Roundtable Discussion: Targeted Therapies for Relapsed/Refractory Multiple Myeloma

Kenneth Shain, MD, PhD (moderator)

Associate Member, Malignant Hematology Program

Moffitt Cancer Center

Chair, Department of Oncologic Sciences

University of South Florida Morsani College of Medicine

SHAIN: My only comment here is when we look at what he has been through. We probably need a line of therapy before we get belantamab mafodotin [Blenrep] and CAR [chimeric antigen receptor] T-cell therapy approved, because [it’s] only the third line of therapy we were on. I would say there’s still carfilzomib [Kyprolis], pomalidomide [Pomalyst], and dexamethasone left over as another line of therapy. But…an important factor here is the enthusiasm around CAR T because this is something that I would share as well.

SHAIN: What goes into thinking of next line? We think about risk factors; we think about what he has had in the past. Is he eligible for transplant or CAR T? That’s an important question—what does eligibility look like to you? Chances for long-term responses, safety and tolerability of the therapies you’re going to give, preferences, organ function, performance status, access, those kinds of things. Please give me your thoughts on why you would pick CAR T-cell therapy.

AMIN: I chose CAR T…but it’s not easy to get CAR T. He’s going to need something bridging treatment before that. The reason I chose CAR T is because that has the highest overall response rate [ORR] in a true refractory setting, as we know so far. But belantamab, selinexor [Xpovio], or carfilzomib could be bridging treatment. Belantamab and selinexor probably have the same response, around 30% in the refractory setting. Carfilzomib and pomalidomide, like you say, is [also an] option.

But I understand the [situation] is ultimately that the patient will need CAR T because none of those [other] treatments are going to be effective for too long, and that’s why I answered CAR T.

SHAIN: What we [at Moffitt Cancer Center] talk about all the time as a CAR T center is getting the patients here as fast as you can because there are limited slots….The faster we get them lined up and ready for CAR T, by the time there is something ready, it’s time [to get treatment]. I think it’s a great answer. As soon as you think about it, you should send them for that kind of consultation and get them hooked up [for CAR T-cell therapy], if you’re not doing it yourself.

Any other thoughts on things that would go into helping you make a decision one way or the other, like renal impairment? Is that going to influence any decisions on that list? History of eye issues, will that change anything on that list?

CASTANEDA PUGLIANINI: Yes, I completely second what you’re saying about referring the patient early, as soon as you’re thinking about CAR or thinking CAR is in the future for this patient. Yes, the sooner the better, so we can deal with the logistics around the CAR T treatment.

Things that you’re mentioning, like renal insufficiency, are important to consider in what is going to be the next line of therapy. I think this patient still has some options that are a standard of care. But the other thing that we want to transmit to our partners is that a clinical trial is also very important. This patient has already been exposed to a proteasome inhibitor and anti- CD38 antibody, has progressed on those, and has also seen transplant.

A clinical trial, which could include CAR T—there are cohorts in some of the studies ongoing—or bispecifics, that [is something] this patient may be eligible for. Those are the other things that we also need to keep in mind because that’s the only way we are going to keep learning about how we are going to be sequencing things before or after CAR T.

The other thing I think about is extramedullary disease— this patient, with what looks like clonal evolution now, 50% of the marrow involvement with del(17p). Those are things that heavily impact what the next step is for this patient.

SHAIN: Not just immunotherapy clinical trials, but…lots of other therapies…are being developed and need trials and… patients. Patients need them to manage their disease, so always think of that as your first thing.

PARRONDO: I would agree with Dr Castaneda [Puglianini’s] comment. I chose clinical trial. The patient only had 2 lines of treatment, so he doesn’t qualify for Abecma [idecabtagene vicleucel] or Blenrep yet. He’s triple-class refractory, so he would meet criteria for most clinical trials. I don’t like that he has del(17p); that makes me a little anxious, the clonal evolution, so I would try to get him on a B-cell maturation antigen [BCMA] bispecific T-cell engager [BiTE] or a CAR T trial, whichever slot I had open.

MALHOTRA: What would keep me away from using [certain therapies] would be if somebody already had eye issues; that’s quite important in terms of how the eye monitoring [must] be done.

NAHAS: I’ve used it before. You’re talking about a 30% ORR, with 2% [stringent] complete response [CR] rate seen in the DREAMM-2 trial [NCT03525678].¹ The 1 patient I used it in had exactly that, almost no response. I’ve been a little underwhelmed by the regimen in a setting of a new target, which is something that was attractive to a triple-class refractory patient. It is a little bit burdensome with regard to coordination with eye [examinations] and whatnot, as well.

PARRONDO: I’ve used it. I usually start with a 2.5-mg dose. Almost everyone gets keratopathy. When that starts to happen, I lower the dose to 1.92 mg and I give it every 6 weeks. That seems to be better tolerated. In a patient, I combined it with low-dose thalidomide [Thalomid]; she’s been on that combination for a year and it was…remarkable. She had nonsecretory disease with a lot of skeletal lesions. They all went away. I drop the dose almost always and space out the interval.

GREENBERG: I have used it as well…it’s cumbersome because patients have to get eye exams before they start the therapy, then before each dose….Aside from that, my impression of the response data, the responses that I’ve seen in my patients, [is] it’s been limiting.

I think now, with BCMA-directed CAR T-cell therapies, that is probably going to be my way to go, prior to using belantamab mafodotin.

SHAIN: How about anybody who has not been using it? Are there hurdles you see, or are there reasons you haven’t [been using it]?

DANDAMUDI: I tried to use it in a patient who has already had 5 lines of treatment. By the time I got everything set, the patient had COVID-19 and passed away in the hospital, so I could not get it. But I did all the homework of getting the REMS [Risk Evaluation and Mitigation Strategies] program and getting the ophthalmologist to see him. It’s definitely a tedious process.

SHAIN: Yes, it can be, without question….My experience is not too dissimilar to what we’ve heard already. I’ve had some very nice responses and control of disease over time. I think Dr Parrondo hit it on the nose—we [must] think about what the dosing schedule looks like, making it easier for patients both from a toxicity/tolerability and burden perspective, and what is the real need for dosing. Three weeks [was the initial design, and there are many] studies going on trying to figure out how we can spread that out….Missed doses in between don’t impact the long-term control. That 6 weeks makes life a lot easier for patients; it gets them to eye doctors less frequently, adverse events [AEs] tend to be a little better. It is something we have to keep an eye on.

PARRONDO: Have you combined it with anything?

SHAIN: I have not done it with anything else, and generally I’ve been holding it for [patients] who are a little later in disease state than it was approved for. Most of the belantamab mafodotin I’ve recommended is to my colleagues in the community because we have trials here, and I think it’s a little easier for patients that way, so they’re not traveling back and forth. I haven’t tried to push hard.

There are…nice combination data we’ll be learning more about. Pomalidomide [plus carfilzomib] is one of the combinations, as well as other agents we have going on….There’s going to be a move toward how to better blend [belantamab] with our current therapies, without question.

MALHOTRA: I’ve used it in 1 patient. He had relapsed [multiple times] and was not a candidate for transplant. CAR T was not an option until a while ago. Diarrhea was the main challenge, and then fatigue. He seemed to get benefit for maybe 3 months [with selinexor/dexamethasone]; it was not a dramatic response, and he subsequently passed on.

GREENBERG: Right now, I don’t use the doublet—I use the triplet with bortezomib, selinexor, and dexamethasone, which I find is much better tolerated using selinexor once rather than twice weekly, and the bortezomib once weekly. I’ve seen, [in] my limited experience, longer responses with the triplet than with the doublet, and less gastrointestinal toxicity.

SHAIN: That’s a very good point. To add onto that, we did a lot with selinexor…as a single agent, then going to doublet. I think triplets, and the correct lower dosing [or] weekly dosing, is the only way we’re going to keep patients on it long term without too much toxicity.

NAKKA: I have 2 patients on selinexor. The most significant [AE] in both…was fatigue, just not able to get out and do what they wanted to do. They’re still continuing [but] it’s a whole lot of fatigue.

SHAIN: Have you dropped the dose significantly for them?

NAKKA: No, and [I give it] once a week.

SHAIN: Sometimes lower doses make [patients] feel a lot better. Nausea, vomiting, fatigue, diarrhea—those are things you have to battle. Cytopenias seem to get a little better after the first cycle….It’s something we all [must] think about, but using it in triplet seemed in my experience as well to give us a much better feel for our ability to drop the dose a bit, and you still maintain that activity.

AMIN: I used [the regimen] in a patient but it was late, based on the STOMP data with the selinexor and carfilzomib [NCT02343042]. But it was late-stage disease and the patient progressed through multiple lines. I didn’t get much response. I have used the regimen in the BOSTON trial [NCT03110562], and the patient had CR in that time.

I’m using it more and in an earlier line as a combination with bortezomib or, if the insurance allows it, I try to use it with pomalidomide or carfilzomib.

PARRONDO: I usually give Zyprexa [olanzapine] when I give [selinexor], and that helps with the nausea.

SHAIN: That’s what I do as a rule….Zyprexa [or] Zofran [ondansetron] at home, make sure they have lots of Imodium [loperamide], and call us with other things they need for the other side. Nausea has always been my biggest concern with this. The lower doses make it a little easier; usually you can tweak it to find the right place.

AMIN: That’s very interesting, because when I had a patient back…when the BOSTON trial started. The patient did not have any [AEs]. The patient was on an antipsychotic drug for psychiatric reasons. I don’t know if that prevented nausea or did not.

PARRONDO: At Mayo Clinic [in Jacksonville, Florida], we’re pretty good about getting them to see the ophthalmologist. [The ophthalmologist] basically writes a note with an eye exam; they don’t even really grade it. I have to read their note and determine the grade. That information is helpful so I can put it into REMS so they can release the note. The REMS booklet [for belantamab] is helpful.² It has a table that tells you exactly what to do. With grade 1, you keep going at the same dose and interval. With grade 2, you’re supposed to hold it until the keratopathy resolves to grade 1. Anything above grade 3 or grade 4, you’re supposed to hold and reduce the dose when you restart.

SHAIN: We have someone who is local. At the University of South Florida [Morsani College of Medicine]…we see [the patient] and we email back and forth; it’s an easy communication. It’s been great. That’s something that’s been set up, so I would be curious about how it’s worked in the community and what are the obstacles? How has it worked out for those who’ve used this?

MALHOTRA: One of my local ophthalmologists…called me and said he had seen some cases—one of my colleague’s patients—and he said he’s gotten up to speed on it. He said if I had any patients, he was happy to get them in right away and take care of them, and…monitor. I felt encouraged; that’s a big hurdle for us, so I do have in my community an ophthalmologist who’s willing and keen to do it, and so I’m more encouraged to use it.

AMIN: For one of my first cases, I had to talk with [the ophthalmologist] a while to explain to him the grading system. Eventually, in subsequent cases, it was helpful. I’ve been using him for a while now, and I have a trial also, so it was protocol-driven; a lot of education was given to him in terms of the grading system. But I still have a talk with [him about] every case after his report, because there is some confusion about how he grades and what he sees. It’s not clear yet, but I’m sure as the time goes [on] we’ll get there.

SHAIN: In theory, GlaxoSmithKline is able to help find those individuals in the community for you and help try to educate them to help the communication process. That is something to think about, if you haven’t done so. [If] you’re thinking about using belantamab, there is help, so your representative should be able to help you from that perspective.

How resistant have your patients been to this additional step? My biggest hurdle is patients [being resistant to going to an ophthalmologist or optometrist], more than anything else. If I give someone 2 options, they’re almost unanimously going to take an option that doesn’t involve seeing another physician. How have you dealt with that, or are your patients [ready to do it]?

DANDAMUDI: Especially because this is after 4 lines of treatment, if the patient performance status is good, usually they agree to see the ophthalmologist and follow up regularly….At the same time, if the performance status is going down, that is a difficult situation. They don’t want to travel from one clinic to another. That’s a big problem in the community setting.

SHAIN: I’ve been surprised by the steadfastness of the patients. I consider myself pretty good at trying to sell a regimen, so it’s interesting. Maybe it’s just the last couple, but it stuck in me.

GREENBERG: I think now, with the availability of CAR T-cell therapies, belantamab is probably going to be pushed back…further, maybe 1 or 2 lines after getting CAR T-cell therapy. I think there are multiple options until that point.

NAHAS: There are clever ways to use these agents, and maybe even in combination with other drugs. But I agree that with some of these other BCMAs, which objectively have…good ORRs and CR rates, I probably would go after those for a regimen as opposed to this antibody-drug conjugate. But I don’t know; it’s hard to say, especially with CAR.

With CAR Ts, the waiting time and the slot time are very difficult, but…it will be interesting to see what happens to something like belantamab in the setting of BiTEs, which [are hopefully] going to have a nice ORR, nice numbers, in the setting of being essentially an off-the-shelf agent for us.

SHAIN: Absolutely. That’s a truly exciting group of agents there.

MALHOTRA: In patients who are multiply relapsed/refractory, and the fact that these are non–cross-resistant, usually, to the other drugs we use, they are very useful additions. I think this discussion helps me lower my barriers to [using belantamab]—hearing other [doctors’ experiences], getting your insights into it. I’ll be more open to using it in the right patient.

SHAIN: [When] we have these agents, you’re going to find a patient for everything. Every patient’s going to need everything you can think of, is my way of looking at it. How you are going to sequence those drugs, where you are going to use them, and how you are going to introduce them are really the critical part. Learning about them is the first step in how you get your patients the right drugs at the right time.

DANDAMUDI: One thing that I learned is those patients who respond [to belantamab] may respond for a long time, so that’s the key. We can encourage the patient to use that, and after 1 or 2 cycles, if he doesn’t respond we can move on. But those [individuals] who respond, we can intermittently dose the patient.

CASTANEDA: We are seeing, or we are even recommending in some patients to use belantamab as a bridge to CAR even though there is no patient with prior BCMA therapy on…the ciltacabtagene autoleucel trials. But it’s not a contraindication, if that’s the only thing that the patient may have for bridging. That’s also something that you should keep in mind in case you are thinking about what else [to use] to bridge this patient to CAR….That’s still a reasonable option.

The word out on the street is that patients are still responding. We are going to narrow this with real-world data that will be coming out from those experiences, and for what we are doing.

_REFERENCES

_{1. Lonial S, Lee HC, Badros A, et al. Belantamab mafodotin for relapsed or refractory multiple myeloma (DREAMM-2): a two-arm, randomised, open-label, phase 2 study. Lancet Oncol. 2020;21(2):207-221. doi:10.1016/S1470-2045(19)30788-0}

_{2. Risk Evaluation and Mitigation Strategy (REMS) document; Blenrep (belantamab mafodotin) REMS program. FDA. Accessed January 25, 2022. https://bit.ly/3GWBpFD}