Graham Jackson
Hello, and welcome to this session. We’re going to talk today on learnings from ASH 2021 on multiple myeloma, and this discussion obviously sponsored by VJHemOnc. I’m going to be leading the discussion. My name is Graham Jackson. I’m a consultant hematologist from the Northern Centre for Cancer Care at the Freeman Hospital in Newcastle, and I’m joined by my friend and colleague who I’m going to allow him to introduce himself, Rakesh.

Rakesh Popat
Hi everyone, and thank you, Graham. My name is Rakesh Popat. I’m a hematologist based at University College London Hospitals in London in the UK. My pleasure to be here.

Graham Jackson
It’s great to have you here, Rakesh, and there’s a lot to discuss, isn’t there? ASH 2021 was really an amazing conference for multiple myeloma. And I think we’re gonna go through a number of different factors, but I guess one of the big studies that really caught the headlines at ASH 2021 was the iStop study. An amazing study, screening 75,000+ people in Iceland. What were your main take home messages from that particular dataset?

Rakesh Popat
Yeah, Graham, so a remarkable dataset and credit to the Icelandic team. being able to pull off quite a major feat. When you think about the numbers of patients being screened and keeping up with that sort of data and keeping it tight, it’s very, very impressive and I haven’t seen anything of that sort of scale before in terms of a prospective trial. So this really, I think, is almost once in a lifetime type of study. There were some key points that came through. There were a couple of oral presentations, one focusing on MGUS and one on smoldering myeloma.

I think if we start with the MGUS story, what becomes very clear is that once you start looking for these conditions, they become more apparent. And the key take home message from one of the presentations was demonstrating that if you actually look for MGUS, smoldering myeloma and myeloma, you’ll find it at much higher proportions then if you let patients self present, which is the current standard. Because of course, the way this study was set up was that patients had screening blood tests performed as part of their routine blood tests, which were being conducted in Iceland. They were randomized to one of three arms. One was where no further action was undertaken. So they were not told of their diagnosis. The second was that they had ongoing monitoring according to IMWG criteria. And the third was that they performed a much more intensive sort of follow-up, with whole body cross-sectional imaging, and bone marrow biopsies, and various other blood biomarkers. And when you look across the three different arms, you can see the substantial increase in pickup rate of both MGUS and smoldering myeloma, but also a few cases of multiple myeloma, which were undetected. And I think that’s really important, because that same group have also demonstrated that if you’re aware that you have a precursor condition, then your overall survival is improved compared to if you were unaware of that condition.

So I think if you try and interpret that, then you would assume that those patients who were detected earlier can potentially be advantageous compared to those that weren’t. And that’s quite an important, powerful message to get through. But clearly there’s still lots to understand about this, because what we don’t know is the impact upon discovering all these low risk cases. And that’s the other key point that came out of this, Graham, is that the majority of these cases were actually low risk, which is completely different to the sort of studies that we’ve been seeing in smoldering myelomas or the MGUS studies, which have been prompted by patients seeking medical attention. This is, because it’s a screening study, the majority of cases are low risk and need nothing but expectant management. So that unravels a whole new other ballgame of what do we do by picking up very low risk cases, which have a low chance of predisposition. I don’t know what you thought of the data, Graham? It’s in a really interesting one.

Graham Jackson
Yeah, there are two balances here, aren’t there Rakesh? I mean, they did pick up a lot of the smoldering multiple myeloma cases. So you know, the incidence surprised me, 0.5% of the population have smoldering multiple myeloma. I think that was quite a headline. As you say, though, most of them were low risk, so they’re going to be followed up. And I guess the balance to all of that is the massive, massive psychological impact of lots of people knowing they have MGUS, which is probably never going to impact on them. And it’s that balance between discovering cases early versus the psychological impact of people knowing they have MGUS when it possibly is never gonna impact on their life at all. So I think that was interesting. The other thing that came out was that people with MGUS have no extra risks from COVID-19, which has been very important for our clinic as well. So I think we’re gonna see a lot more quality of life data come out from iStop, and I think that’s gonna be interesting. We do have to balance finding these cases that were undiscovered versus the impact we have on all the people who were never going to be impacted by the discovery of MGUS.

Rakesh Popat
Yeah. Just about the MGUS story, I think the incidence of MGUS was about 5%, which is what we saw with a previous study from the Mayo clinic. And so if you think about a screening study to pick up 5% of the population, that’s gonna be larger numbers of patients. and I think you’re right. The majority of them are low risk and will not turn into multiple myeloma. So it’s, I look forward to seeing more data coming out for that. I think the COVID point was actually incredibly important. The other bit I thought was interesting about that talk was that you have to standardize the data or normalize the data according to age and comorbidities, because MGUS is seen more commonly in patients who are older. And so you will see higher numbers of COVID cases in older patients, but once you standardize that, MGUS doesn’t add an increased risk. The only bit that I was unclear about, and this may represent the population in iStop, is that what we’ve seen, particularly in the UK, is that there does seem to be a variation according to your ethnic or racial predisposition in terms of your risk of severity of COVID-19. And that bit quite hasn’t been teased out. And that just needs to be looked into a bit more.

Graham Jackson
I think there’s, from iStop, there’s lots more to come and it maybe takes us a step closer to national screening, but we really need it to be more targeted, I guess. And hopefully we’ll get some hints from what they’ve discovered as to which portion of the population we really need to target. Is it going to be older? Is it going to be particular ethnic groups that we need to think about more carefully?

Let’s go on to frontline therapy ’cause I think for me there were three major frontline therapies that reported out. There was GRIFFIN, MASTER and OPTIMUM, which is Martin Kaiser’s UK based study. Of these three studies, what did you take away from these data, Rakesh?

Rakesh Popat
So lots of interesting data and a little bit of confusion as well in my mind, if you throw in the CASSIOPEIA updates that came in as well, which we could discuss. So I think overall, if you take a step back with this data, the incorporation of daratumumab as part of frontline strategies for transplant eligible patients is massively positive. What we’re seeing, whether it’s a dara-velcade combination or a dara-carfilzomib combination, which we saw in the MASTER study, is incredibly high response rates and high MRD-negativity rates. The GRIFFIN, particularly, a 98% response rate following four cycles of induction with DVRd. I mean that is a really major benefit for newly diagnosed patients. And then you can see that the extensive uplift in MRD-negativity following on. And I think DVRd is a well-tolerated regimen. I don’t think that this four drug combination is particularly taxing for a younger, fitter patient.

The bit that I am still struggling with, and I’d really like to know your views, Graham, is the role of daratumumab as maintenance following autologous stem cell transplant. Because what we can see in GRIFFIN is that the MRD-negative rates following stem cell transplants are higher for the DVRd population if you receive DR maintenance. But when you look at the magnitude of increase, actually they’re about the same in terms of the multiplication of numbers of MRD-negativity as time goes on from one year, two year, afterwards. And so what I’m not clear is, are we simply seeing an amplification of the substantial response that we got with the incorporation of daratumumab induction. When we look at CASSIOPEIA, we know that there was no progression-free survival benefits for patients receiving daratumumab maintenance who received daratumumab induction. However, patients who had DVTd and dara maintenance had the highest MRD-negativity rates, shown at ASH. So maybe we need to wait a bit more. I don’t know, Graham, do you have any kind of insights on that?

Graham Jackson
Yeah, I think first of all, the CASSIOPEIA data on daratumumab maintenance was really almost surprising, wasn’t it? That if you had dara induction, that dara maintenance possibly didn’t bring a lot to the table. I really wish they’d done a dara versus Revlimid comparator. I quite, I think two things about the GRIFFIN study I like. We know that from CASSIOPEIA, although dara-VTd is a good regime, we both, I think, feel very conscious of the neurotoxicity of VT. Whereas VR seems to me intrinsically probably better tolerated and I would prefer a GRIFFIN type regime from the neurotoxicity point of view. I think the dara-rev versus rev maintenance question, again it’s slightly tied up by the fact that there isn’t a crossover randomization. It would have been really nice if they’d done a crossover randomization of DR versus R, not just kept the patients on dara who had dara induction. So I think that is still lost. And until we see a good study, I don’t think there will be a lot of people that will be able to justify adding dara to maintenance until we get that data.

Rakesh Popat
Yeah, I agree. I mean, I’m certainly reluctant about that. And it may be that the Perseus data set, once that reports, being a Phase III trial will give us some additional information, but I completely agree with you. I think that the problem that we have with VTd at the moment is the neuropathy that we’re getting with thalidomide. And adding in daratumumab doesn’t come overcome that, obviously. It simply gets you higher response rate. So I guess when you look at Martin Kaiser’s OPTIMUM study, we do see that dara-cyclo-VRd is very well tolerated for newly diagnosed patients. And there was a very good compliance I thought, with quite an intense regimen. And bearing in mind that these patients continue to receive velcade peri transplantation, and then went straight into a triplet consolidation strategy and then gradually reducing the dexamethasone thereafter.

So just to talk a little bit about OPTIMUM, this was a study for ultra high risk patients two genetic adverse risk lesions or primary plasma cell leukemia. And what Martin showed was a comparison against historical Myeloma XI data. And firstly, just to say what an excellent trial design. I mean, clearly these are such high risk patients, so to put them on a control arm, I think wouldn’t have been ethical. So congratulations to the team for managing to think of this innovative control arm. But clearly DCVRd induction, DVRd consolidation is really pushing the boat out in terms of progression-free survival. Unfortunately some patients are still refractory to this and you know, that opens the door to the immunotherapy, which we can talk about in a little while, but I think generally the outcomes with the OPTIMUM study are quite positive.

Graham Jackson
Yeah. I think the OPTIMUM trial design and comparing it to Myeloma XI data was really, really neat. And I think also sets the tone for how we might have to investigate myeloma in the future. That we can’t have one size fits all mega trials. It’s not appropriate, necessarily, to put people with multiple high-risk abnormalities in the same study as people with standard risk disease. And that’s one thing Martin nicely showed. And I think for me, Rakesh, one of the things I noticed in the MASTER study is that although patients did very well on that study, particularly if they achieved MRD-negativity, which was the aim of the study, the patients with two or more high-risk cytogenetic abnormalities still didn’t do fantastically well and probably not as well as they did on OPTIMUM. So I think the high risk group of patients really probably need to be separated out, and we probably need to be brave. And a little like Martin did, that one high-risk abnormality probably isn’t enough to make you into high risk group. And I don’t know what you think? Maybe you have to have a trial of ultra high risk, single high risk and then standard risk and almost separate out into three groups.

Rakesh Popat
Yeah. You know, Graham, I think that’s a really good suggestion. And just to throw into the mix, that the definition of plasma cell leukemia has recently been revised to drop that percentage down. So we are going to see more patients being labeled with plasma cell leukemia. And so I think in that setting, you can now run a study of ultra high risk myeloma plus plasma cell leukemia, and probably get sufficient numbers of patients. So I think you’re right. We should probably do have separate arms, standard risk, high risk and ultra high risk arms. Just to talk about MASTER in a little bit more detail. I think maybe one of the issues with MASTER was that patients were coming off if they had sustained MRD-negativity. And probably what this tells us is that those patients with two or more high-risk lesions should not come off treatment, even though they achieve sustained MRD-negativity. And I never forget my conversation with Sagar Lonial where I talked to him about VRd consolidation and he recently published this 1000 patient data set in the JCO with risk adapted consolidation. And his pearl of wisdom was that for a ultra high-risk patient, when you go with consolidation, just keep them going for as long as you can. And I think that’s probably correct. They should just maintain that, despite achieving MRD-negativity.

Graham Jackson
That’s a really good point, Rakesh. And do you think that explains some of the difference we see between MASTER and OPTIMUM in terms of how those patients perform in that MASTER took patients off treatment? And we know ultra high risk patients can get to MRD-negativity. It’s sustaining it that’s important. And in Martin’s OPTIMUM study, the treatment really did continue on. And I would agree with you, Sagar’s pearl about continuing treatment is very important. Go on, Sorry.

Rakesh Popat
No, no, I think you’re right. And the other point was to remember that MASTER had carfilzomib in their treatment compared to Velcade. And despite having a more potent proteasome inhibitor, we’re still seeing that relapse with the ultra high risk patients. So I think you’re right. It’s the continuation of treatment that is also important, not just the intensity or the potency of the compounds that you have.

Graham Jackson
Yeah. Yeah, I think that’s one of the things that was my take home comparing OPTIMUM and MASTER. Certainly. So shall we move on to CAR-Ts, because there was a lot of CAR-T data as well. I guess what were your take home CAR-T messages, Rakesh, from ASH 2021?

Rakesh Popat
So I think CAR-T still is an amazingly exciting area. We’re still seeing unprecedented levels of deep response and MRD-negativity. And I think, particularly with cilta-cel, the durability of the response for multiply relapsed patients is very impressive. And that was updated and shown at ASH. We also saw the LocoMMotion study, which was a comparison of cilta-cel versus standard of care agents. It does get a little bit of criticism in terms of how that study was run and where the patients were enrolled from. But in terms of providing what information we can about CAR-T versus standard of care, I think that was a important study to show that improvement in PFS.

Graham Jackson
I’m just gonna stop you there, because I think it is difficult to do that comparison. And I agree with you, you can criticize the LocoMMotion and when you compare it with CAR T-cell therapy, but one of the things that is so difficult with CAR-Ts is to have equipoise in any sort of Phase III study. So even if you don’t completely believe the LocoMMotion data the difference between the two outcomes in terms of how they do, which we as clinicians recognize is probably about right, is stunning despite our misgivings about the LocoMMotion comparator.

Rakesh Popat
Yeah, absolutely. I think the data is spot on, And I think it will be important when we take that next step, which is getting regulatory approval and reimbursements, which is vital. Otherwise this novel therapy will not be available for patients.

Graham Jackson
And you mentioned high-risk patients, do you get the sense that CAR T-cell therapy might be even useful in the sorts of group of patients that we saw in Martin’s study, the high-risk patients, do you think CAR T-cell therapy will have a role, even against the most difficult disease?

Rakesh Popat
Yeah, so I think they will still be able to induce very high responses and high MRD-negativity rates. I think it will still struggle in terms of the durability. And that’s where this forward look with the next generation of CAR-Ts are coming through, there’s talk about combining it with standard of care agents. I think there probably needs to be a little bit more for those ultra high-risk patients. If I just bring in the CARTITUDE-2 study, Graham, here at this point, because that study was looking at the len-refractory population. So not quite the ultra high-risk that we’re talking about before, but still a difficult to treat population, I think. Again, the response rates are incredibly high, over 90%, very high VGPR and CR rates. And so far the durability looks very good. So I’m sure CAR-T will be very helpful in that high risk population.

Graham Jackson
I might just come to a particular point because there was two things about longevity. We saw in CARTITUDE-2, the updated data, which still seems to be pretty good for those people who are CR and MRD-negativity. And the 2-year updates seem to imply that the technology was performing even better than we expected. And I’d like to sort of mention bb2121R, because that is an innovative way of looking at trying to project greater longevity in terms of responses.

Rakesh Popat
Yeah. So bb21217 I thought, had some quite nice data. So this is the CAR-T that’s cultured with PI3 kinase to try and develop that memory T-cell phenotype. And I thought that the PFS was looking a bit more impressive and the management profile was certainly looking very good. I think over all, the cytokine release syndrome and neurotoxicity for bb2121 is very favorable in fact. And it’s quite an easy CAR-T to deliver. So you’re absolutely right. It’s that sort of approach that I think we need to start taking to try and really push the boat out with the CAR-T story.

Graham Jackson
And two of the, I think before we move on to maybe other things, the two other things that really struck me was the MCARH109. A new target, a non-BCMA target. And also the ALLO-715 data continues to evolve. I think it’s quite nice to see two innovative ways in which we might use CAR T-cell therapy. They’re actually already looking clinically effective.

Rakesh Popat
Yeah. So I mean, I think new targets are really important and we’ll come to that with the T-cell engagers. And trying to overcome… So I think what’s interesting is that the way that some of the GPRC5D CAR-Ts can try and overcome some of the toxicity that you get with repeated administration of the T-cell engager. With the allogeneic CAR T-cells, and I’m curious, Graham, what you think about the risk of double strand DNA breakage? Because I don’t think that was quite clarified in the ASH presentation, about the safety of using this type of gene editing technology.

Graham Jackson
I think that’s going to be a big question mark over the allo CAR T-cell story for a while to come. And because we’ve got such great autologous CAR T-cell therapy and T-cell engager therapy, I think a question mark over allogeneic CARs is going to mean that we’re going to be, want to see long-term safety data on that type of treatment before that becomes mainstream. So an interesting concept, but I think that those worries about double stranded breaks, the technology and possibly also long-term immunosuppression. Maybe we haven’t seen long enough follow-up to see that there may be some chronic GvHD emerging. So I think the jury is still out on allo-CARs and they come out in the face of such effective T-cell engager and autologous CAR T-cell technology. So I think in the interest of time, I’m gonna come on to T-cell engagers because there was a lot of T-cell engager data as well. And an impossible task to summarize. But again, what were your highlights from the T-cell engager data?

Rakesh Popat
Yeah, again, so lots and lots of information on these products. I think that the take home message is that BCMA directed T-cell engagers are very effective. The response rates are high. They’re not quite as high as CAR T-cell therapy and MRD-negative rates aren’t quite as high, but I think given the improvement in tolerability, you can give it to your older patients, a little bit more frail patients. And that is very clear across the board. The Regeneron compound looked incredibly safe, I must say, compared to some of the other CAR-Ts. But we just have to bear in mind that these are very small studies, very small numbers in very selected patients. So I’m reluctant to draw too many comparisons between the products. What was really nice was we started to see some of the first data with combinations. So we starting to see data with teclistamab in combination with daratumumab. We saw data with talquetemab, which is the GPRC5D T-cell engager, again in combination with daratumumab and that appears to be safe and the response rates appears to be high. So I think that’s really interesting with these combinations coming out now.

Graham Jackson
And I’ve got that down as something to particularly mention, the TRiMM-2 trials, the talquetamab and teclistamab therapy because that’s an interesting concept. And they seem to work in patients who’ve previously been exposed to anti-CD38 technology. That interaction with the NK activity in the immune system was really quite a fascinating insight into where we may go next. Double immunotherapy, potentially.

And I think we did see also the other targets, the cevostamab and the talquetamab as you mentioned. They continue to be exciting as well. So we have those two extra targets for people who may have been anti-BCMA exposed. And there was certainly a feeling that we’re starting to see data weren’t we, in patients who’ve been exposed to the anti-BCMA agents responding to other therapies.

Rakesh Popat
I thought that was a fantastic presentation that came out, just discussing about how you can salvage patients for then CAR T-cell therapy and indeed T-cell engagers. And belantamab, because of course, belantamab is widely available now, and many patients will be exposed. So the fact that you can salvage these patients with T-cell engagers, I think, is incredibly important. There was also some really nice kind of nuggets of day-to-day tips on how to manage some of the toxicities with the T-cell engagers. And particularly with GPRC5D engagers. You get this skin rash and taste disturbance. And I thought that was really helpful just to see what sort of skin creams and steroids that you can use to manage that. Because again, these are effective treatments and we do need to try and manage the side effect profile optimally.

Graham Jackson
Yeah, I think there is, one of the senses I got from ASH 2021, is there’s definitely a move to step up dosing, as well, as you say, in terms of reducing toxicity. With these agents aren’t without significant toxicities. We have to be very careful and certainly stepping up doses seems to reduce the early incidents of CRS and ICANS. And I think that was a picture I took away. And I’d be, just in terms of last comment, is going to possibly come down to convenience with some of these drugs, isn’t it? If they’re equally effective, is it gonna be about the subcutaneous route? Is it gonna be about the frequency of administration? It’s gonna be tricky to see which compound becomes the one that we will go to the most.

Rakesh Popat
Yeah. Yeah. There’s so much choice at the moment. It’s it’s baffling, is the truth. So let’s see where we go with this. But it’s a nice place to be, Graham, compared to where we were before.

Graham Jackson
It is. And I know you’re a big international expert on belantamab. There was the DREAMM 5 data. Did you like that data? It looked quite interesting, combining it with feladilimab, which is difficult to say, but that combination of anti-BCMA targeted therapy with a T-cell co-stimulator. That was quite interesting data, I thought.

Rakesh Popat
It was. And I think the whole concept of DREAMM 5 really is about trying to augment the responses with belantamab by adding various different, immune oncology agents. And interestingly isatuximab one of the arms as well. So that’s an interesting combination to come. And the idea is that hopefully you can reduce the dose of belantamab and minimize the corneal toxicity that you’re getting by enhancing the effects. And I’m really interested to see the gamma secretase arm once that report is out as well, because that’s another combination that can allow you to reduce the dose of belantamab by increasing BCMA expression and then hopefully limit that corneal toxicity, which is a little bit of a problem for patients. But certainly the data set for DREAMM 5 was looking interesting and a nice combination. And what a novel combination that we haven’t seen before, which I thought was quite good.

Then there was another belantamab abstract just to briefly mention, which was looking at quality of life as a surrogate marker of needing ophthalmology examinations. And I think that’s really interesting. That’s something that we’re gonna take forward in the UK with our trial called PROMISE, where we’re gonna run that in the double blind fashion to understand if we can get away with not doing ophthalmology exams.

Graham Jackson
Yeah. That looks like a really interesting study, Rakesh. And I think just to conclude the T-cell engagers, you mentioned combinations with dara, we’ve mentioned the DREAMM 5 combinations, and I think the other thing is we’re starting to see these being combined with IMiDs. You know, the elranatamab combination with lenalidomide and pomalidomide. Very, very preliminary data. So we’re gonna have to watch that very, very closely.

Now I’m gonna come on to other studies and one of the most important things that you brought to ASH, and you have been a key voice in this, is looking at racial inequality in patients accessing studies. So would you like to talk a little bit about the data that you took from our UK studies to the ASH 2021 meeting, Rakesh?

Rakesh Popat
Yeah. Yeah. Thanks, thanks, Graham, for highlighting this. So we looked at patients over the last 15 years that were enrolled into our frontline and first relapse academic studies. So Myeloma VII all the way through to Myeloma XI. In fact, newly we actually captured some of the initial data from Myeloma XIV. And essentially we looked at the ethnicity of patients that we enrolled into studies and compared it to the national registration dataset, which is called NCRAS. And the reason why I wanted to do this is because there’s a lot of data coming out from the US which shows that patients from different races or ethnic minorities were not being enrolled into clinical trials or were having inferior outcomes. Now, of course, the healthcare system in the US is very different from UK. We have a national health service and there’s equitable access to care throughout. So we’re interested to have a look and see whether the same was being born out. And unfortunately it was. So when we compare against the national cancer registration data sets, probably we were enrolling 50% less patients from the black or the Asian ethnic origins into our frontline studies than we should be. And this was particularly found in the elderly, the non-transplant eligible studies, where there was a real reduction. In fact, in the first 150 patients treated on Myeloma XIV FITNEsS, not a single black patient is enrolled. So we had a really nice poster discussion at ASH with this. And one of the comments that was being made from the panel was that this is the first data coming outside of the US, which is showing exactly the same problem. So it highlighted it isn’t simply that healthcare systems which are at play here and there’s many more features that we need to look into. So there is some work that’s coming out of Blood Cancer UK, and we hope to try and incorporate that into some of the future work we’re gonna do.

Graham Jackson
It’s fantastic you’re taking a lead on that. And intuitively I was slightly surprised because my intrinsic bias was that it, that the US data was because of their health care systems. So it was a shock to me to see that our data in the NHS was just the same. And we really have to understand and overcome the issues that are causing that disparity, which is, which is a shock, real shock.

And in terms of other data that came out of ASH, what were the other highlights? We talked about frontline therapy. We talked about T-cell engagers, CAR T-cell therapy, iStop. Was there anything else that caught your eye?

Rakesh Popat
Yeah, so there’s always a few novel agents coming through. And the one that I found quite interesting was TAK-573.

Graham Jackson
Oh, I agree. That was the one that really caught my eye too. I’m glad you had the same thought.

Rakesh Popat
Yeah. It’s because, so the reason why I find it particularly interesting is that we’ve struggled, I think with CD38 retreatment. There’s some data that published telling us that isatuximab is not effective in dara-refractory patients. And what was interesting about this particular compound is that this is a CD38 antibody that is linked into an interferon alpha, attenuated interferon alpha molecule. And this was the first-in-human Phase I study. So again, the data was incredibly preliminary, but it clearly does seem to have some single agent activity in CD38 refractory cases. And I thought that was incredibly interesting. It does cause some myelosuppression, but I think that’s a compound that we do need because there is this unmet need of what to do with CD38 refractory patients. And we haven’t quite got a monoclonal to, to pick up that problem beside belantamab. So I think this is an interesting compound to take. I mean, do you think, Graham, that this is a compound that we can combine? So one of the things that struck me was the neutropenia and thrombocytopenia with it.

Graham Jackson
Yeah. I think the hematological toxicity is a concern. I do, like you, it was a concept that I like. We know interferon has some single agent activity in multiple myeloma. So it’s a, but it’s obviously fallen by the wayside because of its side effects and we’ve got much more effective therapy. But I do potentially think that it could be deliverable as a combination. If you’re getting alpha interferon, anti-CD38 antibody, into that milieu of the disease, then maybe on top of that, a T-cell engager, a CAR T-cell therapy. I don’t know, maybe an IMiD, you think, you could start to imagine how these sort of combinations attacking the plasma cell in so many different ways and engaging the immune system in so many different ways, potentially is exciting. But obviously as you say, hematological toxicity is going to be significant. I think the other thing that we’ve been watching very closely over the last couple of ASHs, is the emergence of the CELMoDs. We saw some more iberdomide data at 2021 in combination, again in penta-refractory patients, patients who are refractory to lenalidomide and pomalidomide. It’s nice to see that you can overcome the resistance of myeloma to IMiDs by using a CELMoD. Perhaps slightly disappointing response rates? What do you think?

Rakesh Popat
Yeah. I mean, I’m part of this study and so know the data fairly well. I think from my perspective is two-fold. The first is that it just demonstrates how difficult it is to treat triple class refractory patients. And I think we tend to underestimate this because we’re used to seeing incredibly high response rates with CAR T-cells being presented all the time. And this just brings us back down to earth, is that actually it’s a tough population to treat. The second thing to say is iberdomide is incredibly well tolerated. My patients are doing really well on it and describe it as one of the best treatments they’ve ever had. So what we’ve got to remember when treating patients with multiple myeloma is that we have patients come from all different walks of life, with different comorbidities and frailty. So whilst CAR T-cell therapy will be applicable to a small proportion, T-cell engagers to another, antibody-drug conjugates to another, we’ll still have another group of patients who will need a treatment that is very well-tolerated. And iberdomide I think fits in that gap with being a very well tolerated treatment that I think has its own niche. Now, of course, because it’s so well tolerated, it can be combined. And that’s really where the future of iberdomide is. So I think I wouldn’t rule it out just because the response rate was lower than we see with CAR T-cell therapy. I still think it’s got a nice role.

Graham Jackson
Oh, that’s great wisdom, Rakesh. I guess I wasn’t, we get slightly greedy about response rates. Well, I think one of the conceptual things that I’m gonna come back to on, iberdomide can overcome rev, pom resistance, highly effective, well-tolerated. In any other walk of life where we’re treating cancer, that would become the drug we’d want to use upfront. And we’ve almost got the IMiDs, the IMiDs and the CELMoDs the wrong way around. Do you think we’re gonna start seeing a reversal, that instead of using the weakest IMiDs first, we could, we absolutely need to switch that around and use the best drugs first.

Rakesh Popat
Yeah, no, I think you’re right and actually, you’ll start seeing the frontline studies coming through, right, with iberdomide. Again, I think it’s superb tolerability really lends itself to a frontline treatment for a newly diagnosed patients. We shouldn’t be reserving an effective, well-tolerated treatment for triple class refractory patients. I think soon we’ll start seeing it, the studies for frontline, the maintenance types of studies are already happening in the EMN. So I think it’s a place that’s gonna expand quite rapidly.

Graham Jackson
Okay. And I think we’re gonna finish soon, but I, there was two bits of data, I thought that talked to personalized medicine. There was data on dendritic cell vaccination, which was an amazing study, a huge effort, but perhaps somewhat disappointingly didn’t show a great deal of activity. So that area of personalized medicine didn’t perhaps work, but we did see an update on the venetoclax data. I think that confirmation that that particular drug with Velcade and dexamethasone in 11;14 translocated patients is going to be an important part of our therapy for those patients. Do you think?

Rakesh Popat
Yeah, I mean, I think, unfortunately the BELLINI dataset has some confounding issues in there. And one of the bits that was highlighted was that we didn’t quite see a very strong survival advantage for those patients receiving Velcade and venetoclax. And I think it’s just a lot of confounding noise within that, but I would agree that venetoclax-Velcade, I think, is a strong treatment for patients with 11;14 myeloma. What’s not clear in my mind is what is the best partner for venetoclax because the daratumunab-venetoclax data is also very strong. And whether it’s dara or Velcade is yet to be seen. But certainly venetoclax, we’re hoping will be licensed and available soon for this cohort of patients.

Graham Jackson
Do you think outside of 11;14, do you think BCL2 high expressors are gonna be included in a therapeutic option? And I think one thing we can say from ASH 2021 is there is no activity of this agent, particularly outside of that group of patients.

Rakesh Popat
Yeah. You’re right. So this is where unfortunately I think the trial is just too muddy to be able to work out. And I think you need some well designed biomarker studies to really tease this out. I mean, certainly the BELLINI dataset does show activity of ven-Velcade in BCL2-high patients. But I think it’s just not quite clear enough to be able to hang your hats on it and give it to a patient who’s not 11;14 positive, but BCL2 high. So that’s something that we need to work on.

Graham Jackson
Okay. And final comments from ASH 2021, Rakesh. Great optimism?

Rakesh Popat
Yeah absolutely.

Graham Jackson
Fantastic. Going forward, it’s good. It’s looking good.

Rakesh Popat
Absolutely. So, I must admit, going into ASH this year, I wasn’t too excited. I thought we’d seen already the best and I didn’t know what ASH was gonna give me, but actually I came out jumping around for joy. I think it was a fantastic meeting. I think the future for myeloma is incredibly bright. We’ve got really powerful drugs coming through. We’re learning how to use them better and in a more sensible way. And I think that this will translate to tangible benefits for our patients. And so I’m really enthused.

Graham Jackson
Sorry, sorry. We’re already seeing some of these come through. I mean dara-VTd, just been approved. CAR T-cell therapy, you just get the sense that it’s not far away from being approved in the UK. So a lot of these exciting innovations are actually not that far away from being clinically available.

Rakesh Popat
Yeah, absolutely. And what a difference it’s gonna make, you know, give them dara-VTd for frontline patients is a major change. And as you say, if, fingers crossed, we get access to CAR T-cell therapy at the end of this year, that will be another major change for our patients. So myeloma treatment is gonna look completely different to what people were used to seeing. And that’s such a major positive.

Graham Jackson
And with that, I’d like to thank you, Rakesh. Now again, a great kudos to you for doing the racial inequality study. I always love talking to you about things like this because you have such a wealth of knowledge and an insight and a great way of approaching some of these studies. So I’d like to thank you, Rakesh, for this conversation. I’d like to thank VJHemOnc for allowing us to talk about multiple myeloma in their space. I am Graham Jackson and thank you very much for your attention.

Rakesh Popat
Thank you.