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Elotuzumab for the treatment of multiple myeloma.

ABSTRACT: Elotuzumab is one of the first two monoclonal antibodies that gained FDA approval for the treatment of multiple myeloma (MM). It targets SLAMF7, which is highly expressed in normal plasma and MM cells as well as natural killer (NK) cells. Elotuzumab demonstrated significant anti-myeloma activity in preclinical studies, and its mechanisms of action include mediating antibody-dependent cell-mediated cytotoxicity, enhancing cytotoxicity of NK cells, and inhibiting MM cell interaction with bone marrow stromal cells. In clinical trials, elotuzumab in combination with immunomodulatory drugs and proteasome inhibitors has demonstrated an excellent efficacy and safety profile in treating MM.

SUBMITTER: Wang Y

PROVIDER: S-EPMC4946088 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Elotuzumab for the treatment of multiple myeloma.

Wang Yucai Y Sanchez Larysa L Siegel David S DS Wang Michael L ML

Journal of hematology & oncology 20160715 1

Elotuzumab is one of the first two monoclonal antibodies that gained FDA approval for the treatment of multiple myeloma (MM). It targets SLAMF7, which is highly expressed in normal plasma and MM cells as well as natural killer (NK) cells. Elotuzumab demonstrated significant anti-myeloma activity in preclinical studies, and its mechanisms of action include mediating antibody-dependent cell-mediated cytotoxicity, enhancing cytotoxicity of NK cells, and inhibiting MM cell interaction with bone marr ...[more]

PMID: 27417553

Similar Datasets

Elotuzumab: the first approved monoclonal antibody for multiple myeloma treatment.

Project description:Elotuzumab is a monoclonal antibody directed against the SLAMF7 receptor, expressed on normal and malignant plasma cells with a lower expression on other lymphoid cells such as natural killer (NK) cells. Elotuzumab has no significant antimyeloma activity when given as a single agent to patients with relapsed or refractory multiple myeloma (RRMM). However, when combined with other antimyeloma agents, it results in improved response and outcome. Owing to the results from the landmark ELOQUENT-2 phase III clinical trial, which compared lenalidomide and dexamethasone with or without elotuzumab in patients with RRMM, elotuzumab in combination with lenalidomide and dexamethasone was approved by the American Food and Drug Administration (FDA) in November 2015 for multiple myeloma (MM) patients who received one to three prior lines of therapy. This review will give a brief description of the signaling lymphocytic activation molecule (SLAM) family receptors, the unique SLAMF7 receptor and the mechanism of action of elotuzumab. Thereafter, we will give an overview on its antimyeloma activity in preclinical and clinical trials, including its toxicity profile and management thereof.

| S-EPMC4959642 | biostudies-literature

Treatment of multiple myeloma with the immunostimulatory SLAMF7 antibody elotuzumab.

Project description:Elotuzumab is a humanized monoclonal antibody targeting the extracellular domain of signaling lymphocytic activation molecule F7 (SLAMF7) highly expressed in multiple myeloma cells. Upon binding to myeloma cells, elotuzumab exerts its cytotoxic effects through antibody-dependent cellular cytotoxicity, the antibody-induced selective lysis of tumor cells by activated natural killer (NK) cells. Furthermore, elotuzumab has been shown to directly induce NK-cell activation by binding to SLAMF7 expressed on NK cells and to indirectly modulate T-cell function by promoting the secretion of cytokines from NK cells. In combination with lenalidomide and low-dose dexamethasone, elotuzumab has shown remarkable effects in patients with relapsed or refractory multiple myeloma. In these patients, the risk of disease progression or death was significantly reduced by 30% on elotuzumab. Currently, elotuzumab is being evaluated in various myeloma patient populations and combination regimens. This review discusses the use of elotuzumab as an antimultiple myeloma agent and provides an update on the results of recent clinical trials evaluating the safety and efficacy of elotuzumab for the treatment of multiple myeloma.

| S-EPMC5026292 | biostudies-literature

Profile of elotuzumab and its potential in the treatment of multiple myeloma.

Project description:Although the introduction of novel drugs has improved outcome significantly in multiple myeloma (MM), many patients still eventually relapse. Monoclonal antibodies (mAbs) targeting MM-related antigens can complement currently available therapies. CS1 (also known as CD2 subunit 1, SLAMF7, CD319, and CRACC), a cell surface glycoprotein receptor that is a member of the signaling lymphocytic activation molecule (SLAM) family, is highly and nearly uniformly expressed in myeloma cells at the gene and protein level, but not expressed in other tissues, including hematopoietic stem cells, making CS1 a compelling target for the design of immunotherapies directed at MM. Elotuzumab (formerly HuLuc63), which is a humanized IgG1 mAb recognizing the extracellular region of human CS1, has been shown to be effective in preclinical and early stage clinical investigations, and its efficacy and safety will be further validated in ongoing Phase III trials. Integration of elotuzumab into multidrug therapeutic paradigms seems logical, as elotuzumab is more effective when combined with other agents, such as immunomodulatory drugs or proteasome inhibitors. The functional role of CS1 in MM pathogenesis and the consequences of elotuzumab on normal immune cells should be further investigated. Identification of potential biomarkers and exploration of resistance mechanisms are important issues for elotuzumab-based therapies, as is determining the best clinical placement of elotuzumab, not only in the relapsed/refractory setting but also in upfront therapy for high-risk frank MM, smoldering MM at high-risk of progression, and in maintenance regimens. This review will cover the biological characteristics of CS1 in normal immune cells and MM cells, the efficacy profile and mechanisms of action of elotuzumab from preclinical and clinical investigations, and its potential impact on the treatment of MM.

| S-EPMC4438995 | biostudies-literature

Spotlight on elotuzumab in the treatment of multiple myeloma: the evidence to date.

Project description:Despite advances in the treatment of multiple myeloma, it remains an incurable disease, with relapses and resistances frequently observed. Recently, immunotherapies, in particular, monoclonal antibodies, have become important treatment options in anticancer therapies. Elotuzumab is a humanized monoclonal antibody to signaling lymphocytic activation molecule F7, which is highly expressed on myeloma cells and, to a lower extent, on selected leukocyte subsets such as natural killer cells. By directly activating natural killer cells and by antibody-dependent cell-mediated cytotoxicity, elotuzumab exhibits a dual mechanism of action leading to myeloma cell death with minimal effects on normal tissue. In several nonclinical models of multiple myeloma, elotuzumab was effective as a single agent and in combination with standard myeloma treatments, supporting the use of elotuzumab in patients. In combination with lenalidomide and dexamethasone, elotuzumab showed a significant increase in tumor response rates and progression-free survival in patients with relapsed and/or refractory multiple myeloma. This review summarizes the nonclinical and clinical development of elotuzumab as a single agent and in combination with established therapies for the treatment of multiple myeloma.

| S-EPMC5063562 | biostudies-literature

Update on elotuzumab for the treatment of relapsed/refractory multiple myeloma: patients' selection and perspective.

Project description:Monoclonal antibodies (mAbs) targeting antigens expressed by plasma cells demonstrated major clinical activity in multiple myeloma patients and therefore became a new major class of drug for these patients. Elotuzumab is a humanized mAb targeting the cell surface signaling lymphocytic activation molecule family member 7, a glycoprotein highly expressed on plasma cells, that is the second mAb approved for the treatment of myeloma patients. The mechanism of action of elotuzumab includes natural killer cell (NK) mediated antibody-dependent cellular cytotoxicity and direct activation of NK-cells. Elotuzumab has been approved in combination with lenalidomide and dexamethasone (Elo-Rd) and pomalidomide and dexamethasone (Elo-Pd) for the treatment of relapsed myeloma patients. The present review will focus on elotuzumab, providing a summary of the mechanism of action, efficacy and safety and taking into consideration patients' selection.

| S-EPMC6645600 | biostudies-literature

Clinical potential of SLAMF7 antibodies - focus on elotuzumab in multiple myeloma.

Project description:Elotuzumab is one of the first monoclonal antibodies to be approved for the treatment of multiple myeloma. It is a humanized immunoglobulin G kappa (IgGκ) antibody that targets signaling lymphocytic activation molecule family member 7 (SLAMF7), a surface marker that is highly expressed on normal and malignant plasma cells. This review summarizes the preclinical and clinical data that led to the approval of elotuzumab, along with a discussion on the ongoing and future clinical investigations.

| S-EPMC5367738 | biostudies-literature

Immunotherapy: A New Approach to Treating Multiple Myeloma with Daratumumab and Elotuzumab.

Project description:ObjectiveTo review the clinical pharmacology, efficacy, and safety of daratumumab and elotuzumab for the treatment of relapsed refractory multiple myeloma (RRMM).Data sourcesA literature search of MEDLINE, PubMed, the US National Institutes of Health Clinicaltrials.gov, the Food and Drug administration, and relevant meeting abstracts was conducted using the terms daratumumab, elotuzumab, multiple myeloma, anti-CD38, HuMax-CD38, HuLuc63, SLAMF7, and anti-CS1 STUDY SELECTION/DATA EXTRACTION: Human and animal studies describing the pharmacology, pharmacokinetics, efficacy, and safety of daratumumab and elotuzumab for MM were identified.Data synthesisDaratumumab (anti-CD38) and elotuzumab (anti-CS1) have been recently FDA approved for the treatment of RRMM after showing efficacy in clinical trials. Elotuzumab approval was based on phase III data, and daratumumab gained accelerated approval based on phase I/II trials. Daratumumab has demonstrated significant single-agent activity, with an overall response rate (ORR) of 36% in patients with a median of 4 prior lines of therapy. Elotuzumab has not been shown to have single-agent activity. But the efficacy of both these antibodies in combination with lenalidomide and dexamethasone in RRMM showed an ORR exceeding 80%. Tolerability of elotuzumab and daratumumab seems to be acceptable, with the most common adverse event being infusion reactions.ConclusionDaratumumab and elotuzumab have shown encouraging results in RRMM that led to their FDA approval. Both are well tolerated with minimal toxicities. Phase III clinical trials will define optimal combination and place in therapy of daratumumab and elotuzumab.

| S-EPMC5533303 | biostudies-literature

Overcoming Proteasome Inhibitor-Refractory Multiple Myeloma With Elotuzumab, Bortezomib, Nelfinavir, and Dexamethasone.

Project description:Multiple myeloma is a common plasma cell malignancy with a median overall survival of fewer than 10 years. Proteasome inhibitors comprise an important part of the treatment regimen for this disease. The present study reports the case of a 57-year-old man who experienced a second relapse of multiple myeloma 6 years after initial treatment with bortezomib, lenalidomide, dexamethasone (VRD) followed by autologous hematopoietic cell transplant. The first relapse had been successfully treated with VRD, but this approach failed to control his second relapse. Given the lack of response to VRD therapy and relapse while on bortezomib maintenance, the patient was deemed proteasome inhibitor-refractory and received a new treatment of elotuzumab, lenalidomide, and dexamethasone. Four and a half cycles were completed before the treatment was stopped due to grade 4 cytopenias. The patient received a novel combination of elotuzumab, bortezomib, nelfinavir, and dexamethasone. After six cycles, the serum M-protein level was improved to 0.6 g/dL and the kappa light chains dropped from 3.49 to 1.04 mg/dL. A bone marrow biopsy conducted after five treatment cycles demonstrated < 1% plasma cells by immunohistochemistry and achievement of minimal residual disease status. Overall, this case study suggests that proteasome inhibitor-refractory multiple myeloma may be successfully re-treated with proteasome inhibitors when co-administered with nelfinavir.

| S-EPMC7011904 | biostudies-literature

Emerging combination therapies for the management of multiple myeloma: the role of elotuzumab.

Project description:Treatment options for patients with multiple myeloma (MM) have increased during the past decade. Despite the significant advances, challenges remain on which combination strategies will provide the optimal response for any given patient. Defining optimal combination strategies and corresponding companion diagnostics, that will guide clinical decisions are required to target relapsed or refractory multiple myeloma (RRMM) in order to improve disease progression, survival and quality of life for patients with MM. Elotuzumab is a humanized monoclonal antibody that targets signaling lymphocytic activation molecule F7 (SLAMF7), approved by the US Food and Drug Administration (FDA) in 2015 and the European Medicines Agency in 2016 for the treatment of MM. SLAMF7 is expressed in normal and malignant plasma cells and has lower expression on natural killer (NK) cells. Experimental evidence indicates that elotuzumab exhibits anti-myeloma activity through 1) antibody-dependent cell-mediated cytotoxicity, 2) enhancing NK cells cytotoxicity and 3) interfering with adhesion of MM cells to bone marrow stem cells (BMSCs). Although elotuzumab has no single agent activity in patients with RRMM who have received one to three prior therapies, the combination of elotuzumab with anti-myeloma agents, such as immunomodulatory drugs-lenalidomide, or proteasome inhibitors (PIs)-bortezomib, remarkably improved the overall response rates and progression-free survival in MM patients with only minimal incremental toxicity. In brief, the clinical data for elotuzumab indicate that targeting SLAMF7 in combination with the use of conventional therapies is feasible and effective with a tolerable safety profile for the treatment of RRMM.

| S-EPMC5513822 | biostudies-literature

Enhanced SLAMF7 Homotypic Interactions by Elotuzumab Improves NK Cell Killing of Multiple Myeloma.

Project description:Elotuzumab (Elo) is an IgG1 monoclonal antibody targeting SLAMF7 (CS1, CRACC, and CD319), which is highly expressed on multiple myeloma (MM) cells, natural killer (NK) cells, and subsets of other leukocytes. By engaging with FcγRIIIA (CD16), Elo promotes potent NK cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and macrophage-mediated antibody-dependent cellular phagocytosis (ADCP) toward SLAMF7+ MM tumor cells. Relapsed/refractory MM patients treated with the combination of Elo, lenalidomide, and dexamethasone have improved progression-free survival. We previously showed that Elo enhances NK cell activity via a costimulation mechanism, independent of CD16 binding. Here, we further studied the effect of Elo on cytotoxicity of CD16-negative NK-92 cells. Elo, but not other SLAMF7 antibodies, uniquely enhanced cytotoxicity mediated by CD16-negative NK-92 cells toward SLAMF7+ target cells. Furthermore, this CD16-independent enhancement of cytotoxicity required expression of SLAMF7 containing the full cytoplasmic domain in the NK cells, implicating costimulatory signaling. The CD16-independent costimulation by Elo was associated with increased expression of NKG2D, ICAM-1, and activated LFA-1 on NK cells, and enhanced cytotoxicity was partially reduced by NKG2D blocking antibodies. In addition, an Fc mutant form of Elo that cannot bind CD16 promoted cytotoxicity of SLAMF7+ target cells by NK cells from most healthy donors, especially if previously cultured in IL2. We conclude that in addition to promoting NK cell-mediated ADCC (CD16-dependent) responses, Elo promoted SLAMF7-SLAMF7 interactions in a CD16-independent manner to enhance NK cytotoxicity toward MM cells.

| S-EPMC6774869 | biostudies-literature

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