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Efficacy and Safety of Monoclonal Antibodies for Multiple Myeloma

Insights From:Jatin P. Shah, MD, MD Anderson Cancer Center;Ivan Marques Borrello, MD, Johns Hopkins University;James R. Berenson, MD, Institute for Myeloma and Bone Cancer Research
Published: Wednesday, Aug 03, 2016


Transcript:

Ivan Marques Borrello, MD:
The ELOQUENT-2 study, which was a study in the relapsed setting for multiple myeloma, compared Revlimid with dexamethasone to elotuzumab/Revlimid/dexamethasone and showed a significant improvement of progression-free survival at 1 year, 2 years, and 3 years. And what the trial was looking at was in patients that were not very heavily pretreated, of which less than 20% of them had previously been treated with Revlimid, and compared the treatment of these outcomes in these both arms.

And what this showed, specifically with regard to the three-drug combination, is that clearly there’s a better response. I think this better response can be potentially explained by a few things. One is that elotuzumab is not only targeting the tumor cell directly through its interaction with SLAMF7 on the tumor cell, but potentially also on the NK cells, which have the SLAMF7 that, interestingly, can translate into an augmentation of an NK response. But also, I think when you compare the single-agent to triple-agent efficacy of elotuzumab, the reality is that lenalidomide (or Revlimid) is being used as an immunomodulator that is also potentiating this response. And so, taken together, we’re seeing a specific tumor-targeted therapy and an immune benefit that is being induced both in the use of the monoclonal antibody, as well as by the IMiD.

Jatin P. Shah, MD: Daratumumab is a monotherapy currently based on a single-arm phase II study. Daratumumab is approved in relapsed/refractory myeloma in patients who’ve either had more than three lines of prior therapy, including an IMiD and a proteasome inhibitor, or patients who are dual-refractory to the combination of an IMiD and a proteasome inhibitor. So, it’s currently approved in that relapsed/refractory setting for patients who’ve seen most of our current therapeutics. And it’s based on a single-arm phase II study, called the SIRIUS study, where approximately 100 patients were treated on this, and there was about a 30% response rate in these patients who had progressed after a prior IMiD or a proteasome inhibitor. And that’s where the data are approved currently.

However, I think this is a very rapidly evolving space, and we’ll see that use of daratumumab be rapidly moving into the earlier lines of therapy. Excitingly, we’ll see here, at ASCO, the results of the CASTOR study, a randomized phase III study which looked at bortezomib and dexamethasone plus or minus daratumumab in patients with one to three lines of prior therapy. So far, the hazard ratio was 0.39, and we’ll see the rest of the results at ASCO 2016. But I think that these are very exciting data demonstrating the benefit of daratumumab in patients with earlier lines of therapy. And importantly, at EHA 2016, we’ll see the results of the POLLUX study, again looking at a phase III study of lenalidomide and dexamethasone plus or minus daratumumab, with a very similar hazard ratio of 0.39.

I think that even though it’s currently approved as a single-agent monotherapy in patients who’ve had multiple lines of prior therapy and been refractory to IMiDs and proteasome inhibitors, in the very near future, as it’s a very rapidly evolving field, you’re going to see that moving up into earlier lines of therapy, as well. That’s exciting news for our patients and an exciting opportunity and option for our treating physicians.

One of the important things when you start administering these monoclonal antibodies, either daratumumab or elotuzumab, is to really understand the infusion-related reactions that you can anticipate, your patients can anticipate, and your nurses can anticipate. And importantly when you think about, for example, daratumumab, there are lots of infusion reactions that you can potentially see in the first infusion. So, this is similar to our experience that we saw with rituximab where it can be really prolonged infusions at times that we see due to the infusion reactions.

Oftentimes, we’ll do lots of premedications for these patients with Tylenol and Benadryl and H2 blockers, things that we’ll typically use with Rituxan that we are comfortable with. However, what we’ll typically see is that with a second or a third or subsequent infusions of daratumumab, it becomes better and better tolerated. So, as infusion reactions really diminish, there will be minimal infusion reactions that you’ll see subsequently, similar to our previous known experience with rituximab. However, it’s very important to really understand that you can see significant infusion reactions in these patients who are getting daratumumab for the first several infusions. And that’s important for our patients to know, so they allocate that amount of time. These things can take up to 8 to 12 hours to infuse, for example, and it’s important for our nurses to know this, as well, so when we start scheduling infusion times, we know not to schedule later in the day, but first thing in the morning. In fact, we have also seen that sometimes patients need to be hospitalized for their first infusion reaction or separate them out over 2 days. And so those are anecdotes that we’ve seen, as well, but it’s important really to highlight the fact that the first infusion of daratumumab can be prolonged with significant infusion reactions. It’s important to premedicate these patients. However, the subsequent infusions become much better tolerated though they’re still rather long.

This is actually an interesting comparison to elotuzumab where actually we see that, although it’s also a monoclonal antibody, there are very few infusion reactions with elotuzumab. So, though you may see more in the first infusion, subsequently you really will see very few infusion reactions. And, importantly, now we’ve gotten to elotuzumab being infused over 2 hours, or a very rapid infusion, and that’s very important for our patients, as well as the nurses scheduling chair times and for physicians that we schedule for patients. I think that’s important. The difference is in the infusion reactions. I think the better prepared that we are, the better we can manage these, and it’s very important for patients to understand that, as well.

Transcript Edited for Clarity
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Transcript:

Ivan Marques Borrello, MD:
The ELOQUENT-2 study, which was a study in the relapsed setting for multiple myeloma, compared Revlimid with dexamethasone to elotuzumab/Revlimid/dexamethasone and showed a significant improvement of progression-free survival at 1 year, 2 years, and 3 years. And what the trial was looking at was in patients that were not very heavily pretreated, of which less than 20% of them had previously been treated with Revlimid, and compared the treatment of these outcomes in these both arms.

And what this showed, specifically with regard to the three-drug combination, is that clearly there’s a better response. I think this better response can be potentially explained by a few things. One is that elotuzumab is not only targeting the tumor cell directly through its interaction with SLAMF7 on the tumor cell, but potentially also on the NK cells, which have the SLAMF7 that, interestingly, can translate into an augmentation of an NK response. But also, I think when you compare the single-agent to triple-agent efficacy of elotuzumab, the reality is that lenalidomide (or Revlimid) is being used as an immunomodulator that is also potentiating this response. And so, taken together, we’re seeing a specific tumor-targeted therapy and an immune benefit that is being induced both in the use of the monoclonal antibody, as well as by the IMiD.

Jatin P. Shah, MD: Daratumumab is a monotherapy currently based on a single-arm phase II study. Daratumumab is approved in relapsed/refractory myeloma in patients who’ve either had more than three lines of prior therapy, including an IMiD and a proteasome inhibitor, or patients who are dual-refractory to the combination of an IMiD and a proteasome inhibitor. So, it’s currently approved in that relapsed/refractory setting for patients who’ve seen most of our current therapeutics. And it’s based on a single-arm phase II study, called the SIRIUS study, where approximately 100 patients were treated on this, and there was about a 30% response rate in these patients who had progressed after a prior IMiD or a proteasome inhibitor. And that’s where the data are approved currently.

However, I think this is a very rapidly evolving space, and we’ll see that use of daratumumab be rapidly moving into the earlier lines of therapy. Excitingly, we’ll see here, at ASCO, the results of the CASTOR study, a randomized phase III study which looked at bortezomib and dexamethasone plus or minus daratumumab in patients with one to three lines of prior therapy. So far, the hazard ratio was 0.39, and we’ll see the rest of the results at ASCO 2016. But I think that these are very exciting data demonstrating the benefit of daratumumab in patients with earlier lines of therapy. And importantly, at EHA 2016, we’ll see the results of the POLLUX study, again looking at a phase III study of lenalidomide and dexamethasone plus or minus daratumumab, with a very similar hazard ratio of 0.39.

I think that even though it’s currently approved as a single-agent monotherapy in patients who’ve had multiple lines of prior therapy and been refractory to IMiDs and proteasome inhibitors, in the very near future, as it’s a very rapidly evolving field, you’re going to see that moving up into earlier lines of therapy, as well. That’s exciting news for our patients and an exciting opportunity and option for our treating physicians.

One of the important things when you start administering these monoclonal antibodies, either daratumumab or elotuzumab, is to really understand the infusion-related reactions that you can anticipate, your patients can anticipate, and your nurses can anticipate. And importantly when you think about, for example, daratumumab, there are lots of infusion reactions that you can potentially see in the first infusion. So, this is similar to our experience that we saw with rituximab where it can be really prolonged infusions at times that we see due to the infusion reactions.

Oftentimes, we’ll do lots of premedications for these patients with Tylenol and Benadryl and H2 blockers, things that we’ll typically use with Rituxan that we are comfortable with. However, what we’ll typically see is that with a second or a third or subsequent infusions of daratumumab, it becomes better and better tolerated. So, as infusion reactions really diminish, there will be minimal infusion reactions that you’ll see subsequently, similar to our previous known experience with rituximab. However, it’s very important to really understand that you can see significant infusion reactions in these patients who are getting daratumumab for the first several infusions. And that’s important for our patients to know, so they allocate that amount of time. These things can take up to 8 to 12 hours to infuse, for example, and it’s important for our nurses to know this, as well, so when we start scheduling infusion times, we know not to schedule later in the day, but first thing in the morning. In fact, we have also seen that sometimes patients need to be hospitalized for their first infusion reaction or separate them out over 2 days. And so those are anecdotes that we’ve seen, as well, but it’s important really to highlight the fact that the first infusion of daratumumab can be prolonged with significant infusion reactions. It’s important to premedicate these patients. However, the subsequent infusions become much better tolerated though they’re still rather long.

This is actually an interesting comparison to elotuzumab where actually we see that, although it’s also a monoclonal antibody, there are very few infusion reactions with elotuzumab. So, though you may see more in the first infusion, subsequently you really will see very few infusion reactions. And, importantly, now we’ve gotten to elotuzumab being infused over 2 hours, or a very rapid infusion, and that’s very important for our patients, as well as the nurses scheduling chair times and for physicians that we schedule for patients. I think that’s important. The difference is in the infusion reactions. I think the better prepared that we are, the better we can manage these, and it’s very important for patients to understand that, as well.

Transcript Edited for Clarity
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