Introduction

DR LONIAL: Alright. Well, good afternoon, everybody, and welcome to “What Clinicians Want to Know: Addressing Current Questions and Controversies in the Management of Multiple Myeloma.” I’m Dr Sagar Lonial. I’ll be moderating this session today.

Here are our faculty, and I think we’re going to have a really lively discussion today from a lot of our experts from around the world, so look forward to that, and we look forward to this session as well.

Here are the faculty’s relevant conflict of interest. And this is available in the booklet if you’d like to see that as well.

And again, this program is due to educational grants from GSK, Janssen, Janssen Scientific Affairs and Karyopharm Therapeutics. And again, the planning staff and team have no financial conflicts to disclose.

This will include the discussion of non-FDA-approved agents, and please refer to official prescribing information for the specifics on each drug.

Okay. So we’re going to now begin. Dr Love did interview 6 general medical oncologists, during which they posed cases and queries on a number of key clinical issues. Video excerpts from those interviews will be featured throughout the program as well.

Management of Newly Diagnosed Multiple Myeloma (MM) — Dr Orlowski

DR LONIAL: So this is our agenda for today. We will begin with our first video, and we’re going to cover the gamut of therapy in myeloma, including newly diagnosed, integration of novel therapies into the management of relapsed/refractory myeloma, CAR T-cell therapy, bispecifics, and then I will wrap up with novel agents and strategies under investigation.

So I think we’re ready to begin with our first video.

DR LOVE: Good afternoon, everyone. I’m medical oncologist Dr. Neil Love from Research To Practice, today joined by 6 community-based medical oncologists: Dr Susmitha Apuri, Shams Bufalino, KS Kumar, Eric Lee, Yanjun Ma and Henna Malik, who will present cases from their practices with questions for the faculty, beginning with a patient of Dr Lee.

DR LEE: 61-year-old male diagnosed with light chain multiple myeloma. He had 1q deletion in TP53, so he was put into the high-risk category.

I started him on a quad regimen, dara, bortezomib, lenalidomide and dex.

He achieved complete response after 3 cycles. He was able to successfully complete autologous transplant. Because of the high-risk status at diagnosis, I put him on proteosome inhibitor and lenalidomide maintenance. He didn't want to come in for the bortezomib injections, so I used ixazomib for him plus lenalidomide. And he's been under excellent control.

So my question: Do we have any data for using a CD38 antibody in the maintenance setting?

Do investigators use ixazomib in the maintenance setting? It's an oral drug. It's very easy to take. They take it once a week. And kind of a lower burden for the patients to have to come in and get their injections.

DR LOVE: So I see this patient was African American. Any questions about the lack of benefit that was seen in the DETERMINATION trial evaluating autologous transplant in African American patients?

DR LEE: Part of me wonders whether the lack of finding of a transplant benefit for African American patients has to do with like a disparity of care. We know that certain groups have less access to care.

DR LONIAL: Okay. So we’ve got a couple of questions based on that case. What is your approach for induction therapy for younger patients with standard risk, what about those with high risk, and how to you define high risk? Are there any situations in which an anti-CD38 antibody should not be used? So I’m going to start with Professor Moreau. Do you want to take 1 or all of those questions to get us started?

PROF MOREAU: Okay, yes. Definitely for transplant-eligible patients with standard-risk disease our standard of care is a quadruplet combination, VTd/dara or VRd/dara, followed by stem cell transplantation and lenalidomide maintenance. We are not yet using combination of len plus a CD38 antibody. For high-risk disease, in Europe, many of us are using a tandem stem cell transplantation, and we can combine in the maintenance setting lenalidomide plus a proteasome inhibitor, but more and more, and we are going to discuss those data, we have good data with the combination of len plus a CD38 antibody following the PERSEUS study, the AURIGA study, and probably Dr Orlowski will discuss those very important studies.

DR LONIAL: Alright. Thank you. Noopur, do you want to talk about maintenance therapy for transplant-eligible patients?

DR RAJE: Sure. So this patient specifically was a high-risk patient, and I would have done exactly what Dr Lee did. I would have done a dual maintenance approach, a PI with len. I think the slight difference is for the younger, fitter patients we tend to use carfilzomib, so carfilzomib/len/dex with an anti-CD38, either isatuximab or daratumumab, and then maintenance is with a PI and the immunomodulatory drug.

DR LONIAL: Paul, do you want to talk a little bit about where you might consider ixazomib in this context and about the transplant question?

DR RICHARDSON: Sure. Thank you very much, Sagar. Well, I think the ixazomib question that Dr Lee posed is a very interesting one because at the end of the day there is that convenience of weekly oral administration.

We certainly explored this more during the pandemic. That was certainly true. However, the only caveat to this in my view is that every 2 weeks for either carfilzomib or bortezomib in the appropriate setting, from the point of view of a treatment burden, may not be that much, and then at least you have the ixazomib in reserve as a next line of therapy as part of a combination.

I think the very interesting question from Neil was this observation that we’ve made in the DETERMINATION trial, not so much that African American patients don’t benefit from transplant, but just that those patients who did not undergo early transplant, our median PFS for these patients has not been reached. So it’s not that they don’t benefit from transplant. That would, I think, be misinterpreting the information. It would be really that the transplant-sparing approach has resulted in substantial clinical benefit, exceeding by quite a margin, what we would have expected. And we’re trying to better understand what that means.

Our working hypothesis, Sagar, is actually revolving around Duffy null and what that may mean in terms of pathobiology. So we’re exploring this further and more to follow.

DR LONIAL: And Bob, I wanted to get your take in terms of maintenance for high risk, maintenance for non-high risk, and the role of ixa.

DR ORLOWSKI: Yeah, definitely. I think as Philippe mentioned, the combination would be the way to go for high-risk maintenance, and we have more data for now with lenalidomide and a proteasome inhibitor, but there are emerging data about len and daratumumab. I’ll show some of them later. And I think that in a patient who is either intolerant of a PI or cannot get a PI for other reasons coming in with a len and anti-CD38 for maintenance is very reasonable.

DR LONIAL: Alright, good. I didn’t want to steal your thunder with the len/dara question. Why don’t we cut to our second video and hear another case.

DR LOVE: The next case was presented by Dr Apuri with a follow-up question from Dr Ma.

DR APURI: She’s an 80-year-old, prior diagnosis of a Stage II breast cancer. She was treated with chemotherapy and anti-HER2 agents. And she did 10 years of endocrine therapy.

Came back to clinic for a review of a mammogram. She was reporting fatigue and feeling tired, and she was reporting jaw pain. So we did a routine CBC, and her hemoglobin is 8.4 g/dL, which was very new.

So we were investigating the jaw pain further, so she went to see a dentist to undergo a biopsy, which unfortunately came back as a plasmacytoma.

So she underwent a bone marrow biopsy, which demonstrated a lambda-restricted plasma cell myeloma with 80% cellularity, and imaging showed extensive osseous bone lesions and a hypermetabolic right mandibular lesion, which is what she was reporting.

So she’s 80 years of age. She lives alone. She has very little support.

So my question to the experts is do you prefer to proceed with a 4-drug regimen in an 80-year-old woman with a decent performance status.

DR MA: Traditionally we have been using the GRIFFIN induction for patients who are transplant eligible, because traditionally not transplant eligible I will take the bortezomib out. But it sems like now I’m getting more back that says you should go ahead and include it. I’m just curious. Do they make those differences based on the risk factors, based on cytogenetics, or what factor do they consider in that?

DR LONIAL: So I think this question of a patient with breast cancer who you biopsy something and it turns out to be myeloma, it’s not as uncommon as I think many would anticipate. I’ve certainly seen it. I’m sure all you have as well. Noopur, do you want to give us your take on the 80-year-old, quad versus triplet, how do you approach the use of bortezomib?

DR RAJE: Yeah. So a really good question, and it’s not the easiest to answer. And I think all of us struggle with this a lot. If I’m able to give a quad safely in a patient that is my preference, and the beauty of using a quad, even in an 80-year-old, you’re going to get a really good response. The data we have for the transplant-eligible and ineligible patient population with PERSEUS and IMROZ suggest using a 4-drug regimen, and one can dose reduce all of the drugs and hopefully allow patients to tolerate all.

Having said that, if somebody’s been on treatment before, like this patient with breast cancer, and her counts are going to be marginal, then doing something like a MAIA-like regimen would be perfectly reasonable as well.

DR LONIAL: So Philippe, I’m going to ask you this, not because I think you have expertise in this specific area, but more because I think we know that deeper responses usually translate to better long-term outcomes. But in the elderly patient population safety and toxicity may counterbalance that. How do you think about those issues?

PROF MOREAU: A very important point. And when looking at the recent data that we have with quadruplets in elderly patients, we have the IMROZ study, the CEPHEUS study, and the BENEFIT STUDY, so we have 3 trials now showing that a quad is better than a triplet. But into those studies only fit patients were enrolled up to the age of 80 years, so we have very, very few data with quad combinations in frail patients and in patients above the age of 80 years.

So in my practice and during this meeting we will have very important — the first Phase III study looking at frail patients, showing that lenalidomide and daratumumab without dex is associated with a very good outcome. So I would not push for a quad in an elderly and frail patient, but from 70 to 80 years in fit patients, yes.

DR LONIAL: So just to reference that presentation, it’s dex for the first 2 cycles, right?

PROF MOREAU: Yes. Only, yes. You are right.

DR LONIAL: That’s right. That’s right.

So Paul, do you want to talk a little bit about how these are managed, and particularly this question of high risk? Fortunately, in older patients the fraction of high risk is smaller, but certainly how to manage them in this 80-year-old certainly is an issue.

DR RICHARDSON: Yeah. I agree, Sagar. I think the question of risk in the elderly is a little — is a little complex, isn’t it, because if you look at beta2, if you look at other features of pathobiology that may be adverse, they’re actually higher in the elderly, and they’re more — and there may be more immune dysfunction and immune exhaustion that we have to deal with.

So I’m a little — I very much embrace Noopur’s approach, which is to use all the assets that we have but just dose adjust. Obviously, our work with RVd-lite, and our oldest patient in that study was in his mid 90s, and he tolerated treatment extremely well, has taught us that you can exploit all 4 major arms of your quad, but you must dose reduce and manage their symptoms proactively, and dosing schedule can be really adjusted.

So in that context I would agree that we don’t push too hard, that efficacy is all about managing toxicity as much as activity, but we also mustn’t underestimate that typically in the older patient your first line of therapy is your best asset in terms of their long-term outcome. So we tend to embrace the quad, but based on RVd-lite and RVd-lite/dara and RVd-lite/isa type approaches, adapt accordingly.

DR LONIAL: And Bob, knowing — I don’t want you to steal any thunder from your talk, but Texas patients are pretty hardy. Tell me how you approach this.

DR ORLOWSKI: I think in terms of the frail, really advanced elderly population I would completely agree that one has to be careful, and you have to use your best judgment. If you feel a quad is not appropriate, then so be it. But just to amplify a point that Paul made, remember that in your younger patient population you’re more likely that those people will do well and be able to get a second- and a third-line therapy. But in your older, frail patients, more of them will get only 1 line of therapy, and if they can tolerate it, you should give them the best possible combination. And so I think a quadruplet with isatuximab as the anti-CD38 in the future perhaps daratumumab as an anti-CD38, keep those in mind and dose adjust.

DR LONIAL: Alright. Well, thank you. I think these are some good questions for us to think about as Bob updates us on the management of newly diagnosed myeloma.

DR ORLOWSKI: Alright. Thanks very much, “Neil Lonial.” A pleasure to be here to talk about what to do for both transplant-eligible and transplant ineligible patients. One of the nice things is that whereas in more advanced disease you’ve got many, many Category 1 recommendations, things have actually gotten a little bit simpler in newly diagnosed disease, because as you can see, for transplant eligible patients really there’s just the 1 quadruplet regimen that has Category 1 recommendation, and that’s from the PERSEUS study. By the way, that’s the Greek God Perseus up there as a photo. And this was, of course, a combination of dara with VRd versus VRd followed by transplant, then consolidation with whatever they got for induction, and then maintenance with either DR or R.

The response and durability data are shown here, with the durability in terms of progression-free survival showing a pretty clear advantage for the quadruplet over the triplet, and although the overall survival data are not yet different, they are separating a little bit, and I think we’re all confident and hopeful that that will continue to be the case moving forward.

The common adverse events were things you’re probably already used to seeing with anti-CD38s, with mostly a little bit more of an infection signal than without an anti-CD38.

And if you look at the subgroup analyses almost all of the patients in these different subgroups had a better benefit from the quad than was the case for the triplet.

And that, of course, led to the FDA approval of this combination, and many of you and many of us now use this fairly routinely.

For transplant-ineligible patients there’s a slightly wider array of options, which include a triplet, dara, len and dex, for patients who maybe are a little bit more frail, especially if they’re 81 or older, where there was a good population of those on the MAIA trial. And now we also have options to think about quadruplets, including isatuximab with bortezomib, len and dex, and that came from the IMROZ study. Don’t let the fact that there was a disreputable senior author involved here cloud you to the fact that the data are really quite good.

This was the study design here, where again VRd induction followed by Rd as continuous therapy versus isatuximab with VRd, and then later on people got isa with Rd.

Here you can see the response data on the left, and a little bit of durability, MRD, on the right. You can see the overall response rates were a little bit similar, in part because isatuximab can interfere with determination of a CR, but the quality of response in terms of VGPR or better was higher, and the MRD negativity rates were better as well. You can see a nice separation in the progression-free survival curves here, with a large benefit for the isa/VRd arm.

And again, overall survival not yet matured but looks like if you look further out there the quadruplet is going to do better, although in fairness the number of patients that are that far out is not yet as large as we would like it to be.

And as was the case for CEPHEUS here there were no unusual, unexpected adverse events, just a little bit more cytopenias and sometimes a little bit of a greater infection risk.

Subgroup analyses again shows that the quadruplet benefits almost all of the relevant subgroups.

Other notable findings are that if you got to MRD negativity the group that got isa/VRd actually did a little bit better than the group that got VRd, suggesting that although this was measured at either 10^-5 or ^-6, you do still get a deeper level of MRD with the anti-CD38. And PFS2 data are shown here. This is now patients do on their next line of therapy. If you’re worried that better treatment up front gives you drug resistance later, in fact this shows the opposite, that the quadruplet up front leads to a better response to second-line therapy later on. So you don’t have to worry that you’re going to run out of options because you use all 4 drugs at that time. And of course this led to the FDA approval.

There also is the BENEFIT study that Philippe briefly mentioned and knows well, and this actually asked a different question, which is whether the addition of bortezomib or a proteasome inhibitor was still potentially of benefit. And, in fact, I’ll skip forward.

What we found from this study is that the addition of the PI did improve the overall response rate, as well as the complete response rate, and also improved the MRD negativity, which was the major endpoint here. And although PFS was not the major endpoint, and the data are not yet mature, it does look like the quadruplet is going to be better, and these are the overall survival data.

And I won’t review the common adverse events because those are similar to those that were reviewed in the previous study.

Now, at the International Myeloma Workshop that was a couple of months ago there were data presented on the CEPHEUS study, and this was essentially VRd versus dara/VRd for this transplant-ineligible patient population. There are some small differences in the populations, in particular here. This trial did allow patients who were willing to defer transplant, and so may therefore have been eligible for transplant otherwise, could have been a slightly healthier group. But otherwise the data were fairly similar in terms of what patients were allowed. Primary endpoint was MRD. You can see the D-VRd did better than did VRd, as you would expect, and also complete response rates were higher.

These are the durability data, which you can see also show a benefit for the quad versus the triplet. And if you look down there at a hazard ratio of 0.57 that means essentially a 43% reduction in the risk of progression or death, which is pretty darn good for the addition of a very well-tolerated drug.

And these are some additional MRD data that really show the power of a quadruplet as opposed to a triplet.

Longer-term follow-up, as with the other studies, is not yet mature, but certainly looks like it’s trending in favor of the quad over the triplet. And again, almost all of the relevant subgroups that you see in your practice are really benefitting from the quad as opposed to the triplet. And no unusual safety or adverse events that were noted.

Moving briefly on to maintenance, which we’ve discussed already a little bit, lenalidomide is still a preferred regimen overall, according to the NCCN. Other options, which we’ve mentioned a little bit already, are car/len or dara/len, and also bortez/len, particularly Sagar’s group did a lot of work in that area, and ixazomib can be considered as an option as well.

A couple quick studies that have bearing on this setting. There’s the AURIGA study. This is a trial that took patients that were MRD-positive after transplant and randomized them to either R or DR as a maintenance. And as you would imagine, the MRD conversion rate to MRD negativity was better if you got dara with R than if you got R alone, so nice data there. And the subgroup analysis here shows, again, that pretty much every group had a better chance of getting to MRD negativity if they got the combination. Longer-term data not yet mature but still looking like the combination will be better.

And then finally we have updated CASSIOPEA data. Many of you may remember that this was a study that looked at VTd induction versus dara/VTd, and then later on patients were randomized either to observation or to dara as a maintenance. So there actually were 4 groups here. The primary randomization showed a benefit for dara/VTd, as you would imagine, and overall survival data are also trending in that direction.

These are the PFS data from the second randomization, which was dara versus observation. No surprise that the dara group is doing better. But one of the pieces here that is really interesting as an update is at the initial presentation of the data all 3 of the groups at the top there who got either dara induction or dara maintenance or both looked like they were pretty similar, and now there’s a small separation in the curves suggesting that getting dara in induction and during maintenance gives you a bigger benefit. So a different conclusion than some folks had from the beginning.

So just to wrap up kind of take-home messages, for the transplant-eligible and transplant-ineligible population, as you’ve heard already, quadruplets are the way to go. Triplets are still reasonable. For example, if you’ve got somebody with severe neuropathy that you don’t want to give a PI to, or if they’re really frail, 90 years old, multiple comorbidities, then a triplet is still reasonable.

In the maintenance setting I would actually say that len with an anti-CD38 is an emerging standard of care. There is an ongoing SWOG study, which should complete enrollment this month, which will answer the question ultimately of whether len or len/dara is better irrespective of prior induction therapy.

Thanks very much, and I’ll turn it back over to “Sagar Love.”

DR LONIAL: Thank you, Bob. Great discussion. We’ve got time for 2 very quick questions, and then I’m going to make an observation. We’re going to move to the second module here.

So (1) Noopur, tell me about consolidation. Yes/no? If yes, why? If not/no, why? Quick.

DR RAJE: No consolidation.

DR LONIAL: Okay.

DR RAJE: Transplant, if you consider consolidation, that’s my consolidation.

DR LONIAL: Got it.

DR RAJE: No separate consolidation.

DR LONIAL: Okay. Bob, tandem transplant, a role in 2024?

DR ORLOWSKI: None.

DR LONIAL: Okay, good. Alright. And I just want to get some consensus. As we go through the PFS in the eligible and ineligible with the quad induction one thing that strikes me is 4% per year relapse rate for the transplant group, 6-8% relapse per year with the nontransplant approach. So I’m going to say, and you guys can in 1 word say yes or no, I still think transplant remains a standard for fit patients.

PROF MOREAU: Yes.

DR RAJE: Yes.

DR RICHARDSON: Not sure.

DR ORLOWSKI: No.

DR LONIAL: No. Alright. So we started with good, and we finished with Bob.

Integration of Novel Therapies into the Management of Relapsed/Refractory MM — Dr Richardson

DR LONIAL: Alright. Let’s get to our next case. Okay.

DR LOVE: The next case was presented by Dr Apuri, a 60-year-old woman with standard risk disease treated on a clinical trial in 2013 with RVd, followed by autologous transplant with bortezomib maintenance, followed by multiple regimens for progressive disease.

DR APURI: She did undergo CAR-T in 2021, and she was able to achieve a complete response.

So far, she has done very well, and it’s been 3 years post CAR-T, which is amazing to see in multiple myeloma.

So my question for the experts is what do you do if this patient develops relapsed disease. Do you treat them with repeat CAR-T therapy because she has done so well with the first CAR-T? Or would you go to a bispecific therapy?

DR LOVE: So basically, she’s been off therapy since the CAR T, 3 years now.

DR APURI: Yes.

DR LOVE: What’s it been like for her to be off therapy from a quality-of-life point of view compared to prior to that?

DR APURI: I think it’s amazing when they don’t have to come to the clinic for multiple treatments, lab work appointments, imaging. I personally think they feel liberated. Most of our patients are very grateful that they have a treatment-free interval.

DR LOVE: Any other questions about this case?

DR APURI: Since she has seen so many medications up front, how do you sequence the therapy if the patient develops recurrence, in light of her poor tolerance to the IMiDs and the proteasome inhibitors?

DR LONIAL: Okay. So we’ve got a few questions here. Sequencing of therapy for patients with poor tolerance of IMiDs and PIs. Paul, I’m going to have you start. Again, short answers because we’ve got to get through a lot of these questions, so…

DR RICHARDSON: Yeah. I think it’s a complex question, but obviously reaching for antibodies in the setting of IMiD intolerance and proteasome inhibitors makes sense, as well as next-generation novel agents.

DR LONIAL: Okay. Sorry. Noopur, and in which situations do you recommend trying somebody with selinexor?

DR RAJE: Typically bridging therapy, selinexor with carfilzomib, is something I do use.

DR LONIAL: And when you do that, what’s your starting dose?

DR RAJE: Once a week. I use about 60, 40 to 60, depending on the seli.

DR LONIAL: Okay. And Bob, tell me about some preemptive stuff you do to help manage that, if you’re going to use that as part of a bridge or as salvage therapy.

DR ORLOWSKI: Yeah, definitely. I think that using a combination can be helpful, and there are a number of those that seem to work well with selinexor. PIs work well. If you’ve got a PI-intolerant patient, you can try dara with selinexor. You have to be aggressive about antiemetic regimens, as well as consideration of intravenous fluids for people who get a little bit dehydrated, but it’s definitely a manageable and can be a very effective regimen.

DR LONIAL: And Philippe, we know that you don’t always have the same freedom to do things like we do. How do you approach it in France?

PROF MOREAU: We are never using selinexor, in fact. Never. So we have access quite easily to bispecific antibodies, and as soon as patients are triple-class refractory or triple-class exposed and refractory to the last line, we are using bispecific antibodies in the majority of the cases. We don’t have access yet to cilta-cel, so the choice is between ide-cel and bispecific antibodies. 70% of the patients are receiving bispecific antibodies.

DR LONIAL: Okay. Got it. Got it. Alright. Let’s do our next case.

DR LOVE: The next case, a 64-year-old man, is presented by Dr Kumar.

DR KUMAR: He came in with acute renal insufficiency, hypercalcemia, extensive bone marrow involvement and a large lytic lesion in the skull parietal bone and a left chest wall mass and a compression fracture of T7 and T11.

So because of the renal failure, he was treated with CyBorD at the hospital.

Once renal function returned, I was going to change his treatment.

We gave him radiation to his left chest wall mass as well as to the skull. The skull mass was about 5 to 6 cm in size.

When we radiated the skull mass, it just disappeared and formed a big hole in the skull. You can just feel it so soft. I was so concerned if he bumps it he will bleed.

So we sent to the neurosurgeon, and we put a titanium plate to cover that area.

I have him now on dara-VRd. He is tolerating well. He is getting ready to go for a bone marrow transplant.

DR LOVE: Any questions for the faculty?

DR KUMAR: Is it necessary to change from CyBorD to dara/VRd or could I have continued dara/CyBorD?

DR LONIAL: Okay. So Bob, why don’t you start with that question he posed?

DR ORLOWSKI: I think certainly dara/CyBorD is a reasonable option to consider, especially for people with (AL) amyloidosis, where it’s the only regimen that’s FDA approved. But unless there are tolerability issues with an immunomodulatory drug or some kind of insurance issues, I think we have enough data to say that dara/VRd will outperform dara/CyBorD, so I do try to switch people over after the first cycle.

DR LONIAL: Yup. Paul, you have a quick —

DR RICHARDSON: I agree. I think you do CyBorD initially with a CD38 antibody and then convert with the appropriate — appropriate adjustment, sorry, of lenalidomide dosing for renal impairment. But I think the construct of alkylation, synergizing with your proteasome inhibition and CD38 antibody, then moving to leverage the immunomodulator really makes sense.

DR LONIAL: And Philippe, I know there was a randomized trial from France looking at renal insufficiency, VCd versus Vd. Do you want to tell us about that?

PROF MOREAU: Yes. In fact, while the study was quite interesting, I would say, a long time ago, now that we have the ANDROMEDA results, et cetera, we are all of us choosing CyBorD plus daratumumab as induction in those patients, so this study is unfortunately old fashioned.

DR LONIAL: Alright. So let’s talk a little bit about a patient with radiation necrosis in the skull. Anybody have experience with titanium implants?

DR RAJE: No.

DR RICHARDSON: No.

PROF MOREAU: No.

DR ORLOWSKI: No.

DR RAJE: But that was pretty innovative.

PROF MOREAU: There is a consensus for the no.

DR LONIAL: Well, no experience. I think the alternative is probably to wear a helmet all the time, which I suspect people don’t want to do.

Let’s talk about kyphoplasty. Tell me about your experiences with that. Noopur?

DR RAJE: So we do tend to use vertebral augmentation a lot if you have a vertebral compression fracture. It’s usually in situations where patients have pain. It doesn’t have to be a kyphoplasty. So the difference between a vertebral and a kypho is vertebral you’re just injecting cement. Kypho, it’s actually a balloon and injecting cement into the balloon. And really, we leave it up to the operator. We have one of our best interventional radiologists, and we leave the decision making to him.

But if you have vertebral compression fractures, either send those patients to your orthopod or your interventional radiologist, and use this, because it does help with pain control. This whole notion of increasing vertebral height and restoring height is less of an issue. It’s mostly to be used for pain control.

DR LONIAL: So let’s talk about something that I think I at least see a lot when patients get referred in to me, and that’s the use of radiation, particularly to the spine, when there isn’t cord compression. Granted there’s pain, but you haven’t really even started therapy yet. Paul, do you want to touch on at least at our practice we’re using 80% less radiation therapy now than we did 15 years ago.

DR RICHARDSON: Well, I would completely agree, Sagar. We have also been radiation sparing in the absence of failure to respond to systemic therapy, so for all sorts of good reasons. But the efficacy of initial treatment, the efficacy of combination strategies, is making — opening the door to be radiation sparing.

DR LONIAL: Yeah. Bob, you’re nodding your head like you agree.

DR ORLOWSKI: Yeah, I totally agree. I do think radiation can be helpful for pain control if there cannot be optimal medical management. But otherwise, in the absence of cord compression, we don’t do a lot of radiation.

DR LONIAL: Okay, good. Good. I mean, this was a tough case with that large area in the skull. I think it’s important to also probably mention those things probably shouldn’t be blind biopsied, because I’ve heard of terrible outcomes surgically when people try and stick a needle in them.

DR RICHARDSON: I would make 1 other additional comment, though. In fairness we do — obviously, myeloma is exquisitely radiation sensitive, and so in the setting of bulky extramedullary disease that’s symptomatic in a different sense, perhaps, we certainly think there’s a role for disrupting that architecture and making systemic drug delivery that much more effective. So I wouldn’t want to diminish the value of radiation in the appropriate setting.

DR LONIAL: Okay. So why don’t we — wait. Let’s go back. I think we’re going to turn it over to Paul to talk about integration of novel therapies into the management of relapsed/refractory myeloma.

DR RICHARDSON: Sagar, thank you very much. Well, my remit for this afternoon, ladies and gentlemen, is to touch with you on isatuximab and selinexor primarily to give you a context of how to think about these important agents.

So as I think about isatuximab I really wanted to emphasize that we do think there are some differences with daratumumab. Importantly, there’s this engagement with a different epitope, which translates in the preclinical setting into a number of different properties, and I think a couple of takeaways that may be relevant to what we’re seeing in clinical practice. I think the most important one, in my view, is this direct apoptosis that doesn’t require crosslinking.

There is also this evidence that with 1q amplification in the cytogenetics of any particular myeloma, there may be benefit to isatuximab in that group through the fact that it’s less dependent on complement-mediated killing than daratumumab is. I think what’s also very important is this effect on the — immune suppressive effects of adenosine, which raises the question of whether or not in the context of isatuximab use there are qualitative differences that may translate into clinical benefit.

Well, with the caveat of cross-trial comparisons, I think there’s some important data points to share. the ICARIA trial, which it was my privilege to be part of with Michel Attal and others, demonstrated clearly the benefit to the combination of isatuximab and pom and dex. But I think what’s important is to bring to your attention the subgroups. And in that regard, what we saw was, there was benefit in renal impairment, clearly in high-risk cytogenetics, and interestingly in frailer, elderly patients, and for that matter also in particular subgroups, including East Asian patients, interestingly enough.

Now, when we look at the final overall survival analysis for ICARIA, which we published fairly recently in Haematologica, we can see some improved long-term outcomes that are really quite distinct in terms of the hazard ratio being a 0.78 for median overall survival, and the PFS2 also translating into clinical benefit. So long-term benefit from isatuximab in this setting was clearly demonstrated.

Now, at this meeting we have a number of updates on isatuximab, but one thing I did want to bring to your attention — to you was the rapid, or hopefully rapid availability of subQ isatuximab, which we’re hoping will be coming very soon.

And then in terms of additional studies of isa/pom/dex at ASH, I just want to bring to your attention a few abstracts that will all be presented by Evangelos Terpos and other investigators, and they’re summarized here. I think probably what’s most interesting here is a large, multicenter real-world study from the Italian group, which really confirms the findings from ICARIA, and at the same time also in other parts of the world, such as the Russian Federation, a similar benefit being seen.

Now, I think there’s a very important study with isatuximab, which I think was a landmark in fact, and this was led by Philippe. And in this context, IKEMA, which compared carfilzomib and dexamethasone, probably our most powerful doublet currently available, to isatuximab/Kd, clearly showed a dramatic benefit in terms of PFS in favor of isatuximab, carfilzomib, and dex. And this translated into a number of correlative studies, or correlative surrogates, that confirmed the benefit of this approach.

And Philippe recently updated this analysis, both in terms of benefit and safety, and as you can see, there is clearly a powerful trend for survival benefit being shown in terms of the triplet over the doublet, so I think this is established as a standard of care in the relapsed/refractory setting.

And then in terms of additional studies, because it’s always nice to see these validating observations, you can see that isa/Kd at ASH, this is a real-world study for want of a better term, led by David Vesole, and what you can see here is very similar outcomes from this single-arm trial.

So there are a number of isatuximab-based combination quadruplet regimens and novel combinations in relapsed/refractory myeloma being studied. I wanted to bring your attention to one in particular, being led by my colleague and also in partnership with Noopur, the ISABELA — ISABELA study, which is a combination of isatuximab/belantamab and pom/dex. And this study is underway, and we’re very pleased to report that so far, every patient treated has responded with an excellent tolerability profile. And there are a number of other studies that I think will show the benefit of quadruplet approaches in this setting. Similarly, the combination of isatuximab with other novel agents is ongoing.

Now, I want to change gears a bit and talk to you a little bit about selinexor. Now, as we heard from Philippe, this is obviously not available in every country, and in the US certainly we fortunately have access. I think all of us would agree that the mechanism of action is intriguing.

And one way of thinking about it is as if there’s a rave going on at home, and I’m borrowing from a metaphor from Joe Mikhael, and basically the parents have left the house, and the kids are going wild, and there’s a lot of social media flying around. And this is basically the pathobiology of what’s going on in the nucleus of the myeloma cell. And what essentially happens is selinexor brings the parents back to shut the rave down and shuts off the social media, and so as a result of that there is stabilization of the pathobiology of disease. And this is particularly important as you think in terms of the reduction of tumor or rather the increase in the nuclear levels of tumor suppressor proteins and their activation, and most importantly the restoration of sensitivity to glucocorticoids, and at the same time synergy with other drug combinations.

What is, however, true, is that when we first started exploring selinexor as a doublet we recognized its activity, but it’s tolerability was a challenge, particularly at the dosing schedule that we explored. And there was a pivotal paper, led by Ajai Chari, published a few years ago now in New England Journal, which established this and provided nonetheless the platform for accelerated approval.

Further studies have looked at selinexor combined with dexamethasone and have shown this consistency of result. But I think what’s most important is when you combine selinexor with proteasome inhibition things change, and the BOSTON study exemplified this. And this was the Phase III study that led to the full approval of this triplet by virtue of a clear PFS benefit, as well as other parameters of clinical response. I think what’s also important is this study explored weekly bortezomib against a twice-weekly control and clearly in that setting established not only less neurotoxicity but still demonstrated benefit, so an important trial for selinexor going forward.

There are some additional studies being presented at ASH in this session — or this meeting I should say. This is an intriguing, I think, Phase III randomized study from our colleagues in China, and this confirmed similarly the benefit in the Chinese population from this approach.

Now, a comprehensive is being made with selinexor to combine it with other drugs, and I’ll move through this quickly in the interest of time, but essentially combining selinexor with bortezomib or carfilzomib has clearly resulted in clinical benefit in this series of studies. And similarly combination approaches with ixazomib, interestingly enough, have proven feasible and active.

This is then a summary of a variety of additional selinexor combinations under trial, and what you should know here is that basically consistency of signal has been demonstrated. But as Noopur mentioned earlier, this construct of weekly dosing at lower dose makes the tolerability that much better.

So in that spirit, how do we best combine selinexor with pomalidomide, which has been an important dark spot in a wood sally? And a couple of important points to share. (1) That if you dose at 60 mg once a week it’s well tolerated, and (2) that you can actually look at doses as low as 40 mg once a week and still see evidence of clinical benefit. But I want to be a little cautious here because in real-world studies the 60 mg once a week may be very important. Nonetheless, that 40 mg dose is clearly active. So a number of important takeaways.

Now, in that regard, there’s a very important ongoing trial from the European Myeloma Network looking to establish the role of selinexor in combination with pom/dex compared to an elo/pom/dex control, and we’re awaiting the results of that trial with great interest.

Now, we touched on a moment ago about the combination of selinexor with daratumumab, Bob mentioned this, and certainly that’s being shown to be efficacious. Then if you combine it with bortezomib, so you’ve got basically dara/Vd plus selinexor, we see clearly striking results, with an 82% response rate and impressive durability of disease control.

Now, I think very excitingly the combination studies are ongoing with selinexor, and one I want to bring to your attention is led by my colleague, Dr Clifton Mo, and this is the combination of selinexor with mezigdomide and dex, which in the context of CAR-T therapy in BCMA-exposed patients we think is particularly promising and exciting.

Now, what about the safety profile? Well, a couple of things to share here. Managing this becomes very important, go low, go slow; weekly lower dose and escalate. And very importantly prophylaxis and management of GI toxicity is key. In the interest of time I’ve included these in the PDF, so please do read these because they’re very helpful. And then this basically goes into the guidelines around fatigue and thrombocytopenia. But I think as long as one understands that these side effects are manageable with proactive approaches to care our experience has been very favorable.

So with that in mind, concluding takeaways for this afternoon. In terms of isatuximab for relapsed/refractory myeloma, I think we can clearly say that isatuximab-based triplets have established standards of care in the management of early-relapse patients, and clearly the combination with both pomalidomide and with carfilzomib have been approved on that basis.

Now, I think what’s very interesting is because we’ve got quadruplets with daratumumab now established the question is how do we then integrate isatuximab in that setting, and certainly one can think of it in the relapsed setting accordingly, although, of course, it’s now moving up front.

So this is a challenging area, and the feasibility of CD38 retreatment, I think, remains an area of active study, but nonetheless the takeaway that you can use isatuximab in the relapsed setting for higher-risk disease, for example, after perhaps prior exposure and cessation of daratumumab earlier in the front-line setting, I think is supported. But clearly, we see the value also of BCMA approaches earlier, so I think we have to think about this as we sequence therapies.

Now, I think what’s also very important is that isatuximab-based quadruplets are now very much under study, and we’re looking forward to seeing results of that to further guide us in terms of choices of treatment. And multiple novel isatuximab-based combinations are under investigation, and 1 example, as I’ve mentioned, is the ISABELA study, where we’re combining isatuximab, belantamab, pomalidomide and dex; excellent tolerability and responses so far, is 1 example.

So finally then to selinexor. What about the conclusions for this particular approach? I think obviously we see combination approaches matter. T-cell-exhausted patients, in particular, might benefit from this in combination with other strategies, particularly high-risk patients may benefit also, 17p in particular.

As we think about supportive care, this is vital, but please bear in mind this strategy in the era of CAR-T therapy in BCMA-exposed patients. And finally, last but not least, by no means least, as we enter the era of CELMoDs, which we’ll hear about in a minute from Sagar, think about this in combination with these new agents to improve outcome.

I want to thank you very much for your kind attention.

DR LONIAL: Alright. Thank you, Paul. We’ve got a couple of questions from the audience. Philippe, I want to start with you, and you can take more than 1 word to answer this question. MRD depth of response, does it correlate with survival? Do you want to talk about the IMS and the MRD workshop?

PROF MOREAU: Yes. In fact, we have a very large database now, and we worked, the academic groups with the pharma companies, to define the I Square project. And with I Square we have more than 12,000 patients analyzed for MRD, and we were able to demonstrate that MRD was a surrogate for PFS and OS. And now the FDA is accepting MRD as an endpoint for clinical studies, and we are trying to reproduce the same with EMA, with the European authority. So I believe that MRD will become very, very important in the future.

We also did organize very recently a workshop on the new definition of response. The response criteria were published in 2016, 8 years ago now, so we need to update, of course, those response criteria, and we are going to incorporate systemically MRD in this new response criteria.

Chimeric Antigen Receptor T-Cell Therapy for MM — Dr Raje

DR LONIAL: Let’s move on now to the next module, and we’re going to start with a video here.

DR LOVE: The next case was presented by Dr Apuri, a 67-year-old woman with standard risk myeloma who was treated in 2021 with RVd followed by autologous transplant.

DR APURI: Post-transplant she did achieve VGPR, and she was initiated on lenalidomide maintenance followed by bortezomib.

Unfortunately, she did struggle quite a bit with the maintenance therapy with fatigue and pancytopenia, so there was a significant amount of dose reductions.

And after that she was initiated on daratumumab, trying to manage her pancytopenia and fatigue.

Unfortunately, she progressed 2 years post-transplant and was initiated on pomalidomide and dexamethasone. She was then referred to a tertiary center for CAR T therapy.

She’s relatively young and good performance status outside of the severe fatigue that she was experiencing and some cytopenia.

My question for the experts is how would you modify your treatment prior to CAR T so the patient can get the maximum benefit of the therapy.

My second question would be how do you pick the CAR-T. Is there a difference between 1 versus the other?

I know there is some discussion that selinexor can help prior to CAR-T therapy. I know we tend to use it like in later lines of treatment for the most part because we have a lot of approvals in the myeloma field, so sequencing the medications does become a challenge.

So in this patient, because she’s young, I was hoping she could tolerate the selinexor prior to CAR-T.

DR LOVE: Have you ever used selinexor?

DR APURI: I have used it on 1 patient, but I had to use it like as a fourth line of therapy, and she was an elderly patient. I have seen toxicity with selinexor, so I would like to know what would be a preferred starting dose for somebody who has used this more often than me.

In her case, I had to do significant dose reductions for her to be able to tolerate the medication.

DR LONIAL: Okay. So Bob, I want to start with you. Tell me a little bit about bridging when you’re thinking about a CAR with the story we heard from this patient.

DR ORLOWSKI: Well, it really comes down to what have they had before and what was the response. If they have drugs that they had before that worked, to which the myeloma is not refractory, it’s perfectly reasonable to go back and reuse something that worked before or to do it in a new combination. Otherwise, I think we’ve talked about selinexor as a potential bridge. I think alkylating agents are a reasonable bridge if you’ve already collected the T cells, of course. You don’t want to give bendamustine or other alkylating agents before you do the T-cell collection. But there are a number of these drug categories that can still be very successfully used.

DR LONIAL: So Noopur, let’s — I know you’re going to touch on this in your slides. Tell me a little bit about how you think through the process of early/late CAR given that we have the ability, in the US at least, to give it in the second- or third-line therapy.

DR RAJE: Yeah. I think the good news is the approval is early, and as we’ve all been talking all afternoon is we’re using combinations. So what used to be a penta-refractory patient is actually a quad- or a penta-refractory patient at first relapse.

So thinking about CAR T cells early is the key. Figuring out how to bridge them for that short period of time is important. And then looking at things, and when we do my part of the discussion, really looking at non-myeloma-related mortality and what are the risks that we’re exposing our patients to are the things which come into our decision making mostly, Sagar.

DR LONIAL: Okay. Thanks, Noopur. And Paul, do you want to talk about this data on selinexor prior to a CAR?

DR RICHARDSON: I think it’s very interesting, and I think there’s this evidence that there is this potentiation and augmentation of T-cell quantity and function, so certainly worth thinking about. I think the oncologists on the interview is making a very important point though about dosing schedule, wasn’t she, in terms of lower dose and weekly. And I think I would just — right now there’s a fashion for doing 40 versus 60. I’d just be a little careful with that, just because I do think there’s a dose response with seli. But broadly speaking for CAR-T therapy it’s very interesting.

DR LONIAL: Philippe?

PROF MOREAU: Yes. I wanted to ask Noopur, but maybe you are going to speak about this during your talk, what about bispecific antibodies as a bridge before CAR T-cell therapy after harvesting the T cells, instead of selinexor? That, in my opinion, is suboptimal.

DR RAJE: Yeah, no. We agree 100%. I think the key takeaway from this would be do the bridging after you’ve collected with the bispecific, because if you do it before that’s when you run into problems.

DR LONIAL: Okay. Let’s hear about the next case.

DR LOVE: The next case presented by Dr Ma is a 51-year-old woman who presented with myeloma and renal failure in 2019 and had a suboptimal response to induction treatment and autologous transplant but then entered a clinical trial of CART therapy, which was later followed by lenalidomide maintenance. She continues in remission currently.

DR MA: Her response had deepened over time on repeat marrow biopsy. I’m curious, is that considered a residual CAR T long-term benefit that we see patients have deeper and deeper response over time?

Right after the CAR T consolidation, in March of ’20, on her repeat marrow she still had 1% to 2% residual plasma cells. So then we repeated a marrow in ’23. We don’t have any visible disease, but ClonoSEQ® can detect still 133 copies.

And then the response got even improved in ’24 when we repeated. The copy number had decreased to 44. So it seems like the response has deepened over the last 2 to 3 years since finishing the CAR T treatment.

As a community practitioner I know if ClonoSEQ comes back negative for minimal residual disease it’s a good prognostic factor. But how reliable are these copy numbers when we see a decline? Are these a pretty accurate assessment, or these are not always a true reflection of the disease status?

DR LONIAL: Okay. So let’s start off with the deepening responses over time. Noopur, do you want to take that one?

DR RAJE: Sure. So in myeloma traditionally we’ve seen deepening responses over time. Specifically with maintenance treatments we see responses deepening 2 and 3 years down the road as well. This patient obviously was put on an immunomodulatory drug.

I do think what you do for maintenance is dependent on what CAR product you end up getting. And we’ll talk a little bit about the differences in the different CAR products, so not every CAR should be followed by maintenance, but deepening of response is absolutely seen. And the issue of copy number, that’s why we say don’t go by 1 MRD alone, and doing more than 1 is what should trigger at least changes in treatment. That work is still ongoing, and there are clinical trials addressing that, so I wouldn’t necessarily change treatment just based on copy number increases in some of these patients. So MRD-negative to becoming positive on 1 reading is not enough, for me at least right now, to change treatment.

DR LONIAL: So Bob, I want to ask you, is there a timepoint in disease response post-CAR that you look at and say this person is or is not going to do well, and maybe I need to intervene here, as opposed to maintenance, which I think Noopur addressed?

DR ORLOWSKI: Yeah. It’s a great question, and definitely, unlike this patient, I can’t think of a patient I’ve seen where they’ve had such a prolonged downward trend in their disease burden. Typically what we see is a huge reduction in myeloma disease burden very early on and MRD negativity developing early. But usually within about 3 months, if they have not achieved MRD negativity, then that’s probably a patient, quite frankly, that is not going to unless you give them some additional help.

DR LONIAL: Philippe?

PROF MOREAU: I would like to add that MRD negativity is very, very important for sure in the follow-up of patients treated with CAR T-cell therapy, but we are systematically adding imaging and PET/CT because we know that those patients, very advanced, have very often extramedullary disease. And to be sure that your patient is in CR you need to not only have MRD negativity but also PET/CT negativity.

DR LONIAL: Yeah. Go ahead, Paul.

DR RICHARDSON: No. I was just going to say I would echo that. I’ve just recently had a patient of mine who was MRD-negative CR after CAR T for 10 months, and then out of the blue a PET/CT lit up even though the MRD remained uninformative in that regard. So I completely agree, Philippe.

I think what’s also struck me, Sagar, is honestly that I’m a little bit concerned that the MRD negativity seems to be a little unstable in certain settings in CAR T. There are lots of reasons for that, which we’ve discussed before, but I don’t see that same — the same degree of stability that we see, say, from the up-front setting in CAR-T.

DR LONIAL: Yeah. So Philippe, I want to ask you this last question before we get to Noopur’s presentation. When I see a patient with an M protein of 0.2, and then it becomes 0.3, or it becomes 0.1, I always say to them, when you’re in a car, and you’re going 55 miles an hour, are you really going 55, or are you going 57 or 53, right? There’s a lot of play in those numbers. What’s the play in an MRD copy number assay? What do you say is noise versus real differences?

PROF MOREAU: Well, we are just starting a very — well, analyzing a very important study that we did in France on 400 patients treated with CAR T-cell therapy, ide-cel, and we want to know how many timepoints do we need to be sure that the patient is remaining in — with a very good prognosis. We are now trying to do after 1 month, 3 months, 6 months and 12 months, together with imaging, and we will see what is — what are the best timepoints, probably, because we cannot propose bone marrow aspirate to patients every 3 months, for sure. So we need more data. We need more data. And probably Noopur will discuss this during her presentation.

DR RAJE: Alright.

DR LONIAL: Alright, Noopur.

DR RAJE: So that was a perfect setup, so I’ll talk about CAR T cells in the next 10 minutes, and I wanted to focus on a couple of issues here.

So these are the 2 constructs, which are approved. You have ide-cel. You have cilta-cel. Both of them are BCMA directed. Remember that ide-cel has a murine scFv, whereas cilta-cel is llama-derived 2xVhH. Why am I saying this? There are subtle differences between these 2. With the murine scFv you have more of immunogenicity; the CARs don’t persist as much. With the llama it’s a much smaller, little region that binds to the antigen, so with that you get better binding. With that better binding you get better expansion, and that may be why we are seeing differences in responses of these patients.

We’ve all seen data on the KarMMa trial. This was the ide-cel registration trial, which actually got the drug product approved for the first time around. 128 patients. Overall response rate about 80%. And if you look at patients who achieved a complete response, which was about 35%, 36%, their PFS was close to 22 months, and their MRD-negative rate was about 25% to 28%.

Switching gears now and talking about cilta-cel. This was CARTITUDE-1, which actually got cilta-cel approved. Now the response rates are very different, and this is why I was talking about the llama binder versus the murine scFv. So every CAR product is not the same, even if they’re targeting BCMA. Out here you see the response rate for cilta-cel is close to 100%, and if you look at the VGPR rate or the CR rate it’s 80% compared to what we saw with ide-cel of about 25%, 26%. So obviously both of these CAR constructs are very different.

This translated into a median progression-free survival of about 34 months in patients who got cilta-cel. And if you look at MRD negativity, now MRD negativity not just at 1 timepoint, but more than 6 months or more than 12 months, the progression-free survival of these patients was a whole lot better. And the overall survival of patients who achieved that MRD negativity, specifically the sustained MRD negativity was very significantly improved.

In terms of CRS and neurotoxicity, I don’t think we’ve seen any new signals. The important thing to remember is with cilta-cel we are seeing a higher incidence of a delayed neurotoxicity. Having said that, we see that with ide-cel, as well, but the numbers are a lot lower. And again, this may be to do with how these CARs are binding to the tumor-associated antigens of interest.

Now if you look at the safety, and this is something — as we move all of these CAR products earlier, this is going to become more and more important. If you look at the deaths on the CARTITUDE-1 study, we had 30 patients who actually died, 14 of them from progressive myeloma, which is completely allowed. But the rest of them, so 16 patients, died of non-myeloma-related mortality. And this is the way we make the decisions of where to use these CAR T-cells. So there was a few second cancers here, leukemia, infection risk is also present.

So as we start moving these CAR T-cell therapies early, we have KarMMa-3 now. This was ide-cel versus standard of care, and with this study it is now approved in patients who’ve had 2-4 lines of treatment. The important thing to remember here is the majority of these patients were daratumumab refractory. This translated into response rates which were quite similar to the earlier study and a PFS of a little — a little short of 2 years.

CARTITUDE-4, again, earlier lines. This is a lot earlier. This is in patients who had had 1 to 3 prior lines of treatment. And if you look at dara refractoriness it was just about 25%. Less than 25% of these patients were dara refractory, just telling you that these 2 studies were in very different patient populations. Again, overall response rate on an intent-to-treat analysis was 85% with the cilta-cel, and as you move CARs earlier the PFS seems to improve in this patient population.

Again, no new signals. We still have the same toxicity as we’ve seen with the earlier trials.

We do have long-term data now with CARTITUDE-4. Remember, CARTITUDE-4 did not allow for crossover. You’re never going to get the survival data with KarMMa-3, because KarMMa-3 patients were allowed to cross over. And when you look at this, which was presented at the IMS meeting a couple of months back, you see that there is a survival benefit for patients who got cilta-cel compared to those who got standard of care. And the median follow-up of 33.6 months, the median PFS is not yet reached, with about 60% of patients remaining without evidence of disease.

We do have trials which are ongoing. We have CARTITUDE-5. This is for the transplant-ineligible patient population, where it is being compared to RVd. And we also have CARTITUDE-6, and the question here is can we finally replace an autologous stem cell transplant with something like cilta-cel. This is an ongoing trial. This is accruing as we speak, and we’ll see whether or not this pans out and is a positive study.

What about some of the emerging CAR T-cell therapies in the relapsed/refractory setting? We have a few. We have 1 from BMS. This is targeted GPRC5D. This is the same target that uses talquetamab. This is essentially present on all myeloma cells, all plasma cells.

And we don’t quite understand the function of GPRC5D. If you look at the response rates with this CAR T-cell, very high response rates. And the important thing to note is a lot of these patients have had prior BCMA. So if you’ve had prior BCMA you can still use another CAR T-cell, because this was a question in one of the videos that we had earlier. A lot of these patients had high-risk disease and also had extramedullary disease.

The median duration of follow-up on this study is only 9 months. This data is being updated at this meeting, so we’ll see this data later on during the course of this meeting as well.

Obviously, with all CAR T cells the FDA has warned us about second cancers, and the risk does exist. But when you look at a whole dataset, and this was the dataset of lymphoma and myeloma patients, in close to 500 patients the risk of second cancers absolutely exists, but it is a small risk. It’s about less than a percentage point. And then when you weigh the risks and the benefits, I think most of us who use these therapies would argue and say that using CAR T cells is the right approach.

There’s a lot of questions, lots of challenges, as we move these therapies early. What do we do with sequencing of some of the other therapies? So we’re already talking about moving them up front. The issue, again, is do we then use maintenance, and that was brought up on one of the videos as well, and should we be using this in isolation or can we begin to think about combining some of the assets that we have in myeloma already.

So a little bit of data on sequencing. And this is largely real-world data. Some of it is from CARTITUDE-2. If you look at this data, if you’ve had either an ADC or a bispecific on CARTIDUDE-2 against BCMA and then give them cilta-cel, the outcomes are quite poor. ADC exposed, the median PFS is only 9 months. Bispecific exposed, it’s only about 5 months. Again underscoring the fact that if you’re planning CAR T cells do not expose your patients to an ADC or to a bispecific, but really refer those patients earlier.

Same thing is true for ide-cel as well. If they’ve had either an antibody-drug conjugate or a bispecific the response to that CAR T-cell is really not great, and the median PFS was something like 3 or 4 months only.

The converse, however, is not true. So if you’ve had CAR T cells you can always go at the backend with a bispecific. And this is data with both teclistamab, as well as elranatamab, and I’m sure Philippe is going to show us more of this data. So again, reserve the TCs or the TCRs, the bispecifics for after a CAR T-cell if that is the plan in what you’re going to be doing.

Again, I think — this we’ve already talked about. The big question in my mind is should we be thinking about CAR T cells and bispecifics in isolation, and I would argue and say really not. Why don’t we use the benefits of both?

So we are as we speak doing a current study. In this case we’re using ide-cel after 3 or 4 lines of treatment, and following ide-cel, because of what you saw in terms of complete response rates, we have room to improve the impact of ide-cel. We’re actually using a fixed duration of a bispecific. In this case we’re using elranatamab. So I do think we can use them sequentially, and we’ll see. This trial is accruing as we speak. We’ll see what the data looks like once we have this.

Again, in terms of CAR T cells, I believe we’re just about scratching the surface. We are at the second generation of CAR T cells, that’s right here. We have all of these, which will be used. We already have a third-generation CAR, which we are using in the clinic. It’s called the TriPRIL CAR. It targets TACI, as well as April, and we’re seeing good responses with that. But we’re just about beginning to do these studies, and the future of CAR T cells, where you can do dual targeting, you can use intracellular signaling to augment the CAR T cells, is yet to be — the benefits of that is yet to be seen, I believe.

DR LONIAL: Okay. We’ve got a couple of questions. Thank you, Noopur. One question, Noopur, for you, and then I’ve got 1 quickly for the group. Does the llama dual binder higher affinity drive the parkinsonian toxicity?

DR RAJE: We don’t know that for sure, but I do think it — when you have the llama construct it allows for better binding. The other thing with the cilta-cel is it’s biepitopic binding, so is the binding so tight to BCMA? Because we do know that BCMA expressed on neural tissue, it may be one of the factors.

DR LONIAL: Yeah. That makes sense.

DR RAJE: But we haven’t proven that as yet.

DR RICHARDSON: Yeah. Just to echo that. Noopur and I shared a case of a person who unfortunately perished from late Parkinson’s after ide-cel. So I think clearly the complexity of this lies in the BCMA expression in the midbrain.

DR LONIAL: Okay. And Bob, I’m going to ask you this in terms of what do you say to the patient who you’re recommending a CAR for, and they say but the FDA says there are T-cell malignancies and second cancers, and I’m scared.

DR ORLOWSKI: I think it’s definitely a legitimate concern, and there are a couple of cases that have been reported of T-cell malignancies, but the benefit, as in part shown by Noopur, in this setting really far outweighs the risk, and I would say that the risk of them dying from poorly or incompletely treated myeloma is much higher by several orders of magnitude than the risk of developing a second malignancy of T-cell origin because of the CAR.

DR LONIAL: Yeah. Yeah. I think that’s helpful. Thanks, Bob.

Bispecific Antibodies for the Treatment of MM — Prof Moreau

DR LONIAL: Alright. So let’s get to the next case as we go into Module 4.

DR LOVE: The next case, presented by Dr Malik, is 72-year-old woman who was treated in 2015 for standard-risk myeloma with RVd followed by auto transplant and bortezomib maintenance, because of poor tolerance to lenalidomide, which had to be discontinuation because of persistent rash. In 2022, 7 years after transplant, she had disease progression.

DR MALIK: I decided to start her daratumumab and pomalidomide. And she responded well for some time, but she then did develop some shortness of breath, and after CT evaluation, there was concern for interstitial lung disease by pulmonary.

So I decided at that time to switch her to daratumumab and carfilzomib. But she started having a lot of nausea and vomiting related to carfilzomib, so I switched her over to daratumumab and bortezomib.

And she started progressing again. I referred her back to our transplant center just to kind of get in line what we may do next. And they recommended possibly doing another autologous bone marrow transplant because she had such a long duration of response. And so I had referred her over for CAR T evaluation just so patient could get information.

In the meanwhile, the bispecifics have played a big role in myeloma, so one of my questions is how we would determine what would be best for this patient. Would it be an autotransplant? Would it be CAR-T or bispecifics?

She’s a patient with a good performance status. She has a very active lifestyle. She goes for a walk every day and is very healthy.

Are there any trials that compare bone marrow transplant to CAR-T telling us which patients may respond longer? Or do we have any genetic mutations in the bone marrow that we know for specific patients, such as the 1q minus or TP53, with myeloma that do better with transplant versus CAR-T?

DR LONIAL: Okay. So we’ve got a couple of questions here. One that actually came at the end of the last session that I think fits better here, the use of either radiotherapy during or around bispecifics or the use of — or bispecifics in patients with dialysis. Does anybody have experience they want to speak to?

PROF MOREAU: I can take the question regarding dialysis. In fact, we have published very recently the French experience. So with bispecific antibodies really no issue. You can use with the full-dose, full-dose patients.

DR LONIAL: Okay.

PROF MOREAU: And the response rate is very good indeed. Yeah.

DR LONIAL: Yeah. It’s an antibody, so I think just like any other antibody it’s not really an issue.

The question specifically was about higher incidences of neurotox in patients with — who are on dialysis who are getting a bispecific. It’s not suggesting there is, it’s asking the question. Nobody’s seen it.

DR ORLOWSKI: We’ve treated a few folks with bispecifics on dialysis, and no problems of neurotox.

DR LONIAL: Okay. Alright. So let’s go back to this first question here. Patients who are intolerant of len maintenance, what are you going to think about doing in that situation? Paul?

DR RICHARDSON: Well, there is clearly now a role for proteasome inhibition in maintenance, so in the past we certainly always would think about bortezomib or in the appropriate setting carfilzomib or ixazomib, either of the 3. I think now with the antibodies established, I think that it is reasonable to consider dara monotherapy in the appropriate setting as well. I do think, however, one has to be thoughtful about risk, and I think if you’ve got a higher-risk patient, if there’s a strategy, for example, around a proteasome inhibitor and a monoclonal, if it’s true intolerance, fair enough. That wouldn’t be unreasonable in my view to think about.

DR LONIAL: Okay. And this other question about second transplant for patients with prolonged first responses. Bob’s shaking his head. He said no to transplant earlier, but he’s coming around.

DR ORLOWSKI: I thought you might pick up on that. Yeah. I think for me if somebody’s had at least a 5-year progression-free survival after the first transplant, and you’ve not given them 10 lines of therapy in between, where it doesn’t matter, then I think a second transplant is certainly reasonable and will still probably give you a better PFS than any of the things we’ve talked about here so far.

DR LONIAL: Yeah. Philippe, do you want to —

DR RAJE: I’ll just add 1 thing to that.

DR LONIAL: Yeah. Go ahead.

DR RAJE: We are presenting data tomorrow where we’ve looked at exposure to high-dose melphalan and outcomes with CAR T cells. In patients who’ve had high-dose melphalan T-cell health never really recovers. Their outcomes are a little bit worse.

The other thing I would say is for a second transplant we’re talking about it in 2024, we have so many different options. We’ve always collected for 2 transplants, but when we look at our database, we hardly ever use the second stem cell for a transplant. We’ve used it for other reasons, but not necessarily for transplant.

DR LONIAL: It’s a good thing Paul’s sitting between the 2 of you. Go ahead, Paul.

DR RICHARDSON: Very quickly. I would wholeheartedly agree with Noopur just touched on. I think another point to share is the Mount Sinai group presented at ASH a couple of years ago their real-world experience in 70 CAR T patients and the incidence of MDS. We touched on the T-cell malignancies, but the MDS signal in that group was 25%. And if you looked at where those patients came from, they were typically exposed to chemotherapy and high-dose melphalan.

And I think in the CARTITUDE studies — CARTITUDE-2, there were 3 cases of AML and at least 1 of MDS. So I think we just have to be thoughtful about this because at the end of the day magnifying that second cancer risk in CAR T with excessive exposure to alkylation may not be wise.

DR LONIAL: Okay. Let’s get to the next case.

DR LOVE: The next 2 patients, presented by Dr Bufalino, both received bispecific antibodies, beginning with a 56-year-old man with multiply relapsed disease who was not a candidate for CAR T because of comorbidities.

DR BUFALINO: Luckily at that time is when teclistamab was approved, and he started on that. And he was on about a year and a half of therapy and did very, very well. Achieved a very deep response with it and then eventually progressed.

And then I rechallenged him with talquetamab, which he’s currently on now. And he’s had a lot of toxicity with this. A lot of nausea. He’s had a lot of diarrhea as well.

And so I just wanted to pose the question of how are we managing these toxicities.

Dysgeusia has definitely been reported as a very frequent toxicity. I don’t know if anyone’s had any tricks or ways to keep people on treatment with that side-effect profile.

DR LOVE: How about your 64-year-old woman?

DR BUFALINO: She relapsed. She was offered referral for CAR-T therapy and refused. And we moved on to teclistamab.

And she achieved a very rapid response to therapy, but then developed neutropenia requiring dose reduction and the frequency of the administration. So she was only really able to tolerate every-2-week of therapy.

So I wanted to just discuss the frequency of administration and the toxicity of BiTE therapy in multiple myeloma. How often are we seeing neutropenia? And how often is that resulting in delay of dosing and decrease in the frequency of administration?

DR LOVE: What’s her current situation?

DR BUFALINO: So she’s been on therapy probably a little over 9 months, and she has had a very nice response. Her free lambda light chain is totally normal, and she has no detectable M protein.

Has anyone had experience with CAR-T cell after BiTE? And does that cause T cell exhaustion? And how is that tolerated?

DR LONIAL: Okay. So let’s get to this question about — and Noopur, you touched on the sequencing issue during your talk a little bit here, but I want to get to this question of dosing schedule. Noopur, do you want to touch on your clinical practice with dosing schedule for bispecifics?

DR RAJE: Sure. So early on, I think when you’re doing the step-up dosing, we’re doing it by convention over the course of the week. With talquetamab, which you brought up, most of us go to the every-other-week of talq. That’s way better tolerated, and some of the toxicities which were mentioned by the physician out there of dysgeusia, weight loss and nausea, those are hard to treat. And the only way that we can come around those, in my experience, is by holding drug, so delaying dosing. And even for the other bispecifics I think we move very quickly to every other week and even once a month, once they’ve gotten the response, to mitigate the toxicities.

DR LONIAL: Okay. So let’s talk about this second question here. What’s the interval — we’ll start with Bob and then come down this way. We’ve got a minute for this question in total. Somebody’s progressing on a BCMA CAR, what’s the interval that you’d feel comfortable thinking maybe I’ll rechallenge them with a BCMA bispecific?

DR ORLOWSKI: I wouldn’t necessarily look at the interval, but we have assays available for BCMA expression, as well as sequencing, and if they still have wild-type BCMA at a reasonable level of expression, then I would feel comfortable rechallenging. If they’ve had mutations or deletions, then probably not.

DR LONIAL: Okay. Paul, Noopur, do you want to add anything?

DR RICHARDSON: I think it’s very thoughtful what Bob just shared, but I also think moving to a different target makes sense, right? GPRC5D we’ve found helpful in that setting as a point.

DR ORLOWSKI: I agree.

DR LONIAL: Okay. Alright. Well, I think we’re going to get to Professor Moreau.

PROF MOREAU: So thank you, Sagar. So let’s speak about bispecific antibodies. And we are strongly believing when patients are refractory to IMiD, PIs and CD38 antibodies the best option is probably an anti-BCMA strategy. And Noopur nicely discussed the role of CAR T-cell therapy, so we can use also anti-BCMA bispecific antibodies.

You know that we also have different constructs when discussing about those antibodies. And construct B, for example, without the Fc portion, is no longer used because we know that the half-life is very short, and we need a continuous IV administration. So currently we are using mostly the construct A, with 1 arm targeting a myeloma antigen and 1 arm targeting CD3. But we are in the future to use trispecific antibodies, and during this meeting, next Monday, we are going to use — to listen to very important data with those new constructs. It will be possible to target 2 different myeloma antigens or to target a T-cell or an NK cell at the same time, for example.

So on the surface of the myeloma cells we have different antigens. BCMA is the most important one, for sure, but we also have other antigens that are commonly expressed, such as GPRC5D, FcRH5, and next Monday we are going to hear about the cevostamab data targeting FcRH5 for example.

So let’s speak about teclistamab and elranatamab, the 2 bispecific antibodies targeting BCMA that are currently approved by FDA and EMA, but we have others in development for sure.

So teclistamab was first reported in 2022, in fact, based on the MajesTEC study, and you see the construct targeting the T cells with a T-cell expansion and targeting BCMA, redirecting, in fact, the T cells close to the myeloma cells, inducing the myeloma cell death.

We are using systematically step-up doses, 2 step-up doses to reduce the toxicity during the first week and subsequently full dose, 1.5 mg subQ, weekly. And when you’re looking at the response rate in this Phase II MajesTEC-1 study, on a large number of patients, 160 patients, the overall response rate is 63%. So two thirds of the patients are going to respond, in fact, and interestingly the median progression-free survival is 11 months. That’s very close to the results achieved with ide-cel. But most importantly, when you’re looking at the median duration of response with this update analysis, 24 months.

So in front of you, you have a patient that is responding. And the responses are very quick, in fact, within the first month you are going to know if your patient is responding yes or no. So in front of you, you will be able to say to your patient and to the family okay, you’re responding to the drug, and potentially the median duration of response will be 2 years, so that’s very important information.

What about safety? The safety profile, in fact, is rather good, as you know, but when we first reported the data infection, Grade 3 or Grade 4 infection rates was quite high, in fact, and in this update analysis 55% of infection. So that’s really the most important adverse event. So we need systematically to use IVIg replacement in order to decrease, in fact, the rate of severe infection. And also, we can use, after 6 months, in patients with a very good response, we can use this bispecific antibody every 2 weeks instead of the weekly schedule, and we are going to reduce, as well, the rate of infection.

So what about CRS. CRS is very predictable. The time to onset is 2 days. The median duration is 2 days. But we don’t have any Grade 3 CRS, mostly Grade 1 or Grade 2, so that’s really manageable in the outpatient setting. And we know that we can also use prophylactic tocilizumab, and we have some data now, in order to reduce this rate of CRS that overall is 70%.

The second in class is elranatamab, developed in the MagnetisMM-3 study. Cohort A, 123 patients had never received previously any BCMA-directed treatment. So elranatamab is very active. The response rate is almost the same as teclistamab, 61%. But we know that for those 2 bispecific antibodies some subgroups of patients have a poorer response. Patients with extramedullary disease, patients with ISS III, or patients that are truly pentarefractory. The response rate is close to 30% or 40% only.

So the study was published and updated very recently, and we see now the median PFS of 17 months, which is quite good, as well, and median overall survival is 2 years. So to my opinion, those 2 bispecific antibodies have similar results compared to ide-cel. That’s not cilta-cel. That is really the best BCMA therapy. But nevertheless, there is big competition between those 2 bispecific antibodies and ide-cel.

But we have to keep in mind that some subgroups of patients are not benefiting at all from those bispecific antibodies. And you see here that if you are combining an ISS III and 2 cytogenetics the response rate is 0%. The same for ISS III plus EMD; response rate is 0%. So you can select potentially some treatment according to that very important information.

The CRS, exactly the same rate in the MagnetisMM-3 study. No Grade 3. And infection, as always, 40% Grade 3 or 4. So you should use systematically after the first month of treatment IVIg replacement.

So what is the outcome of patients that are really quad-refractory, refractory to IMiD, PIs, CD38 and BCMA treatment? In our experience in my department the overall survival is 6 months, so a very poor outcome, with the exception, in red on the right-end part of the slide, of some patients who are about to receive talquetamab. So you can salvage patients failing BCMA with other agents targeting other antigens.

And this is the picture of what you can do when patients are quad-refractory. Of course, clinical studies, as always, you can use new drugs, iberdomide, mezigdomide, but we can also use new bispecific antibodies, and talquetamab was developed in this setting. We have now 2 bispecifics targeting GPRC5D, talque and forimtamig, and we are going to hear about the update analysis of cevostamab next Monday.

So talquetamab is now approved by FDA and by EMA targeting GPRC5D. And you see that the response rate in the MonumenTAL-1 study is very good, with 2 different doses, 0.4 or 0.8. And that’s quite convenient to have these 2 dosages because you can adapt the treatment. And if you have a significant toxicity, the oral toxicity, the dysgeusia, the weight loss, you can switch from 0.8 to 0.4, because dose reduction is probably the only thing that we can do, dose reduction or dose delay, when we have this significant toxicity.

So the data will be updated at the optimal dose, 0.8 mg/kg every 2 weeks. The median PFS is 14 months.

What about toxicity? We spoke about the skin-related adverse events, the weight loss, the dysgeusia, because GPRC5D is expressed on the central region of the tongue and on the skin and on the nails, so dose reduction and dose delay as soon as you have those adverse events that are occurring.

So what about sequencing? Teclistamab post BCMA/immunotherapies was tested in the MajesTEC-1 study. The paper was published very recently, but you see that the median PFS is not that good in fact. The median overall survival is 15 months. So you can rescue patients, but the duration of response is not optimal at all.

The same is true for elranatamab. Maybe better results. This is a subanalysis of the MagnetisMM study. But for those patients that are going to respond after a prior BCMA exposure the median duration of response is quite good. It’s better than 1 year probably.

And can we sequence from a BCMA agent to GPRC5D? We have a subanalysis of MonumenTAL-1. When patients were treated with talquetamab, and where all of them previously exposed to a T-cell redirection treatment, that’s only 51 patients, but nevertheless the response rate, on the right-hand side of the slide, is 62%. So good response rate. But look at the median PFS at the bottom of the slide, 5 months only, so that’s not optimal. Definitely we can sequence, but nevertheless the results will not be that good.

So what about combination treatment? And we have good data of the combination of talquetamab and teclistamab in this RedirecTT-1 study presented twice in different meetings. The optimal dose, the full dose of tec, 3 mg/kg every 2 weeks, and 0.8 mg/kg talquetamab every 2 weeks in fact.

And the responses are very good indeed, 80% response in very heavily pretreated patients, including 60% of response for patients with extramedullary disease. And when you are looking at the duration of response, well, to my opinion, very interesting results, especially for patients with extramedullary disease. You see this 81% of response at 1 year. And the progression-free survival is also very good. So in the future probably we are going to combine bispecific antibodies but also combine bispecific antibodies with different agents, such as CD38 antibodies or IMiDs for sure.

So to conclude, I will say that those agents are off the shelf, immediately available, inducing high response rates, inducing also long duration of response. You can treat easily outpatient, so to my opinion this is really a revolution. And I thank you for your attention.

DR LONIAL: Alright. Thank you, Philippe. I’ve got 1 question for the group here. Given that we know that there’s a third BCMA bispecific that’s in the wings, does linvo offer anything that the currently available bispecifics don’t necessarily offer? Or how do you think you would use it?

DR RAJE: Linvo, I think, the way they designed it is it can be done outpatient, at the most 1 day of inpatient hospitalization. Step-up dosing is once a week, so I think it’ll be easier for folks to use.

Having said that, with elran and with teclistamab we already have programs at all our centers. We’re moving them to outpatient use, so…

DR RICHARDSON: My impression of linvo is that there may be a — I think there is a tolerability advantage to it, which may be an asset. I think all of these agents, as Philippe so nicely mapped out, are generating similar response rates. So I think this convenience and this true off-the-shelf capability, rather than the need to hospitalize for step-up dosing, is going to be a very important next step.

But I also think we shouldn’t underestimate some of the side effects that we’re seeing. Our own experience with talquetamab has been quite challenging I would have to say, and I think we’ve also seen significant toxicities with the BCMA platform as well. So it’s good to see, for example, with linvo, a real effort to try and exploit that therapeutic index.

DR LONIAL: Okay, thanks. Bob, 1 last question from the audience. The CD38 plus car/dex, no matter which flavor of CD38 you use, appear to have the best PFS in first relapse. Given that cilta-cel was never compared head to head, how do you think through? Do you do CD38/Kd, or do you do cilta-cel?

DR ORLOWSKI: I think it depends a little bit on the scenario, of course —

DR LONIAL: Yeah, yeah.

DR ORLOWSKI: — of the patient, but definitely I would be comfortable doing either Kd with an anti-CD38 or to do a BCMA/CAR T.

DR LONIAL: Okay. So it really depends on the discussion you have with the person in front of you.

DR ORLOWSKI: Yup.

DR LONIAL: Got it. Thanks, Bob. Okay.

Other Novel Agents and Strategies Under Investigation for MM — Dr Lonial

DR LONIAL: So we’re going to get to the next case presentation.

DR LOVE: The next patient was presented by Dr Lee.

DR LEE: This is a 59-year-old male. He was diagnosed with high-risk light chain multiple myeloma, TP53 positive with complex cytogenetics.

I started him on a quad regimen; dara, bortezomib, lenalidomide and dex.

However, his response was suboptimal. I think his M-spike was only reduced by maybe 50%.

I referred him to an academic center for transplant versus CAR-T versus bispecific. In the end the academic center didn't have any options for him.

He's the sole caregiver for his elderly mother who has very brittle diabetes. And, in fact, he told me that when he was initially hospitalized for his initial diagnosis of myeloma, because he wasn't at home when he was in the hospital for a week, his mother ended up being admitted to the hospital for diabetic ketoacidosis. And it broke my heart because he's the only one that takes care of her.

So my question in this case, it's a unique social situation but also a particularly refractory disease, he absolutely cannot get admitted to the hospital. Potentially if belantamab comes back to the market that might be an option.

So I was hoping the investigators can pull something out of their magic hat that might be an option for this patient should he progress.

I changed him to daratumumab, carfilzomib, pomalidomide and dex. And that did deepen his response.

DR LOVE: Anything you'd want to hear them discuss about belantamab?

DR LEE: I would. In the DREAMM-7 data the visual impairment was transient, and patients recovered from it if it was caught early enough and if they did a dose interruption or dose adjustment. My understanding was that the amount of Grade 3 toxicity of ocular toxicity was actually quite low.

So I would like to hear what investigators think about the latest combination belantamab data because I have never used belantamab although my colleagues in my practice have used it, and we have not encountered issues with visual impairment that led to patients needing to discontinue therapy.

DR LONIAL: Okay. So Paul, why don’t we start with the first question, and really put it in the context of that high-risk, D-RVd, suboptimal response, won’t let us put him in the hospital. What are your tools?

DR RICHARDSON: Well, I think it’s a wonderful question, and I want to applaud Dr Lee for being very patient focused and very holistic. I think bela combined with other agents in this particular patient’s case makes great sense. I think the bela data — in short, belantamab is back. DREAMM-7 and DREAMM-8 generated PFSs that were remarkable to all of us, and we’re going to hear at this meeting, next Tuesday, I think it is, Monday or Tuesday, survival data that I think is going to be very encouraging.

So putting that all together, bela combined with other agents really has a role, in our own experience, in our own center, where we, like you, Sagar, have been involved with belantamab since DREAMM-1 onwards, has been very favorable. And the eye toxicity is indeed a challenge, but very manageable. And in combination I would say it’s always reversible in our experience, and in combination there’s not much else that goes on with bela, which is, I think, very positive. So I personally think that it’s got a real role, and I’m very, very hopeful it will be back very soon.

DR LONIAL: Okay. Anybody have experience using bela after a prior BCMA-directed therapy?

DR RAJE: We do.

DR LONIAL: Yeah.

DR RAJE: And we have patients. Paul mentioned the ISABELA trial, and we have a very similar situation. I think we underestimate the logistics it takes to get patients through CAR T cells and even bispecifics, and for a very similar kind of a situation we’ve actually put the patient on ISABELA. Now, on ISABELA the bela dosing is every 9 weeks and it’s 1.9 mg/m². So it really doesn’t cause the ocular toxicity, and yet you’re getting responses. And these are patients who’ve had either CAR T cells or even bispecifics, and we’re still seeing responses.

DR LONIAL: Bob, do you want to talk about some of that? I know Hans Lee at your place did a lot of work with bela. What have been some of the strategies you all take to either mitigate or manage or address them?

DR ORLOWSKI: Yeah. I think as you’ve heard, trying to do dosing over a longer period of time, more time in between doses, and lowering the dose are really the best strategies. We don’t have any direct interventions right now, unfortunately, other than those.

DR LONIAL: Okay. Paul, you want to…

DR RICHARDSON: Only to say that the ocular toxicity, we’ve found, especially with expert involvement, can be very manageable. And just beware of the so-called Grade 3 ocular toxicity, because obviously ophthalmological findings that are “Grade 3” based on microcyst density is an observation from the ophthalmologist under the microscope, basically clinically it’s important to ascertain where the patient sits. And our own experience with this has been exactly as Noopur so nicely outlined, dosing schedule. And if you’re dosing every 12 weeks with a combination strategy, to Dr Lee’s point, his gentleman’s going to be able to look after his mum.

DR LONIAL: Yeah. I think, and I’ve got a — I think I’ve got a nice graphic to show.

DR RICHARDSON: Yeah.

DR LONIAL: It can look like it’s Grade 3, but there’s no obstruction of the visual field, if you will.

DR RICHARDSON: Exactly.

DR LONIAL: So I think those are subtleties that are often lost.

Let’s get to our next case. 80-year-old.

DR LOVE: The next case presented by Dr Ma is an elderly man initially treated with lenalidomide/dexamethasone, which resulted in difficult to manage cytopenias followed by disease progression. He then entered a clinical trial and received daratumumab and iberdomide.

DR MA: This is a wonderful patient, a Laotian guy in his 80s. Exercises every day. So he got put on this new medication on trial, iberdomide. This is the very first time I have been utilizing this medication. And when I look at the mechanism, it’s supposed to be a cereblon modifying agent. I’m not quite familiar with the signaling pathway.

And what about the side-effect profile?

He’s having a great response right now.

DR LOVE: So any tolerability issues with the iberdomide?

DR MA: No. He had really bad cytopenia going into the trial. He almost didn’t make the inclusion criteria for the trial. But since then, actually, I find this much easier tolerated than prior lenalidomide that I gave him.

I find iberdomide, in his case at least, is a little easier for the cytopenia.

With iberdomide I’m curious what line of treatment are we looking at when it gets approved and what’s the panel’s opinion on comparison to lenalidomide as far as efficacy and tolerability?

DR LONIAL: Alright. So Paul, why don’t you start us off here. We’ve got len and pom. I think we’ve for the most part given up thal. But where do iber and mezi fit into the treatment paradigm?

DR RICHARDSON: Well, I think, Sagar, first and foremost I love the descriptions you had of iber being so well tolerated. Because as you pointed out some years ago, there are a lot of zeros in the non-heme toxicity columns for iber, and with your leadership in the iber program, where I think we’ve seen clearly that iberdomide, to my mind, belongs up front and in maintenance, particularly as it may have advantages over len in the context of second cancer risk and so forth. And above all, it is distinct. It is active in the setting of len and pom failure.

So I’m very excited by the CELMoDs. I think mezigdomide, I’m sure you’ll touch on, but in our hands in the relapsed/refractory setting that has been a true gamechanger, so we’re very pleased with the performance of these drugs.

DR LONIAL: So Noopur, you have iber in your pocket right now. You could use it. Where would you use it today?

DR RAJE: If I could, I would use it up front in combination, dara, instead of R, iber. I think the biggest challenge with all of these newer CELMoDs is their myelosuppression, so dose reduction and dose adjustment is critical. But they’re way better tolerated than len and pom in terms of other side effects like rashes and neuropathy et cetera.

DR LONIAL: And Bob, you’ve got mezi in your pocket. Where would you use it today?

DR ORLOWSKI: I think in the relapsed/refractory setting in a variety of combinations potentially. This was mentioned briefly earlier, after prior T-cell engaging or CAR-T therapy. There’s some data to suggest that it may at least ameliorate or potentially even reverse T-cell exhaustion, so that’s potentially an interesting application of it.

DR LONIAL: Okay. Alright. Well, I think I’m going to go ahead and get started with the last module, the last talk of the last module, and I titled this “Other Novel Agents in Development.”

And we’re going to start off talking about a little bit about bela. And this was a slide published a few years ago in terms of the potential for BCMA as a target in myeloma. What you see is both the ADC, and the CAR T-cell, as well. But what I think is really quite interesting and unique about bela, which is an antibody-drug conjugate, is that it has a number of different mechanisms of action, including direct engagement with BCMA, internalization of the toxin and killing cells. It also brings in effector T-cells to ultimately kill the cell and has a potential for inducing immunogenic cell death, which I think in many ways makes it an ideal partner for a number of drugs that we’re talking about and that we’ll touch on in the next few slides.

Now many of you may know before bela was pulled it was actually approved based — on the basis of the Phase II DREAMM-2 study. This was a randomized trial of 3.4 mg of bela given every 3 weeks versus 2.5 mg of bela given every 3 weeks. There was intensive study by ophthalmologists of the visual — of the exam and of the eye.

And I think as Paul alluded to before, that is both a help and a hinderance in the sense that we want to know what patients could experience, but at the same time what sometimes an ophthalmologist sees may not necessarily reflect what the patient can or cannot see. That was not an intended pun there. So I think — so there’s a little bit more to the story than just an ophthalmologist saying Grade 3 keratopathy.

What we learned from the DREAMM-2 study, particularly with longer follow-up, is that the overall survival at that timepoint in 6 or more prior lines of therapy was quite striking at 14.9 months. You saw a median progression-free survival of about 3 months, but you also saw a duration of response close to a year. And remember, this was a single agent before we really had sig access to other agents that targeted BCMA. And so this was approved based on this trial because it clearly offered a new opportunity for patients that didn’t have great opportunities at that time point.

And here is the DOR, as well as the overall survival curves with longer follow-up in the DREAMM-2 study.

Now, I think this really gives you some sense of the grading. And one of the things that’s interesting about the keratopathy is this idea that it tends to start peripherally and then work its way centrally. And where I suggested there was a disconnect between an ophthalmologist’s exam and what a patient can or cannot see is that you can have Grade 3 in the periphery, but it doesn’t necessarily impact vision.

And so I think this is an important highlight. At the same token, when you hold the drug, and the keratopathy reverses, and in nearly all cases the keratopathy reverses, it reverses from the center out. And so the first thing you’ll see is recovery in visual acuity that may take longer on the periphery, and this is why many times I’ve had patients that told me my vision is back to normal, and yet the ophthalmologist is still calling it Grade 3 because they’re seeing those microcysts in the periphery that likely are on their way out.

And so if you look at the DREAMM-2 you can see here in terms of the frequency of events about 72% of patients had some form of keratopathy, about 56% had some change in their visual acuity, but only 18% had change in their visual acuity to greater than 20/50. So it was a relatively small group of patients. And remember, this was at a time when we were saying try to give it every 3 weeks if you can.

And I think an important part of bela coming back, if it hopefully does come back, is going to be that we’re going to have a different dosing strategy, similar to what we’ve done for almost every drug we’ve talked about today. Bortezomib, we changed the dosing schedule. The IMiDs, we’ve changed dosing schedule. The bispecifics, we’re going to change the dosing schedule is my guess. I think we’re learning how to do that with an antibody-drug conjugate as well.

Now, I think the data that led to the resurgence of belantamab really was this data from the DREAMM-7 trial demonstrating significant improvement in progression-free survival, 36 months PFS, as well as an improvement in overall survival. You can see the MRD and the overall response rate data there.

But I think this really highlights the beauty of that synergy between bela and a proteasome inhibitor, that both potentially induce immunogenic cell death, and the fact that if you look at when patients got the drug the median dosing interval is between 8 and 12 weeks. So even giving it relatively infrequently you still got this 36-month progression-free survival in partnership with bortezomib and dexamethasone, and we know Vd in this context is likely a median PFS of about 9 months. So it really was a significant increase, a synergistic increase if you will.

Now, a couple of things that were interesting from DREAMM-7 really was this identification that perhaps patients with high-risk disease may gain benefit from the use of bela. And this has now been seen in more than 1 study, and actually at our center is the reason why we’re using bela plus pom/dex as part of a trial for high-risk maintenance for patients post autologous stem cell transplant. And so far, the data looks really, really quite intriguing.

Now, this is that early survival data in terms of DREAMM-7 in terms of its pending difference. And there will be an update of this on Monday, where I think we’re going to see updated survival curves suggesting that the triplet is better with bela/Vd versus — versus dara/Vd.

Now, the other study that I think also led to this resurgence is the data with DREAMM-8. And DREAMM-8 was bela/pom/dex versus bortezomib/pom/dex, so PVd versus BPd. And this trial, again a randomized Phase III trial, 302 patients, and what I think you see again is a substantial difference in progression-free survival for the triplet including bela versus the triplet that did not include bela. And in fact, it looks like the PFS is going to be on par, if not greater, than 36 months.

And in fact, this to me is the really exciting one because, not that the other was less exciting, but I like the IMiD combination with an immune therapy because I think that just makes good sense to me in terms of activating immune function while you’re giving an immunotherapy-based approach. You can see this was higher overall response rate, higher MRD negativity rate and again a hazard ratio of 0.5 in terms of progression-free survival.

And again, high-risk patients who got bela seem to be doing a little bit better. And so this, to me, is again a secondary confirmation that perhaps this agent not only has good partner activity but may have significant activity in terms of helping us to deal with the challenges associated with high-risk myeloma.

Now, if you look at adverse events of interest, I think there are a couple here that are worth reviewing. You can see blurred vision, dry eye, foreign body sensation that did occur, again, with the intent that you were going to try and give this every 3 weeks. But what we now know from Dr Terpos’ study in newly diagnosed myeloma is that if you dose every 8 or every 12 weeks most of this starts to go away. And in fact, what I think is really quite interesting is the idea that you may not even need an ophthalmologist to see the patient every time they get a dose of bela. If you’re going that infrequently, and patients are not reporting changes in visual acuity, do you really need to have them see an ophthalmologist with each dose? That’s also being piloted in a couple of studies. We’ll hopefully have more data on that in the near future.

Now I’m going to switch gears a little bit and talk about the CELMoDs that we talked — that we touched on just a moment ago. The new kids on the block are iber, and this was CC-92480, now known as mezigdomide or mezi. These are structurally different. They have been synthesized in a way that allows them to be more potent at activating T cells and NK cells than len or pom. So that’s why they’re called CELMoDs, because they really seem to be ideal partners for immune-based therapy.

And what we know about iberdomide and dex, for instance in relapsed and refractory myeloma, this cohort had a 34% response rate in BCMA-resistant or -exposed patients. And you can see, as Paul alluded to earlier, all of those zeros in the Grade 3/Grade 4 adverse events, in the lower right.

But what I also want you to pay attention to is the immune markers that you can see here. And what I think you’ll see, as Bob alluded to earlier, you see reversible T-cell exhaustion and T-cell activation even among patients that have had 5, 6, 7 prior lines of therapy. And so the simple way I think about this is that iberdomide is like cappuccino for T cells. It wakes them back up and lets them be effective in partnership or alone in terms of management of relapsed and refractory myeloma.

Now, Paul also alluded to mezigdomide, or mezi. This was a Phase I/II study of mezi plus dex and dara or mezi plus dex and elo; really high overall response rates. And one of the things that really has struck me about mezi, and we may have time in the Q&A afterwards, is unlike the entire IMiD class of drugs, which do not penetrate into extramedullary tissue, mezi seems to have a propensity to get into the tissues and be more effective at treating extramedullary disease.

And so when I think about, again, perhaps bispecifics can do this, but if you partner it with a drug like mezi maybe you’re really able to get durable responses in extramedullary myeloma that we know is a pretty significant challenge in general.

Now the last topic I’m going to cover is venetoclax, there was a question that I saved because I knew I had slides on venetoclax, from the audience about the role of venetoclax in the 11;14 patients. I think it’s clearly there.

This is data presented by my colleague Jonathan Kaufman, where they looked at venetoclax in combination with dara and dex, looking at 2 different doses of venetoclax. You’ll recall that the ven/dex trial used 800 mg of venetoclax, and I’ve certainly found that many patients don’t like taking that 800 mg dose. The GI side effects make it a little challenging. It looks like the 400 mg dose is just as effective, PFS is just as good, and the adverse events are significantly lower. And so for that reason I think it really — 400 is what I’m using now when I use venetoclax in the context of an 11;14 patient.

And as you’ve also seen before, the addition of venetoclax to carfilzomib. This was an initial really good preclinical idea combining a PI with a Bcl-2 inhibitor. You can see the progression-free and the overall survivals from this trial suggest that this combination is highly active and effective as well.

And so with that I will stop.

I just want to highlight again, thank you for joining us today in terms of this great symposium. We had a great discussion. With that I’ll thank my colleagues and thank you all for attending here today.