Emerging Combination Therapies for the Management of Multiple Myeloma: The Role of Elotuzumab

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Advances in treatment options for patients with multiple myeloma (MM), unfortunately, have not improved overall survival, particularly for those with relapsed or refractory (RR) disease. A significant challenge is to identify which combination strategy will achieve an optimal response in the patient. Factors associated with poorer prognosis include: age (65 years and older), sex (risk is slightly greater for men), race (African Americans are more susceptible than whites), family history of MM, obesity/overweight, and a history of other plasma cell diseases.

Progression-free survival is improved with high-dose chemotherapy and autologous stem cell transplantation, but older patients often have comorbidities that prohibit use of these options. Survival appears to be improved with immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). However, resistance to these agents and tolerability are clinical challenges.

Monoclonal antibodies (mABs), which are designed to target highly expressed antigens on cells, are an emerging treatment option. Elotuzumab is a humanized mAB that targets signaling lymphocytic activation molecule 7 (SLAMF7); it was approved for the treatment of MM by the FDA in 2015 and the European Medicines Agency in 2016.

In this article, the current evidence on elotuzumab is reviewed. The authors discuss its mechanism of action and clinical experiences with the agent as monotherapy (safe but not sufficient to produce a tumor response in RRMM) and in combination therapy. Studies on combination strategies that were discussed investigated the effectiveness of elotuzumab in combination with one or more of these agents: lenalidomide, bortezomib, pomalidomide, thalidomide, and/or cyclophosphamide.

The authors conclude that early clinical results of studies with elotuzumab are promising. Understanding how to best combine targeting SLAMF7 with other treatment strategies may lead to improved outcomes for patients with MM.

Cancer Management and Research
Cancer Management and Research

Abstract: 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.


Keywords: elotuzumab, SLAMF7, relapsed/refractory multiple myeloma (RRMM) 

INTRODUCTION

Multiple myeloma (MM) is the second most common hematologic malignancy, featuring abnormal proliferation of plasma cells in the bone marrow. Although the etiology of MM remains unknown, patients with MM often suffer end-organ damage, including hypercalcemia, renal disease, anemia and bone lesions, also known as the CRAB characteristics.1,2 Factors associated with a poorer prognosis include: 1) age, who are >65 years of age; 2) gender: men who are at slightly greater risk than women; 3) race: African Americans who are more susceptible than white Americans; 4) those with a family history of MM; 5) obesity/overweight and 6) those with a history of other plasma cell diseases.3,4

Patients with MM who are <65 years of age, treated with high-dose therapy and autologous stem cell transplantation (ASCT) have improved progression-free survival (PFS) and overall survival (OS) compared with patients who do not receive ASCT. Many patients with myeloma are elderly or have comorbid conditions which may not allow for ASCT.4 New approaches for MM treatment, especially immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs), appear to improve response and extend survival.5 Although the mortality rates of MM have declined in the past decade, the overall incidence rate of MM continues to increase, and <50% of patients are alive for 5 years after their initial diagnosis.6 Current challenges in the clinical management of MM include resistance to PIs and IMiDs and tolerability. The estimated median OS of the patients with MM who are refractory to PIs and IMiDs is ~9 months and the median event-free survival is <5 months.7,8 Monoclonal antibodies (mAbs) designed to target highly expressed antigens on cells have emerged as a potential strategy for targeted cancer therapies. More than 10 mAbs were approved by the US Food and Drug Administration (FDA) for various solid tumor and hematological malignancies since 1997. Understanding lineage or tumor restricted expression of surface receptors could lead to increased specificity of antibody strategies for killing tumor cells. Indeed, compared with standard chemotherapy, this antibody-targeted approach has shown efficacy with less severe toxicities.9

Recently, a number of novel agents with different mechanisms of action have been developed based on an increased knowledge of the pathophysiology of MM, including new generations of PIs, IMiDs, mAB, vaccines, other immunotherapies, histone deacetylase inhibitors, alkylating agents, kinase inhibitors, and the heat shock protein inhibitors.10–15 Therapeutic mABs may directly induce growth inhibition by interfering with receptor–ligand interactions, induce antibody-dependent cellular cytotoxicity (ADCC) stimulate apoptosis signaling cascades, or act as a carrier of chemotherapy (antibody drug conjugate) or radioisotopes.

Elotuzumab is a humanized mAB indicated in MM patients after failure of one to three prior therapies. Eotuzumab was granted “Breakthrough Therapy” designation for MM by the FDA in May 2014 and was approved by FDA in November 2015 and by European Medicines Agency in May 2016 for patients with RRMM. Elotuzumab was labeled for use with combination chemotherapy to treat MM.  

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