growth Factor Receptor Inhibitor Panitumumab in the Treatment of Colorectal Cancer

Leading Article

Key Pharmacokinetic Essentials of Fixed-Dosed Combination Products: Case Studies and Perspectives

Original Research Article

Prediction of the Effect of Renal Impairment on the Pharmacokinetics of New Drugs

Original Research Article

Predicting Cortisol Exposure from Paediatric Hydrocortisone Formulation Using a Semi-Mechanistic Pharmacokinetic Model Established in Healthy Adults

Original Research Article

A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus Following Pediatric Renal Transplantation