Introduction

DR LOVE: Good afternoon, everyone. I'm Neil Love from Research To Practice and welcome to “Cases from the Community,” as today our clinical investigator faculty will discuss the management of relapsed/refractory multiple myeloma and we're also going to talk a little bit about or a lot actually about what happened at the ASH meeting as it relates to relapsed myeloma. We have a great faculty today, Dr Sagar Lonial from the Winship Cancer Institute in Emory University School of Medicine in Atlanta, Georgia and Dr María-Victoria Mateos, the director of the myeloma program at the University Hospital of Salamanca in Salamanca, Spain.

Today, we're going to talk about relapsed/refractory myeloma and particularly what happened at ASH. As in all of our programs, we will be discussing the use of unapproved agents or regimens. So please consult the prescribing information for each product for more. As we do with many of our programs, we have a bunch of general medical oncologists in community-based practice who are going to be presenting cases here today in addition to talking about what happened at ASH.

Sagar is going to do a presentation focusing on a bunch of papers, many of which relate to belantamab mafodotin, just recently approved after a long saga, as everybody's very familiar with. And then María-Victoria is going to present a bunch of other papers on CAR T and bispecifics.

Here's our agenda. We're going to start out chatting about what Sagar calls the belle of the ball in terms of myeloma at ASH. There were 2 late-breaking papers, one by MariVí that we're going to talk about. Then we'll get into cases and each one of our faculty also has a presentation reviewing some of the key presentations at ASCO.

Best of ASH Multiple Myeloma

DR LOVE: But I want to begin with these 2 papers. This really is kind of mind blowing, Sagar, what they actually have done here. It's amazing new therapy. I personally had never heard about it until I saw this paper come out. Can you talk a little bit about what was seen here in terms of, I guess, sort of an off-the-shelf CAR T like strategy? It seems like that's what it is, but maybe you could explain what this is, Sagar.

DR LONIAL: Yeah, thank you very much. And again, appreciate the opportunity to be here with you and with MariVí. So this really, to me, is likely a direction that many diseases are going to head in. We know that one of the challenges with CAR T-cell therapy is the ex-vivo manufacturing, the delay between the collection of the CAR and the actual delivery of the CAR, and what happens to the patient and their disease during that interval.

And so what this trial really attempted to do was look at in-vivo creation of CARs. And so rather than giving the cells after they've been manipulated and grown outside and then giving them back, this was actually giving viral particles back to the patient that targets T cells using the CD3 receptor. And then it's a nonreplicating virus that basically causes those T-cells that it binds to to upregulate the CAR receptor and generate that CAR in the patient. So there's no need for lymphodepletion chemotherapy. There's no need for the delay or ex-vivo manufacturing. It's one-stop shopping. They get the infusion of the viral particles and about 2 weeks later, you start to see CARs beginning to form and develop in the patient.

And I think what's really quite exciting was that in the first 4 patients, all 4 patients achieved an MRD-negative CR as early as 1 month, so not dissimilar from the speed of response that we'll often see with an ex- vivo CAR. And, in fact, the responses were quite brisk. The free light chain, the M-spike and the soluble BCMA levels all dropped relatively quickly, and it was associated with a relatively minimal side effect. There were a few patients that may have had infusion reactions or low-grade CRS. There was a little bit of anemia associated with it.

But other than that, there was really no neurologic toxicity, no ICANS, nothing else. And again, you saw in the first 4 patients, very brisk disease responses. So very exciting concept and execution.

DR LOVE: So, MariVí, any thoughts about this and any predictions in terms of timetable, in terms of how long it's going to take to get this into the clinic?

DR MATEOS: Well, I think that this is amazing because, well, I think that Sagar clearly exposed the main problems with the conventional autologous CAR T. There has been another situation in between the allogeneic CAR T-cell therapy, but the allogeneic CAR T, it seems that they are not being expanded as we expected. And I think that the in-vivo CAR T is going to be something that we will see more and more in the near future. This is the first evidence we have, and with only 4 patients, it was accepted as late-breaking abstract session at ASH. So this means that in the upcoming years, and we know that other companies are developing this strategy that will allow maybe to receive CAR Ts to more patients because basically this strategy avoids the main issues we have with the autologous CAR Ts.

DR LOVE: So, MariVí, the other paper was one that you presented, Phase III study, teclistamab and daratumumab. Sounds like a great idea in terms of combination. What did you see there?

DR MATEOS: Well, this is a Phase III clinical study in which we combined teclistamab plus daratumumab and compared this combination with 2 standard of care, daratumumab plus pomalidomide and dexamethasone or daratumumab in combination with bortezomib and dexamethasone. And the patients were relapsed/refractory after 1 to 3 prior lines of therapy. All patients were exposed to PI, 80% of the patients were refractory to lenalidomide and approximately 5% of the patients were previously exposed to anti-CD38 monoclonal antibodies.

And the progression-free survival was the primary endpoint. It is maybe one, if not the best, PFS curve we've seen for patients with multiple myeloma, with a hazard ratio of 0.17, unlike a plateau phase from month 6, with 83.4% of the patients alive and progression free at 3 years. But there is also benefit in terms of overall survival with a hazard ratio of 0.46.

Curves closed because some patients early died because of infections in the tec data, but this was mitigated with adequate prophylaxis. And you can see also like there is a plateau phase in the overall survival. So this can represent a potential new standard of care for relapsed/refractory myeloma patients after 1 prior line of therapy.

DR LOVE: So, Sagar, any comments about this? Is the idea that you would just add on daratumumab when you're going to use teclistamab, or do you think that maybe looking at this combination, it'll end up getting used earlier?

DR LONIAL: Yeah, I mean, I think this is really just spectacular data. I think, congratulations to MariVí and her team for not just the abstract, but also the paper in The New England Journal. I think this is really, really exciting data. I think it is going to get brought earlier and earlier. This was probably, I think, between 2 and 3 prior lines of therapy. I suspect that this is going to be one of the decision trees that patients make in the context of first or second relapse.

Is it going to be something like a CAR? Is it going to be something like this? Or is it going to be something like another BCMA-directed approach such as belamaf? I think those are the patients, those are the questions that patients and physicians are going to be dealing with in the coming 2 years.

Case: A man in his late 50s with t(11;14) IgA kappa myeloma discovered during workup for new Stage IV kidney disease who has a chest wall plasmacytoma receives daratumumab with CyBorD and radiation therapy to the plasmacytoma with minimal response — Jeremy Lorber, MD

DR LOVE: So, we're going to go back and forth today between ASH presentations as well as cases from the community. Sagar, in a second, you're going to get into a talk that's going to include a discussion of a paper looking at venetoclax. So I want to just get warmed up for that.

I want you to hear about this 59-year-old man, t(11;14) IgA kappa myeloma, a patient of Dr Lorber, who this was discovered during a workup for Stage IV kidney disease. He had a chest wall plasmacytoma, got daratumumab and CyBorD and radiation therapy to the plasmacytoma with minimal response. You'll hear about the case. And Dr Brenner, who also has a patient on the venetoclax combination, has some questions. But we'll start out with Dr Lorber.

DR LORBER: He was switched in second line to venetoclax/daratumumab/bortezomib/dexamethasone and then followed by venetoclax/daratumumab. He had a pretty rapid response and has continued on this regimen for about 3 years now. He had a bone marrow biopsy and showed MRD negativity. Would it be reasonable to stop therapy in this case and just monitor? Assuming he doesn't stop therapy and continues venetoclax, is this something you would continue in future lines of therapy for myeloma, or is it 1 line and then done?

DR LOVE: I have a question. I want to know whether they've seen a case like this? This is incredible.

DR LORBER: Yeah, I mean, I expected he may respond when I switched him to venetoclax, but I didn't expect such a radical benefit given that he didn't respond to first-line daratumumab based regimen.

DR BRENNER: In patients who have 11;14 translocation, should venetoclax be used at first relapse versus later relapse? Are there are other myeloma patients, besides those patients who have 11;14 translocations, who may respond to venetoclax? Are there other tests available besides the 11;14 translocation to determine who may respond to venetoclax? Can venetoclax be combined with other agents besides bortezomib? Do patients receiving venetoclax require ramp-up dosing like we do in CLL? Do investigators ever use twice-weekly bortezomib dosing anymore?

DR LOVE: So we call Dr Brenner our question person. It's like a cognitive test to see if you can remember all the questions he has. But let's start out with you, MariVí. What about this issue, before we get into using it today with 11;14, of going beyond 11;14. I think there's a Bcl-2 assay that's been looked at. Do you think there are other patients besides with t(11;14) who might benefit from venetoclax, and how do we identify that?

DR MATEOS: I don't think so. I think that in principle, patients with 11;14 or maybe overexpression of Bcl-2 are the right patients that can benefit from venetoclax-based combinations. Based on the previous studies like the BELLINI, in which allcomers were included and we observed how the great benefit was observed within patients with 11;14 and/or Bcl-2 overexpression, I would say that I will restrict today the use of venetoclax-based combination for this population. And I will go, of course, beyond venetoclax, bortezomib and dexamethasone.

The combination with the anti-CD38 monoclonal antibody is quite good, as it was exposed by this patient. And we know that patients with 11;14 translocation present specifically, specific biological characteristics. Sometimes these patients take more time to reach MRD-negative but the survival is excellent. And I think that I will restrict the use of these combinations for patients with 11;14.

DR LOVE: So, Sagar, where specifically are you using venetoclax combination? Which combination do you use? And how often do you see responses like this? I think this patient's been on it for a couple years now.

DR LONIAL: Yeah. I think for us, what we've learned is that the earlier you give ven, the more likely you are to get a long-lasting response. Because when you get into later lines of therapy, you acquire new genetic abnormalities, and that can sometimes mitigate the efficacy or reduce the Bcl-2 dependence in that context. So, I typically will use it in first relapse, and I'll combine it with dara, I think, as MariVí suggested. So ven/dara/dex, I think, has from small Phase II studies has a median PFS of almost 36 months. So really, really quite good data.

One other point I'd make with relation to this case is, we've seen these kinds of responses in first relapse with venetoclax. I've seen those kinds of responses even in some patients with fifth relapse, depending upon what they've been treated with. But one point that's really important is that the Bcl-2 dependent or the 11;14 patients are incredibly sensitive to high-dose melphalan. And so, these are patients, actually, that I strongly recommend consolidation with high-dose therapy and autotransplant because many of them will never need therapy again. I think in this case, I probably wouldn't keep all the drugs going. I think that was one of his questions. I'd probably try and get it down to ven and dara, maybe, and that's enough. But certainly, the idea of stopping therapy right now, I just don't know that that's a good plan with this class of drugs.

DR LOVE: So, in a second, Sagar is going to go through a presentation. He's going to talk about a number of papers with belamaf. Just to remind everybody, this was finally approved in October. Before you begin, though, MariVí, we got a question from the chat room about the tec/dara paper trial, which is, what about patients with prior anti-CD38, either exposed or progressed on CD38? Were they included in the trial? Would you use this doublet in that situation?

DR MATEOS: Yeah. In the clinical trial, it was allowed to be sensitive to daratumumab or anti-CD38 monoclonal antibody, but being refractory to anti-CD38 was not allowed. Five percent of the patients included in the trial were previously exposed to anti-CD38, and the hazard ratio was the same, 0.17. This means that in patients previously exposed but not refractory, this combination can be used without any problem.

However, if the patient is refractory to daratumumab, this population was not included in the trial, and in principle, maybe it will be better to switch to another different compound and to consider the retreatment with anti-CD38 monoclonal antibody, maybe in the subsequent line of therapy, but not immediately one after the other.

DR LOVE: So, before you get started, a quick case from the chat room, Sagar, from Vaishali, 55-year-old, 11;14 translocated, treated with VRD and transplant, now on rev maintenance, 1 year into it, doing well. The question is, if the patient progresses, do you use ven-based therapy or tec/dara?

DR LONIAL: Yeah, I mean, I would probably do ven/dara in that patient, only because, again, the longer you wait, the less likely benefit you are to get from ven. Doesn't mean you're closing the door on teclistamab, which can be used later on. But the advantage 11;14 patients have is they have one more weapon to treat their disease, and I'd like to use that a little earlier if I can, but MariVí may disagree with me.

DR MATEOS: No, no, no, I don't disagree. The problem is to discuss with the patient the role of venetoclax because it is not approved, and if the patient is well-informed, they can ask you about BELLINI or CANOVA study, and if they see tec/dara, maybe the patient will prefer to go to the novel combinations, but I agree with you. This is a targeted therapy, and it can be very effective.

DR LOVE: It's great to have options.

Antibody-Drug Conjugates and Other Emerging Novel Therapies for Relapsed/Refractory (R/R) Multiple Myeloma (MM) — Dr Lonial

DR LOVE: Alright, Sagar, let's take a look at some of these data.

DR LONIAL: Alright, thank you. So I'm going to spend the next few moments talking about some data around antibody-drug conjugates as well as some other compounds in the context of the data that was presented at ASH. So the first few abstracts are really focusing on belamaf, and so we're going to talk about long-term responders from the DREAMM-7 study of bela/bortezomib/dex versus dara/bortezomib/dex. And really what I want, when they were trying to identify who those long-term responders are, one of the keys are that they were earlier lines of therapy, so tended to be first or second relapse, and they quickly achieved a very deep response.

So if you look at patients who were in the bela arm, for instance, almost 90% of them achieved a VGPR or better, compared to a much lower percentage in the non-long-term responders that you'll see on the right side of this graph. If you then again begin to look at MRD negativity, the really long-term responders had a much higher incidence of MRD negativity, over 70% compared to only 60% in the group that were not long-term responders.

So I think the keys here are earlier lines of therapy, achieving a deep response relatively earlier and achieving MRD negativity. And that translated in to a better long-term outcome with bela-based combinations overall.

Interestingly enough, the safety issues were no different between the long-term responders and the other patients, so it wasn't as though you were getting more side effects if you achieved that deep response. That was, in fact, not the case. So I think that that's an important take-home message that if you're going to use bela, try and push for that very early deep response overall.

The next one was looking at pomalidomide in combination with bela versus PVd, again, the DREAMM-8 study. And again, what I think you see is the MRD negativity rates are significantly higher with the pom combination. If you ask me, my personal preference, just from a preclinical perspective, I like the pom combination better. I think it synergizes nicely with an antibody, and unlike other antibody-drug conjugates, bela does, in fact, fix complement, so it does work through ADCC and ADCP, similar to other unconjugated antibodies, so you get multiple mechanisms of synergy when you combine bela with pomalidomide and dexamethasone.

And this translated into an almost 36-month median progression-free survival and an improvement almost 20 months over PVd in terms of the clinical benefit that you saw with progression-free survival.

And so, again, similar conclusions to what we've already talked about so far. So one question that comes up and one fear that I think both patients and docs have is about the impact of changes in visual acuity or ocular side effects on quality of life. And one point that always gets brought up to me is this is an older patient population, impacting their vision can be pretty significantly debilitating. What did it really do with quality of life? And just to give you a snapshot on health-related quality of life, it actually was not any worse than DVd.

And I think that is an important take-home message. That much of what we're describing, and I'm going to get to that in the next abstract, in terms of ocular adverse events, while it may look like Grade 2 or Grade 3 in terms of the objective measurements, many patients did not have significant reduction in their visual acuity. And so, their quality of life was actually quite good. This is comparing head-to-head with dara/bortezomib/dex. This is looking at delayed onset in deterioration of physical functioning, so it wasn't until well after potentially long-term that you began to see that. So you had improvement in physical functioning while you were on bela/bortezomib/dex.

And so, I think one question that comes up over and over again is, what about the quality of life for patients? Well, these directed instruments showed no negative impact on quality of life. And if they were, they were transient only in people that had visual acuity that got worse than 20/50 and once it recovered better than 20/50, that quality of life came back up again. So I think then the question is, what percentage of people developed that significant impact on quality of life? And that's really what I showed in this poster as well that was presented at ASH this year, where we're looking at reversibility and the true impact of changes in visual acuity.

And so, remember that when we're using the KVA scale to grade changes in vision, it's made up of 2 parts. The first part is the corneal eye exam, which is a physical exam finding that an ophthalmologist does, and then the second part is a Snellen eye chart for best corrected visual acuity. And when you're grading changes in vision, you pick the worst of the 2. You don't pick the best. You pick the worst, and you only pick 1 unilateral vision. You don't pick bilateral or binocular vision. And what our ophthalmology colleagues have told us is that it's not uncommon to have Grade 2 on the exam findings but have 20/30 or 20/20 vision, that that can still happen.

And at the same time, if you look at impact on unilateral vision changes, you can see that unilateral 69% of patients may have changes in visual acuity, but when you look at binocular vision, only 34% do. So, in many ways, all the metrics of assessment are inflated to look at the worst possible outcomes, not necessarily what we know that the eyes can overcome, which is through both eyes, you actually see better than you do through one. And so I think that that, to me, is very reassuring. I provide that reassurance to patients.

And at the same time, ocular events were reversible in nearly all patients. The only ones where it was not found to be reversible were patients that were lost to follow-up when they had progression off the study. So that, to me, again, is a nice thing to be able to let patients know that they can do well with.

Now, we know that belamaf is an important drug, and it's being brought into earlier lines of therapy. This was an abstract from Dr Usmani and his colleagues at MD Anderson or at Memorial, where they were combining belamaf with RVd and are planning to go head-to-head, bela/RVd versus dara/RVd, so quad versus quad, to see what happens. And what really struck me was 100% overall response rate, regardless of the dose and schedule that were used, that a significant fraction of patients achieved MRD negativity with this combination.

And just like we saw bela was better partnered with bortezomib/dex compared to dara/bortezomib/dex, this will be tested now in an ongoing Phase III trial to see whether depth of response and potentially progression-free survival will be better. And the ocular findings with spreading out the doses were no worse than what you would expect for this combination. So there isn't synergistic toxicity by combining with an IMiD and a proteasome inhibitor as part of newly diagnosed multiple myeloma.

Now, I'm going to switch gears a little bit and talk about some of the other targeted drugs that I think are exciting. The first is iberdomide, which is a CELMoD and to me makes a perfect partner for all immune therapy approaches, and you're going to see an example of that after this abstract. This is iberdomide, carfilzomib, daratumumab and dex. So basically taking KRd, dara-KRd, and replacing the R with I. So dara-KId is what this is. And this really looked at the ReKinDLE study. So looking at this combination in relapsed and refractory disease, and again, very high overall response rates, deep MRD negativity rate.

And what we know about iber is that it is far more potent than lenalidomide, and it does induce MRD negativity at a higher rate when partnered with drugs like bortezomib and daratumumab. So clearly, you're going to see more of these types of studies coming in the near future.

Now we talked about Bcl-2 inhibition and 11;14. There are 2 abstract that talked about combining venetoclax or Bcl-2 inhibitors. The first was venetoclax with iberdomide and dexamethasone in first or second relapse with patients with 11;14. And what we saw was very high overall response rates, very deep response rates, better than the data we saw with lenalidomide as a partner. And this, to me, again, has a better adverse event profile. And the only main side effect was neutropenia, which in managing heme malignancies we're pretty good at overall.

And finally, we looked at elranatamab, which is another BCMA bispecific, and partnered it with iberdomide. And so again, to me, this is another ideal partnership, a BCMA anti-bispecific with a CELMoD. And what we saw from the MagnetisMM-30 study is that if you adjust the dose and schedule of elra to match iberdomide, you can get 100% response rate in dose level minus 1. That did, in fact, translate into substantial proportions of MRD negativity, and ultimately, that translated into long and durable responses for patients overall as well. And so I think with that, I think I've got 9 seconds, and I'll turn it back to you, Neil.

DR LOVE: Great job there. So MariVí, Virgilio in the chat room asked a question about belamaf, which is, do we have any evidence about whether holding the drug or not because of eye toxicity compromises efficacy?

DR MATEOS: Yeah, this has been evaluated in both DREAMM-7 and DREAMM-8, and we had the opportunity to see how majority of the patients moved to low dose and especially to less frequent doses. And majority of the patients received belantamab every 9 or every 12 weeks, and we've seen how the incidence of ocular events clearly declined, and the efficacy was not compromised. So this is what we are going to do in the clinical practice to move to less frequent doses and this is going to be a very convenient schedule of treatment for patients with myeloma.

Case: A man in his mid 80s with severe obesity and coronary artery disease, chronic heart failure and sleep apnea receives belantamab mafodotin with low-dose pomalidomide for multiregimen-relapsed myeloma — Neil Morganstein, MD

DR LOVE: So I don't know whether we've ever seen a saga like what happened with the FDA and with this drug getting pulled off, now coming back. A really amazing story. Our mind is very focused on ADCs. We just got back from the San Antonio Breast Cancer Symposium. You know in breast cancer, they already have 4 ADCs that are approved and another one that probably will be approved. We did an entire CME program in San Antonio just on ADCs, and actually an ADC, T-DXd, trastuzumab/deruxtecan, was just approved as first-line therapy, I think, today in the United States for HER2-positive breast cancer.

So there's a lot of experience with ADCs in general medical oncology, but this one is different in many ways, and I have a couple of questions here from docs in practice about it, beginning with Dr Morganstein, who has an 84-year-old man who is obese, coronary artery disease, congestive heart failure, sleep apnea, multiregimen-relapsed disease, who as part of expanded access previously, both of these, all these docs didn't, were not aware of the approval at the time I talked to them, but this patient actually received belamaf with pomalidomide. Here's what happened, and here's Dr Morganstein's questions.

DR MORGANSTEIN: This is an 84-year-old gentleman who I've been taking care of for over a decade. We were able to get him belantamab mafodotin as part of expanded access. And he's been on this now for a couple of years. He's done extraordinarily well. He's on it with low-dose pomalidomide. He'll get about 3 to 4, maybe up to 6 months of therapy. The eye toxicities are very real. So we've had to hold him multiple times due to eye toxicity, but the eye toxicities are always reversible. When he progresses, we're able to put him back on, and this has been at least 3 times now and he goes right back into remission. Quality of life has been unbelievably excellent on this medication.

DR LOVE: So any questions you have about the case?

DR MORGANSTEIN: Yeah. So, where do we use belantamab in the treatment of later lines of therapy of multiple myeloma? How do we sequence this or utilize it in the setting of CAR T therapy and bispecific antibodies? Where's the niche? And then what is the dosing sequence and utilizing with other medications? In my N-of-1, this is my favorite drug. This drug has had no side effects outside of reversible keratitis. It'd be interesting if the experts can kind of weigh in on, if we ever get belantamab back commercially available, what would be their first choice and the sequencing of it?

DR LOVE: So, MariVí, belantamab has sort of a different second name, I guess, different payload than a lot of the ADCs we're used to. Last week in San Antonio, we were talking about mucositis, acute nausea and vomiting, cytopenias, diarrhea with all these ADCs. Belantamab, it seems like the main issue here is the ophthalmic thing. Can you talk a little bit about your experience with the efficacy? How often do you see cases like they've described?

Efficacy-wise, it reminds me a lot of stories we hear in solid tumors about people responding much better than they would to chemotherapy. Any comments? Also, I understand, I guess, belamaf was designed to minimize neuropathy, which I was not aware of. Any thoughts about whether this is a typical scenario and how you're sequencing belantamab and with what combination, MariVí?

DR MATEOS: Yeah, so I think that belantamab in combination with pom/dex for this 84-year-old patient is an excellent BCMA targeted therapy. The ocular toxicity is based on the payload. Belantamab mafodotin releases monomethyl auristatin F, and this is the reason why the target is the eye, the cornea, the epithelium of the cornea, and this is the reason why we see eye toxicity. And as you point out, with other antibody-drug conjugates, we can see hepatic failure or peripheral neuropathy. This is based on the cytotoxic agent.

But as Dr Morganstein said, it is completely reversible. Well, what we do in the clinical practice, we start with the full dose, 2.5 mg/kg, but as soon as we see ocular toxicity, that it is going to be very frequent in majority of the patients, the first approach is to put on hold and to wait until there is recovery. And at the moment of recovery, so what we can do is to move to less frequent doses, less frequent doses every 8 weeks, even every 12 weeks, and if the toxicity is maintained, what we do is to reduce the dose. In combination with pomalidomide and dexamethasone, after the first cycle, we use immediately 1.9 mg/kg.

And majority of the patients are receiving now 1.9 mg/kg every 3 months in combination with pomalidomide. I see very appropriate what this doctor did, reducing the dose of pomalidomide because maybe we are going to see more neutropenia, more risk for infections, and in this 84-year-old, I think that this combination is excellent. The patient is 2 years on treatment, and the patient can be maybe other 2 or 3 years receiving this combination.

DR LOVE: So actually this summer —

DR MATEOS: I mean —

DR LOVE: Sorry.

DR MATEOS: No, I was going to say that in terms of CAR T, some bispecific monoclonal antibodies, how to sequence. We have to consider that this antibody-drug conjugate, they don't utilize at all the T-cells. So the T-cell function is going to be preserved. This patient is a bit old in order maybe to be eligible for CAR T, but if it will be possible to utilize bispecific monoclonal antibodies after belantamab, I think that there will not be a major problem if the target is there, that in principle it will be, or it will be possible to utilize GPRC5D or other target, and the T-cell function is going to be preserved.

DR LOVE: So, yeah, I was just going to say that after wanting to do this for a long time, this summer for the first time we did a program on ophthalmology for the medical oncologist where we got into, you know, to me it's all about the cornea, but you can check that out. We're about to also do diabetology for the oncologist because all these drugs that are coming out that target AKT cause diabetic problems.

Case: A man in his mid 60s with a history of stroke with aphasia receives teclistamab for multiregimen-relapsed MM after daratumumab, proteasome inhibitors, immunomodulatory drugs and selinexor — Justin Favaro, MD, PhD

DR LOVE: But Sagar, I'd like you to listen to this next case, a 64-year-old man, a patient of Dr Favaro, status post CVA with aphasia, multiregimen-relapsed disease, who's had dara, PIs, IMiDs, also even had selinexor, currently on teclistamab, and Dr Favaro has a question in terms of what might be next, and Dr Rudolph also has a bunch of questions. Here they are.

DR FAVARO: We started him on teclistamab, and he did well. I gave him prophylactic tocilizumab before the first dose. I admitted him after the first 3 doses each time. He had no CRS. Although he does have baseline aphasia from the stroke, we could not detect any ICANS. He has done very well. He is on IVIG and PCP prophylaxis. He does have neuropathy from his prior treatment. He uses a walker. He does have a CVA. He does have some aphasia.

And the question is after somebody progresses on a BCMA BiTE therapy, what would be a good option for him? Somebody that has his comorbidities. Up until this point we have not really considered him a good CAR T therapy candidate. What about belantamab? Or talquetamab, a GPRC BiTE therapy agent?

DR LOVE: So just curious. Would you like to have belantamab available now, yourself, from what you know?

DR FAVARO: I would. I’ve actually used it, but when it was approved before. The patient had no problems, tolerated it very well, heavily pretreated, and it controlled his disease for about 6-9 months.

DR RUDOLPH: I'm happy that belantamab mafodotin is making a comeback. I think it's well deserved. I think it has really a special place in treatment of relapsed myeloma because it can be administered in the community setting. At this point, we're quite familiar with ocular toxicity for most of these antibody-drug conjugates across the board for multiple tumors. Back in the day when belantamab was initially approved, it was, I think, the first drug with reported ocular toxicity, which frightened a lot of us. But now that we're so familiar with management of ocular toxicity, that's not even a concern, I don't think, for me.

What are the quick take-home points that we can give to our patients as well as our community ophthalmologists or optometrists as far as managing or preventing ocular toxicity with this drug?

DR LOVE: So, Sagar, the gynecologists have mirvetuximab also that has ocular issues. Any comments about, as Dr Rudolph was saying, your take on sort of bottom line and how you deal with the ocular issues? And also, Dr Favaro's patient who has a stroke. I was trying to figure out how you assess for ICANS in a patient who is aphasic. But, in any event, what you might be thinking about next for a patient like that?

DR LONIAL: Yeah. So, let's start off with Dr Rudolph's questions first. To me, I think I try and give the first 2 doses of bela 3 weeks apart because that's when the highest amount of soluble BCMA is still in the blood. And so it acts like a sink to potentially bind the drug, just like it does with any BCMA-directed therapy. And so after the first 2 q3 week doses, that's when I immediately go to q8 weeks or in the right patient, I may go to q12 weeks. So I would preemptively change the dose and schedule so that I can get to the less frequent dosing once I've shown a response and I've given those 2 doses back-to-back.

I think in the other patient, to me, talquetamab would certainly be a very appropriate second-line or next-line therapy for that patient. They've tolerated a bispecific and the infection issues are less with talquetamab, but the GI and the skin issues are a little bit bigger issue but can be managed. I would consider bela in this patient if you could prove that BCMA was still on the surface of the cell. And we're doing a test called PlasmaSeq where we actually look for mutations in BCMA. And if I don't see a mutation and I know BCMA is there, then I would consider using another BCMA-directed therapy in that context.

Integrating Chimeric Antigen Receptor (CAR) T-Cell Therapy and Bispecific Antibodies into the Management of R/R MM — Dr Mateos

DR LOVE: Alright. So let's get back to the ASH meeting. And MariVí, you have a presentation here talking about CAR T and bispecifics, some of the key papers.

DR MATEOS: Thank you very much for the opportunity. This slide represents the treatment landscape for myeloma today. And I am going to focus first on the CAR T-cell therapy for patients, triple-class exposed or triple-class refractory. We have available cilta-cel and ide- cel, but we have here anito-cel, another new BCMA CAR T that it is using a novel D domain binder.

And this anito-cel has been evaluated in 117 triple-class exposed relapsed/refractory myeloma patients, 18% with extramedullary disease, 40% with high-risk cytogenetic abnormality, and majority of the patients were triple-class refractory. The median follow-up was 16 months. But in terms of efficacy, we can see how basically all patients responded and the complete response rate or better was over 70% with majority of the patients achieving minimal residual disease negative. The median follow-up was 16 months.

And we can see how at 12 months, at 18 months, between 67 and 82% of the patients remain alive and progression-free with an acceptable safety profile with no delayed neurotoxicity, no second primary malignancies, no enterocolitis or other autoimmune events. So this means that anito-cel is a very promising BCMA directed CAR T-cell therapy with efficacy, I would say, quite similar to what we've seen with the cilta-cel, but with, in principle, a better safety profile.

And also, we know that we have ide-cel evaluated in the KarMMa-3 in an earlier line of therapy in patients after 2 to 4 prior lines of therapy. And we know that in this KarMMa-3 study, ide-cel was compared with the different standards of care. And in this presentation, others decided to focus on the population older than 70, 20% of the patients were older than 70. In principle, these patients presented less high-risk cytogenetic abnormality also less triple-class refractory, and with a longer time from the last line of therapy.

And in terms of efficacy, they observed how the overall response rate, as well as the progression-free survival were better than in the population younger than 70. And the median PFS was approximately 18 months, one and a half years. And if we remember, the median progression-free survival in the overall population was around 14 months, with a good safety profile. And the main conclusion is patients older than 70 from the KarMMa-3 experienced the benefit from ide-cel treatment.

I think that the main characteristic for ide-cel is a better safety profile. If we have patients older than 70, in which we consider that CAR T can be an option, maybe ide-cel can be an opportunity because the safety profile is going to be more predictable, better, with a good efficacy, with median PFS of approximately one and a half years.

If we move to earlier lines of therapy, we know that cilta-cel is approved in relapsed/refractory myeloma patients after at least 1 prior line of therapy. What is the best, the better population, the best patients to what we can offer cilta-cel? This is what it has been evaluated in this presentation. And if we focus on patients with standard risk, we can see how the overall response rate is 100%. And indeed, the complete response rate or better is over 90%.

And in terms of PFS, and also in terms of overall survival, this is the subgroup of patients in which the progression-free survival at 3 years can be over 80%. So this would be the best population. And in line with this reported in CARTITUDE-4, after a median of 2 prior lines of therapy. It's true that it is also possible to see how in CARTITUDE-1, after a median of 6 prior lines of therapy, also patients with a standard risk presented a better progression-free survival. So if we wanted to select the best population eligible for cilta-cel, if we focus on standard risk, the outcome is going to be excellent.

Also there was a presentation basically based on the immune fitness as well as the tumor microenvironment with cilta-cel. And again, the earlier the use, the better fitness of the T-cells, as well as the better immune microenvironment, and this can potentially justify or explain the better outcome for these patients. This was evaluated in CARTITUDE-4, but also from the T-cell repertoire in CARTITUDE-1 in the heavily pretreated population. It was observed how the CD4 memory T-cells were higher in those patients who remain alive and progression-free at 5 years, as well as a TCR repertoire diversity higher than in those patients in which the PFS was shorter than 5 years.

If we move to the bispecific monoclonal antibodies, teclistamab and talquetamab, evaluated in relapsed/refractory myeloma patients, all of them triple-class exposed, majority of them triple-class refractory and 46% with true extramedullary disease. And what is important in this combination is in allcomers, the overall response rate, 80% and 60% of CR rate, CR rate is higher than the efficacy we observed with teclistamab and talquetamab as single agent.

But for me, what is important is the efficacy observed in patients with true extramedullary disease with a complete response rate or better or 40%. Because we know that this population is an unmet need in which with the conventional therapies, the overall response rate is 20% and the median progression-free survival, 3 or 4 months. And with this combination in the population with extramedullary disease, the median progression-free survival is almost 2 years.

In terms of infections, in terms of safety profile, we have to focus mainly on infections, 43% Grade 3/4 with some opportunistic infections. So we have to prevent these infections with the adequate prophylaxis support with immunoglobulins. And also, we have to consider the on-target of tumor toxicity for talquetamab.

Today, from my personal perspective, I will select this combination for patients with true extramedullary disease, although there is a Phase III clinical trial ongoing, MonumenTAL-9, that will evaluate the role of this combination in allcomers. And until these data are available, I will utilize this combination in patients with extramedullary disease.

Another bispecific monoclonal antibody, not targeting BCMA, not targeting GPRC5D+, but FcRH5, is cevostamab. And cevostamab had reported previously efficacy data in relapsed/refractory myeloma patients in intravenous administration. And now we have some data about the subcutaneous administration in heavily pretreated myeloma patients.

And of note, almost 50% of the patients had been previously exposed to CAR T, belantamab or bispecific monoclonal antibodies. Overall, in all patients, the overall response rate is closer to 30%. And I would remark the efficacy in the population BCMA-naïve. Because honestly, in the population BCMA-exposed, the overall response rate 25% is, from my point of view, a bit slow and a bit lower than expected. Safety profile is good. Of note, cevostamab is given fixed duration, 13 cycles.

And for me, although the role of cevostamab is interesting, because the target is different in order to sequence, I would be more in favor of combinations based on cevostamab. And we know that cevostamab combines quite well with the IMiDs like pomalidomide.

Another BCMA bispecific monoclonal antibody is etentamig. Etentamig is a bit special, because it has 2 binding domains to BCMA. The Fc region is silenced in order to allow to deliver etentamig monthly since the beginning. And also, the affinity by CD3 is lower, and this means that the safety profile is better. And this has been demonstrated in some clinical studies with etentamig single agent.

And here, we are going to see etentamig in combination with pomalidomide and dexamethasone. And the efficacy is great, with overall response rate higher than 80%, with many patients in complete response, with encouraging progression-free survival and overall survival. But from the safety profile point of view, infections Grade 3/4, 52%, and neutropenia maybe was the most frequent hematological adverse event.

There is an additional cohort with this combination, including a step-up dose 1 and pomalidomide included a cycle 2 day 1. And this is going to improve definitely the safety profile from the infectious perspective, as well as from the neutropenia point of view. But also, interesting combination from my point of view.

Ramantamig transpacific monoclonal antibody, 36 patients. This is monoclonal antibody targeting BCMA, GPRC5D and CD3. The efficacy is quite impressive in 36 relapsed/refractory myeloma patients, majority of them triple-class refractory. And the overall response rate at the recommended Phase II dose is similar to the CAR T with encouraging progression-free survival.

What is also important is this trispecific monoclonal antibody is given flat dose, 100 mg, monthly since the beginning, and with just 1 step-up dose. From the safety profile, it is good, and the infection rate is not very high. But we have to consider the on-target of tumor toxicity we know for GPRC5D in majority of the cases, Grade 1 and 2. But we have to consider, and from my point of view, we are going to target BCMA and GPRC5D and it is important to know the activity in some patients, like those with extramedullary disease, in order to select the combination versus the trispecific monoclonal antibody.

And finally, low dose of tocilizumab for mitigation of CRS in patients with bispecific monoclonal antibodies. The use of 4 mg instead of 8 mg/kg was quite effective in terms of reduction of the CRS, as well as the severity. And this can be a useful approach that will be cost-effective from the clinical point of view. And I stop here.

DR LOVE: So really interesting about this extramedullary impact of the tocilizumab/talquetamab combination. As Sagar was telling me, he actually uses that combination off-protocol for patients with extramedullary disease. I want to try to squeeze in a couple more cases. Also, to say that Dr Rudolph, who was asking those questions about belamaf, apparently is in the chat room, says, that's very helpful. Thanks. I just started someone on it.

Case: A man in his early 70s with kappa light chain myeloma experiences complete response on cilta-cel CAR T-cell therapy with hypogammaglobulinemia requiring IVIG and develops melanoma of the abdominal wall — Bhavana (Tina) Bhatnagar, DO

DR LOVE: Here's an interesting case with an interesting question. Sagar, I'd like to hear what your thoughts are. This is a 71-year-old man, kappa light chain myeloma. A patient of Dr Bhatnagar who gets a CR on cilta-cel, has hypogammaglobulinemia, is getting IVIG, but also develops a melanoma. Here's the case.

DR BHATNAGAR: He's actually a funeral home director who has kappa light chain myeloma, recently had mostly disease progression involving the bones and he ended up getting CAR T in April of this year. He did very well, but the only other interesting thing that happened with him is he had no CRS, he had no neurotox. His myeloma labs indicate that he's in complete remission. He is hypogammaglobulinemic, so I am curious to know how IVIG is being folded into the care of these patients?

And then one kind of interesting thing that happened with him is maybe a month or 2 after his CAR T-cell infusion happened, he was diagnosed with melanoma on his abdomen. He ended up having a wide local excision for that and he's currently being monitored. But I am curious to know about what the overall concern is for these second cancers and when they're being seen, at what time point after the CAR T therapy and whether the more recent data that shows this increased risk for second malignancies, how that has impacted utilization of CAR T cells?

DR LOVE: Any other questions to the faculty?

DR BHATNAGAR: I guess I would be curious to know what factors they take into account when choosing a CAR-T product? And what the advantages are for one over the other?

DR LOVE: So, Sagar, choice of CAR T and also this issue of second cancers, what are the presumed mechanisms? We heard about T-cell lymphomas, what's the update?

DR LONIAL: Yeah, I mean, I think, the hard part is that many of the studies with CARs are in heavily pretreated patients that have had a lot of treatment. Seeing a relatively pale patient who's in their 70s who develops either a melanoma or something else is not unexpected whether or not they necessarily got a CAR, to be honest with you. Now, is the likelihood higher in somebody that's immunosuppressed? Probably. But is it a true second cancer? I think that's a harder, that's a harder attribution for me to make.

So I think the hypogam is something, and certainly for at least the first 6 months after CARs, they get monthly IVIG, so similar to what we do for bispecifics. If after 6 months they still remain really low, and for me that's less than 400, then I'm going to keep going even longer and then retest them typically at the 1-year mark. But I don't necessarily — first of all, the therapy is already given, so it's not like you can say I'm going to stop giving it. And a melanoma that's caught early and treated without systemic therapy or the need for systemic therapy to me is not a reason not to give a CAR.

I think the choice of a CAR, I think 9 times out of 10, we're probably using cilta-cel. I think the upside of ide-cel over cilta-cel is that it probably has a little bit less toxicity, but the efficacy of cilta-cel is just so good that I think it's hard not to go with that for most cases. There may be a few exceptions here and there.

DR LOVE: Yeah, and actually Dr Kumar in the chat room points out a lot of these people have had lenalidomide in the past also in terms of the second cancers.

Case: A man in his mid 50s with heavily relapsed MM who received multiple prior lines of therapy, including CAR T-cell therapy, receives talquetamab — Priya Rudolph, MD, PhD

DR LOVE: Let me see if we can just squeeze in 1 more case because MariVí, I'd like to — you don't run into too many general oncologists who have used talquetamab. Dr Rudolph, who we were just talking about, has a 56-year-old man, multiple prior lines of therapy, has gotten cilta-cel, teclistamab, now on talquetamab.

DR RUDOLPH: We switched to treatment with talquetamab, and he struggled quite a bit with multiple toxicities, in particular nail toxicity. He has lost all of his nails. I want to see if there's anything out there that I can do to prevent nail toxicity with talquetamab, or if that is something that's just bound to happen? Likewise, talquetamab also is associated with weight loss because of dysgeusia.

Is there anything that patients can be doing to keep up their weight while they're on this treatment, whether it be things like megestrol acetate, that we give for appetite stimulation, or it could be as simple as chew on a peppermint or a lemon drop? I have found it easier to manage side effects with teclistamab compared to talquetamab.

It's interesting that dose reductions are not allowed on teclistamab or talquetamab. These patients do run into significant cytopenias. The guidelines are on the package insert to simply hold a dose if their neutrophil count drops below 500. There is no mention on the package insert to give growth factors. I'd love to know if the experts are using growth factors and pushing through the weekly doses rather than holding dose as prescribed on the package insert.

DR LOVE: So, MariVí, quality of life toxicities with talquetamab and any other things you want to say about this therapy?

DR MATEOS: Yes. Point number 1, it is possible to use G-CSF with no problem for managing neutropenia. The only recommendation is to try to avoid the G-CSF during the step-up dose in order to avoid the cytokines overlap. Point number 2, it is possible to modify the dose and schedule of administration, especially for talquetamab because the conventional dose is 0.8 mg/kg every other week. But in order to manage the loss of weight or even the oral toxicity, it is possible to move to 0.8 monthly or even 0.4 monthly. And this is something that it is possible to do.

In order to manage the nails toxicity, so we know that it is quite frequent and it is present in up to 50% of the patients. And the median duration can be up till approximately 3 months. And the management strategies include the use of emollients, cuticle oil, vitamin E oil, nail hardeners, good hygiene. And basically, this is what it is possible to do to manage the nail toxicities.

In terms of the oral toxicity, it is more frequent because it is going to be present in over 70% of the patients. And from my point of view, the median duration can be longer. And what we have to do is to educate the patients and to inform about this toxicity and to establish nutrition recommendations with appetite stimulants if necessary, recommendation based on sitting upright, small bites, small sips with meals, so on.

Well, people in the audience has to know that there is a clinical trial ongoing in order to try to investigate the strategies to be used as prophylaxis to prevent the oral toxicity with dexamethasone mouthwash, with clonazepam or with pregabalin. And now they are going to incorporate the use of topical tacrolimus or cyclosporine because it is possible that the mechanism is based on the T cells.

So it is like graft versus host disease after allogeneic stem cell transplantation. And all approaches they can potentially use, they can be effective for these patients. But from my personal perspective, the best approach with talquetamab is to move to less frequent doses, every month or even every other month. And with this, all this on-target of tumor toxicity will improve.

DR LOVE: Wow, so interesting. I saw Sagar shaking his head almost every time you were bringing up a point there. So, first of all, I want to thank all the docs who presented cases today. We didn't get to Dr Lee's case, a patient who actually got diagnosed with metastatic prostate cancer while he was being treated for myeloma. It's amazing what happens in the real world. But thanks so much to these docs for working with us and then putting their therapy out there.

Thanks so much, MariVí. Thanks so much, Sagar. Thanks, audience, for attending.

Be safe, stay well, and have a great night. Thanks so much, MariVí. Thanks, Sagar.

DR MATEOS: Thank you very much.

DR LONIAL: Thank you.