Potential Role of Daratumumab in Multiple Myeloma

Transcript:Keith Stewart, MB, CHB: I think I'd like to move on to another drug that was just approved. I'm going to ask any one of you that wants to jump in here to tell us about what daratumumab is and what it does in myeloma. So anybody who feels that they haven't said any. Sagar?

Sagar Lonial, MD: Daratumumab is an anti-CD38 monoclonal antibody that works through a number of different mechanisms. It does all the immune things that we think about, like ADCC and ADCP and CDC, in terms of its mechanisms for killing cells. But CD38 also has important signaling pathways within the cell itself that may be important for single-agent activity. What we've shown at ASCO this year, and then Saad Zafar Usmani is updating at this meeting, is about a 30% single agent response rate in a median of five prior lines of therapy. And if you think about putting that in perspective, that's sort of like where we were in 2002 with bortezomib. Single agent, roughly the same sort of ballpark. And patients are achieving not just a response, but there's some, about 10%, are achieving a VGPR or better, which I think is even really more impressive.

It appears to be independent of the number of prior lines that you've had, at least in this very heavily pretreated group of patients. And I think because of its safety profile, it's a monoclonal antibody. It also lends itself to great partnership, which there's data at the meeting on lenalidomide and then data in combination with pomalidomide, as well.

Keith Stewart, MB, CHB: And you actually are going to present at this meeting some updated data on daratumumab. Can you tell us a little bit or did you just cover most of that?

Sagar Lonial, MD: Yeah, I think I covered it.

Paul G. Richardson, MD: I would echo Sagar's points. And I think the thing that's very nice is Sagar led the SIRIUS trial. And then we had this very large phase I study with this big phase II component to it, which really both studies validated each other, the 16-mg/kilo dose. What's very interesting about daratumumab is dose does seem to matter. And to Sagar's point, these multiple mechanisms of action through which the antibody works probably explain why it is active as a single agent, whereas in contrast, for example, elotuzumab as a monotherapy is not.

Keith Stewart, MB, CHB: I don't have the label in front of me, but if I recall, it's also more restrictive because it's phase II trials.

Paul G. Richardson, MD: Right.

Keith Stewart, MB, CHB: Does anybody want to have a shot at what the label says there?

Ajai Chari, MD: Three lines of prior therapy or refractory to both a proteasome inhibitor and an IMiD.

Paul G. Richardson, MD: Yeah.

Keith Stewart, MB, CHB: So three lines of therapy or refractory. And what does refractory mean, just for everybody's clarity?

Ajai Chari, MD: By IMWG criteria, it's progression while receiving therapy within 60 days.

Keith Stewart, MB, CHB: So this is probably, at least for now, going to be used in a more heavily pretreated population. So let's talk about the infusion…

Sagar Lonial, MD: Do you want to hear the pomalidomide data first?

Keith Stewart, MB, CHB: Sure.

Sagar Lonial, MD: He hasn't had a chance to tell his pomalidomide story yet.

Keith Stewart, MB, CHB: Well, let's go ahead with that.

Ajai Chari, MD: Well, I think two of the interesting things you didn't take credit for [motions to Sagar] from your study of single-agent daratumumab was that the overall survival of that population was actually pretty impressive.

Paul G. Richardson, MD: It was, thank you.

Ajai Chari, MD: And even though the PFS was short, and there's question that maybe because of a long half-life of these monoclonals, perhaps salvage therapies might be more efficacious. But also I think one of the preclinical findings that are coming out in terms of mechanism of action of daratumumab is potentially this T-cell clone that may come out by perturbation of the different regulatory cells. And that clone seems to correlate with response. And I bring that up because in ASCO, there was a presentation that CD38 is also upregulated by pomalidomide. So it's a both preclinical and clinical rationale for combining them. It's now 100 patients have been accrued, and we'll be presenting the 75-patient data. But as you would expect, the response rate was doubled with the addition of daratumumab, and the PFS was not yet reached—it’s early follow-up.

Keith Stewart, MB, CHB: So just to clarify: Pomalidomide and daratumumab with steroids?

Ajai Chari, MD: Yes.

Keith Stewart, MB, CHB: A 60% response rate?

Ajai Chari, MD: 65%, in the abstract, and it'll be a little bit better.

Keith Stewart, MB, CHB: And is this the same population as the pomalidomide/dexamethasone was originally tested?

Ajai Chari, MD: Yes.

Keith Stewart, MB, CHB: So quad-refractory?

Ajai Chari, MD: Well, so this by definition, it's similar to the pomalidomide population, right? So there was a median of four lines of therapy and about 65% were double-refractory to both lenalidomide and bortezomib.

Sagar Lonial, MD: Several from our center were 17P-deleted, so it's not a cherry-picked group of people.

Keith Stewart, MB, CHB: Very nice. And let's talk about any toxicities to this drug, daratumumab?

Ajai Chari, MD: I think it's minimal. I mean the two things to be aware about, particularly for the coming in oncologists, is number one, a red cell implication. So daratumumab coats the red cells and it makes the indirect Coombs, or type and screen, look positive across the board, making it difficult to find the blood. But we actually have a poster showing that it's more of an artifact and you can either phenotype the blood before transfusion or there's some laboratory agents like DTT, which can strip the daratumumab off the red cells and allow more accurate typing. With those interventions, there have been no complications with transfusions. And then the second thing is the infusion-related reactions, which are typically grade 1, grade 2, manageable, with dose reduction.

Keith Stewart, MB, CHB: What are those? Because they're a little bit different than some of the other antibodies we use. Paul, what have you experienced with that?

Paul G. Richardson, MD: Well, I think that the important thing about the infusions is that they're obviously substantially longer than we do with elotuzumab, but for good reason.

Keith Stewart, MB, CHB: How long does the infusion take?

Paul G. Richardson, MD: Well, it varies. The thing is, you start initially; it can last a whole day, and then there is an effort to sort of titrate and pull back. And there is actually ongoing studies now looking at subcutaneous dosing to do it. But we're talking up to 12-hour infusion times, and now we're bringing it back. So it's substantially longer than elotuzumab. Having said that, with the appropriate premedication, you can have these early first-dose type effects. But then they seem to not be an issue. One of the most interesting things is the use of potentially leukotriene inhibitors for some of the pulmonary symptoms, which are more histaminergic, that may be an issue.

Keith Stewart, MB, CHB: I've read or seen that that's scratchy throat.

Paul G. Richardson, MD: Yes, absolutely.

Keith Stewart, MB, CHB: And even throat swelling a little bit?

Paul G. Richardson, MD: More of a sort of COPD, sort of asthmatic-type picture. But they were seen early in the phase I. We saw some of this and then quickly got on top of it with appropriate premedication and so on. So it's really not the issue. But I think some people said, ‘Oh my goodness! No, it isn't.’

Keith Stewart, MB, CHB: CD30, I remember one of the trials, is expressed on the bronchial lining.

Paul G. Richardson, MD: Yeah.

Ajai Chari, MD: I want to clarify. For the vast majority of patients that we've treated across all the daratumumab studies, maybe 70, the median first infusion is probably about seven to eight hours.

Sagar Lonial, MD: Right.

Ajai Chari, MD: I think it's manageable (in six).

Paul G. Richardson, MD: And then you could can pull back, right?

Ajai Chari, MD: Six is the official number.

Jatin J. Shah, MD: Just from a practical perspective though, if you're going to do this, you have to start in the morning, as opposed to starting an infusion at 2:00 or 3:00 in the afternoon. And that's really relevant because infusion clinics close at 5:00 or 6:00.

Keith Stewart, MB, CHB: So I think the relevant points to impress to the physician are [to] start out in the morning, pre-medicate, and be aware that you can get some of this bronchial irritation. Don't be surprised by it; slow the infusion down to half.

Paul G. Richardson, MD: Right.

Keith Stewart, MB, CHB: Pre-medicate and you should be fine. But plan on that it could take up to 6 hours on average, but sometimes it could go longer.

Sagar Lonial, MD: Yeah. So the expression of CD38 is probably most relevant on basophiles, which may mediate a lot of the sinus stuff.

Keith Stewart, MB, CHB: That's a good point, yeah.

Sagar Lonial, MD: And so you treat it like you would allergic.

Keith Stewart, MB, CHB: All right. So we're really excited about this one.

Paul G. Richardson, MD: And if I may, Keith: one additional study to mention with daratumumab is the lenalidomide platform as well, because that data is being presented at the meeting as well, and it sort of echoes very much what Ajai said.

Keith Stewart, MB, CHB: Well, this is where I was going with this: that the approval is a single agent, but 30% response rate isn't that good, you know. We'd like to do better, right?

Paul G. Richardson, MD: Yup.

Keith Stewart, MB, CHB: So are you going to use it as a single agent, which is what the label allows us to do officially? Or do you think people will quickly move to combinations?

Jatin J. Shah, MD: So I think the randomized phase III data, if you're going to be talking about that, really still supports if you're going to be moving it up-front with lenalidomide plus elotuzumab…

Keith Stewart, MB, CHB: Well, even in the relapsed refractory setting, are you going to add cyclophosphamide or carfilzomib or pomalidomide or ixazomib?

Ajai Chari, MD: Dr. Usmani's data in combination with Dr. Lonial's is interesting in that when you look at the PFS curves for the daratumumab patients, it splits up into three groups. The ones who respond do great. The stable disease, minimal response, they actually do pretty well; they may not. And I think it's important in a quad-refractory, relapse refractory, stable disease that's durable [that] it's also a meaningful benefit. And I think it's that the problem is we don't know who those few are. That third of patients that have progressed very quickly may not even get a chance to benefit from daratumumab. So I think in the very fulminantly progressing patient, I probably would do a combination therapy, admittedly off label. But if somebody's quad-refractory, perhaps.

Paul G. Richardson, MD: Ajai, if I may, just to be a little careful there because what we have for combinations is pomalidomide, Revlimid, and bortezomib. We actually don't have data yet on carfilzomib with daratumumab.

Ajai Chari, MD: That will be coming shortly.

Keith Stewart, MB, CHB: We need to find the doses probably.

Paul G. Richardson, MD: My only caution is activated endothelium expresses CD38, and knowing what we know about vascular toxicity, just be a little bit careful about that. But having said that, I completely agree, Ajai. I think if you've got someone who's in trouble, a combinatorial approach would be very rational with phase II data to support it, yeah.

Keith Stewart, MB, CHB: Where is it going? Where are we seeing daratumumab in the next two to three years? Jatin?

Jatin J. Shah, MD: So I think we're looking forward to the phase III data, and that's going to really help guide us in terms of how we best…

Keith Stewart, MB, CHB: This is an up-front trial or a first relapse, or both?

Jatin J. Shah, MD: So I think there were trials both in newly-diagnosed myeloma as well as in relapsed myeloma, both in combination with Velcade as well as Revlimid. I think we really need good randomized phase III data just because we have other options now with carfilzomib, ixazomib, elotuzumab, and panobinostat in randomized phase III trials. So I think we need randomized phase II trials for daratumumab before it moves farther up-front. Elotuzumab, I think, is very active and it will move there. I think we need that in the short term before I think we move forward with that and daratumumab.

Sagar Lonial, MD: But I think if you're practically talking about a four-drug induction regimen, which I suspect we're all moving there now, that there's almost universal agreement, that three is a standard, the fourth drug is probably going to be an antibody.

Paul G. Richardson, MD: I agree.

Sagar Lonial, MD: Because it's just so easy to add.

Paul G. Richardson, MD: I agree. I think the other one would be an HDAC inhibitor.

Jatin J. Shah, MD: Exactly. Because we have very compelling data already right now with HDAC inhibitors having 50% CR rates at four cycles and similar MRD rates at four cycles. So I think we still have to look at that as well.

Keith Stewart, MB, CHB: Yeah. So daratumumab we see moving earlier into the treatment of myeloma with combinations. And then we're going to have to decide which of the antibodies we're going to use. And whether we'll sequence them.

Paul G. Richardson, MD: And again, I don't see this as a zero-sum game. I think there's going to be a clear place for elotuzumab. It's well tolerated and it's got the short infusion time. And practically speaking, daratumumab a six-hour infusion. I think the subcutaneous initiative is really interesting. If that pays off, that will also make daratumumab a very convenient antibody to give.

Transcript Edited for Clarity