María-Victoria Mateos:
Good morning, good afternoon, good evening, depending where you are, and welcome to this roundtable discussion organized by Video Journal of Hematological Oncology. My name is Marivi Mateos from Salamanca, Spain, and I would like to welcome to Tom Martin and Nina Shah, both from the University of San Francisco in California – because, they will be joining with me today in this discussion. We’ll have the opportunity to discuss about, well, the news we have just had at ASH meeting. So welcome Tom and Nina. And let’s go to start, and first, I would like to discuss with you about the newly diagnosed myeloma patients. And if we focus on the transplant eligible population, the hot topic or the debate about the possibility of skipping autologous stem cell transplantation in the upfront setting has been a continuous topic of debate.

María-Victoria Mateos:
And during this ASH, we had the opportunity to see the update of the French study, with a very long follow-up, approximately nine years. And all the transplant continues to being superior in terms of progression free survival. No differences has been reported in terms of overall survival. And the European Myeloma Network trial reported, by contrast, a significant benefit for transplant even in terms of overall survival. And well, these two studies utilize the different induction regimes. And in addition, we have the default study with a KRd or KCd, as part of the induction. But again, transplant continues to be superior in terms of progression for survival with no benefit so far in overall survival. What is your opinion about the role of autologous stem cell transplantation? We have to continue offering transplant in the upfront setting to our patients or do you consider that some patients can potentially escape a transplant in the upfront setting? Tom, do you want to start?

Thomas Martin:
Sure. So I’m still in favor of doing autologous transplant as part of upfront therapy for a couple of reasons. Although the French IFM study did show it, eight years down the road, that the overall survival was exactly the same. Patients do, I think, benefit from having a longer progression free survival – a longer interval initially of after the transplant and on maintenance being on a really low dose of medication, and having quality at that point in time. There was also data from the FORTE trial – we might talk about that more, where in fact, the patients who got KRd for [inaudible] transplant did do better in terms of patients who got KRd without transplant. So I still think there’s this overwhelming, I’d say, energy, inertia for us to move forward with transplant because we get a deeper remission and more patients achieve that MRD negative status, and have a longer initial remission duration. So I still like it.

María-Victoria Mateos:
Nina?

Nina Shah:
Yeah. I agree with Tom, that I am still in the camp of early transplant upfront. I will just point out that the point of the IFM study is early versus late transplant. So this change in PFS – the difference in PFS – reflects that, it doesn’t reflect getting a transplant or not. And so it’s like you have to ask the question reverse that, are there patients who could delay the transplant? Sure. I would tell them that their overall survival if they choose to get the transplant later will probably not be affected, it would only affect the PFS. But can we predict who those patients are going to be? Because, just because you say someone’s going to get a transplant later, doesn’t mean they’re necessarily going to be up for getting the transplant later. And of course, you have to make sure you’ll collect the cells in advance.

Nina Shah:
So, because of that, I agree with Tom, that earlier transplant is better. I thought this ASH kind of nailed that point in and that transplant in first remission is better and I still offer it. I totally agree that it’s a chance to get the patients to go off and get maintenance therapy and return to their normal life, which is our ultimate goal.
María-Victoria Mateos:
Yeah, excellent comment and I think that you pointed out an important comment, that I think that is relevant for the audience. In the French study, approximately 88% of the patients who did not receive a transplant upfront, they received it either at the relapse, so this is what Nina said. This is not a transplant versus no transplant, it is early versus late, and definitely, this is the lack of benefit at the end in overall survival. But maybe, we are going to benefit more patients if we offered them a transplant in the upfront setting.

María-Victoria Mateos:
I think that this is an important message for the audience, and also even for the patients that sometimes they don’t want to go to autologous stem cell transplantation, and at the end, well, it’s not a very complicated procedure. And well, I think that we have to offer the transplant to our patients.

María-Victoria Mateos:
And let me ask, you both are working in the same institution, so what is your standard of care for induction? Is it VRd, or do you prefer to utilize KRd, or do you plan to add anti monoclonal antibody that are [inaudible] based on GRIFFIN study? What is your opinion? Nina, you first, right now.

Nina Shah:
Well, Tom’s my boss though, I want to say what he says but-

María-Victoria Mateos:
No problem.

Nina Shah:
No, I think what I can say, I don’t yet do, I don’t yet do DARA-RVd upfront. And the reason I don’t yet, even though we were participants on the GRIFFIN trial, is that I haven’t seen the PFS and the regimen that’s shown there means you have to do DARA-len for maintenance as well. So that’s a lot of DARA you’re committing the patient to if you don’t yet know about PFS. So, that’s my hesitation to do that. And so I still struggle with the VRd, KRd, ENDURANCE didn’t help me at all, because that trial doesn’t have transplant, and as I already mentioned that we do transplant. So I still use a lot of VRd. I think having seen the FORTE data, I might switch to that regimen KRd transplant KRd, I might… I could consider that. We always have this discussion two weeks after ASH at our group, say, “What are we going to do?” So I guess I’ll turn it over to Tom and see what he thought.

María-Victoria Mateos:
Okay, Tom.

Thomas Martin:
Yeah. So Nina and I practice very similarly. In the transplant ineligible, I really do like the daratumumab, lenalidomide or Revlimid, and dexamethasone, that triplet, it’s extremely well tolerated. And I think the lack of worries with neuropathy is huge for patients, especially for quality of life. Now, in a high risk transplant-ineligible patient, I think we all still do RVd or RVd-lite. For transplant-eligible, I do think that we’ll drift to quads. We will go to DARA-RVd in the future, but it’s about currently being insurance approved. So we don’t get approval for the drugs in California at the current time, so we can’t do that. So probably RVd is our standard. We do KRd because it wasn’t involved in ENDURANCE, in the high risk transplant eligible patients, we will do KRd as induction.

María-Victoria Mateos:
Okay. So in Europe, more or less the same. Our standard of care is basically VRd. We don’t have approval to VRd-DARA, but we have approved the VTd plus daratumumab. But for us, what we are not going to do is to go back to VTd-DARA when you are using VTd. So sometimes we ask our pharmacists in order to prescribe VRd plus daratumumab and this is what I have done just in a couple of patients, but this is what we can envision, we will do more and more, basically, in Europe, in the centers in which VRd is our standard of care. And just that Tom, previously alluded to the transplant- ineligible population with a DARA-len-dec I think that the results are excellent and from my point of view, are the best results we have observed in a Phase three clinical trial conducted in the transplant-ineligible population, go to tolerability. And as you mentioned, no peripheral neuropathy. But I think that in US, many centers continue using also RVd for the transplant-ineligible population. Is this correct and, and is there any explanation, because insurance problems or not?

Thomas Martin:
I think, honestly, it’s more practice patterns. People are used to the same, doing the same thing. We’d probably have had a less than 10% use of DARA-Rd in the transplant-ineligible. I do think that the approval of daratumumab by subcutaneous administration is going to increase the use of it as frontline therapy. It just makes it a lot easier for the patient – they don’t have to sit there for a few hours getting an IV medication, they can get a five minutes sub-Q. I suspect in the next year or two, we’re going to see a significant buy-in to using DARA-Rd as frontline in the transplant-ineligible.

María-Victoria Mateos:
Yeah.

Nina Shah:
Yeah, sorry. I completely agree with you that the sub-Q DARA is going to increase the uptake of DARA-Rd. And I also agree with you that practice patterns are hard to change, and particularly for our institution, we’re a referral center, so a lot of times we see people but we don’t actually see as many transplant-ineligible patients as they see in the community. And so our proportions, what we’re seeing may not reflect what’s actually going on in the community as far as VRd-lite, DRd. But, I have been recommending a lot of DRd in this situation more lately, especially with sub-Q.

María-Victoria Mateos:
Okay, perfect. And now, let’s move on to evaluate the relapse and refractory situation. And I think that the first relapses right now are challenging, at least for us. Because well, more patients at first relapses are basically coming from lenalidomide continuous therapy, and the patients are basically len-refractory. Today, tomorrow will be maybe len and/or DARA-refractory, and we will have an additional problem. But today, I think that most patients we see at first relapse are len-refractory. And well, if the patients I would say that are anti-CD38 monoclonal antibody naȈve. Well, maybe you agree with me that the first option is to select the monoclonal antibody, anti-CD38, in combination with something else. What is the best partner from your point of view for these refractory population, including the anti-CD38 monoclonal antibody? Nina or Tom-

Thomas Martin:
You want to try first?

Nina Shah:
Well, I think that by an efficacy standpoint, I do think that daratumumab, or anti-CD38 antibody and carfilzomib are probably the best data we’ve seen so far. The problem is that it’s not necessarily the best option for the patient because of the intravenous carfilzomib that they have to come three weeks on and one week off. A lot of these patients are still 68 years old, they have a regular life, they don’t want to come to the infusion center three weeks out of four. And for those people, DARA pom-dex is a very outpatient friendly, easy thing to do, and they just come once for the subcutaneous injection every month. So from a patient tolerability standpoint, in fact, that’s easier. But the data that we’ve seen both from CANDOR and IKEMA which Tom will comment on, especially the depth of response is very impressive.

María-Victoria Mateos:
Tom, what is your preference?

Thomas Martin:
Yeah, so I completely agree with Nina. We have two really good choices, anti-CD38 antibody plus pomalidomide and dex, or anti-CD38 antibody plus carfilzomib. Those are really great options. Some people also can… Most of the patients are bortezomib sensitive, so you could potentially do pomalidomide, bortezomib and dex also. I tend not to do that really because of the neuropathy. Often, they still have some neuropathy that’s still bothersome, and so we kind of shy away from that. But if they had no neuropathy whatsoever, that would be a reasonable regimen.

Thomas Martin:
And I think the data… There was an abstract presented by David Siegel with DARA pom-dex as first relapse, showing a PFS over 30 months, which is pretty impressive. And then we presented data on the isatuximab, carfilzomib, and dex, where so far at 20 months of follow-up, the median PFS has not been reached. But based on the hazard ratio of 0.53, it’s probably going to be in the 30 plus month range also. And that’s one to three [inaudible] we just focus on the first relapse, I don’t know, it might be higher than 36, maybe higher than 40 months. I think it will be a really great regimen.

María-Victoria Mateos:
And Tom, let me ask you, I think that the millionth question, do you have any preference or do you think that there is any difference between the two monoclonal antibodies and the anti-CD38, daratumumab and isatuximab?

Thomas Martin:
Yeah, we get that question a lot because we’ve done a lot of isatuximab trials at UCSF. And when we initially did the phase one of isatuximab plus carfilzomib, the premise behind that is that because isatuximab was selected based on its ability to induce apoptosis without cross-linking, that it might partner better than carfilzomib. But both studies, the CANDOR and the IKEMA have both showed really good response rates in the one to three prior lines of therapy. And we don’t have median PFS data from either one of those studies. We have to follow it more longitudinally. If there is one thing that I think stands out with the IKEMA trial is, 1/3 of the patients did achieve MRD negativity with ISA-carfilzomib, and dexamethasone, and that’s really a high level of MRD negativity in the one to three prior lines of therapy. So, so we’ll just have to see what comes up with those data, but it’s provocative that that might be a really great combination.

María-Victoria Mateos:
Yeah. Let me ask you another question. Do you see any role for selinexor in combination with bortezomib and dexamethasone in these relapses – I would say between one to three prior lines of therapy based on the Boston study?

Nina Shah:
Well, I think that selinexor is so interesting because it’s just like belantamab, it’s combining with these things that we’re already using, and it’s hard to go back to them. So exactly as Tom said, that people are not necessarily bortezomib-refractory by the time they get to their [inaudible] third prior lines, that is a possibility. I just don’t see us picking selinexor, bortezomib, dexamethasone over daratumumab, pomalidomide-dex or DARA-car-dex. And what I could see, and based on the ASCO data from Christina Gasparetto’s study, I could see that maybe somebody got DARA-pom-dex in the second line, and in the third line could do selinexor, carfilzomib, dexamethasone because that data looked pretty good. And that would be something that I could see particularly for the 17p deletion population, Where they seem to have some efficacy there. So I think that’s where that drug could go, just because of our experience already that’s good with daratumumab.

María-Victoria Mateos:
Yeah. And another possibility would be just the opposite it to start with Kd daratumumab, Kd-isatuximab and to continue with pom-dex plus selinexor, because, well, I think that the results so far reported with this combination, I think in that are quite effective. And well, you know that selinexor is not approved yet in Europe, but based on the participation in clinical trials, my experience, whether the weekly administration of selinexor, I think that it’s quite tolerable and the toxicity is well-managed with supportive care. And I think that the first comments we heard about, well, the poor tolerability, but it’s not a scene that this experience in my patient receiving selinexor just once per week with supportive care.

María-Victoria Mateos:
So maybe there is a role, and Nina, you mentioned the role on patients with the deletion 17p, something that definitely, we have maybe to investigate.

María-Victoria Mateos:
Before moving to the maybe the key players of this ASH meeting – the cellular therapy and the BCMA targeted therapy and all their targets, any thoughts about the agents with the alkylator properties, like melflufen or cyclophosphamide. Do you see any role for these type of alkylator in myeloma and especially in the US in which, well you usually don’t like very much of the alkylators.

Thomas Martin:
So in terms of melflufen or melphalan flufenamide, I think the initial data is actually quite impressive, in fact, in these triple-class refractory patients, seeing response rates over 25%. And once we do, we’re talking CD38 PI, plus IMiD upfront and then PI plus something, second, and then IMiD-pomalidomide plus something in third, they haven’t seen an alkylator, you know, in quite a long time, maybe since transplant. I do think those patients tend to be alkylator sensitive. We use quite a bit of intravenous cyclophosphamide to try to salvage people at that point in time. Sometimes they need to be hospitalized for that, et cetera. It would be really nice to be able to use the melflufen product with dexamethasone to take up that space. I think there’s going to be a [inaudible] niche for melflufen once it gets approved early next year.

María-Victoria Mateos:
Yeah. Okay. Yeah. And I think that [inaudible] from Canada presented excellent results adding cyclophosphamide to pomalidomide, dexamethasone plus daratumumab in the relapse and refractory situation. And at the end of the day, it’s a cheaper drug we can usually, well, always to utilize in order to combine it with the novel combinations. And I agree with your comment about a melflufen and well, we have quite experienced with melflufen, because of our participation in the clinical trials. And I’ve seen excellent responses in patients with extramedullary disease and extramedullary disease is always a challenging situation in which sometimes we hospitalize them to receive [inaudible] complex combinations. And melflufen is, well it requires just one single administration in 30 minutes, every four weeks. So it can potentially replace this conventional chemotherapies we use in the past for these patients.

María-Victoria Mateos:
And now let’s move on to the well third therapy or the BCMA targeted therapy that I think that we’ve seen the opportunity to listen or to a long list of potential possibilities for targeting BCMA. And for me, well, one of the most impressive data I’ve seen at ASH, was the median overall survival reported with the BB2121, the trial published one year ago in New England Journal of Medicine and for me, it has been quite a surprise, but in a positive way to see how in spite of the median progression free survival was around nine months, the benefit in overall survival is almost three years. And this puts in context how these third therapy is covered in really the unmet medical need that we have in the triple-drug class refractory patients for which the overall survival was not superior to nine months. Nina, do you want to comment to something about that and about well, the next generation of BB2121, 21217 and so on to improve the efficacy?

Nina Shah:
Yeah. I also was impressed with the 34 months that they had from the 401 study, understanding that’s a phase one study, which is pretty unprecedented. They had median, I think, seven prior lines of treatment. So that’s a big deal that they were able to show that overall survival. We know that people went on to other treatments after the CAR-T when they progressed, but usually those people we know already those people were very difficult to treat to begin with. So that was very surprising and impressive data. I think what we saw subsequent to that, all the CAR-T’s in the phase II, ide-cel, which was already presented last year at ASCO, but, this past ASCO, and then the CARTITUDE, which really just blew it out of the water, greater than 95% response rate, just really deep responses.

Nina Shah:
And what looks like at the 12 month that they’re having 77% of people still maintaining their response. That’s what it looks like. So it looks like they’re going to be beat ide-cel, maybe, for the PFS. And that’s what we’re really looking for and, everything else, the new generations of things that the BB21217, the [inaudible], all of this, it’s not even comparable right now because we don’t have phase two and we don’t have the long-term data. And it’s really hard to compare the two, except for just looking at the differences in sciences and toxicity.

María-Victoria Mateos:
Yeah, of course it is not possible to establish cross-trial comparison. As I think that from my point of view, they are covering the unmet medical need. And well, if we have a seen a list of different possibilities with CAR-Ts, I think that the list of BCMA targeted therapies through T-cell engagers has been even longer than for CAR-T. Tom, I don’t know if you are able to pick up just one of them, or do you consider that all of them are similar or comparable? Is true that the efficacy is great and we don’t have much more data, but do you want to comment and what is your opinion? How do you see the role of a T-cell engagers, especially in the context of the CAR-Ts in the clinical practice, maybe in the near future when these approaches are approved?

Thomas Martin:
Yeah. So I think from kind of a high standpoint looking down at all these therapeutics that we have, CAR-T cells are certainly going to be available and going to be accessible by the lowest or the smallest fraction of patients, because they still have one of the 70 centers in the US here and requires significant social support. So it’s going to be less, I think, less than half of the patients with relapsed refractory myeloma that are truly going to be CAR-eligible. Whereas these other drugs like the T-cell engagers, and also belantamab, we should talk about that for a second, too. That those are off the shelf products that are going to be able to be given [inaudible] and are going to be used much more across the country, and in many more patients. I think the T-cell engagers, the majority of patients are going to be eligible for that.

Thomas Martin:
I think 90 plus percent of patients are going to be eligible for T-cell engagers. I was really impressed by two things. One, how many patients have already been enrolled in T-cell engager trials across the world, it’s pretty amazing. And, that we have BCMA targeted T-cell engagers and probably six or seven were presented at ASH, all with response rates between 60 and 80% in this relapse refractory group of patients. Amazing. But we also have the second point [inaudible] T-cell engagers now for other targets, other [inaudible] targets that look as good. So we have a target GPRC5D that’s also expressed on myeloma cells and in lymphoid tissue that might actually have some expression on skin too. They saw some minor rashes, nothing really off target that’s too worrisome. And then the FcRH5, which is a receptor that’s expressed literally just on [inaudible] and this early phase one study also showed at the what’s going to be probably the recommended phase two dose response rates over 60%, pretty amazing.

Thomas Martin:
These drugs, like CAR-Ts have CRS associated with them, but with step up dosing starting low and going higher, this [inaudible] very manageable, and much less lower neurotoxicity. So the T-cell engagers I think, are going to be a huge gain and are going to move [inaudible] refractory to early relapse, and even to frontline based therapy, maybe even maintenance, there’s many places we are going to want to use these.

María-Victoria Mateos:
Yeah. Well, in addition, just one comment because both talquetamab targeting GPRC5D or the T-cell engager targeting FcRH5 include that the patient’s already exposed to BCMA-targeted therapy and they had responded. So they opened the door definitely to plan. I don’t know what is going to be the optimal sequence in therapy because it is difficult to envision right now. But definitely I see that the situation is good. And what is your opinion about the antibody drug targeting also BCMA? How do you position this antibody drug conjugate in the setting of T-cell engagers that are also off of the shelf drug and CAR-Ts.

Nina Shah:
Yeah. I liked the data about the MEDI2228, because it was an antibody drug conjugate against BCMA. And it had like 60% overall response rate. Now their population was similar to the DREAMM-2 populations. So it looks like the overall response rate a little better than the belantamab, which was a 30% response rate. They did have photophobia, which I don’t know exactly what that means to besides keratopathy, how to compare the quality of life signal with those two things. But I think having any issue with your eye is tough and having CRS once is not that tough. So I would prefer the BCMA bites over the ADCs right now.

María-Victoria Mateos:
Tom, what is your opinion?

Thomas Martin:
Well, the nice thing is we have approval for belantamab in the US. So, we have this drug that can be used in triple-class refractory patients. And I’ve been actually quite surprised on, again some patients with extramedullary disease that have responded. Some patients that I had thought had very aggressive disease that have responded to belantamab. I was also impressed at ASH on a presentation by Suzanne Trudel who [inaudible] combination belantamab with pomalidomide, and dexamethasone. And she tried some alternate dosing schemas including split dosing and giving it every four weeks.

Thomas Martin:
And when she gave it every four weeks at the 2.5 milligrams per kilogram, the response rate of pom-dex was 100%, you know, a small population, but still a 100% is 100%, that was pretty impressive. Now, there still was keratopathy when they decreased the dose to 1.9, approximately two milligrams per kilogram the response rate dropped a little bit. It was over 80%, but the ocular toxicity levels dropped a fair number. I do think we’re going to figure out how to dose this medicine. I think it’s going to certainly have a role, especially in triple-class refractory. And if it partner’s nice with some of these other anti-myeloma drugs, at an optimized dosing level, I think it’s going to get some use especially in the US.

María-Victoria Mateos :
Yeah, no, the same in Europe and belantamab has been also approved in Europe as single agent and the results of the DREAMM-2 study, are good data. But from my point of view, it suggested the starting point. I think that the antibody drug-conjugate are going to be easily combined as the way the pom-dex, as you mentioned, and the results presented by Suzanne Trudel were excellent as well as with proteasome inhibitors. And well the clinical development plan is, well it’s moving rapidly to every line of therapy and even to the upfront setting. The main problem from my point of view is to select that the appropriate dose, the appropriate schedule because well, it’s true that some patients had to discontinue and the response is maintain. And so these can allow us maybe to a space and more doses of belantamab and with these maybe the keratopathy will reduce the under the management will be easy if we are able to maintain of course, the efficacy. So I think that there is also a space.

María-Victoria Mateos :
And well just before finishing this excellent roundtable. Just a comment about the quality of life of the patients. I’m also positively surprised because the CAR-T cell clinical trials report that the data in quality of life. And BB2121, as well as [inaudible], report that the quality of life for patients with heavily pre-treated myeloma patients comparable to the normal population. I think that we have never seen a similar situation in relapse and refractory myeloma patients, I don’t know if you want to comment something about this, and this is something that we see in the clinic after CAR-T, and even after the T cell engagers – is the same for you?

Nina Shah:
Yeah. I think the data from the BB2121 had shown already primary quality of life domains to be improved. And now with the secondary domains of life, like social functioning and emotional functioning, all of these, they started out lower than the general population, but actually had significant improvement. And we saw that, we saw that for the patients who had CAR-T and had a good response, those people who did, didn’t have to come back for chemo. And so that was a good thing. I suspect it’s going to be similar for the T-cell engagers, because I’ve noticed also that the patients have a pretty good quality of life thereafter. So I think this is going to help us to choose one or the other, or at least justify that it’s worth doing this very complicated or maybe expensive treatments because they do change quality of life for the patients.

María-Victoria Mateos:
Yeah. And I think that this will help us also to the authorities and even to the payers to approve these drugs because there is a clear impact in the quality of life of the patients. And well, thank you very much, I think that this brings up to the end of this surround table discussion. Thank you very much for joining me today, this meeting and looking forward to seeing you in the near future in another virtual meetings and maybe live meetings very soon. Thank you very much.

Thomas Martin:
Thank you so much Marivi.

Nina Shah:
Thank you.