New Therapeutic Approaches for Multiple Myeloma - Episode 11

Daratumumab Revolutionizing How Myeloma Is Treated

Transcript:Keith Stewart, MD, CHB: Daratumumab. This is approved now in relapsed refractory disease in the United States. I think we’ve all got some experience using it. It’s quickly moving into early lines of therapy, and there have been two phase III trials that have been done. One will be presented at this ASCO meeting and one at the upcoming European Hematology Association (EHA) Meeting. Rafael, do you want to set the stage for us and tell the audience about those trials and what they’ve told us?

Rafael Fonseca, MD: This is coming very fast, and this is going to revolutionize how we treat myeloma. So, two trials are being presented. One here at the ASCO meeting, the CASTOR trial. We haven’t seen the data so we have the public press release that shows that the study had to be stopped because of ethics, with a hazard ratio that is really unprecedented in most of the myeloma trials. And next week comes another press release regarding the EHA presentation that Thanos Dimopoulos will do in combination with IMiD.

This was VD (Velcade plus dexamethasone) versus daratumumab/VD. The other one is lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus daratumumab. It seems to be almost a mirror study. Daratumumab, for those in the audience who don’t know this, the target C38 is a naked antibody. Like every antibody, there are several mechanisms that have been proposed. The bottom line, it works very, very well. And I’ll say, I have had the opportunity to use this now in the practice, both the single agent, as well as off-label and combination. And particularly the combinations are quite impressive—the depth of the response for patients who haven’t responded to any agents. So, I think the anticipation…of course, we’ll see these trials. It will get the label for these combinations, but, ultimately, this will be one of several antibodies. And we’re remiss in not mentioning isatuximab, as well, too, at some point. But daratumumab will be used in the frontline pretty soon.

Keith Stewart, MD, CHB: Ola?

C. Ola Landgren, MD, PhD: I agree with Rafael. This is revolutionary for myeloma therapy for sure. I have also used it quite a lot. I’ve used it as a single drug and off-label in combination with lenalidomide/dexamethasone and with pomalidomide/dexamethasone. In my experience, patients that are heavily pretreated—where virtually no other drugs work—you can see up to 60% of those patients having a good response.

Keith Stewart, MD, CHB: In the combination study.

C. Ola Landgren, MD, PhD: In combinations.

Keith Stewart, MD, CHB: Single agents are a little bit lower.

C. Ola Landgren, MD, PhD: In the range of 30%, which is what the studies have shown so far. And it seems to last for a very long time.

Keith Stewart, MD, CHB: That was one of the impressive things with the single-agent results. Not so much that there was a 30% response rate, but the overall survival—and those patients who were very heavily pretreated—was what, 18 months?

C. Ola Landgren, MD, PhD: Yes, something like that.

Keith Stewart, MD, CHB: Average.

C. Ola Landgren, MD, PhD: Yes, it’s very, very impressive.

Keith Stewart, MD, CHB: Other studies have been more in the 6-month range.

C. Ola Landgren, MD, PhD: Right. I think my readout is that we know that the three-drug combinations for relapse is better than two drugs, and we talked about if you use up front, if you do VRD or KRD, I would use KRD. If you asked me, “What happens when you relapse and you are on maintenance?”, I could see using daratumumab in combination with an IMiD, and dexamethasone could be definitely a rescue for many patients in the future.

Keith Stewart, MD, CHB: Very impressive results. It looked to me almost as if the combination of lenalidomide with daratumumab looked as good or perhaps even better than what we showed in the ASPIRE trial with carfilzomib/lenalidomide. What impact is this going to have?

Jatin P. Shah, MD: I agree, in principle, that I think it’s an exciting new drug. I think it’s going to be incorporated into all the different lines of therapy. I was a bit conservative with just the SIRIUS data last year because I think that the progression-free survival is still on the short list—7 months, which is similar to what we saw with carfilzomib and others. So, as a single agent, I was a little bit cautious. I think it’s an exciting new drug, an option, but let’s wait till we get some more. And I’m going to take the same stance when we talk about this phase III data. I’m very excited about it.

The reason I’m conservative is because of the follow-up, and that’s what I think is a power of these immunotherapies. And so when you look at the follow-up for the study with lenalidomide/dexamethasone, it’s only a 21-month follow-up. That’s a short follow-up, actually. The power of these immunotherapies is, quite frankly going to be in a long-term follow-up. And so when you can see, for example, that elotuzumab with a long-term 3-year follow-up and seeing that maintenance in the plateau phase, that is the power of…

Keith Stewart, MD, CHB: Those curves are pretty far apart for me. It’s hard to imagine them coming together.

Jatin P. Shah, MD: I agree, I fully agree. I’m just trying to be the devil’s advocate in that short follow-up, the power of that drug. And I’m not saying it’s not a bad drug now; I think it’s a great drug. I think it’s going to be even better with long-term follow-up is my point. It’s a great drug; it’s even better with long-term follow up. That’s my only point.

Keith Stewart, MD, CHB: Bill, what do you think? Is this rituximab for myeloma?

William I. Bensinger, MD: I think that’s a very good analogy. I think that this will enable us to construct, essentially, an R-CHOP regimen for myeloma. But we’re also going to see it used, I think, in other areas. It’s going to be used in maintenance trials, and where it could be very active in that situation as well. So, I think these are the beginning of these immunotherapies and really a breakthrough for us in the treatment of myeloma.

Keith Stewart, MD, CHB: And we don’t have much up-front data yet, I don’t believe.

William I. Bensinger, MD: None that I’m aware of.

Keith Stewart, MD, CHB: But trials are ongoing, right?

William I. Bensinger, MD: Yes.

Keith Stewart, MD, CHB: Do you think these trials, from what you’ve seen, will result in an approval and we’ll be using daratumumab in first relapse?

William I. Bensinger, MD: Oh, I think so. Yes.

Keith Stewart, MD, CHB: Any other comments? It’s like a slam dunk for daratumumab here?

C. Ola Landgren, MD, PhD: It looks great. I think it’s very, very exciting.

Transcript Edited for Clarity