Early versus late autologous stem cell transplant for newly diagnosed multiple myeloma (NDMM): Long-term follow-up analysis of the IFM 2009 trial

DR LOVE: Welcome to Oncology Today, a special program focused on key presentations on the management of multiple myeloma from the 2020 American Society of Hematology Annual Meeting, this is medical oncologist Dr Neil Love. For this program, I met with Dr Sagar Lonial from the Winship Cancer Institute in Atlanta, Georgia. And to begin, Dr Lonial commented on a presentation focused on the long-term follow-up analysis of the IFM 2009 trial.

DR LONIAL: This was an abstract that evaluated longer-term follow up from the IFM DFCI trial, and this was the trial that randomized between transplant versus no transplant, with everybody getting RVD induction and then len maintenance. And remember in the French version of this trial the maintenance duration was only 2 years at the most, for most of these patients. So it was really limited-term maintenance and RVD versus transplant as part of the initial therapy.

And one of the pieces, and this was a theme in a couple of abstracts at ASH this year, was that initially if you had a transplant or you didn’t have a transplant it didn’t matter because your MRD negativity rate was relatively similar. But I think what we saw from this abstract really quite nicely was that if you had a transplant and were MRD negative you did much better than if you didn’t have a transplant and were MRD negative. And what that says is that the response rate up front doesn’t necessarily predict the progression-free survival at the end.

And why I think this is important is this was 1 of 2 trials. The FORTE trial also showed KRd followed by transplant versus KRd and no transplant that the group that had KRd and the transplant had a longer remission and more sustained MRD negativity than the group that just got KRd. So I think it continues to demonstrate the benefit of transplant.

DR LOVE: So I kind of think this is like maybe a different message than we got with the initial data set.

DR LONIAL: Yup. Yup. Yeah.

DR LOVE: Can you kind of explain that.

DR LONIAL: Yeah, the initial data set really said that you were more likely to achieve MRD negativity if you had transplant than if you didn’t, two thirds in the transplant versus one third in the nontransplant. And if you did it didn’t matter, that the outcomes for MRD negative with or without transplant, MRD negative were the same. This is not saying that.

This is actually saying — the point that I take from this is not just transplant offers benefit, but that the endpoint of achieving MRD negativity is, as I said on twitter, it’s like reaching the top of Everest. That’s not the whole journey. You still have to get down the mountain, right? That’s the other half of the journey. And so the sustained MRD negativity is probably a better benchmark for assessing success than saying we’re MRD negative and victory, we’re over. And that to me is the important message.

DR LOVE: Sustained MRD negativity.

DR LONIAL: Yeah.

DR LOVE: So for how long?

DR LONIAL: So what we put in the IMWG guidelines is 2 timepoints at least a year apart.

DR LOVE: Wow.

DR LONIAL: And so I think it really does mean that, because what you see in FORTE, for instance, which was KRd with or without transplant, that people achieve a deep response. The response rates were almost identical between the 2 arms when you look at say 6 months or 12 months. But the ability to maintain that remission was lower for the group that didn’t have a transplant. That’s to me the important message.

DR LOVE: Can you just comment on that in a little bit more detail?

DR LONIAL: The FORTE study was a 3-arm randomized trial. One arm got car/cyclo/dex with transplant, one arm got car/len/dex with transplant, and one arm got car/len/dex with no transplant. So it was really 12 cycles of KRd with no transplant in the third arm. And there are 2 take-home messages. The first is car/cyclo/dex was terrible. It was inferior across the board. And that’s not unique to this trial. In every trial where an IMiD/PI has been compared with PI plus cyclo, cyclo loses.

The second is that when this presented a year ago the response rates looked identical, and so everybody said see, you don’t need a transplant. Response rates are the same. MRD negativity, pretty much the same. VGPR or better, pretty much the same. But what we see is that they’re not as durable in the nontransplant arm and that the KRd/transplant arm performed better in terms of maintaining and sustaining MRD negativity.

DR LOVE: So going back to the IFM study, why is it that we kind of got 1 message from the first data set and a different message from the next data set, just more data?

DR LONIAL: Yeah, yeah. I think the longer-term follow up is really the key here. And remember, part of what the IFM trial was trying to do, at least the hypothesis was that if you achieved a deep response transplant didn’t really matter, that you didn’t really offer additional benefit. And there still are rumblings of does transplant really do what it needs to do, there are all these side effects, and going on and on and on.

But I think the reality is that the message from this longer follow up, and with FORTE longer follow up as well, also demonstrated that while you may achieve MRD negativity at 10^-5 or 10^-6, transplant may actually get you lower. It may get you to 10^-7 or 10^-8, which we can’t measure currently, but would be one way to account for this longer PFS in the transplant arm.

DR LOVE: How often do you see patients attaining MRD negativity prior to transplant?

DR LONIAL: If you’re looking by cycle 4 with RVD as the induction regimen, it’s relatively uncommon, maybe 10% of the time. It happens so rarely that we stopped checking pretransplant. Now that we’re doing RVD/dara as our standard up front I’ll have that data for you in about a year because now we’re checking again at cycle 4. With KRd there’s some suggestion it may occur a little bit more frequently. But again if it’s not a durable remission does it really matter?

DR LOVE: In terms of RVD/dara at this point, do you have any informal impression about it? Or you don’t have any data?

DR LONIAL: Well, I think it’s faster and it’s deeper a response than RVD, and that was proven by the GRIFFIN study. I think it’s really going to be very effective. And if we’re going to do anything in the next year it’s going to be switching to that, is going to be the next step.

DR LOVE: So it kind of sounds like there’s not much of an argument assuming the patient’s open to it and wants to do everything possible to delaying transplant.

DR LONIAL: Our center doesn’t take that approach. We take the early transplant approach to try and get people on that top red curve. The way I put it to patients is there’s all this talk about overall survival. There’s no difference in overall survival. I actually don’t think overall survival is the right endpoint when the median survival of a newly diagnosed myeloma patient is 10 years. Overall survival is not the right endpoint anymore. I think it’s deep and durable response, and that’s what the IFM study’s really showing.

DR LOVE: That’s interesting because of course all throughout oncology there’s all kinds of situations where survival — we just had the osimertinib data in lung cancer, 80% reduction in recurrence, and a bunch of people are still saying we don’t see survival. Obviously a very different disease. You don’t see 10-year benefit. But it kind of harkens back to the old iceberg graphic that you used to have and the fact that at this point you all still deeply believe in that, to do everything possible to drive the tumor down for as long as possible.

DR LONIAL: Yeah.

DR LOVE: Just as long as we’re talking about paradigms, the other major paradigm in myeloma has been continuous therapy. Do you consider that still a reality?

DR LONIAL: I do, but I think that the trials to question that now are being designed. For instance, the SWOG trial and the ECOG trial have randomized patients between continuous versus 2 years of therapy. The next ECOG study is actually taking people who are MRD negative and randomizing them to continued therapy versus stopping therapy. So the trials to question that paradigm I think are being done now.

DR LOVE: And I think the American version of the IFM trial I believe looks at that in terms of maintenance len, I think 2 years versus indefinite. Where are we in terms of getting data from that end of the study?

DR LONIAL: Yeah, the US version of the IFM trial gave continuous maintenance, whereas the French version only gave short-duration maintenance. And remember from the IFM study, the French version, it was 48 months was the median PFS for patients who got RVD and a single transplant and len maintenance. In our RVD 1000 data set that was published by our group, Dr Joseph was the first author, our median PFS for RVD, single transplant, and len maintenance with continuous is 67 months. So it’s 2 1/2 years longer than the IFM experience. So I think that’s the benefit of continuous maintenance.

DR LOVE: Yeah, I think I was thinking about the ENDURANCE trial that’s doing a randomization of duration.

DR LONIAL: Yeah. That’s right.

DR LOVE: Right.

DR LONIAL: That’s right.

DR LOVE: Any follow up from the ENDURANCE trial at ASH this year?

DR LONIAL: There was nothing updated from that trial yet. I think we’re waiting on the follow up to be able to answer your question about 2 years versus continuous.

Updated analysis of the GRIFFIN trial: Daratumumab with lenalidomide, bortezomib and dexamethasone for transplant-eligible patients with NDMM

DR LOVE: All right, so how about this paper, Kaufman and your group.

DR LONIAL: Yeah.

The GRIFFIN trial was a randomized Phase II study of RVD versus RVD/dara with everybody getting transplant and everybody getting RVD or RVD/dara consolidation, and then maintenance with either lend/dara or lenalidomide. So it was a more even-keeled trial from the perspective that everybody in the trial got at least basically what we would consider standard of care. They got induction, consolidation, and maintenance. And the question was does dara add a benefit here.

What I think is really important from this trial is at 2 years the curves are beginning to separate a little bit, and unlike the CASSIOPEIA trial, which was VTd/dara versus VTd, where the randomization was at the end, dara versus observation, which I don’t think is a very fair comparison, to be honest with you. Here patients in both arms are staying in remission longer, but at 2 years it looks like we’re starting to see some separation in the curves.

I think the other piece that was really quite impressive to me was this data here, which I snuck into the Kaplan-Meier curves, which is MRD negativity. And what you’ll see is MRD negativity is significantly higher in the group that got dara than the group that did not, both at 10^-5 and 10^-6. and what I think is really important about this is if you can achieve that benchmark pretransplant, then maybe you don’t need all the dara on the back end. And that’s something we don’t know the answer to. But this, in our mind, has justified our switch to RVD/dara for standard-risk myeloma.

DR LOVE: Now what’s the maintenance in this regimen?

DR LONIAL: So the maintenance is either len/dara or len.

DR LOVE: And so do we have any data on that question?

DR LOVE: Not yet. Not yet. The follow up, it’s 2 years right now, the median follow up, so we will get that. The best you can tell is by looking at the PFS curves here where you see at 2 years they’re starting to separate a little bit.

DR LOVE: So outside a clinical trial, I know this is a regimen that you use, a lot of other people right now have not decided to use it, can you talk about what your thoughts in kind of taking that approach? And what you do outside a trial in terms of maintenance?

DR LONIAL: Yeah. So what we are doing now is giving 4 cycles of RVD/dara to standard-risk myeloma. We have not adopted the consolidation and the maintenance daratumumab. So our thought is give it early up front, maximize depth of response, consolidate it with a transplant, and then we’re going with single-agent lenalidomide maintenance. That’s our approach currently.

DR LOVE: And in terms of when you utilize the dara in this regimen, are you using subq from the beginning?

DR LONIAL: Yes, yeah.

DR LOVE: Any situations right now, as long as we’re talking about it, where you don’t use subq dara?

DR LONIAL: That’s not come up. The only situation where we didn’t switch anybody was a patient who claimed that they had more side effects on the subq than they did with the IV, and they wanted to go back to IV. But otherwise everybody has switched.

DR LOVE: That’s interesting. I don’t know how many people you had like that, but when they said they had more side effects, do you think that was really the case, or a placebo effect?

DR LONIAL: Yeah, it’s hard to know. I mean think some people, when they get on that monthly dara run, they’re afraid to change anything because they’re worried it’s going to do something different. And even though you tell them it’s the same drug sometimes people just like what they like, so it’s fine.

DR LOVE: What are some of the induction strategies right now that are being looked at in trials that you feel excited about?

DR LONIAL: Well I think the question about continuous therapy is coming up in induction therapy. I think RVD/dara, obviously we’re waiting on the European study, which is a larger Phase III randomized trial. But I’ll tell you my view is that rather than taking this shotgun approach where we do 4 cycles of a quad, and then we do a transplant, and then we do maintenance, I’m beginning to wonder whether we have enough active drugs in our hands now, that we begin to think about an ALL or a hyperCVAD kind of approach, where you give 3 drugs alternating with 3 other drugs, you go back and forth, back and forth, maximize depth of response, think about consolidation with a different drug, and then come in with something on the back end in maintenance.

So we’ve got these new CELMoDs, we’ve got BCMA-directed therapies, whether they’re bispecifics or CARs. How do we incorporate those into what we’re doing up front to really change the paradigm of therapy? And I think I’m not the only one thinking that. I think many of us are, and the question is how do we do that?

DR LOVE: Any proposals out on the table right now that you think might be considerations or that you’re kind fantasizing or theorizing about specifically?

DR LONIAL: Yeah, so our group has our group meeting in 2 or 2 1/2 weeks, where we lock each other in a room and that’s our goal, is to come up with what that looks like. I think we’re calling it the “cure trial”. What does the cure trial look like?

DR LOVE: Wow. I like that.

DR LONIAL: So it’ll be a small Phase II study, and we’ll see what we can do.

Phase III TOURMALINE-MM2 trial of oral ixazomib, lenalidomide and dexamethasone versus lenalidomide and dexamethasone for transplant-ineligible patients with NDMM

DR LOVE: I’m real curious to hear your thoughts on the TOURMALINE-MM2 trial.

DR LONIAL: So this was an interesting trial for older transplant ineligible patients, where they were randomized to receive IRd/ixa/len/dex or len/dex, so really trying to challenge the paradigm of the first trial. And this is a trial where you can see the PFS and the TTP curves there. I mean the PFS is 35 months versus 21 months. I mean that’s a significant difference in PFS. The TTP is 26 versus 45 months. So again a really big difference that you can see by the space between those graphs. The challenge is it was not statistically different. The p-value was 0.7 for the PFS and for the time to progression it was 0.008, which is significant, but the PFS curve is not. So technically this is a negative study.

What I take from it, though, is that the combination of IRd is a clinically relevant triplet that can be given to patients who can’t come into the office, don’t want to come to the office, and you want to do better than lenalidomide and dexamethasone. So that’s how I take it.

DR LOVE: Right. So yeah, I’ve been curious about ixazomib because it’s kind of hard to get a fix on how it compare to, for example, bortezomib. I don’t know. I’m not sure if there’s any trials direct comparing them. You also have the issue in the maintenance setting. I’m curious what your thoughts are there.

DR LONIAL: Yeah. I mean in the maintenance setting there is a difference, for post-transplant maintenance 27 months versus 21 or 22 months. So there is a statistically significant difference, but it’s not of the same magnitude as lenalidomide. So the way I think about it is if you can’t use len then ixa becomes a reasonable option. But I think the idea of saying that ixa and len are interchangeable for maintenance, I don’t think that’s true. And I think what we’re learning about ixazomib is it is clearly more convenient. There are patients who like the idea of not coming into the office and taking a pill, but I don’t think it’s quite as effective. So it’s are you willing to balance that efficacy with convenience.

DR LOVE: Yeah, that’s kind of the message that we’ve gotten. When you don’t have data, we just go with peoples’ viewpoints who have a lot of clinical experience. And it’s just that I get different feelings about it in terms of how effective it is. And I guess the other thing is the question of the high-risk patient where you’re going to give both len and a PI. Again, are you going to have the patient come in and get bortezomib or ixazomib?

DR LONIAL: Yeah, I mean I think our approach for the most part is for that first year when we’re trying to understand whether we can really control this disease or not. We’ve been using bortezomib and keeping them on the weekly schedule, but if they get out to a year, and they’re “I don’t want to keep coming in anymore”, then we may make that switch to ixa.

DR LOVE: Any practical clinical suggestions in terms of ixazomib? Most people I hear in practice, it sounds like it’s pretty well tolerated. You hear a little bit about GI issues. Any issues come up that you have any pearls about?

DR LONIAL: Yeah, I mean I think it’s certainly not uncommon to hear somebody say for a day I may have a little bit of nausea or a little bit of diarrhea, but nothing that causes them to call into the office about it. So I think for the most part it’s probably Grade 1, Grade 2 at the most, and it’s limited in duration.

DR LOVE: So we were talking before, and of course we talk a lot about subq dara. It’s interesting how much how many people in practice haven’t quite got into that. I don’t know. Maybe there’s a formulary problem. I’ve heard there may be reimbursement challenges in this situation.

Phase III APOLLO study evaluating the addition of subcutaneous daratumumab to pomalidomide and dexamethasone for patients with relapsed/refractory (R/R) MM

DR LOVE: What about these data that were, again, just presented at ASH on the APOLLO trial?

DR LONIAL: Yeah, I think the APOLLO trial was a highly waited for data set, mostly because I think pom/dara/dex is probably the most common salvage regimen used in the US right now. For patients that are progressing on len maintenance, this is the go-to for many of us in this field. And you can look at it from the glass half empty or the glass half full side. I think it clearly demonstrates benefit over pom/dex, so the triplet over doublet piece continues to hold up with the addition of dara to pom/dex.

I think the challenge for those of us who use it in first relapse is that most of the patients on this trial were not first relapse. They were later lines of therapy. So being able to understand what the absolute benefit is to a first relapse patient, you don’t get that answer from this trial. And that’s, to me, what’s most frustrating, is the question I have this trial couldn’t answer. And I’ve said it before in other places, this gets to the idea of designing trials and then waiting a long time to see the results, and then by then the standard of care has already changed. And so how do you put this in context? I think pom/dara/dex is a good regimen. It doesn’t change whether I’m going to use if up front. But I think we will need a trial of pom/dara/dex versus carfilzomib/dara/dex to understand in first relapse what’s the better partner.

DR LOVE: So I’m sorry. What would you have liked to see the trial do?

DR LONIAL: A trial with first relapse. So 11% of patients in this had had 1 prior line, most had had 2 or 3 prior lines of therapy. So the 12 months that they’re seeing in terms of median PFS, I don’t know what that would be in first relapse, right? It’s probably going to be longer, but I don’t know how long. And that’s the real challenge.

DR LOVE: And why is that you’d want to know that, to indirectly compare to other options?

DR LONIAL: Yes. Yeah. Yeah, because we do have trials looking at dara/car/dex in earlier lines of relapse. And so this one, I was hoping, would give us that answer so we could look relative trial to trial to see which was better, and you can’t say that from this.

DR LOVE: What are the other regimens that you consider outside a trial setting in first relapse?

DR LONIAL: Yeah, I mean I think probably dara/carfilzomib/dex is one, from the CANDOR trial. I think certainly the isatuximab folks will make a case that isa/pom/dex or isa/car/dex are reasonable options because there’s Phase III data for both of those as well. And of course you could go back to the CASTOR trial and do bortezomib/dara/dex as a salvage regimen. I think most of us are not really doing that very often. We’re using either pom or carfilzomib as the partner for daratumumab.

DR LOVE: What about isa as an option?

DR LONIAL: Well I think isa’s a reasonable option, and if you ask me is there a significant difference between isa and dara I don’t think that there is. I think they’re similar in terms of their efficacy. I think they’re similar in terms of their side effect profile. I think what dara has now is a subq formulation that makes it very easy to give, and that’s so patient convenient.

DR LOVE: Right. What about elo? Where, if at all, do you fit that in?

DR LONIAL: So elo, I think we tend to look at if they have not gotten pom, but they’ve already gotten dara as part of a salvage regimen, so say dara/car/dex for instance, then we might use elo/pom as a salvage regimen in that situation. So I like to think about using elo when I can partner it with an IMiD, and if there’s an IMiD that hasn’t been used, like pom, or now that we have iberdomide in clinical trials I think about iberdomide plus elo in that situation as well.

DR LOVE: Getting back to the subq dara, do you know what it is that’s the issue in terms of what I’ve been hearing about in terms of reimbursement? Is it more expensive? What exactly is the issue?

DR LONIAL: So it’s interesting. The cost is actually pretty similar, and I think they were pretty intentional about not raising the price even though there is that other compound in there. I think it’s about formulary placement, and it’s about having the right J code and all those kinds of things that have delayed its uptake in the community.

DR LOVE: Interesting.

Selinexor in combination with pomalidomide and dexamethasone for R/R MM

DR LOVE: So we get a lot of questions about selinexor, and particularly management of toxicities from docs in practice. I feel like they’re almost afraid to use it. But maybe you can talk a little bit about this study presented by Chen looking at selinexor combined with pom and dex. And maybe we can get into a little bit about your experience with the drug.

DR LONIAL: Okay. So this was a Phase I/II study evaluating selinexor with pom/dex, as you mentioned. And I think we know that selinexor can be combined nicely with bortezomib. It can be combined nicely with carfilzomib. And the advantage of those combinations is that you cut the dose of selinexor in half. You’re not giving the twice a week dosing schedule as the STORM study included. And when you do that you actually reduce the significant adverse events. So the GI tox, the nausea, the anorexia, the hyponatremia all gets reduced from Grade 2/Grade 3 to Grade 1/Grade 2. So to me that’s one of the real advantages of the partnership.

What they did in this trial was actually combine pom escalating doses with selinexor and demonstrated pretty high response rate, about 58%, in patients who were len refractory but pom naïve, and a median PFS of about 12 months. So again, looks pretty interesting and pretty comparable to some of the other later lines of therapy as well. But you had fewer adverse events because you only used 60 mg of selinexor. So that’s a much lower dose than in the STORM trial and makes it a much easier drug to give.

DR LOVE: Right now how are you utilizing selinexor? Specifically what are you combining it with?

DR LONIAL: Yeah, when we’re using selinexor in our practice we’re using it in the later lines of therapy in combination with either bortezomib or carfilzomib. So we’re giving weekly proteasome inhibitor in combination with weekly selinexor. And we usually have them come into the office 2 or 3 times a week to make sure that they don’t need fluids, that they don’t need antiemetics, that they don’t need blood product support or other things because especially that first cycle the side effect profile can be fairly intense and require that pretty close follow up.

DR LOVE: How long do you continue that close follow up?

DR LONIAL: Well usually once you get past the first cycle you’ve figured out what works for that patient and you don’t have to do it so much anymore. But that first cycle, if you let them get dehydrated, then it creates this vicious cycle that is really hard to catch up on.

DR LOVE: What are some of the specific tolerability issues that come up, and what do you do about it?

DR LONIAL: Well I think nausea is one, so making sure you’ve got the right combination of antiemetics from the front is really important. The second is anorexia. People just don’t feel like eating or drinking. And so making sure that you give them fluids a couple times a week in the beginning, because as I mentioned, when you get dehydrated and you’re nauseous you never catch up. The third is the hyponatremia piece, where patients for some reason seem to get hyponatremia, and so salt supplementation is something that we do to these patients if they get too low. And that probably has to do with the fact that selinexor crosses the blood-brain barrier, and so there’s a central effect that might be causing some of these symptoms and side effects. So those are the big ones.

DR LOVE: So this is an SIADH thing?

DR LONIAL: Yeah. Yeah.

DR LOVE: And when you do this aggressive approach how often do patients say that wasn’t too bad? Or it was not bad at all, so to speak?

DR LONIAL: Yeah. I mean I think you still get adverse events, but it becomes something that you can continue them on as opposed to not intervening, and then I’ve had patients say at the end of 1 cycle say that’s it. I’m done. I’m never doing this again. So you want to prevent that reaction and maximize quality of life.

DR LOVE: How do you sequence it relative to the other post-antibody, post-PI, post-IMiD situation? For example, how do you sequence them compared to belamaf?

DR LONIAL: Yeah, I mean I think they both have different pros and cons. So belamaf, again, is a new target as well, off-the-shelf, BCMA directed, 1 treatment every 3 weeks, but you need the intense partnership with ophthalmology, and know that patients may, in small numbers, have some issues with visual acuity. So I have that discussion with them, and I let the patients drive which way they want to go. I think that in my practice a lot of folks are choosing belamaf, and so selinexor becomes a treatment that you think about after that. But I know many of my colleagues are flipping it the other way around. And so I think it just depends on what you’re comfortable with and what the patient’s comfortable with.

DR LOVE: Although it doesn’t seem like, I don’t hear much about quality of life issues with belamaf, but do you see that other than the ophthalmologic issues?

DR LONIAL: Yeah, other than the eye issues it’s really not a big issue at all.

Interim analysis of the IKEMA trial evaluating depth of response and response kinetics with isatuximab/carfilzomib/dexamethasone for R/R MM

DR LOVE: So you’re talking more about isatuximab being combined with various agents, and here’s one of them, carfilzomib/dex. Can you comment on this?

DR LONIAL: Yeah, this is a longer follow up from the IKEMA trial, and Dr Martin presented an update here, where he very nicely demonstrated that if you got triplet and were MRD negative you had the best PFS of anybody that you can see here.

What is also interesting is that if you look at the patients who got carfilzomib and dexamethasone and were MRD negative, their outcome was identical to the people that got isa/car/dex and were MRD negative. So this again speaks to the MRD negative is all that matters. It doesn’t matter how you get there. Does it take 2 drugs, or does it take 3 drugs?

What is interesting is if you look at the other of it and look at the red line, which is MRD positive, if you got isa/car/dex your PFS was much better than if you got car/dex and were MRD positive. And what that says to me is that triplets clearly are better than doublets across the board and that if you don’t get to MRD negativity you want that triplet because the doublet you’re not going to do as well.

DR LOVE: Is there any biologic pharmacologic reason to think that isa and dara are going to be any different in terms of anything?

DR LONIAL: So there’s some biologic rationale. There’s a difference in their ability to activate CDC (complement dependent cytotoxicity). There’s also a difference in what they can do to inhibit the ectoenzyme at CD38 on the extracellular portion of the cell. I’m not sure that those 2 things translate to clinical differences.

DR LOVE: While we’re talking about CD38 antibodies, just to throw in, I mentioned to you the paper I saw that I thought was really interesting, looking in adding in JAK inhibition in the hope of improving benefit from anti-CD38. Any comment on that?

DR LONIAL: Yeah, I mean I think it’s an interesting hypothesis. We’ve looked at trying to block IL-6 signaling and combining it with a proteasome inhibitor years ago that didn’t pan out in clinical trials with siltuximab. There have been a couple of reports now, for instance, that ATRA upregulates CD38. Panobinostat upregulates CD38. We actually saw that data in the lab as well. Neither of them likely translate to clinical benefits. So it’s one thing to see a phenomena in the lab. It’s another to see it make a clinical difference. So remain a little bit skeptical.

DR LOVE: So just to throw in a very, very common question we get from docs, which is what do we know about using belamaf, for example, before or after CAR T or bispecifics. Do we know right now whether it continues to work? I think about like estrogen receptor in breast cancer, how you can always keep hitting on that, and it still works.

DR LONIAL: You mean BCMA for this one?

DR LONIAL: Yeah. Yeah, so what we know is that the mechanism of resistance is rarely loss of BCMA expression. And so I think there’s every reason to think you can get activity with another BCMA-directed treatment after you’ve progressed on one. So if you progression on a CAR that directed a BCMA, can you give another CAR? Well I think we’ve tried that retreatment with ide-cel, for instance, and we didn’t see significant responses. But there are lots of anecdotal responses of giving a BiTE after a CAR, and it works. So I think the answer is yes, it’s just we don’t know the order yet.

DR LOVE: And again, what about belamaf and CAR T?

DR LONIAL: So none of the trials allowed that to happen. So I don’t think we have formal data. I think we will now going forward because the CAR Ts and the BiTEs and bispecifics are allowing for prior BCMA in a cohort. So we’ll see what that looks like. So I don’t think we know. We have tried belamaf after a CAR in just a handful of patients; have not seen significant responses in that situation.

DR LOVE: Interesting.

DREAMM-2: Single-agent belantamab mafodotin for patients with R/R MM; 1-year outcomes by prior therapy

DR LOVE: So speaking of belamaf, of course we saw more from the DREAMM-2 trial. Can you talk about that?

DR LONIAL: Yeah. So that we presented at DREAMM-2 was really an update of the previous data looking a little bit about progression-free survival, duration of response, and then at ocular events. And what I thought was really important about this is that what we demonstrated is that what we’d seen in the original version of this did, in fact, hold up. That there were no new ocular events with longer follow up. And if you look at, by lines of therapy, for instance, 3 to 6 prior lines of therapy versus greater than 7 prior lines of therapy, the overall response rate was about the same, 34 in one, 30 in the other. So having had more treatment didn’t necessarily handicap your ability to respond later on.

DR LOVE: What about duration of response, both in the trial, as well as your clinical experience?

DR LONIAL: So the DOR in the trial was 11 months. And just to put that 11 months in perspective, when daratumumab was approved the median DOR was 9 1/2 to 10 months. Carfilzomib was 8 1/2 to 9 months. And so I think it’s in that same ballpark, and to me it really speaks about the balance between safety and efficacy. If a drug is effective, you’re going to get a 30% response rate, and you’re going to get a median PFS of about 3 months.

What helps you keep the responders on treatment longer is safety. So the fact that you can keep responders on for 11 months speaks to the fact that management with an ophthalmologist allows patients to get the benefit of treatment.

DR LOVE: I was going to ask you about that because technically, at least in terms of the package insert, you can also use an optometrist. I just think about people in rural areas, et cetera. Any advice you have? How does that work there at Emory, and what kind of input have you been getting from your ophthalmologists? Is it pretty straightforward or you think an optometrist can do it?

DR LONIAL: So when we were at ODAC, Dr Colby, who’s the chair of ophthalmology at University of Chicago, was with us at ODAC. And the statement I always use was hers, so I don’t get credit for this, but she said a first-year optometry or ophthalmology resident could figure this out.

DR LOVE: Wow.

DR LONIAL: So it’s really a slit lamp exam, which they all do after the first week of training, and just quantification may require a little bit of experience. But what you see, the microcyst, is not unique to belamaf. It’s seen in other conditions. And so it is something that I think optometrists can do. We tend to partner very closely with our ophthalmologists, and they know the drill when we call them and saw we’re starting on this day they find a space to see them in the morning, and then we see them in the afternoon and get them their drug that afternoon if they’re doing okay. But I think you’re right. And optometrist could be a good partner if that’s the easiest path for compliance.

DR LOVE: And what exactly is a typical clinical scenario? Does the patient typically have symptoms if they’re seeing an ophthalmologist? What kind of symptoms? Do they resolve?

DR LONIAL: Yeah, so typically you have to see an ophthalmologist before each dose of therapy. So that’s a requirement for the REMS program. Now the most common symptom is actually dry eyes or itchy eyes. So if you think about the spectrum, in DREAMM-2, 72% of patients had some form of keratopathy, meaning that you saw it on a slit lamp exam. 52% of those patients actually had dry eyes or itchy eyes, and only 18% had changes in visual acuity that was 2 or more lines on the Snellen chart. So most patients don’t have visual acuity changes.

DR LOVE: Any local maneuvers that are helpful? Eyedrops, et cetera.

DR LONIAL: Yeah, in DREAMM-2 we randomized people to steroid eyedrops versus no steroid eyedrops. Steroids didn’t work. So all we recommend at this timepoint is lubricating, preservative-free eyedrops, doing that 3 or 4 times a day. And that’s usually sufficient to try and mitigate, not eliminate, but mitigate, some of those nonvisual acuity changes.

DR LOVE: What’s your vision of the pathophysiology of what’s actually going on there?

DR LONIAL: So it’s interesting, it’s an on-target effect with the toxin. So MMAF is known to have an effect on what’s called limbic stem cells, and limbic stem cells are responsible for the generation of new corneal epithelial layers that come up through the bottom all the way to the top of the cornea. So it’s not a surprise that this happens, and the resolution is slow because, again, that stem cell has to mature all the way up to the cornea.

What’s interesting is when it starts it starts at the periphery of the eye. As it continues, it starts to move to the middle of the eye, and that’s what gives you the changes in visual acuity. But when you stop the drug or hold the drug the resolution actually starts at the middle of the eye and works its way peripheral. So while it may be late to happen, it’s actually first to recover.

DR LOVE: And how long does it take to resolve?

DR LONIAL: So the average time to improvement in visual acuity changes is about 20 days. The average time for resolution of keratopathy, the exam finding, is about 70 days. So that takes longer, but the visual stuff, which is really the biggest issue, that resolves pretty quick.

DR LOVE: And what fraction of patients have to have the drug held?

DR LONIAL: So that probably varies a little bit, but I’d say it’s somewhere between a third and a half end up having a drug held at some point. The time to usually see it is somewhere between cycle 2 and cycle 4. I’ve got patients that basically skip every other dose of drug. I have this 1 patient who’s been on for 2 1/2 years, and basically every odd cycle is what she gets. She doesn’t get the even cycles.

I’ve got another patient who’s 80 years old and hasn’t missed a dose yet, and he’s 9 months into treatment. So it does vary a little bit patient to patient.

DR LOVE: One other thing I was just kind of curious about, we’ve been hearing a bunch of ophthalmic issues in antibody-drug conjugates,

But there is one in cervical cancer, it’s called tisotumab vedotin, where they’ve used ice packs on the eyes during the infusion. And apparently it greatly ameliorates — I think there it’s a different type of ophthalmic problem. But based on your understanding of what’s going on here, do you think that that kind of strategy would work with belamaf?

DR LONIAL: Yeah, I think that was tried anecdotally in the DREAMM-2 study. I don’t know that it really made a difference. So that’s really the idea that circulation seems to have an impact on it, but remember the cornea’s an avascular area anyway, so I doubt that you’re going to get much benefit there.

I think the real question, and this is 1 study, the DREAMM-6 study, that’s combining it with bortezomib, looking at the efficacy of these 2 things together.

At ASH there was a trial combining belamaf with pomalidomide as well. And in that study, they’re actually splitting the dose or they’re giving it every 4 weeks instead of every 3 weeks. And so I think looking at alternative dosing schedules will really be the way to try and mitigate this issue partnering it with other drugs.

DR LOVE: That’s really interesting.

DREAMM-6: Safety, tolerability and clinical activity of belantamab mafodotin in combination with bortezomib/dexamethasone for R/R MM

DR LOVE: What about this trial, the DREAMM-6 study? Any comments on that?

DR LONIAL: Yeah, I mean I think this really is proof of principle that you can combine belamaf. I think given some of the hypersensitivity to the ocular issues early on there was a concern that it wouldn’t necessarily be doable. But what they showed was that you could get very high overall response rates. Many of these patients were resistant to bortezomib, so getting that synergy between bortezomib and belamaf, I think, was really exciting. And keratopathy continued to be the most common adverse event, but it was certainly no worse than what I showed you from the DREAMM-2 study.

DR LOVE: Any other comments on this strategy or other combination strategies with belamaf?

DR LONIAL: No, I think like I said, I think Dr Trudel’s combination with pom is really interesting because it opens up a whole new window in terms of other potential ways to combine. They actually split the dose over day 1, day 8, or they gave it every 28 days. And that 28-day cycle seemed to work pretty well. So that’s an interesting way to think about combinations.

DR LOVE: Interesting.

Updated results from the Phase I CRB-401 study investigating the B-cell maturation antigen (BCMA)-directed chimeric antigen receptor (CAR) T-cell therapy idecabtagene vicleucel for R/R MM

DR LOVE: How about this CRB-401 study?

DR LONIAL: So this was an update of the Phase I study using ide-cel or bb2121, and this is probably the CAR T-cell that’s furthest ahead at this timepoint in terms of overall hopefully soon to market. And this really used the different doses that were evaluated, 50, 150, 450, and 800. And what you see is the PFS on the left, the overall survival on the right. But what I put in the middle is the overall response rate.

And what I think is really quite important here is that you’ll see that it looks like the 450 is probably the better dose. It did have fewer CRS and other potential complications. And this is the dose that’s actually gone forward in the KarMMa trial, which was the registration study for bb2121. So this was an update of that study, and I think demonstrates that some patients can continue to have very long and durable responses.

DR LOVE: What’s the status of the KarMMa study?

DR LONIAL: So it is under review at a journal, so it’s been submitted for publication. And I think that the application to the FDA is under review, as well.

DR LOVE: And if it is approved, how do you see it being utilized, and where do you see it being sequenced in?

DR LONIAL: Yeah, I mean I think the label is going to be the triple-class refractory patient, so IMiD, proteasome inhibitor, CD38. I think that this will require referral to a transplant center or a fact-accredited center. I think insurance is going to require that. So I don’t think it’s going to be an option for every patient because I don’t know that every patient wants to come to a transplant center. If you think about who wouldn’t be eligible, it would probably be the really, really old, and very frail patients because this is easier to do than a transplant. And as you know, we go up to 79 for transplants in the right people. So I think it would be a viable option. It’s just which patients are willing to come to the sites and go through the hospitalization, the risk of CRS, all those other things, to get a cell therapy.

DR LONIAL: Where are we right now with CRS? Do you think we are or will see more of it if we use it earlier?

DR LONIAL: I don’t think we’ll see more of it if we use it earlier. I think some of the CRS events, at least from what we can tell, may be a class effect. It seems to be worse with the CD19-directed CAR T cells. It seems to be more Grade 1/Grade 2 with BCMA-directed CAR T cells. Neurotox seems to be less as well. But there still needs to be somebody who can manage that in the hospital whenever it happens. And so I think that’s really the reason why a fact-accredited transplant center makes the most sense.

DR LOVE: Any thoughts about why it seemed that you kind of don’t see the same shape of curves that you see with CD19 CAR T in terms of having a big shoulder? Any thoughts about why we aren’t seeing that and whether we might see that in the future?

DR LONIAL: Yeah. I think that in my mind the idea of a single dose of a CAR T-cell where the persistence may be averaging somewhere around 6 months, is an issue in myeloma. And so I think one of the things that is going to be really important is how do we prolong persistence or think about a second dose at another timepoint to try and maximize that down the road. Because unlike large cell lymphoma and ALL, where persistence doesn’t seem to correlate with outcomes, in myeloma I think it does.

DR LOVE: Of course you do see persistence with CD19. Any thoughts about why? I mean obviously myeloma patients are compromised immunologically, but are there specific immunologic pathways you think that are involved here?

DR LONIAL: Well remember, large cell lymphoma and ALL are intrinsically curable diseases, right? So even with chemotherapy you can cure a substantial proportion. I think with myeloma it’s just not so simple. I think that there’s either a clone or there’s a group of cells that are hidden immunologically and so don’t get attacked by whatever you come in with them. I mean we’ve all had examples of patients that are 8, 10, 12 years out in continuous remission and relapse. And so even the idea of long, durable, unmaintained remissions being cured is not so clear in myeloma right now.

DR LOVE: Interesting.

CARTITUDE-1: A Phase IB/II study of the BCMA–directed CAR T-cell therapy ciltacabtagene autoleucel for R/R MM

DR LOVE: So what about the CARTITUDE-1 study? We saw some more data on that at ASH also.

DR LONIAL: Yeah, so CARTITUDE-1 is basically taking the LEGION construct, the LCAR from China,

And what we saw was a very high overall response rate. You can see that in the middle there, somewhere in the mid to upper 90s for patients in terms of response rates. The follow up is about 12 months in average, and about 76% of patients are still in remission at 12-month follow up.

So on the surface one might make the case that cilta-cel may be better than ide-cel because more patients are in remission at 1 year with one versus the other. I would caution against that logic right now because the studies are only 100 patients each. It’s pretty small. And we just don’t know with longer follow up whether there will be a plateau on this curve. There’s an argument that because they target 2 different places on BCMA that cilta-cel will be better. I think we need more follow up to know that.

DR LOVE: If we do see these agents starting to become approved, at this point what do you say to your patients in terms of what to expect in terms of efficacy. Do you give them a typical duration of response? And I’m curious what you see. I hear a lot of stories about patients feeling really great when they’re off therapy after they’d been off therapy for a long time.

DR LONIAL: Yeah. I mean I think in certainly the bb2121 the average duration of remission is a year. And you could argue in that year they are getting nothing, and so they do, they’re happy with that in terms of overall durability. But as oncologists we’re always thinking what’s next, right? So yes, you were off therapy for a year, but now I’ve got to do something else again. And so I think patients do like that drug-free holiday, but I think for this to be a viable long-term strategy you’ve got to get more than a year out of it. Because that’s, in my mind, not long enough for the cost and all the other things that we’re doing.

Updated results from the Phase I CRB-402 study of the anti-BCMA CAR T-cell therapy bb21217 for R/R MM

DR LOVE: What about this CRB-402 trial with bb21217?

DR LONIAL: Yeah. So bb21217 is basically taking the 2121, the ide-cel construct, and incubating it with a PI3K inhibitor before they give it back, with the idea that you enhance the memory phenotype of the product. And it appears at least from flow cytometry, that that’s correct. What we would hope is that that translates into a better progression-free survival. That persistence is linked to memory T-cell phenotypes, that results in longer PFS.

And this was a Phase I study escalating the dose of the cell construct. So in this overall PFS it’s only 7 months, but remember there were really low cell doses in this as well. So what I think, and I can tell you our longest CAR T-cell responder is on this trial, well over 2 years now. And so I’m hopeful that this will be part of that second wave of CAR T products that takes the model T from the original and makes it better and goes forward.

DR LOVE: What’s the pathophysiology? What’s going on? They give a PI3-kinase inhibitor? Which one?

DR LONIAL: Yeah. There’s a lot of data from a number of different labs suggesting that you skew things towards a memory T-cell phenotype by giving a PI3K inhibitor for a short period in vitro.

Our Emory group has done that.

There’re several groups that have shown this. I think they’re working on the actual mechanism, but it’s not unique to myeloma cells that this is happening.

Iberdomide in combination with dexamethasone and either daratumumab or bortezomib for patients with R/R MM

DR LOVE: So I’m curious about your thoughts about iberdomide and this study combining it with dex and dara and bortezomib.

DR LONIAL: Yeah. Iberdomide, to me, I call it the son of pom because it’s the next-generation or IMiD, or called CELMoD, because it really does focus more on immune function. And this was part of the Phase Ib study, where I reported on the single-agent response rate of iber/dex, which is about 32% in triple-class refractory myeloma. This was the Phase IB combining with bortezomib and combining with daratumumab.

And what you see here is that the response rates jumps in patients who get iber plus bortezomib. Remember, all of these patients are bortezomib exposed and/or refractory, and so increasing the response rate by about 10% or 12% to the addition of bortezomib. And there really were no adverse events that didn’t allow us to combine iberdomide with bortezomib together. And this is the rationale behind the Phase III trial that’s planned, which is iber/bortezomib/dex versus bortezomib/dex.

So that Phase III trial will be coming relatively soon.

DR LOVE: What tolerability, if any, are present with iberdomide?

DR LONIAL: One of the hallmarks of the early-phase development of iber is that it’s tolerated much better than len or pom. Very little issues with fatigue or diarrhea, some cytopenias, particularly in a refractory myeloma patient population. But in general it’s pretty well tolerated, better probably, than its parent compounds of thal, len, or pom.

DR LOVE: Do you see the possibility of it moving up and for example replacing lenalidomide?

DR LONIAL: Yeah. I mean I think whether it’s in the maintenance form, whether it’s part of the induction, I think the idea is to move iber up front pretty quick. And in fact in one of our studies we do have an iber/bortezomib/dex induction arm as well. So just to prove dose and schedule.

DR LOVE: I’m just flashing back on Phil McCarthy’s discussion of this at ASCO, where he had this wild animation. Maybe you could talk a little bit about how far we’ve come in terms of understanding the mechanisms here.

DR LONIAL: Well I think one of the nice parts about iber and its cousin CC-92480, which doesn’t have a name yet, is that they really are engineered in a way to focus more on the cell activation piece. So they’re engineered to activate NK cells and T cells and focus on the immune piece, with some antitumor effects as part of cereblon binding. And so at least in vitro the effects on NK cells and T cells are almost log bigger with iber than they are with pom or with len. And those, to me, really speak to the potential to make immune treatments better, partner with antibodies, partner with bispecifics, partner with CAR T cells. And in fact there is an arm of a CAR T-cell where they give iber afterwards to augment the immune response and improve persistence as well. So I think there’s lots of interchangeability here with what’s coming.

DR LOVE: That’s really interesting. Is iber being looked at in other situations where the IMiDs are being used, for example lymphomas?

DR LONIAL: I think that there is a CELMoD that’s being looked at in lymphomas. It wasn’t CC-220. It was a different CC. And I don’t know where they are in that development.

DR LOVE: Interesting.

Updated results from the Phase I trial of teclistamab, a BCMA x CD3 bispecific antibody for R/R MM

DR LOVE: So we’re hearing a lot of exciting things about the bispecifics. I’m curious what your thoughts are about teclistamab. I don’t know how to pronounce it. You tell me.

DR LONIAL: Yeah. Teclis. So teclistamab is a BCMA bispecific targeting BCMA and CD3. And we’ve seen this data from AMG 420. We’ve seen this data from CC-9269, I think. And this is the data for the teclistamab product, which you can see in their recommended Phase II dose has an overall response rate of 73% in refractory myeloma.

I think that this, in many ways — we need to see the durability of these responses, but in many ways, this is almost one of the easy ways to give BCMA-directed therapy. Relies on autologous T cells to really do the effect. And I didn’t think it would work. I didn’t think a bispecific would work in myeloma because I thought the T cells would be too tired and exhausted to really be able to do anything. This study and other studies have proven that wrong, and this is going to rapidly move up front because I’ve already heard from the Europeans. They’re not planning a quad. They’re planning a pentad induction regimen with carfilzomib, lenalidomide, daratumumab, and teclistamab as part of induction therapy to really try and wipe things out.

And as I said earlier, this is where I start to think about triplets. A triplet for 2 cycles, another triplet for 2 cycles, then go back to that first one, then come back to the second one and alternate cycles to try and keep the tumor off guard, or off balance, if you will. And that may be an alternative way to think about it.

DR LOVE: Wow. Really interesting. What about tolerability issues? Do you see CRS and neurotoxicity for example?

DR LONIAL: Yeah, we did see CRS, no neurotoxicity, but certainly did see CRS, particularly in the first cycle. So the first couple doses are given in the hospital to make sure that you can manage what’s going on. Most of it was Grade 1/Grade 2, very little was Grade 3 or higher. And once you get beyond those first 2 doses, then it goes to all outpatient. And there is certainly a subq formulation, as well, which again will make things a lot more convenient for patients.

DR LOVE: Because I know like blinatumomab, obviously a totally different bispecific. They give 24-hour infusions. These are just regular? And what’s the schedule like?

DR LONIAL: So it’s given twice a week for the first few doses and then goes to once a week after that. And so the idea here is because it’s a long half-life you can give it subq, and it doesn’t require that continuous infusion. So this is more like an antibody and less like a BiTE.

DR LOVE: So again, this is given subq?

DR LONIAL: Yeah. There was a subq cohort, yeah. And subq’s moving forward.

DR LOVE: Wow. Okay.

Activity and safety of the bispecific antibodies talquetamab and BFCR4350A in patients with R/R MM

DR LOVE: Here’s another one, talquetamab.

DR LONIAL: Yeah, talquetamab is an interesting one because this is a new target. So if you’re tired of hearing about BCMA the next couple slides are new targets for the future, and really is what gave rise to my cycling different combinations of drugs because now we’ve got SLAMF7, CD38, BCMA, GPRC5D, FCRH5, that’s 5 different immune targets on the surface of a myeloma cell. And I don’t think it’s practical to say we’re going to combine all 5, but the question is can you do it in cycles that allow you to hit the tumor at different times.

So this is a bispecific also that targets GPRC5D, which is expressed only on plasma cells, again uses that same mechanism as teclistamab that showed you earlier. This is also subq, and at the highest dose cohort an overall response rate of about 73%. So similar to what you saw with teclistamab a moment ago, completely different target. And so again is another way to think about immune targeting of a myeloma cell.

DR LOVE: Again, tolerability issues?

DR LONIAL: CRS was really the only thing, lower incidence than what we saw with teclistamab or BCMA-directed bispecifics, manageable. First dose or 2 is given in the hospital. Beyond that, it’s all outpatient.

DR LOVE: The idea of piling all these drugs up front, what are you going to do if the patient progresses?

DR LONIAL: Well I think the only rationale for piling them all up front, given that we already do achieve MRD negativity with our current therapies in a certain fraction of patients, is either response-adapted therapy, so if they don’t get there then we add something different or the idea that can you really cure patients and stop treatment. And those are the things that we’re going to have to test in the coming years.

Another new target, FCRH5, again almost exclusively expressed on plasma cells. This is an antibody as well. As you can see, in the overall response rate in the highest-dose cohort was about 60%. Small numbers, hard to know, but certainly 41% were penta-refractory, 63% had seen prior BCMA. Responses were quick. Most common side effect again was CRS, and that’s about it.

ANCHOR trial: Updated efficacy and safety data with melflufen in combination with dexamethasone and either daratumumab or bortezomib for R/R MM

DR LONIAL: Melflufen. I’ve been pretty curious about this. I didn’t quite get what it was when I first heard about. I interviewed Paul Richardson about a year ago, but as the year’s gone on I’m starting to realize this is a little more complicated than I thought. Can you first of all explain what it is?

DR LONIAL: Yeah. Melflufen is a conjugate of an aminopeptide plus melphalan. And that aminopeptide allows it to be targeted towards the plasma cells. For some reason, the membrane is more lipophilic, and so it increases the concentration within the plasma cell. And so melflufen, almost in many ways, is a prodrug. It really only gets activated once it’s internalized, and the peptidases actually cleave that aminopeptide off of the melphalan, and then the melphalan does what it’s supposed to do. So in many ways it’s considered a targeted melphalan, although it’s not targeted with an antibody, it’s targeted with that lipophilic piece there.

So this was the ANCHOR study. It was combination of melflufen plus dex and daratumumab, and again was in a median of 3 to 4 prior lines of therapy. Median overall response, was pretty good in terms of the swimmer plot that you can see on the left. And the median PFS for this small Phase II study was about 12 months, suggesting that the combination of melflufen plus dara is a very active salvage regimen for late-lines of therapy, has a good response rate, and again is a safe and tolerable regimen to give to relapsed/refractory myeloma.

DR LOVE: So yeah, I didn’t realize that it was targeted in that way. What’s the whole thing with Oncopeptides, and are there other agents that are being looked at with this kind of strategy? It almost kind of reminds me of being an antibody-drug conjugate. Am I seeing that correctly?

DR LONIAL: You are. You are. It probably is similar except it’s not targeted with a monoclonal. It’s targeted with something else.

DR LOVE: Right.

DR LONIAL: And so I think the idea is that you can take that same construct and put any drug onto it and use it to try and enrich delivery of your drug to that specific cell type.

DR LOVE: So I mean just out of curiosity do you know of other drugs that are being looked at with that kind of Oncopeptides strategy?

DR LONIAL: That’s a good question. I don’t know the answer to that one. I don’t know the answer to that.

DR LOVE: What about melflufen in the transplant situation? Is that being thought about?

DR LONIAL: It is. It is. There are groups that are beginning to think about how to do that, to look at giving high doses of melflufen, and that’s very preliminary data right now.

KarMMa: Efficacy and safety of idecabtagene vicleucel in older patients with R/R MM

DR LOVE: So I think there were a couple other papers. One was I guess the bb2121 in elderly patients that Dr Berdeja presented.

DR LONIAL: Yeah, so that was really looking back at the KarMMa experience and particularly trying to separate it out by age. Was there a discriminator based on age that would tell you they would do better or worse? And I think what was really interesting about this presentation by Jesus Berdeja was that age did not appear to impact CRS. It didn’t appear to impact overall response rate, didn’t appear to impact progression-free survival. So I think he used 70 as his cutoff, over 70 and younger than 70. And in that analysis what it says to me is don’t use age as a cutoff for whether or not to give somebody a CAR.

DR LOVE: Yeah. Actually I was going to ask you before when you were talking about that. Clearly I’m hearing a lot of people talk about the fact that you don’t need to be in the same condition as you do for an autologous transplant. But I mean would you consider it in a healthy 90-year-old?

DR LONIAL: It all depends on performance status. So if they’re very functional, and I think I know the kind of person you’re talking about because I’ve got a few of them in clinic, I would. I would, absolutely.

DR LOVE: What’s the oldest patient your center’s given CAR T to, just out of curiosity?

DR LONIAL: I think 79 is the oldest for us. But it’s not that we’ve said no to anybody. We haven’t had that come up yet.

DR LOVE: Interesting.

Assessment of minimal residual disease by next-generation sequencing and FDG-PET/CT for patients with R/R MM treated with venetoclax, carfilzomib and dexamethasone

DR LOVE: So another paper I wanted to hear your thoughts on was by Costa looking at MRD by next-gen sequencing and PET in patients with relapsed myeloma being treated with ven/CAR/dex.

DR LONIAL: Yeah. Yeah.

So that’s a really interesting data set because what I think it brings up is the idea that MRD by biochemical assessment is probably not sufficient anymore if we really want to understand how we’re doing in terms of overall depth of response. And so the idea of using both imaging and MRD assessment I think is really important. And the take-home lessons from that were that a significant fraction of patients that got ven/car/dex achieved MRD negativity, and that most of those patients actually had PET-negative disease as well. And so the idea of using both together, at the same time we do MRD we will routinely do PET testing as well, just to really confirm that finding as well.

DR LOVE: Interesting. Incidentally, in terms of the combination of ven/car/dex, any thoughts about ven combinations and where that’s heading?

DR LONIAL: Yeah. Those trials are ongoing now. So there’s a trial looking at car/ven/dex versus car/dex in 11;14-positive patients. There’s also a trial looking at dara/ven/dex versus dara/bortezomib/dex in 11;14-positive patients. And those 2 trials are enrolling right now. We just put 2 people on in the last couple weeks. That will help us to get to the FDA approval that will get ven out there for the general public.

DR LOVE: Now these are randomized studies?

DR LONIAL: Yes.

DR LOVE: What’s the randomization?

DR LONIAL: So one of them is car/ven/dex versus car/dex, so using the ENDEAVOR control arm. And the other is dara/ven/dex versus dara/bortezomib/dex, so both arms get a triplet there.

DR LOVE: So just out of curiosity, what would you say the single-agent response rate to ven would be in 11;14, because I kind of wonder, indirectly, how would it compare to, for example, carfilzomib/dex?

DR LONIAL: Yeah. So single-agent response for ven alone in 11;14 is 40%. Ven plus dex is 65% just in the 11;14 subset. So if you add carfilzomib to it, I think you’re going to push those numbers pretty high. So I think it’s a fair randomization. I actually think it’s almost skewed towards venetoclax, because ven will win.

DR LOVE: Yeah, I was thinking maybe it should be ven plus or minus carfilzomib, because this is carfilzomib plus or minus ven, right?

DR LONIAL: Yeah, yeah. The FDA wouldn’t let you do ven plus or minus car because they want a non-ven-containing control arm.

DR LOVE: So just out of curiosity, outside a trial setting when are you bringing ven in in 11;14?

DR LONIAL: As early as we can. We’re treating in first relapse even if we can get ven/dex or put them on the study, that’s what we’re doing.

DR LOVE: I can’t tell you, I can think of at least 3 cases I’ve had presented to me from oncologists who said I’m running out of options here. They’ve already had a PI, they’ve had an antibody, and I see the 11;14 up in their case, don’t even think about it. Which I couldn’t believe it, but they have so many things to keep up with. It’s amazing.

DR LONIAL: It’s tough. And I will tell you, ven in 11;14 is one of the most single active drugs we have. I mean that’s how good it is.

DR LOVE: That’s what I’ve heard. Do you see it moving into up-front treatment?

DR LONIAL: Yeah, yeah. There are already trials designed for the 11;14 subset, adding it to VRd.

DR LOVE: How do you approach the issue of TLS with venetoclax? For example, do you use the CLL guidelines? What do you do with plasma cell leukemia?

DR LONIAL: Yeah. So PCL is a different story, so we’ll take that one in a second. But in the patient that’s starting on venetoclax for us, we don’t do the ramp up, we just start them. What we actually do at our center is we see them in the morning, give them their first dose, and then we check their labs in the afternoon that same day. If their LDH didn’t move at all, then they’re fine, and they’re not going to get TLS. We rarely have seen TLS with ven, even in our good responders.

The PCL story’s a little different, and that is I think if you’re going to use ven you need to see them a couple times a week with PCL if they’re outpatients because that one you’re more at risk for. We’ve still not seen it, but I think the risk is much higher in a PCL patient.

DR LOVE: And how responsive are these PCL patients?

DR LONIAL: We’ve maybe had 1.

DR LOVE: Really.

DR LONIAL: And again they have to be end stage, so it’s not like it’s working in everybody.

DR LOVE: Sometimes I can’t remember where I’ve heard things, but I think it was in myeloma where I heard, yeah I think it was, that in addition to the 11;14 patients, there are these other patients who had some assay for BCL2.

DR LONIAL: BCL2 high.

DR LOVE: Can you explain that?

DR LONIAL: BCL2 high patients. So that was done in the BELLINI trial.

DR LOVE: Right.

DR LONIAL: And so what the BELLINI conclusions are is BCL2 high or 11;14 should be venetoclax sensitive. I’m a little suspicious of the BCL2 high unless we prospectively looked at that separately because I think the 11;14 is a no-brainer. And I want to get this drug out there so that what you describe people don’t know to use it, that goes away. And then if the BCL2 high also gained benefit, then we can add that on afterwards. But I’d just get the 11;14 right now and be happy.

DR LOVE: What about assays for BCL2 in general? I mean obviously venetoclax is being used in a lot of places all the time in CLL and AML. Are assays out there, maybe in the future, that’re are going to be practically used?

DR LONIAL: Yeah. I mean our sensitivity assay’s pretty easy to use, but it’s still an in vitro test. I think there are people trying to develop, whether it’s IHC or other predictors of sensitivity. I mean remember, in CLL it’s a homerun, right? So you don’t really need to test because you know it’s going to work. Follicular’s probably the same way. So it’s probably some of the margins of niche diseases where you need that sensitivity testing. And I’m hopeful at some point some folks in our lab actually are looking at surrogate markers like CD20 expression. That seems to correlate nicely with sensitivity to venetoclax, but it’s not the only answer. Getting that data would be helpful.

DR LOVE: Any other presentations on myeloma or plasma cell disorders at ASH that you want to comment on?

DR LONIAL: I think we’ve hit the highlights. I mean I think the induction therapy setting, I think, is moving towards quads for the fit patients. I think the transplant continues to have an important role. I think that we have lots of randomized Phase III data in early relapse, and now it’s a matter of picking your favorite flavor. What combination, what triple do you want to use in a len-resistant patient? And then I think the challenge for us is with all these new drugs and targets how do we put them together in a rational way to really get to where we want to get with myeloma?

DR LOVE: That’s a theme I’ve heard for a while.

DR LONIAL: Yeah. That’s right. We want the iceberg to go away, right?

DR LOVE: Right. Exactly.

This concludes our program. Special thanks to Dr Lonial, and thank you for listening. This is Dr Neil Love for Oncology Today.