Current and Emerging Therapeutic Approaches for Multiple Myeloma (MM) — Thomas Martin, MD

DR MARTIN: Hello there. I’m Dr Thomas Martin from the University of California San Francisco, and I’m here with Dr Love, and we’re going to talk about current and emerging therapeutic approaches for multiple myeloma.

And what we’re going to talk initially is about newly diagnosed multiple myeloma. There’s been incredible amounts of new data presented in the last 6 to 12 months, and really I want to focus on 6 trials: the PERSEUS trial, the GMMG-HD7, the IsKia trial, the GMMG-CONCEPT trial, the IMROZ trial, BENEFIT trial, and actually I’m going to throw in a little bit on the MAIA trial, an update also. And these are patients who are transplant eligible and transplant ineligible getting front-line therapy, and I think we finally have an answer of what we should do for front-line therapy for the majority of patients with multiple myeloma.

So we’ve seen quite a bit of data on the use of quadruplet-based therapies. Typically it’s an IMiD, a proteasome inhibitor and dexamethasone, our classic VRd, together with a CD38 antibody. And the randomized trials that I’m going to go over mostly compare a CD38 plus VRd versus VRd, with some differences, which I’ll describe.

But the first is the PERSEUS trial that we’ll talk about. And PERSEUS basically was a randomized large trial done by the EMN. It was in newly diagnosed multiple myeloma patients who were transplant eligible. And this was presented both at ASCO this year, as well as at EHA.

And in the design patients were randomized to either receive dara/VRd versus VRd as induction. They got a single autologous transplant, they had a couple cycles of consolidation, with the patients receiving the CD38 continued on CD38 consolidation. Those getting VRd just continued VRd. And then patients went on to receive maintenance-based therapy.

So there was a single randomization at the beginning, so patients who got the dara arm got dara in induction/consolidation and then as maintenance, dara and lenalidomide as maintenance. And maintenance was ongoing except at 24 months into maintenance of dara and lenalidomide if the patients were MRD-negative then they could actually stop the CD38 antibody and would continue just lenalidomide. If they were MRD-positive they continued on doublet maintenance.

The control arm of VRd, transplant, VRd consolidation and then R maintenance, continued lenalidomide maintenance until progression. That was at 10 mg. And those patients never received a CD38 antibody. That was very similar to the DETERMINATION trial.

And as you can imagine, with all myeloma trials more always seems to be better. So for those patients who got the quadruplet versus the triplet, they had a 48-month PFS of 84% versus 68% in the control arm, and big difference in the patients achieving MRD negativity. If we look to the right, overall and sustained MRD negativity rates, they’re actually almost double in the quadruplet arm versus the triplet arm.

And so the quadruplet produced very deep and looks like durable remissions. And this is really a dramatic response, in my mind. For transplant-eligible patients this really is the standard of care for us going forward.

Now, we have other studies to talk about. And one of the ones that was basically updated by Mark Robb was the GMMG-HD7 trial. And this was a trial that used a similar strategy of quad versus triplet but used isatuximab as the CD38 antibody versus daratumumab, and so it was isatuximab/RVd versus RVd. Again, a single — or some patients actually received tandem transplant and then they went on to a second randomization at maintenance. So the second randomization was to randomize patients in the maintenance portion to either lenalidomide alone or lenalidomide plus isatuximab.

So because it’s a dual randomization it sets up 4 arms: 1 arm that will never see CD38 antibody, 1 arm that sees CD38 antibody throughout the therapy, and then 2 arms, 1 gets it in induction and the other gets it in maintenance-based therapy. So this is a really important study for us.

But this was an update just on the primary endpoint, and the primary endpoint was achievement of MRD negativity. And if you look at the patients achieving MRD negativity you see that it strongly favors those getting the quadruplet versus the triplet, and basically this study, again, supports the fact that quadruplets are better than triplet studies. We don’t have the data yet for the second randomization and maintenance, but this, again, in my mind, proves the point that a quadruplet as front line is better than a triplet in terms of induction followed by transplant, the deeper response and an MRD negativity rates being much higher.

During this interim analysis they looked at who are the patients that achieve MRD negativity, and you can see that the patients who are on the quadruplet arm had more patients who basically converted to MRD negativity after induction, after transplant and then during the maintenance phase, but we don’t have a lot of data for the maintenance phase at this current time.

We also saw data at ASH of this past year of a trial called the IsKia trial, and this was a combination of looking at the quadruplet of isatuximab with carfilzomib, lenalidomide and dexamethasone versus carfilzomib, lenalidomide and dexamethasone, and there’s a lot of debate what’s the best — what was the best triplet for induction in transplant eligible, was it VRd or KRd? We’ve never had a randomized trial.

But this was a randomized trial in transplant-eligible patients looking at a quadruplet of CD38 plus KRd versus KRd. Again, they received induction, 4 cycles of induction, single autologous transplant, 4 cycles of post-transplant consolidation, and then they received light consolidation for a year thereafter followed by maintenance. In this study there was only a single randomization, so those who got the CD38 at the beginning continued CD38 throughout the treatment, and they assessed MRD negativity throughout the trial.

And what they found, again, is a markedly improved achievement of MRD negativity in the patients receiving quadruplet therapy versus those getting triplet-based therapy. And probably the most — in my mind, the most impressive thing was to look at the patients who had what we call very high-risk multiple myeloma, or ultrahigh-risk multiple myeloma, those that have 2 high-risk cytogenetic abnormalities, on the far right here, looking at those patients achieving MRD negativity at 10^-6 and also at 10^-5, showing at 10^-6 a more than twofold improvement in MRD negativity rates. So really a very deep response when you use a CD38 plus carfilzomib, lenalidomide and dex as front-line based therapy in the transplant-eligible population.

So we also had data from Katja Weisel’s group from Germany. This is the GMG-CONCEPT trial. This was for transplant eligible and transplant ineligible. It was actually just using quadruplet-based therapy. Those who were transplant eligible got quadruplet, transplant, quadruplet consolidation and then isa, carfilzomib and lenalidomide maintenance for over 2 years. Those that were basically transplant ineligible received 8 cycles of induction of isa/KRd, then 4 cycles of isa/KRd consolidation and then, again, over 2 years of isa/KR maintenance-based therapy. So it was a very long trial, a long administration of front-line-based therapy, but this was meant to be in patients who had high-risk multiple myeloma.

And what we saw was very high overall response rates and very high achievement of MRD negativity, and that was both in the transplant eligible, as well as the transplant ineligible population, again showing deep and durable responses in patients who had high-risk multiple myeloma.

I think all these data support the use of quadruplet-based therapy as front-line therapy in the transplant-eligible population. I don’t think there’s any question right now of what to use as front line. It’s a quad at the current time.

Now what we saw for the first time at ASCO and at EHA this year was data from transplant-ineligible patients, a randomized Phase III trial. It was the IMROZ study looking at the quad versus a triplet in transplant-ineligible patients, and this was presented by Thierry Facon. In this IMROZ study it was isatuximab/VRd versus VRd in patients who had newly diagnosed multiple myeloma.

I’ll just point out some caveats. The patients received basically 4 six-week cycles of induction-based therapy, so 24 months of induction, and then went on to receive continuous therapy. the continuous treatment in the isatuximab arm was isa/Rd. That was maintenance. Maintenance in the VRd arm was Rd, and that was until disease progression.

Now, I’ll point out that after 18 months of therapy patients went on to receive monthly administration of isatuximab, and that was a new thing for isatuximab trials.

And what we saw for the primary endpoint, which was PFS, a markedly improved PFS, 60-month PFS of 63% in the quadruplet arm versus 60-month PFS of 45% in the VRd arm, so marked improvement. And if we look on the far right, the MRD negativity rates, it’s actually double the sustained MRD negativity rates in patients receiving quadruplet versus triplet-based therapy.

For me, these patients, these were less patients — transplant ineligible less than age 80. These patients, some of them did not elect to undergo transplant, so it wasn’t just mainly a transplant ineligible population, but it was transplant — either people who did not want to go on to transplant or people who were ineligible for transplant. It wasn’t particularly, in my mind, the most frail population, but this is a large patient — large population of myeloma patients. Again, I think even in the transplant ineligible, or patients who don’t want transplant, a quadruplet is definitely better than a triplet, in my mind, for front-line-based therapy.

So one of my favorite trials is the BENEFIT trial, and this was presented by the IFM at EHA. And this trial actually was also a randomization of quadruplet therapy versus triplet, but the quadruplet was isa/VRd, and the triplet was isa/Rd, so isatuximab, lenalidomide and dexamethasone. And the difference in the arms is whether or not bortezomib was added to the therapy, so this is different than the other quad-based therapies. The triplet was different.

Now we know from the original MAIA study that daratumumab, lenalidomide and dexamethasone had one of the longest PFSs. So this, in my mind, was going to be a very interesting trial. And I actually was betting on the triplet, but that’s why you do the studies.

And so this was a randomization 1:1 to quadruplet versus triplet-based therapy. This was transplant-ineligible newly diagnosed multiple myeloma patients, and they received standard isatuximab weekly for 4 weeks and then every other week up to cycle 18, and then it was monthly thereafter. The big difference in this, in the isa/VRd arm the bortezomib was given weekly 3 out of 4 weeks, and so it wasn’t twice weekly it was weekly bortezomib. And obviously in the isa/Rd arm there was no bortezomib whatsoever. And the key primary endpoint was MRD negativity, and they also had multiple secondary endpoints.

So if we look at the primary endpoint of MRD negativity, at 18 months it was 53% in the isa/VRd arm, and it was only 26% in the isa/Rd arm, so the MRD negativity rate was doubled in the quadruplet versus the triplet. I thought pretty amazing, actually, results. And if you look at one of the secondary endpoints, and that’s MRD complete remission rates, you also see a 10^-5. 37% of patients achieved that at 18 months in the quadruplet arm and only 17% in the triplet arm. It was as impressive also in the 10^-6 MRD negativity group. So very impressive results of a quadruplet using weekly bortezomib versus the triplet of CD38 plus lenalidomide and dexamethasone.

Now you see there’s better overall response rates in the quadruplet versus the triplet, and actually deeper response rates, so more patients achieving complete response and more patients achieving a VGPR or better.

Now you see the preliminary PFS curve on the right, and there’s not much difference. It’s 85% for the quad at 24 months versus 80% for the triplet, but this is immature. The follow up is only 23.5 months, and I think over time these curves will separate and will show a benefit for the quadruplet therapy, again, showing that quad therapy, even in the transplant ineligible population, is actually very good therapy.

And what I didn’t tell you, but what they showed is that the peripheral neuropathy in the study was quite low, in fact. Only 21% of the patients had Grade 2 or better — or higher peripheral neuropathy in the quad group using weekly bortezomib. So I really like this study, one of my favorite studies of the meeting.

I’ll just mention 2 other newly diagnosed ones. First DETERMINATION trial showing — this was presented by Jeff Zonder at ASH just showing a little bit about diversity. This was from the DETERMINATION trial. The DETERMINATION trial enrolled one of the most diverse populations for a front-line study. They had 18% African American patients in the study, really one of the highest numbers, which is a great effort by everybody.

But it was interesting results in the African American arm — group, the subgroup. The patients receiving RVd alone versus RVd plus transplant, the median event-free survival was very similar, 48 — 47.7 months versus 48.2 months. Really no difference between the two, so it was no difference using transplant in that population. And the odds of achieving a complete response were greater in those getting the triplet RVd, no transplant, RVd alone, versus those getting RVd plus transplant.

So at least this speaks to the fact that we need to enroll diverse patient populations in our trials because there might be differences in the way patients respond, and so I really like this presentation by Dr Zonder, and I think this builds on what we need to do in the future.

So conclusions for the up — front-line newly diagnosed multiple myeloma. Number 1, CD38 plus VRd, quad therapy, it should be our new standard of care both for transplant eligible and ineligible patients. The responses appear to be durable. Right now the projected progression-free survival is greater than 80-90 months in both transplant-ineligible and transplant-eligible patients, so dramatic lengths of the first remission.

And again, in the transplant ineligible the BENEFITS trial showed that weekly bortezomib was very well tolerated and effective. It’s unclear in the transplant eligible whether we should be using weekly bortezomib. It’s also unclear where the benefit of CD38 is. Is it in induction? Is it in maintenance? Do you need to use both? That’s still a big question.

High-risk myeloma appears to benefit from quad therapy. I didn’t show you a lot of the data, but in all these studies the high-risk patients did extremely well, especially in the IsKia trial, where isa/KRd showed MRD — improved MRD-negative rates in those who had high-risk cytogenetics and especially those that had double-hit abnormalities.

And I do think over time our newly diagnosed myeloma trials should further assess differences based on diversity.

DR LOVE: Could I just ask you about the diversity thing a little bit?

DR MARTIN: Please.

DR LOVE: I started hearing about this last summer from Dr Richardson, and I’ve been trying to like figure it out ever since then. I don’t know how deep you’ve gotten into the whole thing, but one thing is anything about the – like the Duffy null connection there and how that would explain the difference?

DR MARTIN: That’s interesting. I will say that I’m not convinced that it’s a Duffy null issue with this, whether there’s more toxicity or whether there’s more benefits in the nontransplant group based on Duffy null. I do think that the genetics of the immune system — for me the genetics of the immune system is much different depending on the population or the subpopulation that we’re looking at. And here you see that in newly diagnosed myeloma perhaps transplant, which may actually not be so based on the immune system, where the rest of VRd, lenalidomide maintenance perhaps, may have a better transplant — excuse me, a better immune component to it. I don’t know. It’s very hard to say.

I will say that in some of the preliminary data from our immune-based therapies, especially bispecific antibodies, the African American population appears to be doing better, appears to have higher overall response rates. So there is something about a difference in the immunity of these groups.

DR LOVE: Well, also it never really got clear like clinically what the deal is. So for example, if you look at African American people diagnosed with transplant eligible verus non-African American, like do they respond better to systemic treatment to induction or not as well?

DR MARTIN: Yeah. We don’t really have great data on that. I think the biggest — the biggest issue in diversity is we always said that the access to good care and the access to getting triplet-based therapy —

DR LOVE: Absolutely.

DR MARTIN: — was really the difference, that it was more that unfortunately the patients who are more challenged financially, more challenged with traveling to the academic center, et cetera, those patients were often treated with a doublet versus a triplet and never received what we would consider good standard of care therapy, and that was the difference. But I think some of these emerging data may suggest maybe it’s not all that. Maybe there is true differences in the way these patients in these subpopulations are going to respond to these initial therapies. The problem is we don’t really have enough diversity in our trials to really tease out what the difference truly is.

DR LOVE: Yeah. That was exactly why I thought it was so amazing to see that, that it wasn’t access, which everybody always writes off. But anyhow, I’m still curious about the whole thing. But anyhow, please continue.

DR MARTIN: So the last data that I’ll update you on is the presentation by Thierry Facon at EHA this past summer looking at the final overall survival results of the MAIA Phase III study. Again, this was daratumumab, lenalidomide and dexamethasone versus lenalidomide/dexamethasone.

And what the investigators showed is with a median follow-up of 7.5 years that dara/Rd continued to demonstrate a very significant survival benefit, and this is overall survival benefit, versus Rd in patients with newly diagnosed myeloma. And the median overall survival actually was about 7.5 years, so median was 90.3 months. And I’ll remind you that more than 40% of these patients actually were over age 75, so this is a really good overall survival for newly diagnosed patients receiving a triplet-based therapy.

And the MAIA study, I think, brought us to using CD38 as front-line therapy, and I think nowadays we’re using CD38/len/dex plus bortezomib, so our quad-based therapy.

Okay. So now we’re going to talk a little bit about relapsed and refractory multiple myeloma. I’ll show you some updates on IKEMA and ICARIA. We’ll talk a little bit about the BOSTON trial and then talk a little bit about the new CELMoDs, specifically mezigdomide, early data with mezigdomide. And then the last, what I consider the comeback kid of EHA and ASCO, and that was belantamab in the DREAMM-7 and -8 studies.

So we did the IKEMA study several years ago now, and we just updated the results. We published these data late last year. We looked at progression-free survival of the triplet, of isa/Kd versus Kd, in patients who had early relapsed multiple myeloma, 1 to 3 prior lines of therapy, and we showed one of the highest PFS rates of 30 — right around 36 months for the triplet of isa/Kd versus Kd. I think now that this triplet is actually one of the ones that we go to as part of our standard of care for first relapse, first or second relapse, especially in patients that have not received a CD38 antibody-based therapy for front-line-based therapy.

In the update we showed very high rates of achieving MRD negativity. It was 33% in the isa/Kd arm versus 15% in the Kd arm. And for MRD-negative CR it was 26% versus 12%. So very deep responses, which is really nice to see in this relapsed/refractory setting.

We also looked at time to next therapy. And if you look at time to next therapy, although the PFS was 36 months, in fact it was about a median of 45 months before patients went on to receive their next therapy. So in fact they almost went 4 years before they had to switch from isa/Kd to the next line of therapy, so pretty dramatic.

And you look on the right, you look at progression-free survival 2, or PFS2, and you see there was no negative connotation of receiving the CD38/Kd therapy as part of early relapse therapy. The PFS2 median PFS was 47 months, and it was actually better than the control arm of Kd. So again, in my mind, if you don’t use CD38 therapy as part of induction therapy it should be used very soon in relapsed/refractory therapy, either as first relapse or second relapse. As soon as you can introduce a CD38, in my mind, the better.

We also saw an update from Paul Richardson on the ICARIA trial, and this was isa/Pd versus Pd. This is some final results. We look at overall survival. There was a survival advantage for isa/Pd of 25 months versus 18 months in the Pd arm, the pomalidomide and dexamethasone.

And if you look at median PFS2 on the right you see that PFS2 again favors isa/Pd versus Pd. There was no negative impact of using the CD38 soon into relapse therapy, and that’s — you can choose — in my mind you can choose a CD38 plus a PI or you can choose CD38 plus an IMiD, pomalidomide, and both actually have good results. These are different populations, but the data shows the longest PFS with isa/Kd or with daratumumab/Kd, but you could choose either, in my mind.

We also looked at the time to next therapy with isa/Pd from the ICARIA study, and you saw 15 months versus 9 months. And then if you look at subsequent therapy, on the right side of this slide, you see that in fact those patients who got pomalidomide and dexamethasone, they could get daratumumab subsequently to this regimen, and they did fine because they hadn’t seen prior CD38-based therapy. So they had response rates that were in the 40%, et cetera.

But if you had received isatuximab/Pd and then you went on to receive a daratumumab combination the response rate wasn’t as good. It dropped from in the 40% range into the 25% range, so using CD38 directly after CD38 probably not a great strategy.

Now I want to talk briefly about the BOSTON trial. We saw an update of the BOSTON trial looking at a median follow up of 28 months. The BOSTON trial was a randomized Phase III trial, again 1 to 3 prior lines of therapy, of weekly selinexor, weekly bortezomib and dexamethasone versus twice weekly bortezomib and dexamethasone, or standard Vd therapy.

And what they showed in this update was basically all subgroups seemed to benefit from the triplet versus the doublet, but there were some specific groups that did actually quite well. And when you look at the PFS curves the lenalidomide refractory did better with selinexor/Vd versus Vd, but the PI negative — excuse me, the PI naïve, those people who hadn’t received a prior proteasome inhibitor, or the bortezomib-naïve patients, those patients actually did really quite well, had a PFS of 29 months versus about 10 months in the Vd arm. And so that’s actually a nice regimen if patients have not received a proteasome inhibitor, that SVd is actually a nice regimen. It’s a fairly convenient regimen, actually. With weekly selinexor, weekly bortezomib it actually was very well tolerated. And if you look at patients who had 1 prior line of therapy they also did quite well.

Now these data were also updated by Dr Jaganath looking at the importance of dose adjustments. Selinexor is not a drug that you can give and say come back in 4 weeks and we’ll start your next cycle. You have to see how they’re doing, and you have to dose adjust based on their side effects. And this shows the importance.

And so the trial had 195 patients on it. 65% of the patients required a dose adjustment. So again, this is — you have to actively manage these patients when they go on. But if you do, they can stay on therapy, and the median selinexor dose was 71 mg — or 70 mg per week. So they actually got a fair amount. It was close to what the target was, 80 mg. Throughout the study those who had a dose adjustment had a PFS of 16.6 months, those that did not have a dose adjustment had a PFS of 9 months, meaning if you dose adjust patients can stay on longer, and they will continue to benefit from that therapy. And you see the overall response rate was also 82% with dose adjustments, with only 67% of the patients did not have a dose adjustment.

Again, the critical thing is when you put somebody on selinexor in combination-based therapy you do have to watch them closely and dose adjust and dose — either hold the dose if they’re having toxicity or decrease the dose from 80 mg to 60 mg weekly, et cetera.

Now the next thing I want to go to is I want to talk about the novel CELMoDs. We all think the novel CELMoDs are our next really big class of medications that we’re all getting excited about.

And Dr Richardson just published these data from the original Phase I/II study of mezigdomide and dexamethasone in The New England Journal of Medicine, late last year. This is a Phase I/II study. There was 77 patients in dose escalation and 101 patients treated at the recommended Phase II dose.

And I’ve highlighted in red on the left the overall response rates. These are heavily pretreated patients who have had 5 or more prior lines of therapy. If you look at the overall response rates of mezigdomide and dexamethasone in dose escalation it was about 25%, but if you looked at the recommended Phase II dosing the overall response rate was actually 41%. Very respectable overall response rates. And these patients, especially when they got to the dose expansion cohort, the Phase II point, 100% were IMiD refractory and 100% were triple-class refractory. Now, the majority of patients got VGPRs, PRs or VGPRs, though there was not as many CRs. But again, this is doublet-based therapy in patients who had very heavily-refractory disease.

Now, when you have a drug that actually has good responses as a doublet, singlet or a doublet, then you go on and you start combining it with all of the other myeloma therapies. And so Dr Richardson presented these data — presented these data at ASH last year looking at the combination of mezigdomide with daratumumab and dexamethasone, and they looked at 3 different subcohorts, B1, B2, B3, and it was just different dosing of mezigdomide, whether to give it 3 out of 4 weeks, whether to give it 2 out of 3 weeks, or whether to give it 1 week on, 1 week off. They were just testing these doses. They also combined it with elotuzumab and dexamethasone, which I’m not going to talk about much.

But if you look at the data for the triple of mezigdomide, daratumumab and dexamethasone, this was in patients who had 2 to 4 prior lines of therapy, and a fair number of them were IMiD or lenalidomide refractory. You see the overall response rate was actually quite good in all the subgroups, with a combined overall response rate of about 78%, and you can see in the swim lane plot that a lot of these are durable.

Now this study, obviously, is patients, some of them have only been followed for 6 to 12 months, and so this needs further follow up to really select the best subcohort. But it shows that these — this combination is really impressive.

And what I will also say about the combination is that the — if we look at what else dose mezigdomide do with daratumumab, it also works as an immunostimulatory regimen. It stimulates the immune system.

And here’s data from Dr Richardson that presented at ASH last year, and also on the right some additional data from Michael Amatangelo looking at the PK and PD of this combination showing increased activity in proliferation of NK cells, increased activated CD4 T cells, an increase in effector memory T cells, and patients with this therapy showing MRD-negative responses. Again, this is in very heavily pretreated patients, so this is a very active regimen, and we’re looking to see which is the best combination here. And mezigdomide definitely has a big future, in my mind, in the treatment of relapsed/refractory multiple myeloma.

I also want to talk about basically the comeback kid, and that is belantamab, and that was based on 2 studies that we saw at ASCO and EHA, and that was the DREAMM-7 and DREAMM-8 studies. In the DREAMM-8 — both of these are large, randomized Phase III studies. In the DREAMM-8 study it was randomized belantamab, pomalidomide and dexamethasone versus bortezomib, pomalidomide and dexamethasone. So this is triplet versus triplet, belantamab versus bortezomib.

And these patients basically were randomized 1:1, 300 patients randomized, and I’ll cut right to the chase. The primary endpoint was PFS, and the PFS showed a significant benefit for belantamab, pomalidomide and dexamethasone versus pomalidomide, bortezomib and dexamethasone. Where the 12-month PFS was 71% with BPd, and it was only 13 months with — excuse me, 51% or 13 months with bortezomib, pomalidomide, and dexamethasone.

So this was a very dramatic — this was a very dramatic response. And it looks like the PFS may actually approach 3 years. This is very similar to what we saw with the IKEMA, one our best studies in early relapsed/refractory myeloma. And I will tell you that these patients, a fair number of these patients actually were lenalidomide refractory. You see an improvement of overall responses, and you actually see deeper responses, more patients achieving complete response in BPd versus PVd and more patients achieving a VGPR or better, again, in the BPd arm. Pretty impressive. There’s also an early overall survival trend, and this actually needs further follow up for us to talk about overall survival, but I just showed that out of interest.

The second study, the DREAMM-7 study, was actually belantamab, bortezomib and dex, so BVd, versus daratumumab, bortezomib and dex, so it was really belantamab versus daratumumab with Vd as the backbone. So a very interesting study. Again, we saw a higher overall response rate in patients receiving belantamab, bortezomib and dex versus daratumumab, bortezomib and dex, higher CRs, higher VGPR or better rates, and a marked improvement in PFS.

So the 18-month PFS was almost 70% in the belantamab arm versus 43% in the daratumumab arm. And again, the median PFS looks like it’s going to be just over 3 years, pretty dramatic PFS. I will say that this regimen was also convenient because it was the bortezomib dosing continued for about 8 months and then stopped, but then after that the belantamab dosing needed to be — there needed to be a number of dose holds and dose reductions.

This slide shows when the dosing actually occurred. You see initially it was every 3 weeks, then it went to every 6 weeks, then it went to every 11 or 12 weeks. And in fact — so there wasn’t actually a patient that received this continuously every 3 weeks. In fact, most of the patients received maybe 4-6 doses in a year. So it’s a very tolerable regimen.

The reason they had to have dose adjustments is obviously because of the ocular toxicity. There was significant ocular toxicity, and that’s — we know that that happens, and you have to watch them very closely in the first 4 doses of belantamab, and after that you can make your dose adjustments, and most of the patients after that time can continue on the therapy. The reason the PFS was so good with this study, and the reason the duration of response was so good in this study, is because they were able to stay on therapy. They didn’t have to stop it because of ocular toxicity.

And so with that I will actually conclude. I’ll conclude by saying a few things in terms of the relapsed/refractory setting. Number 1, the IKEMA study, or CD38 plus PI/carfilzomib, very active regimen, and I think right now it’s the regimen that we all go to in early relapse if patients haven’t received a CD38-based therapy front line. You could also choose CD38 plus pomalidomide. Selinexor and bortezomib and dex in patients that are PI naïve certainly shows impressive results, with a PFS approaching 3 years. Mezigdomide combinations, they’re also showing promise, especially mezigdomide, daratumumab and dexamethasone, both for its direct antimyeloma effects, but also the way it actually stimulates the immune system, and we really want to see combinations of that with some of our new novel immunotherapies. And finally the comeback kid, again, in my mind is belantamab, and the triplet with belantamab is looking quite great.

Now how we’re going to incorporate all of these combinations going forward in the relapsed/refractory space, and how we’re going to incorporate CAR T cells and bispecific antibodies really is going to be an interesting thing for us to figure out over the next 3 to 5 years.

DR LOVE: I’m trying to compute. It was DREAMM-7 that was daratumumab and DREAMM-8 was versus bortezomib, right? Is that right?

DR MARTIN: Correct. It was belantamab versus bortezomib and belantamab versus daratumumab.

DR LOVE: I just can’t compute how it could be better than daratumumab. That doesn’t compute in my head.

DR MARTIN: So it’s very interesting in the study. So yeah. So when the CASTOR trial, which was daratumumab, bortezomib and dex versus bortezomib and dex, the PFS was about 17 months in that Phase III trial. That’s what gave daratumumab, bortezomib and dex approval, that triplet approval, over bortezomib and dex.

Now in this study, the PFS was a little shorter in daratumumab, bortezomib and dex, not that much shorter, but certainly belantamab, bortezomib and dex being 3 years was twice — more than twice as long of remission duration. So it is actually quite impressive, actually.

DR LOVE: I don’t know. To me it’s more than quite impressive. It’s just like I can’t compute it, right? I mean to me daratumumab is one of the most effective drugs that we have in myeloma, right? And now we’re talking about a drug that in the past was kind of considered as a late line.

I did a video with a woman who had been on belantamab for 4 years. Did you see a lot of responses clinically when you used it?

DR MARTIN: So back when we had belantamab approved for use in the United States I actually had a fair number of patients that were on belantamab, and the dosing of it is what’s been most convenient. Meaning you can give a dose, and patients will not get any ocular toxicity if you only give 1 dose and wait 2 or 3 months or 4 months before the next dose. So I had multiple patients that were just coming every 3 months or every 4 months and just getting 1 dose.

DR LOVE: But you’re saying —

DR MARTIN: And that was it.

DR LOVE: But you were doing that because they had eye issues or because you were just doing that?

DR MARTIN: You do have to dose adjust belantamab. There’s no doubt about it. The majority of patients are going to have some ocular toxicity, and when they have that ocular toxicity you either have to lower the dose or lengthen the treatment interval.

DR LOVE: Right, but I’m just saying —

DR MARTIN: Most of the time — yeah.

DR LOVE: But you wouldn’t do that unless they had some kind of toxicity, ocular — you wouldn’t just decrease the dose or would you?

DR MARTIN: So I actually think if patients with — in the first 2 cycles have a dramatic response, and their myeloma goes into remission quite quickly, I don’t think there’s any real reason why we need to push and give another dose 3 weeks later or 4 weeks later or 6 weeks later. I think you could actually hold the dose probably for 2-3 months before you give them their next dose. And so yes, my plan is those that have an early response, they won’t get their next dose for 2 to 3 months.

DR LOVE: So again, excuse my naïvete, so this was just presented for the first time at EHA? It hadn’t been presented before?

DR MARTIN: ASCO and EHA, yes.

DR LOVE: And so are there trials incorporating belantamab in first line?

DR MARTIN: There are, actually, and so there has been some data presented by the Greece group, and the data looks good with combination with lenalidomide and dexamethasone. But as you can imagine, there’s going to be now many different combinations. In fact, one of the — one of the STORM trial combinations, now, that I didn’t talk about in relapsed/refractory, but one of the combinations was selinexor, belantamab and dexamethasone. So we’re going to get combinations of all these drugs. So yes, there’s many combinations ongoing.

DR LOVE: I don’t know. To a simple person like me and people outside of myeloma, I can’t compute it. It’s just like hard to — it’s hard to compute. You have a drug that most people look at as — I don’t know, you tell me. Do you think daratumumab, an anti-CD38 I should say, is the most effective agent we’ve had added to the regimen? I mean, do you think it’s adding more than a proteasome inhibitor or lenalidomide?

DR MARTIN: So I would say I do think it’s maybe slightly more efficacious than the other classes, but the truth of the matter is it’s the combination that has the best effect. That’s why we’re seeing such dramatic responses as quads in front-line therapy. So I do think you need to use all of those drugs together.

But whether belantamab is a better or more potent drug than daratumumab certainly is a question. Whether it’s going to be as good in front line as it’s showing in this early relapse, hard to know. The hard part about belantamab is the toxicity, the ocular toxicity, is difficult for some of the patients, whereas a CD38 antibody is pretty well tolerated for almost everybody. So we certainly will use CD38 in the front-line setting. I think belantamab may actually be a great drug for the patients who are not CAR T cell eligible or are not BCMA-targeted therapy eligible and that belantamab will take up that space, either with bortezomib and dexamethasone or pomalidomide and dexamethasone.

So bortezomib is going on off-patent soon. It’s going to be very cheap, especially outside the US. I think the belantamab, bortezomib and dex combination outside the US is going to be used a lot.

DR LOVE: What about belantamab and daratumumab or belantamab and isatuximab?

DR MARTIN: Yeah. Those studies are going to be done, yes.

DR LOVE: One other question, because again I’m just trying to process this. What would come first? I mean theoretically, putting aside regulatory issues, what comes first, belantamab or bispecific in say somebody not eligible for CAR T?

DR MARTIN: Great question. And there are different toxicities for the two. So with the belantamab it’s the ocular toxicity and with the bispecifics it is the infectious complications. There’s a lot more infections, a lot more pneumonias, sepsis, CMV reactivation, those things. So patients have to be in fairly good shape to get a bispecific, where I think even in frail patients we’ll be able to use belantamab therapy. So I do think there’s going to be a role for both of those, and they may actually be used in nonoverlapping patient populations, and I think there’s substantial populations in both groups.

DR LOVE: Yeah. I mean, again, I just talk to people, but to me it kind of sounds like the ophthalmic thing is really not — is more of an inconvenience, or is it that major for patients?

DR MARTIN: So what the hope is is that by dose reductions and also lengthening the interval that the patients will — who have ocular toxicity will be able to recover quite quickly and then resume dosing at a much less frequent interval. In fact, the majority of patients continued on therapy. They could continue on therapy.

DR LOVE: Right.

DR MARTIN: There are a small percentage, it’s probably less than 5% of patients, that have significant changes in their vision, greater than 20/200 visual acuity. In those patients it’s a real deal. That changes their quality of life at that point in time. And it’s hard to really pick those patients out ahead of time, so patients have to go in knowing there’s a risk that you might have some visual changes for a period of time, that that might take 6, 8, 12 weeks for it to get better, and so they have to be able to get through that period of time. But it’s not a lot of patients that get this ocular toxicity. It is more dry eyes, scratchy eyes, things that are manageable.

Chimeric Antigen Receptor T-Cell Therapy, Bispecific Antibodies and Antibody-Drug Conjugates for MM — Jesús G Berdeja, MD

DR BERDEJA: I’m Jesús Berdeja, Director of Multiple Myeloma Research at the Greco-Hainsworth Centers for Research at Tennessee Oncology. And it’s my distinct pleasure to be here with you again in, what this is called, Year in Review in multiple myeloma. And I’ve been asked to talk about T-cell redirecting therapies in particular. So without further ado, we’ll proceed.

And so we’ll start with CAR T-cell therapy, which you all know very well. But one of the main things that happened in the last year, year-and-a-half is the results of the KarMMa-3 trial. And the KarMMA-3 trial is a Phase III trial of ide-cel, which is a BCMA-directed CAR T-cell, versus standard of care in relapsed/refractory myeloma. So this trial actually looked at patients, 2 to 4 prior lines of therapy. They had to have had a PI, an IMiD and an anti-CD38 antibody. So even though it’s 2 to 4 priors, it’s still a pretty heavily pretreated population. And patients were randomized 2:1 to receive lymphodepleting chemotherapy followed by ide-cel and stop versus investigator’s choice of standard of care. And the standard-of-care therapies were daratumumab/pomalidomide/dexamethasone, daratumumab/bortezomib/dexamethasone, carfilzomib/dexamethasone is the main ones that people used. And so the main primary endpoint was progression-free survival.

And as you can see here, the ide-cel outperformed the standard of care both in overall response rates and in progression-free survival, which was the primary endpoint, with a PFS of 13.8 months compared to 4.4 months and a hazard ratio of 0.49. So just to remind you that 4.4 months is actually what we expect to see in patients who’ve had a PI, an IMiD and anti-CD38 antibodies. So it goes to show you that this was a pretty heavily pretreated population.

They also did a quality-of-life assessment, and this was published separately. And so basically, what this basically showed was the results from the functional domains, the EORTC QLQ-C30 and the EORTC QLQ-MY20 and the EQ-5D-5L. Basically, all of this means that if there’s a positive change towards the CAR T, that means there’s an improvement in function. And so if you look on the right, that’s the top graph there. And so you see that all these parameters are going to the right, meaning that patients actually saw improvement after receiving CAR T versus standard of care. And then at the bottom, you see the results of the symptom domains which are the EORTC QLQ-C30 and EORTC QLQ-MY20. And here, a negative change means an improvement in symptoms. And as you can see, most of these symptoms favored the CAR T side. So again, just sort of showing that patients do feel well after they’ve received a CAR T off therapy.

So from my standpoint, this tells us that this study actually got a new FDA indication for ide-cel. So prior to that, the KarMMA study got ide-cel approved in adults with 4 or more prior lines of therapy. And after the KarMMA-3 study, now ide-cel is approved in relapsed/refractory myeloma after 2 or more lines of therapy, but you have to have had an IMiD, a PI and an anti-CD38 antibody. And there really were no new safety signals seen in this earlier line population.

So similarly, CARTITUDE-4 is a Phase III trial with cilta-cel now versus standard of care. And this was also a Phase III trial randomized 1:1. Patients were 1 to 3 prior lines of therapy. It only required a prior PI and IMiD, and did not specify anti-CD38, but you had to be lenalidomide refractory which is important for the indication. And so, again, patients were randomized to receive a bridging therapy. And usually, that was basically the same — you had to choose your standard of care therapy before you were randomized. And so if you got randomized to the CAR T, you received 1 to 2 cycles of the same therapy you would have chosen as bridging followed by the infusion of the CAR T-cell versus standard of care which was mostly either pomalidomide/bortezomib/dexamethasone or daratumumab/pomalidomide/dexamethasone. And, again, the primary endpoint again was PFS.

And so as you can see here on the left, you have the progression free survival primary endpoint was met with cilta-cel on top here and standard of care group significantly favoring the cilta-cel group. The median has not been reached for cilta-cel. The median for the standard of care, 11.8 months. Hazard ratio of 0.26. So again, showing that this is a different population from the KarMMA-3 study, right? There, the standard of care arm only PFS was 4 months and here, it's almost a year which is what we would expect in a patient with prior PI/IMiD, but not necessarily anti-CD38 antibody. And only, like, less than 10% of patients actually had a prior anti-CD38 antibody in this study. One of the things I will mention, if you look at the PFS curves, there’s this rapid drop of PFS in the cilta-cel group and then it kind of evens out. And so the dotted line shows when the patients actually received cilta-cel. So most of those patients that dropped out were due to progression of disease, going to show that some of the logistic issues with CAR T in a patient that has rapidly progressive disease may not be the best candidate as they may not actually make it to receive their CAR T therapy.

Yes, sir? You have a question?

DR LOVE: Could you just review what constitutes a line of therapy? For example, if a patient gets induction treatment, transplant, maintenance after transplant, maybe they de-escalate the maintenance, is that all still 1 line of therapy?

DR BERDEJA: Yeah. So a line of therapy, as defined by the IMWG, is basically requires that — the easiest way to think about it is any treatment that is given, even if it’s meant to sort of induce a deeper remission. So as long as there’s no progression within that line, that is all considered 1 line. So when patients undergo induction, transplant and maintenance, all of those are done to continue to deepen that remission. So that is all considered 1 line. On the other hand, if a patient actually has initial induction, but then progresses before you go to transplant, you give them a second line of treatment to get them under control and then you do the transplant maintenance, those would be considered 2 lines. And then the other caveat is someone who is having significant toxicity and you have to stop because of toxicity, you restart a different regimen, that would also be considered a new line. So in this case, most patients who were transplant eligible would have had an induction with probably 3 drugs at this point, a transplant and then, like, lenalidomide maintenance, and that would be considered 1 line. And those patients could have gone on to enroll on the study.

So my conclusions on CARTITUDE-4 is similar to KarMMA-3. Again, we had cilta-cel was FDA approved after CARTITUDE-1 for patients with 4 or more lines of prior therapy. But the new indication after CARTITUDE-4 is that patients who relapse after just 1 line of therapy could go directly to cilta-cel as long as they had an IMiD, a PI and they have to be refractory to lenalidomide. So it’s important to remember that that was actually one of the inclusions in their study and the FDA kind of kept that as an indication. So technically, a patient that has 1 line of therapy and gets bortezomib maintenance, for example, and then relapses, they would not be eligible by this indication. Yes, sir?

DR LOVE: Yeah, but they would have had lenalidomide in the induction, right?

DR BERDEJA: Yeah, but the definition of refractoriness, again, by the MWG, and I’m a member of the MWG, so don’t shoot the messenger, but this is sort of kind of what’s been established, is refractoriness means you have to be progressing on the drug or within 60 days of stopping the drug.

DR LOVE: Interesting.

DR BERDEJA: So if you have had induction and then you progress 2 years later on a different maintenance, then you would not be considered refractory to those previous therapies. I know, we like to make things complicated.

So my take on this is, obviously, this is great for patients. This is one of the most active CAR Ts, so we’re very happy to have this option. The truth is that in the previous indication, it was very difficult to get through 4 lines of therapy that were actually active that were truly better than this. So we’re very happy with this new indication. But I will caution that as we kind of learn more with these CAR Ts, and specifically with cilta-cel, there is still that risk of that delayed neurotoxicity, that Parkinsonian type of toxicity that can be irreversible. And also, we’re seeing a significant increase in secondary malignancies, definitely after CARTITUDE-1. CARTITUDE-4 doesn’t seem to have the same incidence although, again, it’s early and also these patients are less heavily pretreated, so perhaps that won’t stand. But there’s definitely a signal for secondary heme malignancies. So in my mind, I really, you really need to kind of discuss that with the patient so that you can make a good decision for them. I personally feel that if a patient has not had a prior anti-CD38 antibody, knowing that we can get a PFS of over 3 years with something like daratumumab/carfilzomib/dex, I may choose to go with that route before I go to the CAR T versus a patient that’s already had an anti-CD38 antibody where I know that the next line of therapy is likely to induce a much inferior progression free survival than the CAR T, and then I would consider that in second-line. And there’s a question.

DR LOVE: When you talk about secondary heme malignancies, you’re talking about T-cell cancers?

DR BERDEJA: Yeah, that’s an excellent question. So that is one of the concerns or potential concerns. But actually, in this case, at least in the studies, these have not been seen. These are actually more like myelodysplastic syndrome and AML, so not T-cell cancers. There was 1 T-cell lymphoma but when they kind of looked, it didn’t have the insertion, the CAR T insertion. So it’s not the ones that the FDA is worried about where you would get sort of insertion of the CAR T in a different cell and then induce a cancer from that standpoint. These appear to be more from, like, the treatment-related type of disorders that we’re used to seeing after chemo.

DR LOVE: And indirectly, do you see more with cilta-cel versus ide-cel?

DR BERDEJA: So again, it’s always hard to say. But if you look at the studies, the percentages reported in the studies seem to be higher with cilta-cel.

DR LOVE: Interesting.

DR BERDEJA: But they have been reported with ide-cel as well, just not to the same degree.

Alright. So we’ll move on to — we also saw sort of further data on earlier use of CAR T. So this was CARTITUDE-2 Cohort B, and this was presented at ASH this year. And basically, patients here had to have 1 prior line of therapy and progressed after less than 12 months after a transplant or start of anti-myeloma therapy. So these patients would be considered functionally high-risk. The expectation right after initial treatment and after transplant is that you would be in some form of response for several years. So progressing after 1 year, that already puts you in a high-risk category. And so the primary endpoint was MRD negativity. So these patients all got CAR T as their next line of therapy. And so you see the overall response rate is 100% with complete response rate of almost 90%. And the MRD result, which was the primary endpoint, was 93%. And the sustained MRD, meaning a year sustained, so you get MRD negativity and then you repeat it a year later, that’s what sustained MRD usually means, and 61% of patients did that. And so you see the PFS curve here. So that actually looks quite good, right? If you think about it, all these patients progressed within a year of their initial therapy. So we don’t expect the second-line therapy to be longer. And in this case, it looks like it might be.

So the same thing with KarMMA-2 Cohort 2b, exact same population except they chose 18 months instead of 12 months from front-line therapy. And these were all patients who have had transplant. So they separated the population so they have 2 different cohorts, so this is just the cohort with transplant. And so again, functionally high-risk patients, 31 patients, so a bigger number. Great response, 100%. CR rate of 71%. And as you can see, the PFS, I can barely read it from here, but it looks quite good. Again, showing that these patients have a better PFS than what they had before their initial therapy. So sort of a proof of principle.

And so then the question also comes up. These 2 studies, again, with KarMMA-2 and CARTITUDE-2, different cohorts, looking at patients that don’t have the optimal response. So we expect patients after induction, after transplant to be in complete response to have the best outcomes. And so patients who did not achieve that were treated with a CAR T as consolidation after their transplant, and that’s what these 2 studies are showing. And as you can see, the KarMMa-2 Cohort 2c study had 32 patients, and overall response rate of 87, CR rate of 77%, and a 36-month PFS of 77%, so quite impressive. And CARTITUDE-2 Cohort D, smaller number, 17 patients. Less follow-up thus far, but these look incredible, right? So 94% response rate, CR rate of 82% and 18-month PFS of 94%. So these are looking quite impressive. And so because of that, there are now 2 studies ongoing that are going to be, the BMT-CTN study is a Phase II study of the same population with ide-cel but now, there’s a KarMMA-9 study which is a Phase III study basically taking these patients who are not in CR after transplant, randomizing them to receive CAR T followed by len maintenance versus len maintenance which has been the standard of care. So it’ll be very interesting to see if the CAR T can significantly sort of change the outcome for these patients.

And then going forward even further is moving the CAR T truly to front line. So CARTITUDE-5 is looking at patients who do not intend to go to transplant. They get induction with VRD for 6 cycles and then they’re randomized to either 2 cycles of VRD consolidation, which was the standard, perhaps you might think differently after you see Dr Martin’s presentation, followed by cilta-cel versus consolidating with VRD consolidation times 2 cycles followed by Rd maintenance until progression. I guess I should say the standard is actually the bottom arm. And so this actually will be a very intriguing study because it will test the possibility that we can use cilta-cel as a way to basically do away with maintenance, which would be nice, right? So these patients would get cilta-cel and no maintenance. So that’s kind of the head-to-head comparison there. And then the CARTITUDE-6 is actually in patients who are intended to go to transplant. They basically are randomized right at the beginning. And so you get the quadruplet of dara/bortezomib/lenalidomide/dexamethasone for 6 cycles followed by cilta-cel and then len maintenance for 2 years versus the quadruplet for 4 cycles, transplant, 2 cycles consolidation of the quadruplet followed by len maintenance for 2 years. So in this case, cilta-cel is going after replacing transplant itself. So pretty intriguing studies. Both of these are already ongoing and accruing very well, so we should have results in the next few years.

So basically, my take from all this is it looks like we definitely are moving very quickly. We know we have the indication now even at second-line with cilta-cel, for example. So all of these are small cohorts, but they’re just a proof of principle to show a couple things that people were concerned about. Can you give CAR T safely when the T-cells are more active? Will you see more toxicity? And so far, we didn’t really talk about the toxicity, but the toxicity actually seems less when you move it earlier, and specifically if you do these as consolidation. So that was one of the concerns. If you kind of get the patient into a CR, will they be able to expand their CAR Ts? And all of these studies are showing that the CAR Ts expand just as well, and perhaps with less toxicity. So I think, in my opinion, this is the best way to use CAR Ts, as more of a consolidation after you have the patient under control. And so I think these data are intriguing and I really look forward to these Phase III trials.

DR LOVE: So just out of curiosity, if these front-line trials are positive, which certainly seems very possible, if not likely, is there enough CAR T around to actually be able to treat everybody?

DR BERDEJA: Yeah, that’s an excellent question. So I think if you talk to the manufacturers, they’ll say yes, there is. But that still remains an issue. It has improved significantly. So in the early days when the CAR Ts were first approved, we would be waiting up to 6 months before we could get a spot for a patient, but that actually has changed. So at least in my, and again, this is early so I have to go with my own personal experience now. But basically, right now if I have a patient, it’s really sort of my group’s ability to get me a date for pheresis that is the hold up. In terms of getting a CAR T product approved, that seems to have gone away. But we’ll see, right? So if people do start — well we’ll know that now because as we go and people are getting now second-line, third-line, that should significantly increase the numbers as well. And so we’ll see if there is a snag because you’re right, that is a possibility.

But the truth is most patients, or a lot of patients, are not necessarily going to be candidates for CAR T, right? So the more frail patients, even if they’re not going through transplant, these are going to be fit patients. They have to meet the criteria to get a CAR T. So those patients are still not going to be going through transplant. Remember, myeloma has a median age of 69. So that’s not a small number necessarily that you would not necessarily consider a CAR T for. But there are similar trials going on with the bispecifics. So it’ll be interesting to see which one actually makes the most splash in the front line.

DR LOVE: I never thought about this, but roughly what fraction of patients in the United States are transplant eligible or go for transplant?

DR BERDEJA: So those are two different numbers. So transplant eligible actually should be high. If you were in Europe, the age has always been 65. So if you’re over 65, then you are not considered transplant eligible. In the US, we never had an age. It’s always been about comorbidities and frailty. And so technically, the numbers for transplant itself should be well over 50%. But if you look at the actual number of patients that get transplanted, it’s less than 20%.

DR LOVE: That makes sense.

DR BERDEJA: So a significant disparity there in terms of who actually gets transplant and who doesn’t.

DR LOVE: Right.

DR BERDEJA: So with that, I just wanted to bring up sort of a new CAR T. So we’ve been talking about the 2 approved products, but this is actually a product that is moving very quickly. It’s called anitocabtagene autoleucel or anito-cel, formerly called CAR T-ddBCMA. And the ddBCMA is basically what makes this different. So this does not use a single chain variable fragment like the other CAR Ts. This is a small D-domain construct that actually, you can see the size difference here. It’s the one in purple versus the scFv for the other, the first one would be ide-cel and the second one is cilta-cel, so a much smaller binding site. And presumably, that actually keeps it from — decreases tonic signaling so you don’t activate each other. Sometimes, when you have the CAR T sitting sort of waiting to be given, sometimes they’ll interact with each other and activate before you actually give them to the patient. And so the small D-domain presumably prevents this from doing so. And they have much more, or they say, they have much more — better transduction efficiency.

So anyway. So they tested 38 patients, 2 dose levels, 100 and 300. They stuck with the 100 just because they saw more CRS at 300, but both were very active. And you can see, overall response rate of 100%. What makes this intriguing is the percentage of patients that had extramedullary disease. So 34% of patients had EMD, and those are patients that true — this was true EMD. So this is disease that is outside of the bone marrow, not contiguous with bone, so subcutaneous or an actual organ. And so those patients usually do very poorly even with CAR T therapy. And so you can see here that those patients responded very, very well to this CAR T with a response rate of 100% as well. And then if you look at the PFS, the PFS for all patients, it’s about — has not been reached, and it’s 56% at 24 months. And it’s basically the same for the EMD patients which is completely different than what we normally see with CAR Ts. Normally, the EMD patients drop very quickly. So we get the responses but then, they relapse much faster, so this is looking very intriguing from that standpoint. And we’re not seeing any of the delayed neurotoxicity that was seen with cilta-cel although, again, with cilta-cel, it’s becoming a little bit less as we move it earlier, we hope. At least that’s what the data seems to look like. But nonetheless, it’s still a scary toxicity. So this one has not reported that.

And so they actually are starting pivotal trials, both to hopefully get indication for the single agent, but then they’re also looking at a — they’re starting a Phase III randomized against standard of care as well just like we saw with KarMMa-3 and CARTITUDE-4. So this potentially could be the next product approved. And since you mentioned about the access, I think having more products is a good thing because obviously, one may not be able to keep up. So I think especially with CAR Ts, I think because of that potential for manufacturing delays and manpower, I think having several products makes a lot of sense. 

And then the last thing I wanted to say about CAR Ts is that now, we have a CAR T that is not going against BCMA. So we have a CAR T that’s going against GPRC5D which you’ve heard about with the bispecifics. And so this is CC-95266, this is the Phase I trial of this CAR T. It was given at 25 up to 450, and 150 was found to be the recommended Phase II dose. And so what was presented this year with this CAR T product was that they had a cohort that allowed patients 1 to 3 prior lines of therapy. And so that’s the one that was presented here at EHA actually just a few weeks ago.

And so again, these patients had an excellent response to the CAR T, 96%, and 42% complete response rates. And we’ll see how durable it is, but it’s looking quite good.

I will alert that in terms of CRS, 81%, mostly Grade 1/2, very similar to the BCMA CAR Ts, ICANS type neurotoxicity, again, very low just like with the other CAR Ts. But what’s interesting is that they did see this neurotoxicity that was seen a little more in the other cohorts, but even seen in this cohort as well, of more of a cerebellar type of toxicity that can result. And so GPRC5D may be expressed in a different part of the brain than BCMA which may be mediating some of these toxicities. But so far, this toxicity seems very reversible. And this seems to be more as you increase the dose. And so because the — and that was part of the reason why the dose, even though it went up to 450, we decided to just kind of stick at 150. I’m sorry, I saw we because I’m in this trial as well.

But before I answer your question, I will point out, just keep in mind these numbers for the on-target, off-target adverse events which we’ll talk about when we talk about the bispecific. We are definitely seeing these toxicities, but we’re seeing much less in terms of percentage and also the degree is much less and also the duration. So, again, just kind of keep this in mind. We’re talking 10% to 20% versus the numbers you’ll see with the bispecific. Yes, sir?

DR LOVE: Just curious. The Parkinson’s-like neurotoxicity with cilta-cel, is that considered a non-ICANS type?

DR BERDEJA: Yes. So ICANS, which is immune effector cell-associated neurotoxicity syndrome, is specifically sort of, it’s usually seen early and it tends to be around the time of CRS although you don’t have to have CRS with it to be ICANS. And it’s a much different syndrome. We still don’t know the exact reason why it happens but when it does, it tends to be a more kind of global effect sort of initially with some confusion. But it can actually eventually lead to whole-brain edema and seizures, et cetera. And so but it tends to be earlier. This other neurotoxicity, and we’re struggling what to call it, but at least for now, it’s sort of this other neurotoxicity that tends to happen later. So with cilta-cel, there were 12 patients that had toxicity later, and some of them were Parkinsonian-like and some of them were sort of cranial nerve-type disorders. And that was seen on average at day 27 whereas the ICANS was seen on average at day 8. So again, it’s kind of later. Usually by day 30, we’re sending patients back to their doctors, right? So it’s a late toxicity. This particular toxicity with the GPRC5D products seems to be, and it has been seen now with 2 products, it’s a little bit less specific in terms of when it can happen. It can start early and then continue, but it can also start later. But yeah, these would be considered different than ICANS which is why here, they’re using the term non-ICANS type neurotoxicity.

So my conclusions with this new CAR T is this is the first — well there’s 3 now that have been reported, but really 2 that are being potentially kind of moved forward, GPRC5D CAR Ts. But none, of course, are FDA approved at this point. We’re seeing efficacy. And one of the things that I didn’t mention here because in this cohort, we didn’t have it, but in the study, the same study with all the cohorts, about half of the patients had had prior BCMA therapies including BCMA CAR Ts, and we saw very good responses. So this may be a nice sort of therapy that can be sequenced with the BCMA therapies. The cerebellar neurotoxicity still needs to be defined. We need to — that’s not a nice toxicity, obviously. And hopefully, it’s true that it’s dose related and as we’re sort of able to move the dose down now that we know this and we’re seeing less, hopefully that will become less of an issue. And then I would argue that the on-target, off-tumor toxicity appears less than with the bispecifics. And so perhaps, this target may be a better target in a CAR T as opposed to a bispecific. But again, more to come on those toxicities.

So with that, I’m going to move over to the bispecifics. And obviously, the first bispecific that was approved was teclistamab, and this was based on the MajesTEC-1 trial. We had an update on this trial which is why I’m showing you these results again. But just a reminder that this was a heavily pretreated population that got the bispecific antibody, BCMA-directed of course, IV and then eventually sub-Q, and then the recommended Phase II dose of 1,500 mcg/kg sub-Q qwk.

And so we saw at ASCO this year sort of longer-term follow-up, now out to 30.4 months. And basically, everything is standing and is looking quite good. So the overall response rate still is about 63%, 46% complete response rates are better. But what we’re seeing over here on the right is the curves, the survival curves, duration of response and progression free survival. So duration of response on the top, the overall, the yellow ones show the overall. And you can see, the median is 24 months and overall PFS of about 11.4 months. But then the red curve actually shows that patients who achieved complete response. And you can see the duration of response has not been reached at 30.4 months which is quite impressive. And the PFS equally has not been reached, and is 61% at 30 months. So going to show that these responses can be quite durable which is nice to see.

And so basically, again, these were patients heavily pretreated. Even though the median PFS is about a year, 11 months or so, the patients who do get a response seem to be staying in remission quite a long time. And so that’s very encouraging. And no new toxicity signals. As a matter of fact actually, we are seeing potentially even less infection. And so what we’re learning is that now with time, there’s some data showing that if you decrease the frequency of the bispecifics once you reach a certain response that you tend to mitigate some of the immunosuppression and decrease the infection risk. And that actually has been shown with this as well. And so they got that FDA approval that after you get a complete remission that you’re able to then decrease the dosing to every other week instead of weekly. Question?

DR LOVE: Yeah, I was just flashing on the fact I think it was your patient that, it was one of the most memorable videos I’ve done since the pandemic. I believe it was your patient who I did a video of a year and a half ago who was on teclistamab the week it was approved.

DR BERDEJA: Yes.

DR LOVE: The man, do you remember him?

DR BERDEJA: Yeah.

DR LOVE: I use him as a perfect example of being — and he’d been on it for a year and a half the day it was approved.

DR BERDEJA: Right.

DR LOVE: I use him as the example. How’s he doing?

DR BERDEJA: He’s still doing well, actually. And I think one of the things —

DR LOVE: He’s still on teclistamab?

DR BERDEJA: He’s still on teclistamab.

DR LOVE: It’s a year and a half later, right?

DR BERDEJA: Yeah, yeah. Some of these —

DR LOVE: A year and half since it was approved.

DR BERDEJA: Some of these patients do really well. Now what’s interesting is that there’s patients that come off for toxicity, and we’ve seen this with all of them, where, for example, you get an infection or for whatever reason, the patient has to be held. And some patients just don’t go back. And I’ve had patients who achieve a remission after even just a couple cycles and stay in remission for, like, a year before we have to restart it. And then when you restart, they go back in remission. So we may not have to give these drugs continuously and we may be able to actually give people breaks, which ideally, would be the ideal. If we knew that if we induce a certain, get to a certain depth of remission that we can actually stop and give people a break and decrease that potential infectious burden. I think that will significantly improve these drugs. But at least for now, they’re all indicated for continuous infusions.

DR LOVE: Yeah. Myeloma can become the new prostate cancer with intermittent therapy.

DR BERDEJA: That’s right. I don’t know if I like that comparison. But yes, at least in terms of — I think in terms of survival though, you’re right. We’re reaching those levels of these sort of more indolent therapy for diseases that —

DR LOVE: Well, I’m talking about intermittent —

DR BERDEJA: I know, I know. But, I mean, I’m saying the comparison is actually not bad because it’s becoming almost like a prostate cancer where people can live many, many, many years with it even in the Stage IV setting, right?

DR LOVE: Yeah. You see the model throughout oncology with MRD and all that. But they’ve had PSA for a long time, so they had a big jump on everybody.

DR BERDEJA: That is true. Alright.

But similarly, we have several BCMA CD3 bispecifics on the market. The second one that was approved — or 2 are approved. The second one is from the MagnetisMM-3 study. This is elranatamab. And so, again, heavily pretreated population, 187 patients enrolled. Here’s the response rate. Very deep response rates as well. But we actually had at EHA this year, again, just a few weeks ago, an update on this also showing a sort of — they had not reported their median PFS. It had not been reached.

But now it has been reached. So if you look again at these curves, here, it’s backwards, so the patients in red are actually all the patients versus the ones in yellow that are patients in CR or better. So you see the duration of response for all the patients has not been reached at 24 months, but is 66.9% at 24 months. And the PFS for the entire group now has been reached, and is 17.2 months. So actually, quite impressive PFS. And then if you see the patients in yellow there, the patients that achieved CR, that 24-month PFS is 90%. So those patients are all staying in that remission, and you saw that it’s about 40% of the patients, so it’s not a small group. And the overall survival looks fantastic for these patients who often were sort of in their last line of therapy or potentially last line of therapy, so almost 25 months.

So again, similar to what we saw with teclistamab, elranatamab is looking fantastic. And it’s also approved in patients with 4 or more prior lines of therapy, prior IMiD, PI and anti-CD38 antibody, which I forgot to tell you. It’s also the same indication for teclistamab. And we now have a median PFS that looks fantastic at 17.2 months, and no new toxicity signals. And this is also a bispecific that allows for you to go from the weekly dosing to every other week after 6 cycles of therapy as long as you have a PR or better. So again, going — and you’ll see this a lot, that that is going to be the trend. And again, hopefully getting to the point where we can actually stop it.

I did want to — at EHA, we saw updates on a couple of, 2 BCMA/CD3 bispecifics that are sort of probably the next 2 to potentially be approved. This is linvoseltamab, and this is the LINKER-MM1 study. And what’s interesting with this one is that the step-up is a little bit different. So with bispecifics, you don’t give the full dose right away. You actually start with the low dose and then you step it up slowly before you give the full dose. And so the step-ups can be 2, 3, even up to 4 steps before you give the full dose. And so after each step-up dose, you need to sort of observe the patient for 24 to 48 hours depending on the bispecific, and sometimes even in the hospital. So that is important. So in this case, they just have 2 steps requiring only 24-hour hospitalization after each of the steps. And they’re a week apart. Most of the others are 3 days. So as you start comparing these, it’s like if they’re all very similar, there will be sort of the easiness of giving some of these may actually help potentially push one over the other. And the other thing that’s interesting with this one is it starts once a week, but you see then it drops to every 2 weeks. And then if the patient’s in VGPR or so after 6 months, it goes to every 4 weeks. And so actually, this is actually even less frequent than what we’ve seen with some of the others.

So again, overall response rate, 71%. The others were similar. All of these are giving very similar response rates, but half the patients had CR or better with a median follow-up of 14.3 months at this point. So looking quite impressive.

And here are their progression-free survival and duration of response curves. And here, same thing. So the purple is all patients and then the green is CR or better. And as you can see, the median PFS for all the patients has not been reached but it’s looking quite good. So it’s definitely going beyond a year. So similar, in my mind, all 3 of these are looking very similar, all quite good.

In terms of toxicity, again, the CRS seems to be a little bit less. But again, it’s always hard to compare between the studies. But is it because they’re giving it less frequent that we’re seeing less CRS? It’s unlikely since the CRS occurs just in the first step-up of the first dose. So anyway, it’s 54% — or less than 50%, which is, you know, most of the others kind of are at 60%, 70%. So it’s unclear if that’s true or not but definitely, at least going in the right direction. Infections still continue to be the main issue. I didn’t really go into this with the others since those were just more sort of longer-term presentations. But you can see that infections occur in 74% of the patients and about half of them had Grade 3 or 4 infections. So again, these are nothing to sort of dismiss, be dismissive about. These are important complications.

So they’re expecting FDA review this summer. And obviously, everyone is hoping and they’re hoping that they will be approved and it’ll be the third BCMA/CD3 bispecific. It’s an IV. The other ones are sub-Q. Whether that makes a difference isn’t clear. But as I said before, the two 1-day hospitalizations versus 3 to 6 days for the other products may be a benefit. But toxicity is similar. So we’ll have to see how we all end up making these decisions about which one to choose.

And then the final BCMA/CD3 bispecific I want to talk about is ABBV-383. They had an update at EHA as well. And this is a little bit interesting. It’s a little bit different in that it has — it’s designed specifically to sort of have a lower affinity to CD3 and higher affinity to BCMA. And presumably, the idea there was that you would still retain the response but because of the lower affinity to CD3 that you potentially may be able to mitigate the CRS and the ICANS, or at least that’s what their thinking was.

And so again, they’re giving, you know, they’ve done the dose escalation. This is their Phase I. And this particular report was about their 3 highest doses, the 40, 60 — 40 or 60 every 3 weeks and then the 60 every 4 weeks. So much less frequent dosing. And actually, the dose that they chose that they think they’re going to move forward with is the 60 every 4 weeks which is nice actually compared to weekly, right?

So again, in terms of toxicity. Some cytopenias which you see with all of them. But look at the CRS. Initially, with both of them 71%, so what we saw with the others. But when you actually look at the q4wk dosing, even though it’s the highest dosing, only 43% and 0 Grade 3/4, so we’ll see. So I don’t know if it’s because of the less frequent dosing or because of the actual low affinity to CD3. But again, the dosing interval shouldn’t matter because once we get beyond the dose escalation, we don’t see CRS after that. So it may be true that the CD3 low affinity may make a difference.

Overall response rate, similar to the others, 65%. You can see the PFS curves here. They’re still pretty early, so they have not reached their median PFS either.

So they’re actually a little bit further behind. But what I like about this is it allows for q4wk dosing, maybe less CRS. We have less infections as what we saw with the others. That seems to indicate that the less frequent dosing may help. So they’re actually starting or they’re in the process of enrolling to the registrational Phase III trial called the CERVINO trial, and that is the dose 60 mg q4wks.

Alright. So I’m going to move now to the one and only GPRC5D CD3 bispecific that is approved in myeloma. It’s called talquetamab. And so here, I’m going to discuss GPRC5D a little more than I did with the CAR T. So GPRC5D is also very specific to myeloma cells. And it’s even actually, the nice thing about it is that it’s expressed a lot more in malignant cells than in normal plasma cells which is not the case for BCMA. BCMA is expressed just as much in both normal or malignant plasma cells. And so we all think that perhaps because of that, you’re seeing less infections with the GPRC5D products. But the problem is that there is a low level of expression of GPRC5D in the surface of the tongue and in the highly keratinized tissues. And so because of that, we are seeing these off-tumor on-target effects including taste disturbances, dysgeusia, dry mouth, rashes, nail dysmorphia, brittle nails, et cetera. And those are actually not unexpected, unfortunately.

Again, so this is MonumenTAL-1. And we had an update at EHA on it which is why I’m showing it to you. But remember that 2 doses are approved, 0.4 mg/kg sub-Q qwk or 0.8 mg/kg sub-Q q2wks. And because this is a GPRC5D, this study was done and allowed prior T-cell redirecting therapies. Most of them, of course, were BCMA. And you can see that 78 of the patients actually had prior BCMA therapies, but they’re pulled off to a different group over here. But you see the overall response rate is quite impressive, about 70% in both arms. And then even the prior TCRs had an overall response rate of about 68%. Very deep responses. Mostly VGPR and CR. And the duration of response, you can see here, it seems to favor the q2wk dosing of 0.8 at 17.5 months. But it wasn’t reported with a prior TCR but if you look at the PFS, the PFS of the prior TCR, it seems to be a little bit inferior to what we saw with the q2wk dosing of 11 months or so. So both doses are approved by the FDA, but I suspect most people are using the q2wk dosing. Again, the numbers look a little bit better. And I know these are small numbers, so we can’t really compare. But also, the less frequent dosing, most patients prefer that versus having to go every single week.

In terms of the adverse effects, again, I wanted to concentrate here — well actually, before I get into that, you can see the CRS rates are in the 70%, so similar to what we saw with the BCMA/CD3 bispecific. Most of them Grade 1/2. But then, you see this, in the box, you see these off-tumor on-target effects. And so you see that the percentages there, both with the qwk and q2wks, we’re looking at skin-related AEs of 60%, nail-related changes in about half of the patients, dysgeusia, which is sort of the taste disturbances, half the patients, rash in about 40% of the patients, and weight loss. So these patients, you know, the dry mouth, they can’t taste, they actually drop their weight. And 40% of the patients had clinically significant weight loss. And the problem with this is that there’s no Grade 3/4 dysgeusia. There’s no Grade 3/4 rash — or nail dysmorphia. So all we can report is up to Grade 2. So the grade here doesn’t really tell you sort of the true quality of life of these patients. And so that is a problem with the current AE grading system. But if you recall with the CAR T, we were looking more at like 10% to 20% of patients. And what’s really interesting is with the bispecific, these symptoms don’t go away until you start either decreasing their frequency and really until you stop the drug altogether. And then, those symptoms go away. But the CAR T, the patients who do get these symptoms seem to get them for about a month or 2 months and then it just goes away. And so presumably, that has to do with the expansion of the CAR T and then you drop the T-cells and so you’re no longer redirecting T-cells whereas here, you’re continuously redirecting T-cells. But that’s part of the reason why I made that comment earlier about perhaps GPRC5D may be a better CAR T target. But nonetheless, this still works really well and it works really well in patients who failed BCMA.

So again, talquetamab is the first GPRC5D/CD3 bispecific approved for myeloma. Same indication as the BCMA bispecifics, adults with 4 or more lines of therapy including an IMiD, a PI and an anti-CD38 antibody. And then obviously, we still need longer follow-up. But the longer follow-up, I guess, data that is shown shows that the q2wk dosing appears more durable. And great responses even after BCMA therapies which would obviously help us in terms of sequencing. And then toxicities, though I didn’t really go into the infections very much. But definitely, they seem to be less and we see less Grade 3/4s than with the BCMAs. And so part of that may be because even after — while you’re on therapy, we start seeing normal plasma cell recovery. And so some of these patients actually do regain some of their humoral immunity even while they’re on therapy and still in response which you don’t see with the BCMA products. And so that may be part of the reason why we’re translating or seeing potentially these infections. But these off-tumor on-target effects can be very difficult for the patient. So in my experience, you really need to counsel patients. And if they’re expecting it, they tend to tolerate it better. If it hits them, if they’re blindsided by it, a lot of patients want to come off very quickly. But I’ve been successful in keeping my patients on and not had anybody come off because of these side effects. But definitely, they can be difficult for some patients.

And then finally, I’m going to end with Lazarus, I guess we’ll call it. And so this is DREAMM-7 which is a study of this drug called belantamab mafodotin which I’ll just remind everybody, it’s a BCMA-directed antibody-drug conjugate that was FDA approved in the same — sort of relapsed/refractory setting just like the bispecifics. And with a response rate of about kind of in the 30% to 40% and a PFS of about 4 months. And it had some ocular toxicity as the main side effect, specifically keratitis that required ophthalmology exams before each dose. They did their confirmatory study which basically randomized patients to belantamab mafodotin against pomalidomide/dexamethasone, and that was a negative study. So because of that negative study, the drug was actually removed by the maker of the drug from our market. And so now, fast-forward to these results of the DREAMM-7 study which is basically a Phase III study randomizing patients to either belantamab mafodotin in combination with bortezomib/dexamethasone versus daratumumab/bortezomib/dexamethasone, so a very well-known standard of care. And so the belantamab here is given at a lower dose of 2.5 mg/kg every 3 weeks and was allowed to actually decrease significantly after the initial therapy. Patients could get it as infrequently as every 3 months.

And so this is what will wow you here is the PFS. You can see the belantamab arm is on top in red and the dara/bortezomib/dex is in yellow. So the median PFS of 13.4 months for dara/bortezomib/dex is what we saw in the initial studies with that combination. But the median PFS for belantamab with bortezomib/dex is 36.6 months, so unheard of, right? So those are numbers we’re seeing with dara/carfilzomib/dex and potentially with cilta-cel, so quite impressive numbers that surely most likely will get this back approved in combination. Same with overall survival, you see we’re already seeing a difference at 18 months.

And so similarly, the DREAMM-8 study was also reported. And this was belantamab in combination with pomalidomide/dexamethasone versus bortezomib/pomalidomide/dexamethasone which, again, is a standard triplet, PVD, randomized. And both of these studies were done in patients with at least 1 prior line of therapy.

And so again, this is a little bit earlier but you see the separation of the curves with the belantamab on top in red. At 12 months, 71% PFS versus 51%, and survival advantage. So again, looking quite impressive.

So I think these results are going to get the drug back on our market. And so we’ll have a — this is the first time we’ve had a triplet versus triplet where the daratumumab triplet was defeated. So this is actually another impressive thing, right? So they actually chose a pretty good control arm. And so I think this data looks fantastic. The ocular toxicity remains an issue. But definitely, I didn’t show you the toxicity here, but it appears improved, especially with the lower dose and the less frequent dosing. And we knew that from the earlier studies. And so we’re starting to move — before, we’ll see what the FDA decides to do with this, but before, the company had been very conservative and the studies were done and required that basically you get an ophtho exam before every single dose. And if you had, even if the patient was asymptomatic, but if Grade 2 keratitis was seen by the ophthalmologist, we had to hold the dose. And now, we’re going to a more sort of symptom-based assessment. So if the patient has this asymptomatic that they shouldn’t even require that ophthalmologic exam and can continue their dosing. So hopefully, that’ll make it less cumbersome. We’ll see if the FDA agrees. But if it’s approved as early as second line, it will make the sequencing of the BCMA drugs very tricky, right? So now, we’re going to potentially have belantamab which is a BCMA/ADC in combination as second-line as well as cilta-cel in second-line. And so we’ll have to kind of decide which one we do first. Part of the problem is, and I didn’t show you this data, is when we talk about sequencing, the CAR Ts don’t work very well after you give a BCMA drug. So in patients, there was a small, 20 patients in the CARTITUDE-2 Cohort C, I believe, where they actually looked at patients after getting belantamab or after getting a BCMA bispecific and were given cilta-cel. And the response rates compared to the CARTITUDE-1 data went down from 98% in CARTITUDE-1 to about 60%. And then the PFS went from almost 36 months to 9 months. And actually, after a bispecific, it was only 5 months. So giving the CAR T right after patients progress on one of these drugs is not a good idea. So it’s going to be tricky. So it’s going to be interesting to see how we do this. Now obviously, if a patient received this in second-line and then they have several lines in between and it’s been a year or more since they received, that may be a different story. But the sequencing, I think, will be challenging.

DR LOVE: Yeah. Just a couple of follow-up questions. First, that last point that you were making. I think that question has been out there for a while, even in CD19 bispecifics in lymphoma. Does prior therapy affect it? And until today when you just made that comment, I hadn’t heard anybody say that. Is this the first or it’s been out there for a while?

DR BERDEJA: Well, we’re learning a lot more. But it’s definitely been out there. So the problem is a lot of these therapies are coming out together, right? So a lot of the data that we have is in really small numbers. And so that’s one of the problems. The other problem is a lot of the data that we have is from real-world settings. And as you know, that always has potential problems in terms of data interpretation. But that real-world is actually the first time that we started seeing these patients that were getting their CAR T and they had been on a clinical trial or had prior belantamab. Because belantamab, remember, was actually the first BCMA-directed drug that was approved by the FDA. So some patients had received ADCs before they got CAR Ts. And so we started seeing that signal. And the idea, I think, is twofold. I think one is if you’re coming off an ADC, are you progressing because you’ve lost BCMA? That’s a possibility. You’re truly refractory to BCMA. And so maybe going after BCMA doesn’t make any sense.

The other is if you’re given a bispecific and you’re progressing on that bispecific, those T-cells have been redirected continuously. So one of the potentials is that now, you have very fatigued T-cells and you’re making CAR Ts out of them and it won’t work. But the other is there was this very nice paper that came out last year from a Canadian group that actually showed that patients on BCMA/CD3 bispecifics develop point mutations at BCMA that prevented binding of subsequent bispecifics. And so theoretically, now you’re adding mutations to the BCMA, you have fatigued T-cells, you can kind of start seeing sort of the writing on the wall that these autologous CAR Ts are just not going to do so well. So most of us, there’s actually some data that if you had a CAR T, one of the nice things about CAR Ts, you’re off therapy for potentially even up to 3 years, right? And so those patients seem to be resensitized to therapies. And so when you look at the data of prior CAR T, especially if it’s been at least 6 months from the CAR T, and then you give a different BCMA drug that you actually are seeing good responses. And we saw that with the talquetamab. We’ve seen that with the GPRC5D CAR T. So all things being equal, most of us, if you ask most of us, we probably would tell you that if the patient is eligible for all 3 types of drugs that a CAR T should be done first, if that patient is going to be eligible for a CAR T. And then if the patient is not eligible for a CAR T, then you kind of go with the others. Or if the patient just, CAR T is just, like you said, there’s a waitlist or can’t manufacture or the disease is moving too quickly that you can’t move to a CAR T, that’s when you start thinking of the others.

But yeah, I think it will be very intriguing. Because obviously, in the community, docs are going to give probably what’s easiest, right? So my guess is we’ll have a lot of patients sent to us who already had an ADC or a bispecific. Right now, only the ADC would be potentially approved early, so that’s the one that I think is going to be more challenging. The bispecifics are still approved pretty far back, but they’ll be moved just like we do everything else in myeloma.

DR LOVE: So 1 final question. It’s certainly not a surprise when you see an ADC that has a big effect. Enfortumab is first-line therapy in bladder cancer. T-DXd, there are lots of ADCs out there that are really impressive. But clearly, these DREAMM-7 and 8, I personally was shocked. I’m sure everybody else was very, very surprised.

DR BERDEJA: Yeah, that’s true.

DR LOVE: I guess the question I have, when belantamab was pulled off the marketplace, it was hard at that time for me, like, talking to you all, to figure out how effective it was. Incidentally, when I did that thing where I interviewed a bunch of patients, I think it was Natalie’s patient, I interviewed a woman who was on belantamab for 4 years. And the thing I was surprised, you know, now that we see the effect of this drug, was that a surprise? You all were using the drug for a while yet it seemed like this came as a surprise.

DR BERDEJA: Well, I think, I’ll tell you what’s surprising. I agree with you that one of the intriguing things about belantamab and the reason why we’re all very, we were disappointed that it was taken off the market is that, A, it’s an easy drug and most patients feel fine on it. But also, in those patients that do achieve deep responses, it’s very durable. We all have those kind of patients like Natalie that basically, they were on it for like 2 and a half years or something or they got remission, they came off because of keratitis and they maintained that remission. So this is not just a simple ADC. I think ADCs in the past in myeloma have not worked very well, and they were truly just basically delivering chemo. But we don’t use that much chemo in myeloma, right? But this is also, I think, an immune therapy. And so I think it’s the combination of the 2 that are making this a little bit different. But I think what we were surprised by was the, A, the response rates with this because they were, like, so much higher. Because bortezomib/dex alone should not be giving you these kind of response rates. So definitely, there’s a synergism with the PIs that I think was impressive. But then also to then have this PFS of 3 years when we know that even the dara/bortezomib/dex is only a year, is the impressive thing. Because even in, you know, the PFS was only 4 months for the single agent of belantamab. So how do we go from 4 months and then dara/bortezomib/dex that maybe is 6 or 7 months, you put them together and now, we’re talking 3 years. So I think that’s what was surprising, the degree that it improved the benefit.