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Safety and Efficacy of Elotuzumab in Multiple Myeloma

Insights From:Shaji K. Kumar, MD, Mayo Clinic College of Medicine; Peter Voorhees, MD, UNC School of Medicine at Chapel Hill
Published: Monday, Apr 18, 2016


Transcript:

Peter Voorhees, MD:
ELOQUENT-2 was a phase III registrational study looking at the efficacy of lenalidomide/dexamethasone and elotuzumab compared with lenalidomide and dexamethasone for patients who had had at least one to three prior lines of therapy for their multiple myeloma. Patients were randomly assigned to lenalidomide and dexamethasone alone, looking at a four-week cycle in which lenalidomide was given on days 1 through 21 of a 28-day cycle. Dexamethasone was given once weekly on days 1, 8, 15, and 22. For the patients that were assigned to the three-drug arm, they received the same doses of lenalidomide and dexamethasone. In addition to that, they received the elotuzumab weekly for the first two cycles and then on days 1 and 15 for cycle three and beyond. In both arms of the study, patients were treated until disease progression.

The primary endpoint of the study was median progression-free survival. Other endpoints included safety signal of the combination, overall response rate, and overall survival. Importantly, there was an increased response rate with the three-drug regimen compared with the two-drug regimen: 79% versus 67%. And this is interesting because there really was no activity with single-agent elotuzumab in the original studies, suggesting that there really is clinical synergy between the elotuzumab and the lenalidomide. More importantly, however, there was an improvement in median progression-free survival. For those patients that were assigned to lenalidomide and dexamethasone, the median progression-free survival was approximately 15 months, whereas with the lenalidomide/dexamethasone and elotuzumab, it was approximately 19.5 months. So, there’s a four-and-a-half month improvement in median progression-free survival, and this translated into a 30% reduction in the risk of progression or death [in] the three-drug arm compared to the two-drug arm.

In addition to an improvement in median progression-free survival, at a pre-specified interim analysis, there was also a trend to improvement in median overall survival as well. Importantly, the side-effect profile of the combination was quite good. There was perhaps a slightly increased incidence of things like fatigue or diarrhea with the three-drug combination. But, overall, the adverse event rates between the two different arms of the study were quite comparable. And, importantly, there did not appear to be an increased risk of infection with the addition of elotuzumab to the lenalidomide/dexamethasone backbone.

Shaji Kumar, MD: Elotuzumab overall is a very well-tolerated drug. Just like all monoclonal antibodies, there is a significant risk of infusion reactions. Overall, if you look at all grades of infusion reactions with the elotuzumab in the phase III trial, it was roughly around 10% to 20%. There were no grade 4 or 5 infusion reactions in the clinical trial. The infusion reactions were mostly isolated to the initial cycles of therapy, and subsequent infusions were very well tolerated. This is very similar to other monoclonal antibodies as well.

In addition to the infusion reaction, the main side effect that was reported in the combination study with elotuzumab and lenalidomide/dexamethasone was fatigue. They also saw some hematological toxicity in the form of neutropenia. It’s hard to know whether that is related to elotuzumab or whether it was related to lenalidomide, since that toxicity is known. The additional side effects or findings related to elotuzumab in the trial was some decrease in the blood counts, especially lymphopenia, in many of these patients. Cough was reported as a side effect in some of these patients. But overall, the drug was very well tolerated and patients could stay on this drug for a prolonged period of time.

One of the things we have to keep in mind with these monoclonal antibodies is the fact that the treatment itself is a monoclonal protein, just like what the myeloma cells have. In many of these patients, especially the patients who have an IgG kappa multiple myeloma, the IgG kappa antibody could be detected as a monoclonal protein. So, in patients who could be having a complete response to therapy, there could be monoclonal protein that is detected, which is entirely the antibody that has been given as therapy and not the myeloma-related protein. That has to be kept in mind when you’re assessing for a complete response. And there is additional testing that can be done by the laboratory to distinguish between what is the therapeutic monoclonal antibody versus what is the monoclonal protein that is coming from the myeloma cell.

Transcript Edited for Clarity
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Transcript:

Peter Voorhees, MD:
ELOQUENT-2 was a phase III registrational study looking at the efficacy of lenalidomide/dexamethasone and elotuzumab compared with lenalidomide and dexamethasone for patients who had had at least one to three prior lines of therapy for their multiple myeloma. Patients were randomly assigned to lenalidomide and dexamethasone alone, looking at a four-week cycle in which lenalidomide was given on days 1 through 21 of a 28-day cycle. Dexamethasone was given once weekly on days 1, 8, 15, and 22. For the patients that were assigned to the three-drug arm, they received the same doses of lenalidomide and dexamethasone. In addition to that, they received the elotuzumab weekly for the first two cycles and then on days 1 and 15 for cycle three and beyond. In both arms of the study, patients were treated until disease progression.

The primary endpoint of the study was median progression-free survival. Other endpoints included safety signal of the combination, overall response rate, and overall survival. Importantly, there was an increased response rate with the three-drug regimen compared with the two-drug regimen: 79% versus 67%. And this is interesting because there really was no activity with single-agent elotuzumab in the original studies, suggesting that there really is clinical synergy between the elotuzumab and the lenalidomide. More importantly, however, there was an improvement in median progression-free survival. For those patients that were assigned to lenalidomide and dexamethasone, the median progression-free survival was approximately 15 months, whereas with the lenalidomide/dexamethasone and elotuzumab, it was approximately 19.5 months. So, there’s a four-and-a-half month improvement in median progression-free survival, and this translated into a 30% reduction in the risk of progression or death [in] the three-drug arm compared to the two-drug arm.

In addition to an improvement in median progression-free survival, at a pre-specified interim analysis, there was also a trend to improvement in median overall survival as well. Importantly, the side-effect profile of the combination was quite good. There was perhaps a slightly increased incidence of things like fatigue or diarrhea with the three-drug combination. But, overall, the adverse event rates between the two different arms of the study were quite comparable. And, importantly, there did not appear to be an increased risk of infection with the addition of elotuzumab to the lenalidomide/dexamethasone backbone.

Shaji Kumar, MD: Elotuzumab overall is a very well-tolerated drug. Just like all monoclonal antibodies, there is a significant risk of infusion reactions. Overall, if you look at all grades of infusion reactions with the elotuzumab in the phase III trial, it was roughly around 10% to 20%. There were no grade 4 or 5 infusion reactions in the clinical trial. The infusion reactions were mostly isolated to the initial cycles of therapy, and subsequent infusions were very well tolerated. This is very similar to other monoclonal antibodies as well.

In addition to the infusion reaction, the main side effect that was reported in the combination study with elotuzumab and lenalidomide/dexamethasone was fatigue. They also saw some hematological toxicity in the form of neutropenia. It’s hard to know whether that is related to elotuzumab or whether it was related to lenalidomide, since that toxicity is known. The additional side effects or findings related to elotuzumab in the trial was some decrease in the blood counts, especially lymphopenia, in many of these patients. Cough was reported as a side effect in some of these patients. But overall, the drug was very well tolerated and patients could stay on this drug for a prolonged period of time.

One of the things we have to keep in mind with these monoclonal antibodies is the fact that the treatment itself is a monoclonal protein, just like what the myeloma cells have. In many of these patients, especially the patients who have an IgG kappa multiple myeloma, the IgG kappa antibody could be detected as a monoclonal protein. So, in patients who could be having a complete response to therapy, there could be monoclonal protein that is detected, which is entirely the antibody that has been given as therapy and not the myeloma-related protein. That has to be kept in mind when you’re assessing for a complete response. And there is additional testing that can be done by the laboratory to distinguish between what is the therapeutic monoclonal antibody versus what is the monoclonal protein that is coming from the myeloma cell.

Transcript Edited for Clarity
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