Elotuzumab and Daratumumab in Multiple Myeloma

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Immunotherapies and monoclonal antibodies have generated a great deal of excitement as potential treatments for patients with cancer in recent years, states Kenneth Anderson, MD. Monoclonal antibodies have demonstrated efficacy in many other diseases, but, until recently, these therapies had not demonstrated efficacy in multiple myeloma. However, new agents in clinical trials have shown high levels of activity, adds Anderson.

The first agent, elotuzumab, is a monoclonal antibody directed against the signaling lymphocyte activation molecule (SLAMF7) antigen, which is expressed on multiple myeloma and natural killer (NK) cells, Anderson explains. Elotuzumab elicits antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), additionally, by reacting with SLAMF7 expressed on NK cells elotuzumab serves as an activator of NK activity. In essence, explains Anderson, elotuzumab can directly target tumor cells as well as augment the activity of effector cells.

In earlier investigations, combining elotuzumab with lenalidomide and dexamethasone achieved 80% to 90% responses that lasted 33 months, even in high-risk myeloma, says Anderson. This efficacy led to the initiation of the phase III ELOQUENT-1 and -2 trials. These randomized trials are evaluating elotuzumab in the relapsed/refractory and newly diagnosed settings.

In findings reported from the ELOQUENT-2 trial, the combination of elotuzumab, lenalidomide, and dexamethasone extended progression-free survival (PFS) and increased overall response rates (ORR) compared with lenalidomide and dexamethasone alone in patients with multiple myeloma who had one to three prior therapies. The median PFS was improved by 4.5 months with the elotuzumab triplet versus lenalidomide and dexamethasone alone and the ORR was 79% versus 66%, respectively.

A second monoclonal antibody class in development targets the CD38 antigen on multiple myeloma cells. The most advanced antibody in this class, daratumumab, mediates ADCC and CDC. Cross-linking CD38 on the surface of myeloma cells triggers apoptosis and inhibits CD38 enzymatic activity, notes Anderson. Daratumumab possesses high activity in relapsed and relapsed/refractory myeloma, including high-risk disease (such as 17p deletion).

Clinical trials have shown that daratumumab augments response when added to lenalidomide and dexamethasone. Additionally, the agent has been explored as a monotherapy. In a phase II study, monotherapy with daratumumab demonstrated a 65% one-year overall survival rate and a 29.2% ORR in patients with double refractory heavily pretreated multiple myeloma. In combination with lenalidomide and dexamethasone in pretreated patients, the ORR reached as high as 92.3%.

In Anderson’s opinion, combination immune approaches are the future. Combining an antibody with an immunomodulatory agent such as lenalidomide, which targets regulatory T-cells and activates NK cells, results in synergistic cytotoxicity.Other ongoing clinical trials are assessing whether adding a monoclonal antibody to an already active combination of targeted treatments can increase response or extend PFS. Antibodies offer the opportunity to maintain responses in individuals intending to receive transplant as well as those who will not undergo transplant, adds Anderson.