Using Antibody-Drug Conjugates in Multiple Myeloma
Keith Stewart, MB, ChB: Let’s start with belantamab. If you’ve had some experience with the drug, please describe in detail what the DREAMM-2 trial has taught us.
Natalie S. Callander, MD: We are fortunate to participate in the DREAMM-2 study. This was a large phase 2 trial looking at patients who were on at least 3 lines of therapy and had to be daratumumab refractory. Using this as a single agent, every-3-weeks IV [intravenous] administration, that’s very quick, with no steroids and patients liked that. The study was able to show that the response rate was about 33%. Two different dose levels were examined; 2½ mg is the dose we’re using. Many people have probably heard about the biggest toxicity. There’s some thrombocytopenia, which is quite manageable. But there is some keratopathy as well. Patients can develop dry, blurry, and irritated eyes. And that seems to be manageable in that, once the drug is stopped for a period of time, these resolve. In most cases, at least in our experience, the drug can be restarted. But we saw some very nice responses, including some sustained CRs [complete responses] using that drug. The research presented at ASCO [American Society of Clinical Oncology Annual Meeting] that Noopur talked about is combining this drug with Velcade, where that seemed to push the response rate up to almost 75%. But that’s a very small study and is just getting off the ground.
Thomas G. Martin, MD: We’ve been using it in the expanded-access program. We’ve put close to 10 patients on the expanded access. I have also been very impressed with the ease of administration, which is once every 3 weeks. We have a good ophthalmology group, so for us, it’s very easy for the patients to go to an ophthalmologist. They look at the surface of the eye. They tell us everything is OK. Patients can then get dosed with their next or subsequent dose. For us, it’s been convenient. We haven’t had a significant toxicity that wasn’t reversible.
Keith Stewart, MB, ChB: What percentage of patients get this corneal toxicity, Tom, either from the study or your own experience?
Thomas G. Martin, MD: Upward of 70% of patients can have some corneal toxicity. And close to half the patients either have to hold the dose or have to dose reduce. It’s a significant number, and they have to be watched closely in terms of the ocular stuff.
Peter Voorhees, MD: To be clear, 70% of patients had corneal findings on ophthalmologic examination. Not everybody had symptoms of those corneal findings, although dry eye, photophobia, and blurred vision were common adverse effects. Because of that, as Tom mentioned, there were a lot of dose holds and dose reductions. It’s going to be important to better understand why this is happening, to explore alternative dose schedules and other potential preventive strategies to mitigate this particular problem, because if it wasn’t for the corneal toxicity, this is a very easy agent to give.
Natalie S. Callander, MD: There was a substudy done looking at the use of steroid eye drops to prevent the keratopathy. Unfortunately, that did not seem to be helpful. But Pete’s right. The secret is probably going to be a change in the dosing schedule or maybe building in some positives, because the half-life of this drug is pretty long.
Keith Stewart, MB, ChB: My experience with this class of drugs—antibody-drug conjugates, targeted BCMA [B-cell maturation antigen]—is that the high toxicity can be quite difficult for patients at times. In at least some of the patients I treated, it took quite a long time for the symptoms to resolve after they stopped the drug. What I found interesting, and I guess other people have seen, is that the response persisted.
Natalie S. Callander, MD: Right.
Keith Stewart, MB, ChB: Even though they were off the drug for quite a long time—and surprisingly so, in my experience, given the stage of disease the patients had—they would be coming 3 three months later. And I’d go, “Wow, you’re still in complete remission [CR]. That’s amazing.” Have others had that experience?
Natalie S. Callander, MD: Yes, absolutely. I had a patient who had a 6-month dose hold because of keratopathy and was absolutely stable. She wasn’t in a CR, but she had a deep PR [partial response] with an M-spike [monoclonal protein] that just sat there at 0.2 for 6 months.
Peter Voorhees, MD: The median duration of response in the updated ASCO [American Society of Clinical Oncology Annual Meeting] presentation is 11 months, which is long compared with, for example, selinexor-dexamethasone from the STORM trial, where the median duration of response was about 4½ months. For those patients who respond, they respond very well in spite of those dose holds.
Natalie S. Callander, MD: Right.
Keith Stewart, MB, ChB: The other thing I noticed was the responses were quite deep. I had a couple of people go into complete remission, which was kind of surprising. It’s definitely a drug to watch. I think you’re right. This issue that the responses can be quite durable—and the half-life of the antibody, of course, is quite long—suggests maybe that, to me at least, the dosing schedule is something to look at rather than stopping and starting. Just have a longer time between treatments if they start to develop problems. Is that logical or illogical? What do people think?
Peter Voorhees, MD: Very logical.
Natalie S. Callander, MD: Yes.
Thomas G. Martin, MD: The combination we’re going to use it in, right? It’s probably not going to be most effective just as a single agent. We probably can use it in a lower dose like we’re talking about with selinexor, in combination with another agent. It’s a race to figure out which one is going to be the best combination.
Keith Stewart, MB, ChB: Noopur, where are you going to use this drug? At what stage of disease?
Noopur Raje, MD: Obviously, BCMA targets are all very exciting. The benefit of belantamab mafodotin is the fact that it is an off-the-shelf antibody. There is no processing. There is no waiting. And the toxicity, outside the ocular toxicity, is very manageable, completely outpatient. Given that we are already using daratumumab at the onset, at the final diagnosis, patients are all going to be daratumumab exposed at first and second relapse. All BCMA targets are going to come on earlier and earlier in their lines of treatment. Second and third line is where we’re going to use it. Just to put things into context, Natalie mentioned the response rate of belantamab mafodotin as a single agent. If you go back to the CD38 antibodies, single-agent CD38 antibodies had a similar response rate. It falls into that same category as a single-agent monoclonal antibody.
Keith Stewart, MB, ChB: Yes, that’s absolutely true. Tom, where do you think you’re going to use it? We should be clear that right now, it’s got a specific FDA approval. Could you speak to that and then say where you think we’ll go in the future.
Thomas G. Martin, MD: I think it’ll get FDA approval in the triple-class refractory or the data exposed. I will point out, though, in the daratumumab-sensitive people, the single-agent activity was 60%. It wasn’t 30%. It was 60%. In the same patients daratumumab and isatuximab were used and got about a 25%, 30% response rate. This got a 60% response rate. This is a quite active agent. And of the BCMA agents, it’s the only 1 that’s not going to require hospitalization. All the other BCMA agents being tested nowadays will require some form of hospital stay. The off-the-shelf nature to it and the ability of the private practice doctor to give this drug—it’s going to be used a lot. This has a bright future, in my mind.
Keith Stewart, MB, ChB: Yes, you’re right, although I do worry about this corneal issue in terms of whether that will limit its uptake a little, particularly if you have other choices in early relapse. That may be something we have to continue to work on with the company.
Transcript edited for clarity.
