Role of BCMA-Targeted Agents in Myeloma


Experts in multiple myeloma review the use of belantamab mafodotin as described in the DREAMM-2 trial and discuss the management of the associated ototoxicity.

Keith Stewart, MD, ChB, MBA: We’re going to talk about probably the most exciting area in myeloma research, which is targeting the cell surface molecule, the B-cell maturation antigen, or BCMA, as we will refer to it. I want to start with the first BCMA-targeted agent to get FDA approval, which is belantamab mafodotin, or BLMF, as we’re commonly calling it. We’re turning to Dr Lonial, because he was involved with the DREAMM-2 study, which resulted in the approval of the drug. Sagar, tell us a little about the study and what you learned.

Sagar Lonial, MD, FACP: Thanks, Keith. This was a relapsed/refractory myeloma trial that assigned randomized patients between 2 different doses of BLMF: the recommended phase 2 dose of 3.4 mg/kg or the FDA’s suggestion of 2.5 mg/kg. What was identified from that randomized phase 2 study was that from intermediate and 6 prior lines of therapy, the response rates were similar between the 2 doses, but the toxicity, particularly heme toxicity, was slightly lower with the lower, 2.5-mg/kg, FDA-recommended dose. That led to the FDA approval of BLMF in patients with 4 or more prior lines of therapy. We know, from an objective data perspective, that the response rate was around 30%, the median PFS [progression-free survival] was about 3 months, which is consistent with pomalidomide, daratumumab [Darzalex], carfilzomib [Kyprolis], and bortezomib in that same population with refractory myeloma. But we also know that the median duration of response [DOR], meaning the time a patient could respond or stay on therapy because they were tolerating treatment well is about 11 months. That duration of response is as long as daratumumab, and there are few other drugs that had a DOR that was that long in the refractory myeloma setting. It was an encouraging trial that led to FDA approval of BLMF. It did, in fact, give us the first FDA-approved, BCMA-targeted drug in myeloma.

Keith Stewart, MD, ChB, MBA: Thank you. when the FDA approved the drug, it came with a black box warning, so I filed a call right away. Joe, you want to tell us about that?

Joseph Mikhael, MD: Yeah. Sagar has described the drug, of course, very well and it’s very effective. But a little over two-thirds of patients will develop what we call a keratopathy on the cornea, so the full mechanism is still to be elucidated. We think it has to do with the conjugate that is part of the drug, it has the BCMA [B-cell maturation antigen] antibody and the toxin that is dropped in and becomes incorporated into the cell. What needs to be done at baseline before their first dose, and indeed before each dose— and the doses are scheduled every 3 weeks— a patient must see either an ophthalmologist, or an optometrist, an eye specialist, to do 2 things: to check their visual acuity by doing the Slit Lamp Exam to look for evidence of keratopathy, and if the patient has grade 1 keratopathy or below, we can proceed. But if that keratopathy gets worse, then there has to be a delay in the treatment. It's a bit of a logistical challenge, although feasible and doable, and, as Sagar mentioned, in those patients that responded to treatment and actually were sick, a significant fraction of patients had to delay doses because of keratopathy but were still able to continue therapy. But pragmatically, a quarter of patients have significant changes in their visual acuity and have blurred vision, so it is an adverse effect and factor that we think of when we're evaluating who's the best candidate for it. My last comment, Keith, is that, with time, like we've been saying throughout this session, we're getting more and more familiar using these agents and we optimize them with time. I personally, without going out too far on a limb, think that the dosing of this drug may be more effective less frequently, and potentially will have less keratopathy. But obviously, we must do the studies to show that.

Keith Stewart, MD, ChB, MBA: I know that the company GlaxoSmithKline plc [GSK] is exploring longer dose intervals and some changes. Cristina, are you using belantomab [Blenrep] yet in your practice?

Cristina Gasparetto, MD: Yeah, I do. I agree with everything that has been said. That, I think is an effective drug. I like the fact that it doesn't have the dexamethasone [Ozurdex], so that could be a selling point for some patients. Of course, we have a phenomenal relationship with our ophthalmologists, and optometry, so the patients are seen before each infusion. I don't feel comfortable, and I will not feel comfortable making that decision without the ophthalmology exam. I like the fact that the majority of patients, even if they miss a few doses, they maintain the response, and that was very interesting. So continuing treatment less often in the future, I think, is going to be the key to mitigating the toxicity. We have some clinical trials, I think, that are ongoing and exploring different scheduling.

Sagar Lonial, MD, FACP: Keith, one point that I'll briefly make to add onto what's been said is that the dose holding, and dose modification was built into the trial design, and unlike other drugs, where missing a dose or getting off schedule often results in loss of response with BLMF [Belantamab mafodotin]—because the half-life is so long—, most patients actually improved, or stabilized, their response during those delays, as opposed to losing their response. So, it's OK to skip doses if you need to.

Keith Stewart, MD, ChB, MBA: Nina, what’s your experience with this drug? And have you been using any prophylactic measures to try and prevent the eye toxicity?

Nina Shah, MD: Well, there's not much to do except for continue rewetting drops, which you actually can get through as a parallel program with a company. I agree with the others, that BLMF has been useful as an off-the-shelf, immediately available drug, if your center has it, for patients who have exhausted all other options, and it is effective. Again, you have to make sure that you follow the REMS program, and they make it easy, on the website, to follow that. It's not that hard. I have found the eye care professionals to be very, very helpful. They always are interested, they do the exam, and I have good communication with them. So that hasn't been the issue. I think we need to learn how to use this drug, just like we're learning how to use cell annex or how we learn how to use all these drugs, to understand the best dosing frequency and to get the most for our money out of it.

Keith Stewart, MD, ChB, MBA: Do you think this will be a standalone drug, which is kind of attractive, with a dose of once every 6 weeks or so? Or do you think this will be a combination drug?

Nina Shah, MD: I think it could be a standalone drug. The reason I hesitate to say it's definitely going to be a combination, is that there are so many other drugs that can be combined already, and by the time you start using this drug, you may have already used the other combination drugs. So, there's nothing particular about this mechanism of action, which I understand, that preclinically should make it work better with another drug. So, I’m not quite ready to say that it would be better in combination. I think it works pretty well in a late line if you're willing to work with eye care professionals to mitigate risk.

Sagar Lonial, MD, FACP: Keith, if I may jump in to say one more thing here, I think we're seeing a pattern in these drugs. If you prove to yourself that you could do it by yourself, that you have single agent activity, and prove that you can partner with everyone else, as we've seen with the C 38 antibodies, and with so many others. So, I agree. I hear what you're saying, Nina, on one hand. But on the other hand, now that relapsed myeloma has become like the Cheesecake Factory menu, you're right. It's ridiculous. We have so many choices. It’s nice to know that we can combine, and there are going to be patients that still, for whatever reason, haven't been exposed to it, or are resistant to pomalidomide [Sarclisa], or to one of these other agents, or now with iberdomide coming, as Sagar explained, I think it'll be nice to know that we can partner belantamab [Blenrep] with these agents and, frankly, every other combination. That's why our lists are becoming so long, but I think that is important because leveraging different mechanisms of action together, especially earlier in the disease course, will be a really important key.

Nina Shah, MD: Yeah. To answer that, the Algonquin data from this past year, which looked at belantamab, pomalidomide, and dexamethasone, had a PFS [progression-free survival] of 4-months. That's just like their bombax. I think there are ways to get the most out of it, and I'm interested to see what kind of treatment will be used– it's like a little race. What agent is going to be combined with what, sooner and earlier in the lines of therapy?

Keith Stewart, MD, ChB, MBA: I'm going to do rapid fires for Sagar. I have 3 of them. Answer 'yes', or 'no', Sagar. Do steroid eye drops prevent ocular toxicity?

Sagar Lonial, MD, FACP: Sorry. No.

Keith Stewart, MD, ChB, MBA: That was easy. And why do you say that?

Sagar Lonial, MD, FACP: In the randomized DREAMM-2 trials, half of the patients got it, and half of the patients didn't. There wasn’t a difference.

Keith Stewart, MD, ChB, MBA: Should we say it in the first line of therapy and first relapse, if you've received quad therapy and a transplant before?

Sagar Lonial, MD, FACP: I think it's looking like BCMA is going to move earlier and earlier in the lines of therapy. And whether it's first relapse, or even incorporation into a high perceived ad-like regimen for induction, I don't know, but it's going to be early.

Keith Stewart, MD, ChB, MBA: Just so nobody runs off against highly perceived ads, you said high perceived ads are like, but nothing like it really in terms of…

Sagar Lonial, MD, FACP: No, just alternating agents. That's what I meant.

Keith Stewart, MD, ChB, MBA: You had everybody getting scared there for a second. What about measuring BCMA? Is it necessary? Do you need to know if it's on the cell surface?

Sagar Lonial, MD, FACP: I don't think it's necessary if it's the first time a patient is seeing it. But now that we're giving multiple BCMA targeted agents one after another, and we’ve seen data that patients with 17p deletion may acquire loss of BCMA as a relapse mechanism, we're starting to test patients if we're going to give them a second BCMA-targeted agent.

Keith Stewart, MD, ChB, MBA: That sounds very sad. Do you do that by flow cytometry? Because that might not be available in many laboratories, I wouldn't have thought.

Sagar Lonial, MD, FACP: We were doing it by IHC [immunohistochemistry]. There is a send-out laboratory that's doing IHC for BCMA flow. At least in our place, the Winship Cancer Institute, it hasn’t been validated yet.

Transcript Edited for Clarity

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