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30-06-2016 | Multiple myeloma | Article

Daratumumab: a first-in-class CD38 monoclonal antibody for the treatment of multiple myeloma

Journal: Journal of Hematology & Oncology

Authors: Larysa Sanchez, Yucai Wang, David S. Siegel, Michael L. Wang

Publisher: BioMed Central

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Abstract

Daratumumab is a human monoclonal antibody that targets CD38, a cell surface protein that is overexpressed on multiple myeloma (MM) cells. Preclinical studies have shown that daratumumab induces MM cell death through several mechanisms, including complement-dependent cytotoxicity (CDC), antibody-dependent cell-mediated cytotoxicity (ADCC), antibody-dependent cellular phagocytosis (ADCP), and apoptosis. Given the encouraging efficacy and acceptable safety profile of daratumumab demonstrated in clinical trials, daratumumab has emerged as a novel treatment option for myeloma and became the first monoclonal antibody approved by the FDA for the treatment of MM.
Literature
1.
Kumar SK, Rajkumar SV, Dispenzieri A, Lacy MQ, Hayman SR, Buadi FK, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516–20.CrossRefPubMedPubMedCentral
2.
Kharfan-Dabaja MA, Hamadani M, Rejlic T, Nishihori T, Bensinger W, Djulbegovic B, et al. Comparative efficacy of tandem autologous versus autologous followed by allogeneic hematopoietic cell transplantation in patients with newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. J Hematol Oncol. 2013;6:2.CrossRefPubMedPubMedCentral
3.
Kumar S, Lee JH, Lauerta JJ, Morgan G, Richardson PG, Crowley J, et al. Risk of progression and survival in multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. Leukemia. 2012;26(1):149–57.CrossRefPubMed
4.
Kellner J, Liu B, Kang Y, Li Z. Fact or fiction—identifying the elusive multiple myeloma stem cell. J Hematol Oncol. 2013;6:91.CrossRefPubMedPubMedCentral
5.
Sondergeld P, van de Donk NWCJ, Richardson PG, Plesner T. Monoclonal antibodies in myeloma. Clin Adv Hematol Oncol. 2015;13:599–609.PubMed
6.
Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiol Rev. 2008;88:841–86.CrossRefPubMed
7.
Malavasi F, FunaroA RS, Horenstein A, Calosso L, Mehta K. Human CD38: a glycoprotein in search of a function. Immunol Today. 1994;15:95–7.CrossRefPubMed
8.
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
9.
Deaglio S, Mehta K, Malavasi F. Human CD38: a (r)evolutionary story of enzymes and receptors. Leuk Res. 2001;25:1–12.CrossRefPubMed
10.
Dianzani U, Funaro A, DiFranco D, Garbarino G, Bragardo M, Redoglia V, et al. Interaction between endothelium and CD4+CD45RA+ lymphocytes. Role of the human CD38 molecule. J Immunol. 1994;153:952–9.PubMed
11.
Funaro A, De Monte LB, Dianzani U, Forni M, Malavasi F. Human CD38 is associated to distinct molecules which mediate transmembrane signaling in different lineages. Eur J Immunol. 1993;23:2407–11.CrossRefPubMed
12.
Deaglio S, Morra M, Mallone R, Ausiello CM, Prager E, Garbarino G, et al. Human CD38 (ADP-ribosyl cyclase) is a counter-receptor of CD31, an Ig superfamily member. J Immunol. 1998;160:395–402.PubMed
13.
Ausiello CM, la Sala A, Ramoni C, Urbani A, Funaro A, Malavasi F. Secretion of IFN-γ, IL-6, granulocyte-macrophage colony-stimulating factor and IL-10 cytokines after activation of human purified T lymphocytes upon CD38 ligation. Cell Immunol. 1996;173:192–7.CrossRefPubMed
14.
Mallone R, Funaro A, Zubiaur M, Baj G, Ausiello CM, Tacchetti C, et al. Signaling through CD38 induces NK cell activation. Int Immunol. 2001;13:397–409.CrossRefPubMed
15.
Sconocchia G, Titus JA, Mazzoni A, Visintin A, Pericle F, Hicks S, et al. CD38 triggers cytotoxic responses in activated human natural killer cells. Blood. 1999;94:3864–71.PubMed
16.
de Weers M, Tai YT, van der Veer MS, Bakker JM, Vink T, Jacobs DCH, 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
17.
Nijhof IS et al. Upregulation of CD38 expression on multiple myeloma cells by all-trans retinoic acid improves the efficacy of daratumumab. Leukemia. 2015;29:2039–49.CrossRefPubMed
18.
Overdijk MB, Verploegen S, Bögels M, van Egmond M, van Bueren JJ L, 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;7:311–20.CrossRefPubMedPubMedCentral
19.
Grugan KD, McCabe FL, Kinder M, Greenplate AR, Harman BC, Ekert JE, van Rooijen N, Anderson GM, Nemeth JA, Strohl WR, et al. Tumor-associated macrophages promote invasion while retaining Fc-dependent anti-tumor function. J Immunol. 2012;189:5457–66.CrossRefPubMed
20.
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. Blood. 2012;120:2974.
21.
van der Veer M, de Weers M, van Kessel B, Bakker JM, Wittebol S, Parren PWHI, 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;96:284–90.CrossRefPubMed
22.
Nijhof IS, Groen RWJ, Noort WA, van Kessel B, de Jong-Korlaar R, Bakker A. Preclinical evidence for the therapeutic potential of CD38-targeted immune-chemotherapy in multiple myeloma patients refractory to lenalidomide and bortezomib. Clin Cancer Res. 2015;21:2802–10.CrossRefPubMed
23.
Nijhof IS, Lammerts van Bueren JJ, van Kessel B, Andre P, Morel Y, Lokhorst HM, et al. Daratumumab-mediated lysis of primary multiple myeloma cells is enhanced in combination with the human anti-KIR antibody IPH2102 and lenalidomide. Haematologica. 2015;100:263–8.CrossRefPubMedPubMedCentral
24.
Lokhorst HM, Plesner T, Laubach JP, Nahi P, Gimsing M, Hansson MC, et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N Engl J Med. 2015;373:1207–19.CrossRefPubMed
25.
Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomized, phase 2 trial. Lancet. 2016.
26.
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. Blood. 2015;126(23):29.
27.
Richardson PG, Siegel DS, Vij R, Hofmeister CC, Baz R, Jagannath S, et al. Pomalidomide alone or in combination with low-dose dexamethasone in relapsed and refractory multiple myeloma: a randomized phase 2 study. Blood. 2014;123:1826–32.CrossRefPubMedPubMedCentral
28.
Siegel DS, Martin T, Wang M, Vij R, Jakubowiak AJ, Lonial S, et al. A phase 2 study of single-agent carfilzomib (PX-171-003-A1) in patients with relapsed and refractory multiple myeloma. Blood. 2012;120:2817–25.CrossRefPubMedPubMedCentral
29.
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). Blood. 2015;126(23):507.
30.
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. Blood. 2014;124(21):84.
31.
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. Blood. 2015;126(23):508.
32.
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]. Haematologica. 2015;100(s1):84.
33.
Palumbo A, Dimopoulos MA, Reece DE, Sonneveld P, Spencer A, Chanan-Khan AAA, et al. Twin randomized studies of daratumumab (DARA; D) plus standard of care (lenalidomide/dexamethasone or bortezomib/dexamethasone [DRd or DVd]) versus Rd or Vd alone in relapsed or refractory multiple myeloma (MM): 547674MMY3003 (Pollux) and 54767414MMY3004 (Castor). J Clin Oncol. 2015;33:TPS8609.
34.
Palumbo A, Chanan-Khan AAA, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Phase III randomized control study of daratumumab, bortezomib, and dexamethasone (DVd) versus bortezomib and dexamethasone (Vd) in patients (pts) with relapsed or refractory multiple myeloma (RRMM): CASTOR study. J Clin Oncol. 2016;34:LBA4.
35.
Mateos MV, Cavo M, Jakubowiak AJ, Carson RL, Qi M, Bandekar R, et al. A randomized open-label study of bortezomib, melphalan, and prednisone (VMP) versus daratumumab (DARA) plus VMP in patients with previously untreated multiple myeloma (MM) who are ineligible for high-dose therapy: 54767414MMY3007 (Alcyone). J Clin Oncol. 2015;33:TPS8608.
36.
Axel AE, McCudden CR, Xie H, Hall BM, Sasser AK. Development of clinical assay to mitigate daratumumab, and IgG1-monoclonal antibody, interference with serum immunofixation (IFE) and clinical assessment of M-protein response in multiple myeloma. Cancer Res. 2014;74(19 suppl):2563.CrossRef
37.
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. J Clin Oncol. 2015;33:8590.
38.
Chapuy CI, Nicholson RT, Aguad MD, Chapuy B, Laubach JP, Richardson PG, et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion. 2015;55:1545–54.CrossRefPubMed
39.
Oostendorp M, Lammerts van Bueren JJ, Doshi P, Khan I, Ahmadi T, Parren PWHI, et al. When blood transfusion medicine becomes complicated due to interference by monoclonal antibody therapy. Transfusion. 2015;55:1555–62.CrossRefPubMed
40.
Chapuy CI, Aguad MD, Nicholson RT, AuBuchon JP, Cohn CS, Delaney M, et al. International validation of dithiotreitol (DTT)-based method to resolve the daratumumab interference with blood compatibility testing. Blood. 2015;126(23):3567.
41.
Martin T, Strickland SA, Glenn M, Zheng W, Daskalakis N, Mikhael JR. SAR650984, a CD38 monoclonal antibody in patients with selected CD38+ hematological malignancies: data from a dose-escalation phase I study. Blood. 2013;122(21):284.
42.
Martin I, Hsu K, Strickland SA, Glenn M, Mikhael JR, Charpentier E. A phase I trial of SAR650984, a CD38 monoclonal antibody, in relapsed or refractory multiple myeloma. J Clin Oncol. 2014;32(5S):8532.
43.
Raab M, Chatterjee M, Goldschmidt H, Agis H, Blau JW, Einsele H, et al. A phase I/IIa study of the human anti-CD38 antibody MOR202 (MOR03087) in relapsed or refractory multiple myeloma [abstract]. Clin Lymphoma Myeloma Leuk. 2015;15 suppl 3:e80. Abstract BP-058.CrossRef
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