State of the Art
Daratumumab, Elotuzumab, and the Development of Therapeutic Monoclonal Antibodies in Multiple Myeloma
JP Laubach,
CE Paba Prada,
PG Richardson,
DL Longo,
Corresponding Author
JP Laubach
Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Correspondence: JP Laubach ([email protected])Search for more papers by this authorCE Paba Prada
Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Search for more papers by this authorPG Richardson
Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Search for more papers by this authorDL Longo
Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Search for more papers by this authorJP Laubach,
CE Paba Prada,
PG Richardson,
DL Longo,
Corresponding Author
JP Laubach
Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Correspondence: JP Laubach ([email protected])Search for more papers by this authorCE Paba Prada
Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Search for more papers by this authorPG Richardson
Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Search for more papers by this authorDL Longo
Dana-Farber Cancer Institute, Boston, Massachusetts, USA
Search for more papers by this authorAbstract
There has been substantial progress in clinical outcomes for patients with multiple myeloma (MM). This encouraging trend derives in large part from the increasing number of effective therapeutic options and the ability because of this to achieve higher quality responses to treatment. The approval of both daratumumab and of elotuzumab in combination with lenalidomide and dexamethasone, in late 2015, was a notable achievement in the field, as daratumumab and elotuzumab represent the first monoclonal antibodies available for use in MM. Given their unique mechanisms of action and favorable side effect profiles, daratumumab and elotuzumab have considerable potential as therapeutic partners with agents in other drug classes and in different clinical settings ranging from newly diagnosed to relapsed disease. This review discusses the development of daratumumab and elotuzumab as well as other monoclonal antibodies currently being evaluated for use in MM.
References
- 1 Kyle, R.A. & Rajkumar, S.V. Multiple myeloma. Blood 111, 2962–2972 (2008).
- 2 Palumbo, A. & Anderson, K. Multiple myeloma. N. Engl. J. Med. 364, 1046–1060 (2011).
- 3 Siegel, R.L., Miller, K.D. & Jemal, A. Cancer statistics, 2016. CA Cancer J. Clin. 66, 7–30 (2016).
- 4 Kumar, S.K. et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 111, 2516–2520 (2008).
- 5 Robinson, D., Kaura, S., Kiely, D., Hussein, M.A., Nersesyan, K. & Durie, B.G.M. Impact of novel treatments on multiple myeloma survival. Blood 124, 5676 (2014).
- 6 Maloney, D.G. et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood 90, 2188–2195 (1997).
- 7 McLaughlin, P. et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J. Clin. Oncol. 16, 2825–2833 (1998).
- 8 Coiffier, B. et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N. Engl. J. Med. 346, 235–242 (2002).
- 9 Habermann, T.M. et al. Rituximab-CHOP versus CHOP alone or with maintenance rituximab in older patients with diffuse large B-cell lymphoma. J. Clin. Oncol. 24, 3121–3127 (2006).
- 10 Maury, S. et al. Rituximab in B-lineage adult acute lymphoblastic leukemia. N. Engl. J. Med. 375, 1044–1053 (2016).
- 11 Brahmer, J.R. et al. Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N. Engl. J. Med. 366, 2455–2465 (2012).
- 12 Slamon, D.J. et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N. Engl. J. Med. 344, 783–792 (2001).
- 13 Cavo, M. et al. Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study. Lancet 376, 2075–2085 (2010).
- 14 Durie, B. et al. Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT): results of the randomized phase III trial SWOG S0777. Blood 126, 25 (2015).
- 15 Palumbo, A. et al. Autologous transplantation and maintenance therapy in multiple myeloma. N. Engl. J. Med. 371, 895–905 (2014).
- 16 Gay, F. et al. Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase 3 trial. Lancet Oncol. 16, 1617–1629 (2015).
- 17 Attal, M. et al. Autologous transplantation for multiple myeloma in the era of new drugs: a phase III study of the Intergroupe Francophone Du Myelome (IFM/DFCI 2009 Trial). Blood 126, 391 (2015).
- 18 Cavo, M. et al. Upfront autologous stem cell transplantation (ASCT) versus novel agent-based therapy for multiple myeloma (MM): a randomized phase 3 study of the European Myeloma Network (EMN02/HO95 MM trial). J. Clin. Oncol. 34(suppl.), abstract 8000 (2016).
- 19 Attal, M. et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 366, 1782–1791 (2012).
- 20 McCarthy, P.L. et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N. Engl. J. Med. 366, 1770–1781 (2012).
- 21 Palumbo, A. et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N. Engl. J. Med. 366, 1759–1769 (2012).
- 22 Benboubker, L. et al. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma. N. Engl. J. Med. 371, 906–917 (2014).
- 23 Nooka, A.K. et al. Consolidation and maintenance therapy with lenalidomide, bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia 28, 690–693 (2014).
- 24 Laubach, J. et al. Management of relapsed multiple myeloma: recommendations of the International Myeloma Working Group. Leukemia 30, 1005–1017 (2016).
- 25 Orlowski, R.Z. et al. Randomized phase III study of pegylated liposomal doxorubicin plus bortezomib compared with bortezomib alone in relapsed or refractory multiple myeloma: combination therapy improves time to progression. J. Clin. Oncol. 25, 3892–3901 (2007).
- 26 San-Miguel, J.F. et al. Panobinostat plus bortezomib and dexamethasone versus placebo plus bortezomib and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol. 15, 1195–1206 (2014).
- 27 Stewart, A.K. et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N. Engl. J. Med. 372, 142–152 (2015).
- 28 Moreau, P. et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 374, 1621–1634 (2016).
- 29 de Weers, M. et al. Daratumumab, a novel therapeutic human CD38 monoclonal antibody, induces killing of multiple myeloma and other hematological tumors. J. Immunol. 186, 1840–1848 (2011).
- 30 Overdijk, M.B. et al. Crosstalk between human IgG isotypes and murine effector cells. J. Immunol. 189, 3430–3438 (2012).
- 31 Krejcik, J. et al. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood 128, 384–394 (2016).
- 32 Hsi, E.D. et al. CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma. Clin. Cancer Res. 14, 2775–2784 (2008).
- 33 Tai, Y.T. et al. Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu. Blood 112, 1329–1337 (2008).
- 34 Collins, S.M. et al. Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC. Cancer Immunol. Immunother. 62, 1841–1849 (2013).
- 35 Lokhorst, H.M. et al. Targeting CD38 with daratumumab monotherapy in multiple myeloma. N. Engl. J. Med. 373, 1207–1219 (2015).
- 36 Lonial, S. et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet 387, 1551–1560 (2016).
- 37 Plesner, T. et al. Phase 1/2 study of daratumumab, lenalidomide, and dexamethasone for relapsed multiple myeloma. Blood 128, 1821–1828 (2016).
- 38 Dimopoulos, M.A. et al. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375, 1319–1331 (2016).
- 39 Palumbo, A. et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N. Engl. J. Med. 375, 754–766 (2016).
- 40 Zonder, J.A. et al. A phase 1, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma. Blood 120, 552–559 (2012).
- 41 Lonial, S. et al. Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma. J. Clin. Oncol. 30, 1953–1959 (2012).
- 42 Jakubowiak, A.J. et al. Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma. J. Clin. Oncol. 30, 1960–1965 (2012).
- 43 Richardson, P.G. et al. Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase 2 results from the randomised, open-label, phase 1b-2 dose-escalation study. Lancet Haematol. 2, e516–e527 (2015).
- 44 Lonial, S. et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N. Engl. J. Med. 373, 621–631 (2015).
- 45 Dimopoulos, M.A. et al. Eloquent-2 update: a phase 3, randomized, open-label study of elotuzumab in combination with lenalidomide/dexamethasone in patients with relapsed/refractory multiple myeloma – 3-year safety and efficacy follow-up. Blood 126, abstract 28 (2015).
- 46 van de Donk, N.W. et al. Interference of daratumumab in monitoring multiple myeloma patients using serum immunofixation electrophoresis can be abrogated using the daratumumab IFE reflex assay (DIRA). Clin. Chem. Lab. Med. 54, 1105–1109 (2016).
- 47 McCudden, C. et al. Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference. Clin. Chem. Lab. Med. 54, 1095–1104 (2016).
- 48 Rosenberg, A.S., Bainbridge, S., Pahwa, R. & Jialal, I. Investigation into the interference of the monoclonal antibody daratumumab on the free light chain assay. Clin. Biochem. 49, 1202–1204 (2016).
- 49 Zocchi, E. et al. A single protein immunologically identified as CD38 displays NAD+ glycohydrolase, ADP-ribosyl cyclase and cyclic ADP-ribose hydrolase activities at the outer surface of human erythrocytes. Biochem. Biophys. Res. Commun. 196, 1459–1465 (1993).
- 50 Chapuy, C.I. et al. Resolving the daratumumab interference with blood compatibility testing. Transfusion 55(6 Pt 2), 1545–1554 (2015).
- 51 Gonsalves, W.I. et al. Improvement in renal function and its impact on survival in patients with newly diagnosed multiple myeloma. Blood Cancer J. 5, e296 (2015).
- 52 Berdeja, J. et al. Pharmacokinetics and safety of elotuzumab combined with lenalidomide and dexamethasone in patients with multiple myeloma and various levels of renal impairment: results of a phase Ib study. Clin. Lymphoma Myeloma Leuk. 16, 129–138 (2016).
- 53 Martin, T.G., Hsu, K., Strickland, S.A., Glenn, M.J., Mikhael, J. & Charpentier, E. A phase I trial of SAR650984, a CD38 monoclonal antibody, in relapsed or refractory multiple myeloma. J. Clin. Oncol. 32 (suppl.), abstract 8532 (2014).
- 54 Martin, T.G. III et al. A phase Ib dose-escalation trial of SAR650984 (anti-CD-38 mAb) in combination with lenalidomide and dexamethasone in relapsed/refractory multiple myeloma. J. Clin. Oncol. 32 Suppl, abstract 8512 (2014).
- 55 Raab, M.S. et al. MOR202 alone and in combination with pomalidomide or lenalidomide in relapsed or refractory multiple myeloma: data from clinically relevant cohorts from a phase I/IIa study. J. Clin. Oncol. 34 (suppl.), abstract 8012 (2016).
- 56 Chauhan, D. et al. Multiple myeloma cell adhesion-induced interleukin-6 expression in bone marrow stromal cells involves activation of NF-kappa B. Blood 87, 1104–1112 (1996).
- 57 Rawstron, A.C. et al. The interleukin-6 receptor alpha-chain (CD126) is expressed by neoplastic but not normal plasma cells. Blood 96, 3880–3886 (2000).
- 58 San-Miguel, J. et al. Phase 2 randomized study of bortezomib-melphalan-prednisone with or without siltuximab (anti-IL-6) in multiple myeloma. Blood 123, 4136–4142 (2014).
- 59 Shah, J.J. et al. Siltuximab (CNTO 328) with lenalidomide, bortezomib and dexamethasone in newly-diagnosed, previously untreated multiple myeloma: an open-label phase I trial. Blood Cancer J. 6, e396 (2016).
- 60 Ikeda, H. et al. The monoclonal antibody nBT062 conjugated to cytotoxic maytansinoids has selective cytotoxicity against CD138-positive multiple myeloma cells in vitro and in vivo. Clin. Cancer Res. 15, 4028–4037 (2009).
- 61 Heffner, L.T. et al. BT062, an antibody-drug conjugate directed against CD138, given weekly for 3 weeks in each 4 week cycle: safety and further evidence of clinical activity. Blood 120, 4042 (2012).
- 62 Kelly, K.R. et al. Indatuximab ravtansine (BT062) in combination with lenalidomide and low-dose dexamethasone in patients with relapsed and/or refractory multiple myeloma: clinical activity in patients already exposed to lenalidomide and bortezomib. Blood 124, 4736 (2014).
- 63 Görgün, G. et al. Lenalidomide enhances immune checkpoint blockade-induced immune response in multiple myeloma. Clin. Cancer Res. 21, 4607–4618 (2015).
- 64 Ray, A. et al. Targeting PD1-PDL1 immune checkpoint in plasmacytoid dendritic cell interactions with T cells, natural killer cells and multiple myeloma cells. Leukemia 29, 1441–1444 (2015).
- 65 Mateos, M-V. et al. Pembrolizumab in combination with lenalidomide and low-dose dexamethasone for relapsed/refractory multiple myeloma (RRMM): final efficacy and safety analysis. J. Clin. Oncol. 34 (suppl.), abstract 8010 (2016).
- 66 Badros, A.Z. et al. A phase II study of anti PD-1 antibody pembrolizumab, pomalidomide and dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). Blood 126, 506 (2015).
