Efficacy and safety of elotuzumab for the treatment of multiple myeloma

Citation:

Gavriatopoulou M, Terpos E, Kastritis E, Dimopoulos MA. Efficacy and safety of elotuzumab for the treatment of multiple myeloma. Expert Opinion on Drug Safety [Internet]. 2017;16(2):237 - 245.

Abstract:

Introduction: Multiple myeloma (MM) is the second most common hematologic malignancy and despite significant outcome improvements with novel agents, the majority of patients will eventually relapse and develop treatment resistance. Immunotherapy is emerging as a promising therapeutic approach in MM. Areas covered: Elotuzumab is a monoclonal antibody directly targeting the SLAMF7 receptor, expressed on normal and malignant plasma cells. Elotuzumab has no meaningful antimyeloma activity when given as monotherapy to patients with relapsed or refractory MM (RRMM). However, it demonstrated significant antimyeloma activity in preclinical studies and when it is combined with other antimyeloma agents (i.e. bortezomib or lenalidomide) in clinical trials, it improved response and clinical outcomes with no additive toxicity. This review provides a brief description of the elotuzumab mechanism of action and an overview on its efficacy in preclinical and clinical trials, including its safety and toxicity profile. Expert commentary: Based on the results of a phase 3 clinical trial (ELOQUENT-2), which compared lenalidomide and dexamethasone with or without elotuzumab in patients with RRMM, elotuzumab was approved by FDA in November 2015 for MM patients who received 1–3 prior lines of therapy. Studies with combinations of elotuzumab with other anti-myeloma drugs in different phases of MM are ongoing. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

Notes:

Export Date: 18 February 2017References: Kumar, S., Rajkumar, S., Dispenzieri, A., Improved survival in multiple myeloma and the impact of novel therapies (2008) Blood, 111, pp. 2516-2520;Attal, M., Harousseau, J., Stoppa, A., A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome (1996) N Engl J Med, 335, pp. 91-97; Palumbo, A., Bringhen, S., Bertola, A., Multiple myeloma: comparison of two dose-intensive melphalan regimens [100 versus 200 mg/m (2)] (2004) Leukemia, 18, pp. 133-138; Palumbo, A., Cavallo, F., Gay, F., Autologous transplantation and maintenance therapy in multiple myeloma (2014) N Engl J Med, 371, pp. 895-905; Gay, F., Oliva, S., Petrucci, M., Chemotherapy plus lenalidomide versus autologous transplantation, followed by lenalidomide plus prednisone versus lenalidomide maintenance, in patients with multiple myeloma: a randomised, multicentre, phase III trial (2015) Lancet Oncol, 16, pp. 1617-1629; El-Amm, J., Tabbara, I.A., Emerging therapies in multiple myeloma (2015) Am J Clin Oncol, 38 (3), pp. 315-321; Dimopoulos, M., Richardson, P., Moreau, P., Current treatment landscape for relapsed and/or refractory multiple myeloma (2015) Nat Rev Clin Oncol, 12, pp. 42-54; Lonial, S., Durie, B., Palumbo, A., Monoclonal antibodies in the treatment of multiple myeloma: current status and future perspectives (2016) Leukemia, 30 (3), pp. 526-535; Liu, Y., Szmania, S., van Rhee, F., Profile of elotuzumab and its potential in the treatment of multiple myeloma (2014) Blood Lymphat Cancer, 2014, pp. 15-27; Veillette, A., Guo, H., CS1, a SLAM family receptor involved in immune regulation, is a therapeutic target in multiple myeloma (2013) Crit Rev Oncol Hematol, 88 (1), pp. 168-177; Shaughnessy, J.D., Zhan, F., Burington, B.E., A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1 (2007) Blood, 109 (6), pp. 2276-2284; Veillette, A., SLAM-family receptors: immune regulators with or without SAP-family adaptors (2010) Cold Spring Harb Perspect Biol, 2, p. 2469; Cannons, J., Tangye, S., Schwartzberg, P., SLAM family receptors and SAP adaptors in immunity (2011) Annu Rev Immunol, 29, pp. 665-705; Tai, Y., Dillon, M., Song, W., Anti-CS1 humanized monoclonal antibody HuLuc63 inhibits myeloma cell adhesion and induces antibody-dependent cellular cytotoxicity in the bone marrow milieu (2008) Blood, 112, pp. 1329-1337; Tai, Y.T., Soydan, E., Song, W., CS1 promotes multiple myeloma cell adhesion, clonogenic growth, and tumorigenicity via c-maf-mediated interactions with bone marrow stromal cells (2009) Blood, 113 (18), pp. 4309-4318; Cruz-Munoz, M.E., Dong, Z., Shi, X., Influence of CRACC, a SLAM family receptor coupled to the adaptor EAT-2, on natural killer cell function (2009) Nat Immunol, 10 (3), pp. 297-305; Hsi, E.D., Steinle, R., Balasa, B., CS1, a potential new therapeutic antibody target for the treatment of multiple myeloma (2008) Clin Cancer Res, 14 (9), pp. 2775-2784; van Rhee, F., Szmania, S., Dillon, M., Combinatorial efficacy of anti-CS1 monoclonal antibody elotuzumab (HuLuc63) and bortezomib against multiple myeloma (2009) Mol Cancer Ther, 8, pp. 2616-2624; Perez-Quintero, L., Roncagalli, R., Guo, H., EAT-2, a SAP-like adaptor, controls NK cell activation through phospholipase Cγ, Ca++, and Erk, leading to granule polarization (2014) J Exp Med, 211, pp. 727-742; Clarkson, N., Brown, M., Inhibition and activation by CD244 depends on CD2 and phospholipase C-gamma1 (2009) J Biol Chem, 284, pp. 24725-24734; Collins, S., Bakan, C., Swartzel, G., Elotuzumab directly enhances NK cell cytotoxicity against myeloma via CS1 ligation: evidence for augmented NK cell function complementing ADCC (2013) Cancer Immunol Immunother, 62, pp. 1841-1849; Roncagalli, R., Taylor, J., Zhang, S., Negative regulation of natural killer cell function by EAT-2, a SAP-related adaptor (2005) Nat Immunol, 6, pp. 1002-1010; Jakubowiak, A., Offidani, M., Pégourie, B., Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM (2016) Blood, 127 (23), pp. 2833-2840; Kim, J., Mathew, S., Patel, R., Altered expression of signalling lymphocyte activation molecule (SLAM) family receptors CS1 (CD319) and 2B4 (CD244) in patients with systemic lupus erythematosus (2010) Clin Exp Immunol, 160, pp. 348-358; Neyer, L., Ding, H., Chen, D., Effect of elotuzumab on circulating lymphocytes, chemokines, and cytokines in multiple myeloma patients (2010) Blood, 116, p. 4070; Lonial, S., Dimopoulos, M., Palumbo, A., Elotuzumab therapy for relapsed or refractory multiple myeloma (2015) N Engl J Med, 373, pp. 621-631; Lee, J., Boles, K., Mathew, P., Molecular and functional characterization of a CS1 (CRACC) splice variant expressed in human NK cells that does not contain immunoreceptor tyrosine-based switch motifs (2004) Eur J Immunol, 34, pp. 2791-2799; Balasa, B., Yun, R., Belmar, N., Elotuzumab enhances natural killer cell activation and myeloma cell killing through interleukin-2 and TNF-α pathways (2015) Cancer Immunol Immunother, 64, pp. 61-73; Zonder, J., Mohrbacher, A., Singhal, S., A phase I, multicenter, open-label, dose escalation study of elotuzumab in patients with advanced multiple myeloma (2012) Blood, 120, pp. 552-559; Jakubowiak, A., Benson, D., Bensinger, W., Phase I trial of anti-CS1 monoclonal antibody elotuzumab in combination with bortezomib in the treatment of relapsed/refractory multiple myeloma (2012) J Clin Oncol, 30, pp. 1960-1965; Lonial, S., Vij, R., Harousseau, J., Elotuzumab in combination with lenalidomide and low-dose dexamethasone in relapsed or refractory multiple myeloma (2012) J Clin Oncol, 30, pp. 1953-1959; Richardson, P., Jagannath, S., Moreau, P., Elotuzumab in combination with lenalidomide and dexamethasone in patients with relapsed multiple myeloma: final phase II results from the randomised, open-label, phase Ib-2 dose-escalation study (2015) Lancet Haematol, 2, pp. e516-e527; Mateos, M.V., Granell, M., Oriol, A., Elotuzumab in combination with thalidomide and low-dose dexamethasone: a phase 2 single-arm safety study in patients with relapsed/refractory multiple myeloma (2016) Br J Haematol, 175 (3), pp. 448-456. , Nov; Dimopoulos, M., Lonial, S., White, D., ELOQUENT-2 update: a phase III, 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 (2015) Blood, 126, p. 28; Usmani, S.Z., Sexton, R., Ailawadhi, S., Phase I safety data of lenalidomide, bortezomib, dexamethasone, and elotuzumab as induction therapy for newly diagnosed symptomatic multiple myeloma: SWOG S1211 (2015) Blood Cancer J, 5, p. 334; Quach, H., Ritchie, D., Stewart, A.K., Mechanism of action of immunomodulatory drugs (IMiDS) in multiple myeloma (2010) Leukemia, 24 (1), pp. 22-32; Jiang, H., Acharya, C., An, G., SAR650984 directly induces multiple myeloma cell death via lysosomal-associated and apoptotic pathways, which is further enhanced by pomalidomide (2016) Leukemia, 30 (2), pp. 399-408; Berdeja, J., Jagannath, S., Zonder, J., 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 (2015) Clin Lymphoma Myeloma Leuk, 16, pp. 129-138; Durie, B.G., Harousseau, J.L., Miguel, J.S., International Myeloma Working Group. International uniform response criteria for multiple myeloma (2006) Leukemia, 20 (9), pp. 1467-1473; Ludwig, H., Miguel, J.S., Dimopoulos, M.A., International Myeloma Working Group recommendations for global myeloma care (2014) Leukemia, 28 (5), pp. 981-992; van de Donk, N.W.C.J., Kamps, S., Mutis, T., Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma (2012) Leukemia, 26 (2), pp. 199-213; Allegra, A., Penna, G., Alonci, A., Monoclonal antibodies: potential new therapeutic treatment against multiple myeloma (2013) Eur J Haematol, 90 (6), pp. 441-468; Tai, Y.-T., Anderson, K.C., Antibody-based therapies in multiple myeloma Bone Marrow Res, , Epub 2011 Mar 2; Richardson, P.G., Lonial, S., Jakubowiak, A.J., Monoclonal antibodies in the treatment of multiple myeloma (2011) Br J Haematol, 154 (6), pp. 745-754; (2015) A Phase I open label study of the safety and tolerability of elotuzumab (BMS-901608) administered in combination with either lirilumab (BMS-986015) or urelumab (BMS-663513) in subject with multiple myeloma (Study 028), , Mar; (2015) Japanese study of (BMS-901608) (elotuzumab) in combination with lenalidomide and low dose dexamethasone, , Mar; (2016) Elotuzumab in autologous stem cell transplantation (ASCT) and lenalidomide maintenance for multiple myeloma, , Mar; (2015) Study of elotuzumab with lenalidomide as maintenanceafter autologous stem cell transplant (ASCT), , Mar; (2015) Study of bortezomib, lenalidomide, dexamethasone & elotuzumab in newly diagnosed MM, , Mar; (2015) Safety study of elotuzumab in combination with thalidomide and dexamethasone in relapsed and/or refractory multiple myeloma, , Mar; (2015) Trial of elotuzumab with or without pomalidomideand low-dose dexamethasone to treat refractory and relapsed and refractory multiple myeloma, , Feb; (2015) A study of Elotuzumab in combination with pomalidomide and low dose dexamethasone (EPd) in patients with multiple myeloma relapsed or refractory to prior treatment with lenalidomide (Study 142) (NCT02612779), , Mar; (2015) Biomarker study of elotuzumab in high risk smolderingmyeloma, , Mar; (2015) Trial of combination of elotuzumab and lenalidomide± dexamethasone in high-risk smoldering multiple myeloma, , Mar; (2015) PH III study of lenalidomide and dexamethasonewith and without elotuzumab to treat previously untreated multiplemyeloma (ELO 1 Sub study), , Mar; (2015) A Phase III trial on the effect of elotuzumab in VRD induction/consolidation and lenalidomide maintenance in patients with newly diagnosed multiple myeloma (GMMG-HD6), , Mar; (2016) Study of Combinations of Nivolumab, Elotuzumab, Pomalidomide and Dexamethasone in Multiple Myeloma (CheckMate 602) (NCT02726581), , Apr

Website