Multiple Myeloma Podcast

Triple-Class Refractory Multiple Myeloma: What Is the Approach? What Are the Challenges?

Joseph Mikhael, MD; Saad Usmani, MD


July 05, 2022

This transcript has been edited for clarity.

Joseph Mikhael, MD: Hello. My name is Dr Joseph Mikhael and welcome to Medscape InDiscussion: Multiple Myeloma. Today we're talking about triple-class refractory multiple myeloma. This is a particularly important topic because for many years, we have had three major classes of agents in myeloma: proteasome inhibitors, immunomodulatory drugs, and CD38 monoclonal antibodies. Despite the great advances of those three different classes, unfortunately, patients will ultimately become refractory to all three. So what do you do in that context? What new treatments do we have available? Or do we just have to recirculate what we've used before? That's really the focus of our discussion today. It's a privilege and an honor to share the microphone with not only a world expert in the field of multiple myeloma, but a very dear friend, Dr Saad Usmani, who is the chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center. Welcome, Saad.

Saad Usmani, MD: Thank you so much, Joe. It's a pleasure to be here with you. I'm looking forward to our conversations on this topic.

Mikhael: I'm looking forward to it as well because I know that you have really been one of the pioneer leaders in a lot of the work that we're going to be discussing today in some of the novel approaches and therapies, including chimeric antigen receptor (CAR) T-cell therapy.

Before we dive right into the topic, let me set the tone with a case. This is the kind of case that I'm sure many of our listeners see on a regular basis, where you have a patient who has gone through four different lines of therapy. They have their induction therapy. In this case, the patient did have autologous stem cell transplant, was on maintenance therapy, and has had three further lines of therapy. Combining monoclonal antibodies and immunomodulatory drugs or proteasome inhibitors. This patient, for example, at one point had daratumumab plus carfilzomib, at another point had elotuzumab plus pomalidomide. So now the patient is truly triple-class refractory and the question is what do we do now. Another doctor asks me, "Well, I know that there are new therapies. I know that selinexor is there. I know that belantamab is there. I've heard that CAR-T is there. I'm not sure I can get it, but how do you decide between those three?" That really is going to be the heart of our discussion today, to walk through those three therapies and get your impression as to how you approach them. When do you choose one over another? Then maybe some pragmatic points that we can share together about how we administer these drugs. In a more generic sense, when that patient is presented in front of you, what kind of algorithm do you use in your head, Saad, to say, "I may go the selinexor path, I may go the belantamab mafodotin path, or I may go the CAR-T path?"

Usmani: You've rightly described a patient scenario that that we get very commonly at tertiary referral centers and even in our practices as patients are doing fine. I think the things that we all pay attention to is the pace with which that relapse is happening. If patients are very symptomatic or they're presenting with high disease burdens, if they have extramedullary disease or even circulating plasma cells, we might favor getting some sort of conventional chemotherapy going first before we think about those subsequent options. But as we're thinking about the next steps in treatment, I always look at what the patient profile is looking like, what kind of side effects they have, what kind of comorbidities they have, because that may help you decide on that next best therapy. We know the safety profile of each of these drugs, selinexor combinations, GI side effects, fatigue, the need to be in an infusion center on a weekly basis to potentially get fluids and supportive care measures. Can our patient handle that? Do they have the social support structure to undergo that kind of treatment? With belantamab mafodotin, if you're thinking about a B-cell maturation antigen (BCMA)–specific treatment, the way that I think about this is, Is my patient able to handle something like cytokine release syndrome (CRS)? Am I concerned that they might be at a higher chance of neurologic neurotoxicity events? If I were to go to the CAR T-cell therapy route for those patients, do I have enough time? It's going to take me 3 months at the very least, even if I register them today to get them that CAR-T infusion. Do they have enough time during this time period to actually wait for CAR-Ts? Do I need to intervene now? And then in in terms of belantamab mafodotin, the orchestration with an eye-care professional, whether patients already have preexisting eye issues, whether they've had corneal transplants or any corneal issues in the past, which would preclude them from getting that kind of treatment. It's a very complex decision-making tree. But it all goes from looking at your patient and patient-related factors, prior therapies, the pace of disease, and then seeing what profile fits best for which patient.

Mikhael: Oh, that's a fantastic answer, as I expected. That kind of rubric is really important. First of all, I like the fact that we have choice. Being a myeloma doctor now for almost 25 years, I remember the days when we didn't have much choice. So having choice is a good thing. One of the things to say from the very start is that these three therapies aren't necessarily exclusionary. Someone may get one and then be able to go to the other or will come back a little bit later to move from one BCMA therapy to another. Let's unpack the three of them a little bit because I really liked how you described that we don't have a cookie-cutter solution for everybody. You have to take into consideration multiple factors and, in particular, the potential toxicities of each. It's amazing that we do have choice, as we said, and these are all very good therapies. We tend to feel that CAR-T likely has the greatest efficacy of the three, although access to it, as you noted, is a challenge. Let's think about selinexor for a couple of moments. This is a drug that's gone through a bit of an evolution. I sometimes say there isn't a drug in myeloma that hasn't gone through an evolution. Almost every drug we use in myeloma, we use it a bit differently now than when it first came out. Bortezomib came out intravenously twice weekly; carfilzomib was twice weekly. Now, for both of those drugs, we pretty much use weekly, at least in my experience. I almost exclusively use selinexor weekly, and often at a slightly lower dose, at 80 mg, maybe 100 mg in some patients. I've really found that to be a tidal shift in being able to use the drug either just with dexamethasone or in combination. But what do you pragmatically do? You intimated a little bit already that you want to make sure, probably for that first month, that they come in every week to get fluids and so on. What do you tell patients in advance? What do you do in that prophylactic setting to prevent some of those gastrointestinal (GI) toxicities that you mentioned?

Usmani: I do prime the patients. Describing the side effects and what to expect to the patients is extremely important, making sure that they understand that they will require antiemetic therapy and a therapy with medications like olanzapine during that first cycle or two — supportive care measures that are going to be extremely important. Creating a calendar for them with exactly what they need to do during those first two cycles of treatments becomes important. I also have a discussion with them about the fact that we will know within the first two or three cycles if this is working or not. So we are going to be keeping a close eye on the myeloma labs. As you know, Joe, I prefer to combine the weekly lower-dose selinexor and dexamethasone with a proteasome inhibitor if I can. I found these data to be compelling. I am actually more impressed with the carfilzomib combination in that later-line treatment than with the bortezomib combination because many of the patients are already coming in with bortezomib resistance and yet, you find them responding to the carfilzomib combinations. Cristina Gasparetto actually had shown these data a couple of years ago.

Mikhael: I agree with you. I have a very similar strategy. I tell every patient that the first month is the worst month. That's when we want to cover, as I call it, head nausea and stomach nausea. There's the classic stomach nausea. Everybody needs a 5-hydroxytriptamine 3 (5-HT3) antagonist. But that head nausea, that's sort of like my teenage daughters on a weekend — feeling of "I don't want to get out of bed." If I describe it in a word, I'd call it "meh." My kids use that word a lot and I found in my multiple myeloma patients that the olanzapine really helps with that and reduces some of that anorexia along with exactly what you've said. They get a check-in once a week. If they're missing more than two meals in a row, we want to hear from them. We really can nurture people through it. I agree with you, carfilzomib is my favorite partner to selinexor. There are times I may have used bortezomib when it was necessary, but I agree with that combination. You're going to know, just like you said, often within the first two cycles, if it's really working or not. Well, let's move on for a minute to belantamab because there's been this tidal shift in the way we do things in myeloma. The very first BCMA-directed therapy is an antibody drug conjugate. What's your strategy with belantamab; how do you think about it and how do you practically administer it?

Usmani: Belantamab came into the market a little bit ahead of time of the Ide-cel/CAR T-cell therapy. But all of us are aware of what was going on from a logistics standpoint in trying to get Ide-cel as a commercial option for our patients. Many centers were just getting one slots or maybe two slots on a monthly basis. BCMA is a very specifically lucrative target in myeloma, more so than CD38. In order to pick that kind of an option for a patient, we need to know that it's going to work. Belantamab mafodotin would work in one out of three patients. That's how I think about this, and if you look at the safety profile outside of the ocular issues, it's really well tolerated. So if I'm picking a patient, I would pick the right patient. You want to make sure that the pace of disease isn't explosive and you're not going to be putting the ocular side effects on top of everything else that is going on with that particular patient. Then, orchestrating from the get-go with an eye specialist and making sure that that piece is worked out, you have to have your preferred partners in the community that you can send patients to right away. So we were able to set all of that up from our clinical trial experience in DREAMM-2 and other DREAMM studies, and we capitalize on that. Doing that would be super important, and here too, you would know within the first two cycles — so within 5 to 6 weeks — if it's working, and if it is working, whether patients are having any eyesight effects or not. So based on that information, if you have a patient who's responding but having no symptoms, you can actually continue to give the drug the way that it's supposed to be given. For patients who are developing eyesight effects, you can back off of the schedule. I've had experiences where, if someone is responding and developing eyesight effects, I've held therapy for up to 12 weeks without losing a response, allowing patients to actually get better from the eyesight effects. Then, you can give it less frequently in lower doses to contain so that they continue to get that benefit. But then if they're not responding and they're having eyesight effects, there's no reason to continue the drug.

Mikhael: I think that's brilliantly put. As we said earlier, every drug goes through its evolution. We're going to probably have an evolution where we use this drug less frequently than the planned every 3 weeks — maybe the first two doses be given every 3 weeks, and then back off. And for clarity for our audience, under the Risk Evaluations and Mitigations Strategies (REMS) program that belantamab is in, every patient must see either an ophthalmologist or an optometrist and have a slit lamp exam and a visual acuity test before each dose. Because this drug has a risk for keratopathy, we think it's probably a function of the toxin that comes with the antibody — the drug conjugate, as it were, somehow leaches out into the cornea. With time, it'll dissipate. But in some people, it seems to accumulate quicker than others, and they cannot have more than grade 1 keratopathy; if they're grade 1, you can continue treating, but if they're grade 2 or higher, the drug has to be held until it's back down to a grade 1. Your experience, Saad, actually is what many of our colleagues have been sharing with us — that this drug works. If patients do respond and if they develop some keratopathy, obviously, by definition of the REMS, we have to hold it. But it's amazing how many people seem to hold their response while we're holding the agent. In patient selection, one of the things I now talk to my patients about is how worrisome would some blurriness of vision be. Maybe that younger executive who's driving to work every day, for those of us still going to a physical place, it may be different than for someone who is already being driven and may not have as much of an issue. That brings us to our third and final topic, which, as I know, is the one that you want to dive right into, which is CAR T-cell therapy. I mean, no disrespect to the molecules we've talked about already, but we've seen in very heavily relapsed setting that drugs like selinexor and belantamab can give us 25%, 30% maybe — as you said, a 1 in 3 response rate; we're literally tripling that with CAR T-cell therapy both with ide-cel that was approved in 2021, and now with cilta-cel, which was recently approved at the end of February 2022. So maybe, Saad, you can just talk to us a little bit about that sort of response and then a little bit on the toxicities. You already mentioned a little bit about CRS and neurotoxicity. Then after, we can talk a bit more about access. But tell us some of the incredible data about CAR-T cell in general.

Usmani: The concept is quite elegant. It's been around for well over 15 years and it started in pediatric acute lymphocytic leukemia (ALL) and B-cell malignancies, but taking a patient's T cell, teaching it how to identify cancer cells and go after them is a very elegant idea. We have two products which are very effective, but they do require preparation. So it's not that patients can get those CAR T-cell therapies right away. While they're highly effective, my general sense is the number of patients who eventually get to CAR T-cell therapy are going to be lower than what we'd like it to be. The point being, there is room for all these different therapeutic strategies for our patients, and their use is going to be mutually exclusive. CAR T-cell therapies will require a patient undergoing what we call lympho-depleting chemotherapy. So dialing down the patient's immune system and existing T cells and B cells, and then giving this engineered T-cell therapy after having collected it from the patients ahead of time. Manufacturing takes about 4 weeks or so. Once patients get this T-cell therapy, we watch them for side effects. We're looking for low blood counts, which will happen as a function of having received some chemotherapy and the CAR-T cells. As these T cells are super active, the body mimics as if it's been infected. These T cells are pouring out chemicals to galvanize the immune system to go after these cancer cells. So patients may feel as if they're in a state of infection, and that's called cytokine release syndrome. That requires early recognition and management. That's why I watch my patients in this setting. But that gets better very quickly. We have learned to recognize it early. It's very reversible. For the most part, it's grade 1 or 2 CRS that patients get that we manage very effectively. The neurotoxicity side effect also happens because of these T cells becoming active. Patients may have several different things that can happen. Either feeling a bit loopy, having some nerve palsies — all of these things end up being reversible as you recognize these kind of changes early and manage them with steroids. So the first 2 or 3 months are fairly labor intensive. But then, when the number counts start to improve and the symptoms have already been taken care of, patients really start enjoying their quality of life because they're not on any other therapy. That's the idea that I really like about CAR T-cell therapy is that yes, you're putting in this effort on the front end, but then once you've recovered, you enjoy a high response rate. You're not on any therapy. You have a better quality of life. That's what's the most appealing part of CAR T-cell therapy. I'm so sorry about the long answer, Joe, but I wanted to make sure that I covered everything.

Mikhael: No, you covered it brilliantly. That one and done concept cannot be underestimated. I had a patient not long ago come and say to me, "Doc, I love you, but I'm glad I'm not seeing you that much" because he'd been off all therapy for 2 and a half years. He felt the best he'd ever felt with myeloma. He had myeloma for almost 10 years now. He's said, "No chemo brain, I feel well." Before we wrap up, we do have to note that there is a challenge getting CAR-T. Of course, as you mentioned, you have to be in a larger center that can do the pheresis and everything. But also, we've had supply chain issues and lots of challenges accessing this. We really hope it's going to improve now that we have two products on the market, and I know that we're all optimistic about it. But realistically, and as I'm sure you're experiencing this even in New York, there is still quite a waiting line for people to get this therapy. So the last question I have for you is if it's going to take a long time for this patient to get the CAR-T, and they end up getting belantamab, for example, are you comfortable taking someone from belantamab to CAR-T if they're doing BCMA to BCMA?

Usmani: I would be comfortable doing that. I don't see that as a major challenge. Interestingly, we now actually have some groups looking at this as a clinical trial question as well. Can you utilize a BCMA-directed strategy before you take patients to CAR-T? Absolutely, yes.

Mikhael: Great. Well, thanks so much for joining me today, Saad. This has been a great discussion, as I expected. I so much appreciate your expertise, your skill, and your passion for patients. It's very clear and it comes through when we have this conversation. We've talked today about triple-class refractory myeloma. This is something becoming more common in myeloma as we use more of these classes early on; patients are going to become triple-class refractory even in earlier stages. Right now, there are three major approaches: selinexor, which, when we use weekly and in combination, is more tolerable and more effective; belantamab mafodotin, which, despite some of the keratopathy issues, can be very effective — but we have to be very careful in managing the keratopathy; and CAR T-cell therapy, which may well be the most effective therapy. We have a triple-class refractory myeloma, and it does come with short-term challenges and may indeed require a longer time before we can have it more accessible. But we trust that it will be more accessible soon. I really appreciate your time with me today, Saad. This has been very helpful, and I trust that our audience has enjoyed it. Thank you for joining me.


Multiple Myeloma

Selinexor Prescribing Information

Belantamab Mafodotin Prescribing Information

Cytokine Release Syndrome

Trending Clinical Topic: CAR T-cell Therapy

Consensus Recommendations for the Clinical Management of Patients With Multiple Myeloma Treated With Selinexor

Selinexor, Bortezomib and Dexamethasone: An Effective Salvage Regimen for Heavily Pretreated Myeloma Patients

Once Weekly Selinexor, Carfilzomib, and Dexamethasone (XKd) in Carfilzomib Nonrefractory Multiple Myeloma (MM) Patients

Ide-cel Prescribing Information

Belantamab Mafodotin for Relapsed or Refractory Multiple Myeloma (DREAMM-2): A Two-Arm, Randomised, Open-label, Phase 2 Study


Blenrep (Belantamab Mafodotin) REMS

Band Keratopathy

Cilta-cel Prescribing Information

BCMA-Directed CAR T-cell Therapy in Adult Patients With Relapsed and/or Refractory Multiple Myeloma

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