Practical Considerations for the Use of Daratumumab, a Novel CD38 Monoclonal Antibody, in Myeloma
- 1.7k Downloads
Monoclonal antibodies (mAbs) are a recent addition to multiple myeloma (MM) therapies and a number of mAbs directed at myeloma cell surface molecules are in development. Daratumumab is a CD38 mAb that has demonstrated substantial activity and good tolerability in four phase I, phase I/II and phase II studies as monotherapy, as well as in combination with current standard treatments in MM. The positive results obtained in the relapsed/refractory setting in patients with advanced-stage disease and in a small number of patients with newly diagnosed disease provide the rationale for the investigation of the agent in a number of ongoing phase III trials. mAbs are generally better tolerated than conventional chemotherapy; however, their use requires other special considerations. Such factors include those common to all mAbs, namely infusion-related reactions, but also factors that are observed with mAbs used in myeloma, such as interference with response assessment, or factors that are related to CD38 mAbs such as daratumumab, for instance blood typing interference. Our review provides an overview of the results from the daratumumab clinical trials conducted to date, as well as practical management considerations for the use of daratumumab based on our experience with the agent.
KeywordsMultiple Myeloma Bortezomib Lenalidomide Overall Response Rate Chimeric Antigen Receptor
Compliance with Ethical Standards
Medical writing and editorial support was provided by Pia Sondergeld (University of Giessen, Germany) and was funded by Janssen.
Conflicts of interest
Philippe Moreau received fees for advisory board participation from Janssen, Celgene, Bristol–Myers Squibb, Novartis, Takeda, and Amgen. Niels W. C. J. van de Donk received a research Grant from Celgene, Janssen Pharmaceuticals, and Amgen. Jesus San Miguel received fees for advisory board participation from Millennium, Celgene, Novartis, Onyx, Janssen, Bristol–Myers Squibb, and Merck Sharp and Dohme. Henk Lokhorst received fees for attending advisory boards on daratumumab (Janssen). Michele Cavo received honoraria from Janssen, Cilag, Takeda, and Bristol–Myers Squibb, and payment for lectures from Janssen, Cilag, and Takeda. Gordon Cook received Grants from Janssen, Celgene, Takeda, and Chugai-Pharmaceutical Co.; consulting fees or honorarium from Janssen, Celgene, Takeda, Sanofi, Bristol–Myers Squibb, Glycomimetics, and Amgen; support for travel from Janssen, Celgene, Takeda, Sanofi; fees for participation in review activities from Celgene, and Glycomimetics; and payment for lectures from Janssen, Celgene, Takeda, Sanofi, Bristol–Myers Squibb, and Amgen. Michel Delforge received a Grant from Celgene (phase IV clinical trial), and honoraria from Amgen, Celgene, Janssen, Novartis, and Takeda. Hermann Einsele received consulting fees or honorarium, payment for lectures, and support for travel from Janssen, Celgene, Amgen, and Novartis. Sonja Zweegman received honoraria for advisory board participation from Celgene, Takeda, Janssen, and Novartis (honorarium for departmental use, not personal use), and lectures for Celgene and Janssen (payment for departmental use only). Heinz Ludwig received fees for participation in data monitoring committees of early daratumumab studies. Christoph Driessen received consulting honorarium related to daratumumab from Janssen–Cilag (not related to the current manuscript). Antonio Palumbo received consulting fees and honoraria from Janssen–Cilag (not related to the current manuscript). Thierry Facon received fees for advisory board participation, as well as support for travel and payment for lectures from Janssen. He undertakes advisory board activities with Janssen and is on the speaker’s bureau for Janssen. Torben Plesner received a research Grant from Janssen, honoraria for advisory board participation from Genmab and Janssen, and payment for lectures from Janssen. Meletios Dimopoulos has received consulting fees or honoraria from Janssen, Celgene, Novartis, and Amgen. Pia Sondergeld received payment from Janssen for the writing of this manuscript. Pieter Sonneveld received Grants from Amgen, Celgene, Janssen, and Karyopharm; consulting fees or honoraria from Amgen, Celgene, Janssen, and Karyopharm; fees for participation in review activities from Celgene and Janssen; provision of writing assistance from Janssen; and payment for lectures from Amgen, Celgene, and Janssen. He has been involved in drug research, i.e. clinical trials, both investigator-initiated and company-initiated, and has served on advisory boards and given lectures in the context of new drug development for multiple myeloma. Maria-Victoria Mateos has received honoraria for lectures and participation in advisory boards from Janssen, Celgene, Takeda, Amgen, and Bristol–Myers Squibb. Hareth Nahi and Dina Ben-Yehuda have no conflicts of interest to declare.
- 6.US FDA. FDA approves Darzalex for patients with previously treated multiple myeloma. http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm472875.htm. Accessed 25 Mar 2016.
- 7.The Myeloma Beacon™. Janssen submits marketing authorisation application for daratumumab for European patients with heavily pre-treated multiple myeloma. http://www.myelomabeacon.com/pr/2015/09/09/daratumumab-european-marketing-authorization-application/. Accessed 25 Mar 2016.
- 14.Partida-Sánchez S, Cockayne DA, Monard S, Jacobson EL, Oppenheimer N, Garvy B, et al. Cyclic ADP-ribose production by CD38 regulates intracellular calcium release, extracellular calcium influx and chemotaxis in neutrophils and is required for bacterial clearance in vivo. Nat Med. 2001;7(11):1209–16.CrossRefPubMedGoogle Scholar
- 16.Fedele G, Di Girolamo M, Recine U, Palazzo R, Urbani F, Horenstein AL, et al. CD38 ligation in peripheral blood mononuclear cells of myeloma patients induces release of protumorigenic IL-6 and impaired secretion of IFNγ cytokines and proliferation. Mediat Inflamm. 2013;2013:564687.CrossRefGoogle Scholar
- 20.Santonocito AM, Consoli U, Bagnato S, Milone G, Palumbo GA, Di Raimondo F, et al. Flow cytometric detection of aneuploidCD38(++) plasmacells and CD19(+) B-lymphocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients. Leuk Res. 2004;28(5):469–77.CrossRefPubMedGoogle Scholar
- 24.Jansen JH, Boross P, Overdijk MB, van Bueren JJ, Parren PW, Leusen JH. Daratumumab, a human CD38 antibody induces apoptosis of myeloma tumor cells via Fc receptor-mediated crosslinking [abstract no. 2974]. American Society of Hematology Proceedings 2012. Blood. 2012;120(21):2974.Google Scholar
- 25.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 [abstract no. 3474]. Blood. 2014;124(21):3474.Google Scholar
- 27.Krejcik J, Casneuf T, Nijhof I, Verbist B, Bald J, Plesner T, et al. Immunomodulatory effects and adaptive immune response to daratumumab in multiple myeloma [abstract no. 3037]. In: American society of hematology 57th annual meeting and exposition, 5–8 Dec 2015, Orlando (FL).Google Scholar
- 28.van der Veer MS, de Weers M, van Kessel B, Bakker JM, Wittebol S, Parren PW, et al. Towards effective immunotherapy of myeloma: enhanced elimination of myeloma cells by combination of lenalidomide with the human CD38 monoclonal antibody daratumumab. Haematologica. 2011;96(2):284–90.CrossRefPubMedPubMedCentralGoogle Scholar
- 30.Nijhof IS, Groen RW, Noort WA, van Kessel B, de Jong-Korlaar RA, Bakker JM, et al. Preclinical evidence for the therapeutic potential of CD38-targeted immuno-chemotherapy in multiple myeloma patients refractory to lenalidomide and bortezomib. Clin Cancer Res. 2015;21(12):2802–10.CrossRefPubMedGoogle Scholar
- 33.Usmani S, Weiss B, Bahlis NJ, Belch A, Lonial S, Lokhorst H, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma [abstract no. 29]. In: American Society of Hematology 57th Annual Meeting and Exposition, 5–8 Dec 2015, Orlando (FL).Google Scholar
- 34.Usmani S, Ahmadi T, Ng Y, Lam A, Potluri R, Mehra M. Analyses of real world data on overall survival in multiple myeloma patients with at least 3 prior lines of therapy including a PI and an IMiD, or double refractory to a PI and an IMiD [abstract no. 4498]. In: American Society of Hematology 57th Annual Meeting and Exposition, 5–8 Dec 2015, Orlando (FL).Google Scholar
- 35.Plesner T, Arkenau HT, Lokhorst HM, Gimsing P, Krejcik J, Lemech C, et al. Safety and efficacy of daratumumab with lenalidomide and dexamethasone in relapsed or relapsed, refractory multiple myeloma [abstract no. 84]. Blood. 2014;124(21):84.Google Scholar
- 36.Plesner T, Arkenau HT, Gimsing P, Krejcik J, Lemech C, Minnema MC, et al. Daratumumab in combination with lenalidomide and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: updated results of a phase 1/2 study (GEN503) [abstract no. 507]. Blood. 2015;126(23):507.Google Scholar
- 37.Mateos MV, Moreau P, Comenzo R, Bladé J, Benboubker L, de la Rubia J, et al. An open-label, multicenter, phase 1b study of daratumumab in combination with pomalidomide-dexamethasone and with backbone regimens in patients with multiple myeloma [abstract no. P275]. In: European Hematology Association 20th Congress, 11–14 Jun 2015, Vienna.Google Scholar
- 38.Moreau P, Mateos MV, Bladé J, et al. An open-label, multicenter, phase 1b study of daratumumab in combination with backbone regimens in patients with multiple myeloma [abstract no. 176]. In: American Society of Hematology 56th Annual Meeting and Exposition, 6–9 Dec 2014, San Francisco (CA).Google Scholar
- 39.Chari A, Lonial S, Suvannasankha A, Fay JW, Arnulf B, Ifthikharuddin JJ, et al. Open-label, multicenter, phase 1b study of daratumumab in combination with pomalidomide and dexamethasone in patients with at least 2 lines of prior therapy and relapsed or relapsed and refractory multiple myeloma [abstract no. 508]. In: American Society of Hematology 57th Annual Meeting and Exposition, 5–8 Dec 2015, Orlando (FL).Google Scholar
- 40.Darzalex™ (daratumumab) injection for intravenous infusion 100 mg/5 mL, 400 mg/20 mL. https://www.darzalex.com. Accessed 25 Mar 2016.
- 46.Zocchi E, Franco L, Guida L, Benatti U, Bargellesi A, Malavasi F, et al. A single protein immunologically identified as CD38 displays NAD1 glycohydrolase, ADP-ribosylcyclase and cyclic ADP-ribosehydrolase activities at the outer surface of human erythrocytes. Biochem Biophys Res Commun. 1993;196:1459–65.CrossRefPubMedGoogle Scholar
- 48.Chari A, Satta T, Tayal A, Jagannath S, Cho HJ, Parekh S, et al. Outcomes and management of red blood cell transfusions in multiple myeloma patients treated with daratumumab [abstract no. 3571]. In: American Society of Hematology 57th Annual Meeting and Exposition, 5–8 Dec 2015, Orlando (FL).Google Scholar
- 52.Axel AE. McCudden CR, Xie H, Hall BM, Sasser AK. Development of clinical assay to mitigate daratumumab, an IgG1κ monoclonal antibody, interference with serum immunofixation (IFE) and clinical assessment of M-protein response in multiple myeloma [abstract no. 2563]. In: Proceedings of the American Association for Cancer Research (AACR) Annual Meeting 2014, 5–9 April 2014, San Diego (CA).Google Scholar
- 54.McCudden C, Axel A, Slaets D, Frans S, Bald J, Schecter JM, et al. Assessing clinical response in multiple myeloma (MM) patients treated with monoclonal antibodies (mAbs): validation of a daratumumab IFE reflex assay (DIRA) to distinguish malignant M-protein from therapeutic antibody [abstract no. 8590]. J Clin Oncol. 2015;33:8590.Google Scholar
- 64.Voorhees P, Weiss B, Usmani S, Huaibao F, Uhlar CM, Khan I, et al. Management of infusion-related reactions following daratumumab monotherapy in patients with ≥3 lines of prior therapy or double refractory multiple myeloma (MM): 54767414MMY2002 (SIRIUS) [abstract no. 1829]. Blood. 2015;126(23):1829Google Scholar
- 67.ClinicalTrials.gov, a service of the US National Institutes of Health. http://www.clinicaltrials.gov. Accessed 25 Mar 2016.