Welcome to The Myeloma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc). This exclusive discussion features leading experts Rakesh Popat & Karthik Ramasamy, who debate the top myeloma research presented at the ASH 2020 virtual Annual Meeting and how the data will impact clinical practice in the UK.
The topics being discussed include the management of newly diagnosed myeloma patients, combination therapies in the relapsed setting, BCMA-targeted therapy including CAR-T, BiTEs and antibody-drug conjugates, and other novel therapies.
“So again, all of this data I think, is really telling us that we need to be offering patients a stem cell transplant early on in their treatment pathway. Now that has always been the approach of those of us who work in Europe and probably contrast against what happens across the Atlantic, in the US. But having said that in this year of the COVID-19 pandemic, we have been deferring auto transplants in some subgroups of patients. And so this brings it up into your mind as to the validity of that approach and whether or not it is the right thing to do or not. Because what I’m finding is now that we are able to defer transplants for some patients because of concerns on severe COVID. Some patients are simply asking the question, actually, do I really need the transplant, or can I just carry on with the treatment and have my transplant later? And I was still looking at this data be concerned about delaying a transplant for a long period of time and I’d be very keen to offer patients a transplant early on, even though we are still dealing with the ongoing COVID-19 pandemic.”
– Rakesh Popat
Combination therapies in the relapsed setting
“Clearly very, very important for us as well as we’ve been waiting for a long time for daratumumab, pomalidomide, dexamethasone combination, and that’s what APOLLO serves up, versus pomalidomide, dexamethasone in patients with relapsed myeloma. The median PFS on the dara-pom-dex arm was just over one year in comparison to about six months on the pomalidomide arm. So significant improvement in progression-free survival with the addition of daratumumab. Well, you can kind of say that is expected, because a) because patients respond very well to CD38 antibody, they are naive to CD38 antibodies and combining CD38 with an immunomodulatory drug has been a success story in the upfront setting, as well as in the first relapse setting. So taking all of that together, dara-pom-dex data presented at ASH clearly confirms that it is a very effective combination. ”
– Karthik Ramasamy
Further discussion on BCMA-targeted therapies and other novel agents
“One would argue that the toxicity profile with the T-cell engagers is somewhat more manageable compared to the T-cell, the CAR-T cells because when you give a patient their CAR-T cells, then you get the rapid proliferation. And as the rapid proliferation occurs, you get the toxicities. Whereas with the T-cell engagers, these are mitigated by means of step-up dosing with pre-medications, including dexamethasone, and by the half-life of the drug itself. And so, what you’re seeing is much lower levels of CRS predominantly grade one and two, and follow those of neurotoxicity because neurotoxicity can be a bit of a problem when you’re giving that. So, so I think there’s some incredibly interesting data playing out between them.”
– Rakesh Popat
Rakesh Popat: Hello everyone. And welcome to the Myeloma Sessions at VJHemOnc. My name is Rakesh Popat, and I’m a hematologist at University College Hospital, and I’m joined with Karthik Ramasamy, a hematologist at Oxford University Hospital. We’ve both been watching the ASH 2020 sessions avidly at the end of our seats, looking at all the latest data that’s coming through to myeloma. But the question is what does this mean to us in the community and also for those of us who are working in the UK? And so I’m really pleased to be having a discussion with one of our leading experts, Karthik, about various different aspects of multiple myeloma. So first, we’re going to kick off, we’re talking about newly diagnosed myeloma. So Karthik, what do you think some of the key takeaway messages from ASH for patients with newly diagnosed myeloma were?
Karthik Ramasamy: Thank you, Rakesh. It’s a real pleasure to talk to you about myeloma. Obviously, we’re missing out on having good chats about interesting data that’s coming through. So obviously in the newly-diagnosed setting, a number of long reads from the major phase three trials that we’ve been seeing over the years, having read out, the first one is the IFM study comparing VRD versus VRD plus transplant, was read out and the same with the EMNO2 trial comparing transplant versus BMP intensification was read out longer-term. Both of these trials have now got about over seven years follow-up in both of them. The interesting thing is the IFM study clearly showed that having a transplant at an 84–month median follow-up did not yet improve overall survival. But clearly the earlier primary endpoint of progression-free survival was significantly better for the transplant arm. And that’s clearly because the MRD negativity we get. Interestingly, the contrast was the EMNO2 trial, which compared a similar sort of strategy of transplant versus no transplant. And they did find that the transplant arm had an improved overall survival advantage in comparison to the BMP intensification arm. So obviously that’s very, very interesting. It’s hard to compare between trials, but we know that the trial designs are different. But one thing that I started to wonder is lenalidomide maintenance meta-analysis have always shown a late divergence in overall survival after about four or five years. We do have one trial stopping lenalidomide maintenance at one year because of the concern around SPM in the IFM study. And then we had the EMNO2 where len maintenance was given until progression. So that’s interesting, but obviously there may be other lots of different reasons as to why we may have the differences, but I found that extremely interesting and striking and an area for us to watch because we all do transplant after induction in our first line setting for our transplant eligible patients in the UK. I don’t know what your thoughts were in that two abstracts.
Rakesh Popat: No, absolutely. So I think these were key, and I think the nice thing about them is that we are seeing long-term follow-up data, which becomes incredibly important when we’re looking at an overall survival endpoint. I guess for me, there are, as you pointed out some key differences in the trial. We’ve got to remember that the EMNO2 trial used VCD as induction therapy and the IFM trials used VRD as induction therapy. And then as you say, there was differences in the maintenance, and we’re still also waiting for the DFCI part of the IFM trial, where lenalidomide maintenance was given long-term until progression. And you’re right, it may be that we’re not seeing a survival difference for the IFM dataset simply because patients stopped lenalidomide maintenance early. The other interesting bit that I took away from the EMNO2 study was the subgroup analysis, which looks at the group of patients who did not have an additional transplant. So they were randomized to have VMP, and then went on subsequently to have a later transplant. And when you look at that data, you can look at the PFS2 and overall survival data for those patients – the PFS2 and overall survival was inferior to the patients who had a stem cell transplant upfront. And also of note, not all patients went on and were able to receive a stem cell transplant at relapse. So again, all of this data I think, is really telling us that we need to be offering patients a stem cell transplant early on in their treatment pathway. Now that has always been the approach of those of us who work in Europe and probably contrast against what happens across the Atlantic, in the US. But having said that in this year of the COVID-19 pandemic, we have been deferring auto transplants in some subgroups of patients. And so this brings it up into your mind as to the validity of that approach and whether or not it is the right thing to do or not. Because what I’m finding is now that we are able to defer transplants for some patients because of concerns on severe COVID. Some patients are simply asking the question, actually, do I really need the transplant, or can I just carry on with the treatment and have my transplant later? And I was still looking at this data be concerned about delaying a transplant for a long period of time and I’d be very keen to offer patients a transplant early on, even though we are still dealing with the ongoing COVID-19 pandemic.
Karthik Ramasamy: I find what you just said is extremely important because obviously individual decisions have to be made based on these situations in front of you, but you would’ve seen the FORTE trial, and I’d be keen to hear your thoughts because obviously you started to compare and contrast the kind of induction approaches, VRd and VCD. It was quite striking to see KRd plus transplant versus KRd. You know, there was a clear evidence that transplant added benefit. I mean, what are your thoughts? I mean, that is quite profoundly, we’ve all felt KRd was probably in a significant add on to VRd, but still there’s a difference.
Rakesh Popat: I think you’re spot on there. So I think even though we’re using one of the most powerful induction regiments KRd, by simply continuing with KRd, you have inferior outcomes compared to the incorporation of a stem cell transplant. So I think what this is telling us is that actually there is a significant role for a switch of therapy to high-dose alkylator with stem cell transplantation. Now, whether or not it’s the effect of a high-dose alkylator and the depths of MRD negativity you get from high-dose alkylator or if the resetting of the immune system through the new formation of the stem cells and the activated T-cells that we typically see on the immune modulation and surveillance that’s observed, I don’t know. But I think it’s becoming very, very clear that there is something specific about high-dose melphalan stem cell transplants that is happening in the myeloma biology, that’s very different from PI, IMiD and corticosteroid treatment. So I look forward to additional data coming out for that. And just whilst we’re talking about new and different induction regiments, I was quite impressed with the DVRd data that’s coming through, which is the GRIFFIN analysis, and surely that’s where we are going to be moving to perhaps in five to 10 years is going to be using the quadruplet of DVRd as induction, stem cell transplant, consolidation, and maintenance. But of course, that is dependent on DVRd being funded and within Europe, that becomes a problem. So I suspect what is more likely to be available for us in Europe is DVTd. And so I wondered, Karthik what your feeling was with DVTd in the data that we’re seeing presented at ASH.
Karthik Ramasamy: Absolutely. So clearly jumping from three drugs to four drug combination regimens of the three important players, CD38, the proteasome inhibitor and the immunomodulatory drug, is really the way to go. We’ve got CASSIOPEIA being read out and also published in Lancet, which is a trial, which compared our current standard of care BTD to the daratumumab, velcade, thalidomide, dexamethasone – significantly improved stringent CR rates, significantly improved MRD negative rates on the daratumumab added to the VTD arm. And also, you know, significant improvement in early progression-free survival that we can see. One of the problems with some of these trials early on is because we’re getting quite a significant improved response rates, you have to wait for long day, even for PFS to emerge in some of these studies. And that’s what the GRIFFIN study has shown. The GRIFFIN study is the comparison of VRD versus daratumumab VRD treatment. And what you can again see is you can see a clear, significant difference in the MRD negativity, but still yet to show a significant PFS difference between the two arms because, you know, we still in the early two to three years of analyzing this data. What I can safely say from that four-drug regimen is you do see very high MRD negativity rates. You already mentioned about the MRD negativity being a key piece of transplant. If that one domain is captured by just the addition of a fourth drug to your induction, as you rightly said, immunomodulation may be part of the important second piece of the puzzle to what transplant gives, and that maybe the drugs alone won’t be able to give, but at least if you’re going to get very deep MRD negative rates, post induction in this patient population, then I think that’s going to do these patients a lot of good down the line with the very long first remission period. But one thing that concerned me, I have to say, Rakesh is… I mean, I shouldn’t say a concern, but it’s an area to kind of follow through is data coming from what you’ve also said previously, the IFM trial has got an American partner in the DFCA component of the VRD versus VRD plus transplant. Very interesting data from Nikhil Munshi’s lab where they compared patients on the VRD only arm who are relapsing after a period of time with patients who are on the VRD plus transplant arm relapsing after a period of time. And doing the mutation analysis and there’s clearly some differences there. And what is your take on that?
Rakesh Popat: Yeah, so I think that’s really interesting data because what we’re seeing is a higher incidence of mutations in patients who received high-dose melphalan. And this is something that’s always been of concern to us by the use of high dose alkylators and potentially the predisposition to clonal evolution and further tumor resistance. And I must admit that many of us were concerned, particularly for patients with a 17p deletion as we know that TP53 is a key gatekeeper of managing mutations and cell cycles. So that’s one area that we’ve been particularly concerned about. And I’d like to just see how that pans out. I’m not sure still; however, what the direct relevance of this is, because whilst we are seeing these additional clones forming, stem cell transplantation still confers an improvement in overall survival and progression-free survival. So it may be that even though there’s a higher splattering of mutations, that it isn’t overall effecting the playing out of what we’re seeing. I know that the recommendations from that abstract was that we should think about using PARP inhibitors. And that may be a role in those patients who’ve gotten a bit of double stranded DNA breaks as a consequence of high dose alkylator therapy, but I’m not sure how effective that will be because the net effect is that the myeloma cells still seem to be not going into complete overdrive – I don’t know if this is kind of data that we’re still learning about.
Karthik Ramasamy: Yeah, I think it’s very interesting, as you said, I think it’s important to follow, but one thing that I’m starting to kind of think about is clearly there’s a big move with EMNO2 data around using, you know, more than one transplant in tandem for patients. Clearly, if you’re driving higher mutational burden, as you rightly pointed out, there was no large-scale deletions or translocations seen. There were no driver genes being changed at least at this particular readout. So we shouldn’t over interpret this, but then more than one transplant starts to sound more concerning, as you rightly said, in those patients with high-risk genetics. Clearly, we need effective therapies at relapse for patients, but I think what would be concerning is whether alkylators, high dose alkylators would drive some of those clonal evolution that would be difficult to be salvaged by the relapsed agents.
Rakesh Popat: Yeah, yeah. Absolutely agree. So the debate on high-dose melphalan continues clearly, so even though ASH is showing some very strong data, I think supporting the role of high-dose melphalan for newly diagnosed patients, there are some concerns being highlighted here with a spectrum of mutations that can occur following high-dose melphalan. So I think overall there’s been some really interesting data coming out for newly diagnosed patients.
Rakesh Popat: So with that, I’d like to move forward and discuss the relapse field for patients with multiple myeloma and some of the emerging data that we saw at ASH. And I think what was really interesting was there was a focus around how to improve the pomalidomide backbone. So many of us are using pomalidomide very commonly at relapse. It’s a very well tolerated and efficacious immunomodulatory agent and has a number of positive attributes, I believe, compared to thalidomide and lenalidomide. In terms of licensed products, isatuximab, pomalidomide and dexamethasone is available for use and is considered to be a standard of care. But many of us have been waiting to see the data for daratumumab in combination with pomalidomide and dexamethasone. And so the APOLLO Phase 3 clinical trial was reported at ASH. So Karthik, what is your take on the APOLLO data set and what is your views on that compared to the ICARIA dataset?
Karthik Ramasamy: Thank you, Rakesh. Clearly very, very important for us as well as we’ve been waiting for a long time for daratumumab, pomalidomide, dexamethasone combination, and that’s what APOLLO serves up, versus pomalidomide, dexamethasone in patients with relapsed myeloma. The median PFS on the dara-pom-dex arm was just over one year in comparison to about six months on the pomalidomide arm. So significant improvement in progression-free survival with the addition of daratumumab. Well, you can kind of say that is expected, because a) because patients respond very well to CD38 antibody, they are naive to CD38 antibodies and combining CD38 with an immunomodulatory drug has been a success story in the upfront setting, as well as in the first relapse setting. So taking all of that together, dara-pom-dex data presented at ASH clearly confirms that it is a very effective combination. The safety signals, which is very important in the relapse setting for patients who’ve had myeloma for a number of years, because often they have poor accounts and side effects from previous therapy. There wasn’t anything that was read out that was particularly concerning for us in using this type of combination. As you rightly say, we now have the ability to use isatuximab, pomalidomide and dexamethasone through the Cancer Drugs Fund, and we’re currently doing it. Obviously, they are slightly different trials, isatuximab, pom, dex only recruited patients who’ve had a minimum of two prior lines of therapy. So you have to have had two prior lines or more is how the ICARIA study was planned. Although you don’t compare, you can kind of look at the hazard ratios within the both studies. And that looks fairly comparable is what I would say. So what you’re getting with the addition of CD38 antibody to pom-dex is fairly consistent across both isatuximab and daratumumab. But the interesting thing is daratumumab-pom-dex in the APOLLO study, a proportion of patients, about 10% of patients were at actually only had one prior line of therapy. So slightly earlier on in the treatment pathway. Obviously playing devil’s advocate, one could ask, well, if that is the case, should you have seen more, but we know that 10% is a very small population. And if you look at a median PFS, you know, you are going to fall in the ballpark of, you know, where [inaudible], if you large, majority of patients are two therapies and over. So for me, it was a very interesting study. In the US they’ve been using dara-pom-dex for a long, long time, but clearly we have isa-pom-dex in Europe. And I think we’d be, you know, very keen to use that for our patients. But I’m going to ask you, I found the selinexor-pom-dex data that was presented, obviously with the COVID spin on it, all oral combination, the Canadian study of selinexor-pom-dex. That was quite interesting. What is your take on it? Because obviously pom combinations are important.
Rakesh Popat: Yeah, and absolutely. I think that was the theme at this year’s ASH was trying to work out the best partner for pom. So selinexor is a very interesting drug. It’s a new class of drug and works in a different mechanism of action to anything that we have before. As you say, it’s an oral agent, and it clearly has an effectiveness in the both triple class refractory and the more refractory populations such as the penta-refractory population, which isn’t a population that we tend to see too commonly in Europe. I think the data with single agent selinexor whilst it shows some efficacy has some problems in terms of the tolerability, particularly at the higher dose, and the constitutional side effects such as the nausea, weight loss, anorexia seem to be quite profound. Now, what I found was quite encouraging, looking at the data that has come out previously, such as the data in combination with velcade. And again, the data that we’re seeing this years ASH, which is in combination with pomalidomide, is that when you’re able to reduce the dose of selinexor by combining it with another agent, it automatically becomes much more tolerable. And I think that if you can get selinexor to be a better tolerated drug, then it becomes a very powerful agent to be used within the myeloma treatment space. So I thought the results were encouraging, selinexor-pom-dex. I mean, they’re still early data, but the responses were good and the tolerability seems to be manageable, particularly with the use of additional anti-nausea agents. So you’re right, we are trying to minimize patients traveling into hospital, and so all versions are very good. Although I think it’s going to be a little bit of time before we see selinexor coming through with pon-dex. And I wonder if rather than you Selinexor as a partner for pom-dex, if we’re trying to minimize hospitalizations, just returning back to the APOLLO study, of course, this uses subcutaneous daratumumab. And if a patient pre-medicates at home, then by the time they reach the hospital, they simply have a three to five minute subcutaneous injection, and then they’ll be able to leave the hospital quite rapidly. So to some extent, whilst they are still traveling into hospital, the exposure is minimal. So there are different ways I think about combining it. But just talking about pomalidomide partners, I was also curious about a study incorporating the addition of cyclophosphamide. Now in the UK and certainly in Europe, we use a lot of cyclophosphamide. It’s an oral agent. It seems to be well tolerated. The myelosuppression doesn’t appear to be too bad, and there’s a very strong scientific rationale in that there is some immunomodulatory effects in terms of the depletion of T regulatory cells. And so we often incorporate cyclophosphamide in our treatment regimens. And for example, pomalidomide-cyclophosphamide-dexamethasone is commonly used. So, Karthik at ASH, there was some data where daratumumab-cyclophosphamide-pomalidomide was being used or pomalidomide could be added to the sara/cy-dex combination at the time of progression. But what’s your views on the addition of cyclophosphamide into these regimens?
Karthik Ramasamy: Yeah. I think that you make very important points. There are two points I probably try to put out. One is, if you look at our natural sequence that has now evolved, you have a VTd induction, then you have a DVd and then you have an IRd. You would have had your high-dose melphalan single hit, but you are very alkylator-naïve at that point. So when you are dealing with a pomalidomide-dexamethasone combination, clearly we’ve just discussed that you can isa-pom-dex, but take for a moment that you’ve had a patient who’s had daratumumab previously and therefore cannot use isatuximab, you’re absolutely right – adding in cyclophosphamide is extremely attractive. There have been previous very small studies that have been done with the addition of cyclophosphamide, our own MUK7 approach had that as the control arm of the study. So addition of cyclophosphamide clearly improves outcomes in these patients. The second point that you make, the metronomic kind of dosing of the cyclophosphamide does have an immunomodulatory capability and people have demonstrated that in different trials, in different combinations. So I think it’s something that we know how well to use. We are using it less, and it does have the immunomodulatory capability, which is important when you go in with pom. And therefore, I think it’s a better useful addition for our patients.
Rakesh Popat: Yeah. And what intrigued me at ASH was that there were two presentations incorporating cyclophosphamide. So we could see clearly that daratumumab-pom-cy-dex was a good combination, but also there was a presentation from Marivi Mateos looking at carfilzomib-cyclophosphamide-dex. And that was also I think, very attractive. And that also talks to the MUK5 dataset that came out of the UK looking at carfilzomib-cy-dex. So I would completely agree with you, I think cyclophosphamide is a drug that maybe is not using so much, but I think has some very strong efficacy in myeloma. I was just also going to touch on another partner for pomalidomide, which is belantamab mafodotin, a BCMA antibody-drug conjugate and Suzanne Trudel presented the preliminary data for belamab with PD. Looking at various different schedules of belantamab to try and minimize the ocular toxicity, which we all know is part of the signal of this drug. And I was really intrigued because the response rates were incredibly high. In fact, they were higher than the response rates published or presented from APOLLO and ICARIA. And the data isn’t quite mature enough to have a progression-free survival output, but I’m beginning to wonder, what is the best partner for pom? Do we think it’s the CD38 antibody? Do we think it’s the BCMA ADC or do we think it’s an alkylator? What are your thoughts, Karthik?
Karthik Ramasamy: Absolutely. I think this area is continuing to unravel, but let’s in a very practical sense, what I would like to say is we are moving CD38 antibodies to the upfront setting. So we are not going to have a CD38 naive patient in relapse refractory setting. So as you rightly said, it’s very sensible for us to look at other combinations. You did say selinexor is a completely new mechanism of action. That is interesting. And belantamab, I mean, I was quite struck by that data. I think it’s a very, obviously a very early data set. We all know that the data on belantamab has been published and it’s approved in the US now and patients are getting benefit from it as a three-weekly infusion of BCMA antibody drug conjugate. And with the addition to pomalidomide-dexamethasone, obviously very, very, very high response rate. I mean, one issue is the eye issue. And as you know, Rakesh, GSK are trying to look at kind of different schedules to try and mitigate against these corneal events. You’ve been involved in some of the early development of this particular agent – can you just shed any further light in this area? I mean, what is the thinking? I mean, clearly patients are responding, and we even have some compassionate use patients are responding really, really well to the agent. It’s important to say, not every patient responds, but those who do respond, respond very well. I mean, what is your thinking? I mean, how do we actually mitigate these corneal events? Because it’s an important combination.
Rakesh Popat: You’re absolutely right. And this is an area which is undergoing intensive research, and there’s a lot of collaborations with our ophthalmology colleagues to try and understand this. The mechanism for the keratopathy is still not quite understood. What we do see is that there are microcysts-like epithelial changes, which appear on the front surface of the cornea. Typically, the deposition is on the periphery of the cornea and then as time goes on, they migrate into the center of the cornea. As they migrate towards the central of the cornea, there is an increased refractoriness of light as it enters the cornea and this leads to blurring of vision, photophobia and a sensation of gritty eyes. Now, we’ve been using belantamab for a number of years now since the first-in-human studies. And there’s a very clear pattern of what happens. You dose a patient, the keratopathy appears, and then the keratopathy moves from the periphery or the cornea into the center and then disappears. And so what you see is this resolution of keratopathy changes. So the main management at the moment we are recommending is dose interruptions and delays. So actually one of the abstracts that we presented at this year’s ASH was looking at some of the long-term follow data from DREAMM-2 study, because one of the concerns people often voices, hang on, we are having to hold belantamab for quite a long period of time because of these keratopathy, what’s happening with the myeloma response? So the dataset that we showed is that we looked at a subgroup of patients who had, had delays of greater than 63 days. 63 days equates to three cycles exist 21-day dosing. And if you look at those patients, the vast majority of these patients maintain their clinical response. And in fact, a significant proportion actually improved the depth of their response despite having no treatments. And it was only a minority of patients who progressed whilst having a delay in their treatment. So it seems like there isn’t a real concern with interrupting treatment. And by interrupting treatment, you allow the resolution of the keratopathy to occur and repeat dosing to happen. Now, in terms of how best to mitigate this, well, if you look at the PK data, when this was presented at the AACR earlier this year, the severity of the keratopathy seems to correlate with the trough levels of belantamab. And so one of the ways to mitigate this will be by giving more extended dosing so that you’re not repeating the dosing before the trough has really reached its NADIR. And so what you’re going to start seeing is more infrequent, or should say less frequent dosing. So for example, in DREAMM-6 study, we are now evaluating less frequent dosing of belantamab in combination with bortezomib and dexamethasone. So you’re going to be seeing six to eight weekly dosing coming out to different schedules to try and mitigate that.
Karthik Ramasamy: Good, good. I think it’s very, very exciting drug. We obviously, we are investigating a number of different combinations moving into upfront, but clearly BCMA targeting is the absolute team in myeloma and a lot of abstracts at ASH focused on, you know, bite T-cell engager, all different ways of T-cell re-direction in targeting BCMA. There was a raft of drugs now for T-cell redirection. What are your thoughts on BCMA redirection and what excited you the most? Or if not, how do you see all the different players working in the myeloma space?
Rakesh Popat: You’re absolutely right. This was a rammed session at year’s ASH – the BCMA targeted therapy space, and what we have essentially playing out is three classes of treatments. We have the CAR-T cells, we have the T-cell engagers, and we have antibody drug conjugates. We’ve already spoken about belantamab, but there is another ADC under evaluation MEDI2228, which is a BCMA-targeted ADC, which has a different payload compared to belamab. And this is PBL, which causes cross-linking of DNA. What that study showed was some really interesting efficacy data, strong monotherapy efficacy, I would say, in the relapsed/refractory population. However, it has its own distinct toxicity profile. And that’s really what we’re seeing with these ADCs. They have their own distinct toxicity profiles. You get some myelosuppression, which one would expect, and you get some neuropathy. What was slightly unexpected when I looked at that was some patients develop grade three pleural effusions, and there was also grade three photophobia. And in fact, the incidents of photophobia led to a high number of treatment discontinuations. These patients had extensive ophthalmology examinations, and they don’t have keratopathy, which you see with belamab. And so it’s really not quite clear as to why they’re getting this photophobia. One of the theories is that it could be the innervation of the cornea that’s being affected. So this is clearly a potent drug. And I just think that a little bit more work needs to be done to try and understand this toxicity because there was quite a high number of discontinuations. So I think that’s really important to watch. The CAR-T cells are still continuing to impress, I think everyone in terms of the incredibly high response rates and a high MRD negativity rates. And the BCMA-CARs are now showing more mature data, the BB2121 data set to show your median progression-free survival of around 12 months at the highest cell-dose, the Janssen CAR, the CARTITUDE study hasn’t quite read out, but the PFS is likely to be over 12 months on that. You are seeing different profiles in terms of cytokine release syndrome and neurotoxicity. And of course, if you look at the bi-specific T-cell engagers, they also have cytokine release syndrome and neurotoxicity. One would argue that the toxicity profile with the T-cell engagers is somewhat more manageable compared to the T-cell, the CAR-T cells because when you give a patient their CAR-T cells, then you get the rapid proliferation. And as the rapid proliferation occurs, you get the toxicities. Whereas with the T-cell engagers, these are mitigated by means of step-up dosing with pre-medications, including dexamethasone, and by the half-life of the drug itself. And so, what you’re seeing is much lower levels of CRS predominantly grade one and two, and follow those of neurotoxicity because neurotoxicity can be a bit of a problem when you’re giving that. So, so I think there’s some incredibly interesting data playing out between them. But what I wanted to just highlight was the role of dual-targeting CARs, because what we saw was some very interesting data of BCMA and CD19 combined CAR coming from one of the Chinese groups. And I think this is a very interesting approach because CD19 whilst is not commonly or highly expressed on plasma cells, is expressed to a much lower level. And we think that potentially CD19 is expressed on more primitive plasma cells, which may be potentially tumor initiating cells. And of course, CD19 is highly expressed in B-lymphocytes. And so this helps T-cell expansion to occur because there’s more antigen around for the CARs to engage with. So I would watch this space with a dual-targeted CARs.
Karthik Ramasamy: That’s very, very interesting. Can I just make one other additional point because you were starting to kind of think through how all this BCMA targeting would work. For us as clinicians in our practice, one thing that was striking for me is obviously the cytopenia that we see with the CAR-T cells is significantly lower in the bi-specific approaches, which is probably because of the lympho-depleting conditioning that is given early on. I mean, we all know how managing our patients is often difficult in the relapse/refractory setting with poor counts. So that looked more attractive to me. And as you rightly said, you could titrate up the dosing as you keep giving it to patients. Do you start to already see an approach where you could have a particular type of BCMA targeting for one age group versus another age group?
Rakesh Popat: Yeah, so when I look at these abstracts, I look at the age range because you look at the median, but what’s important is the top – it’s the eldest patient. And what’d you say is actually, it’s quite interesting that there are some more elderly patients being treated with CAR-T cells, but I really do think that the toxicity is more manageable with the T cell engagers. So certainly at the moment, because these studies are open and in the UK, we’re running these trials, and I’m assessing my patients is that I’m more likely to enrol and to treat more elderly patients who have potentially some more co-morbidities with a T-cell engager compared to a CAR-T cell where actually we don’t quite know quite how that proliferation is going to go. And if you’ve got a patient with a high disease burden, then you could go quite substantial, significant grade three CRS and neurotoxicity. So, so you’re absolutely right, there is this delineation that we’re beginning to see. And I think what’s going to be very important is the PFS, because the difference with the CARs and the T-cell engagers is the continuous dosing with the T-cell engagers versus the CARs, which is a single hit.
Rakesh Popat: With that, actually Karthik, I wanted to see what your thoughts were because what we also saw was just outside of BCMA, was that there was a T-cell engager targeting GPR5CD, which is another target on myeloma cells and one targeting FCR receptor as well. So we’re seeing new targets occurring. Did you see a role of kind of T-cell engagers being given sequentially? I mean, how do you think this is all going to work with different targets coming through now?
Karthik Ramasamy: I have to partly say I quite like that. One of the things that was concerning for me, as you know, because we run clinical trials for BCMA-targeted agents, and some of the trials didn’t allow patients who had prior BCMA and so on. I don’t think that area is quite as settled as if you had a BCMA targeted agent can you have another one and so on. That will come through the wash, but it’s nice to see that you can go after other targets using the similar sort of technology. And I think that’s what talquetamab, which is the Janssen product offers with the GPR5CD and there are both IV and subcut approaches that has been explored with this agent. Over 100 patients treated in this talquetamab study. And I’ve been quite impressed with the response rates that we see. We should always say that early on in these trials, you tend to collect a more indolent patients, so your response rates are going to always look a bit amazing, but I certainly think that availability of talquetamab in clinical trials in the UK, which is planned for next year would be very exciting. And really FCRH5, which is another target that we can go after, you know, present from UPenn data – very, very interesting, very early data, but clearly showing responses in patient population. You start to conceive an idea in your head as to whether you go CD38 targeting, BCMA targeting, and then something else with obviously the PI, the dex and the immunomodulatory drugs added into the mix. So that is very simplistic in our way of thinking, but it’s nice to see that there are other areas, that we can, antigens that we can target. So very, very exciting. I have to say.
Rakesh Popat: And you’re absolutely right. So this is incredibly exciting, but one of the problems that we’re still seeing is the relapses are occurring. And we’re seeing this particularly with the CAR-T cells, we’re seeing that the T-cells don’t seem to persist, past a year, relapses are happening. Of course, the T-cell engager data is still a little bit immature, but I’m sure that this is not a cure. So, so, this is one of my concerns because there are an awful lot of these T-cell redirections and strategies occurring, and I’m thinking to myself, well, actually these T-cells aren’t going to be functioning too well. If a patient relapses off a T-cell redirection strategy, one of the commonest reasons for doing that is because of T-cell exhaustion. And so the question is how are you going to salvage with your patients after that? And which brings you to the question about T-cell fitness and how we should best prepare our patients to receive these immunomodulatory agents? Have you got any thoughts about kind of resistance to these T-cells strategies about some of the data that we’ve been seeing?
Karthik Ramasamy: Yeah, so you’re making very, very important points. We have to all remember that myeloma unfortunately is a disease of the older population, you know 70 plus. So we are going to see a degree of immunosenescence in our patients. So therefore, T-cell reduction strategies could fail because of those fundamental issues, but some work is being done to look at why some patients may actually have resistance to agent. And I found one of the abstracts to be very, very interesting, and that is around a single patient being treated in the US where they got BCMA CAR-T therapy as their fourth-line therapy. Initially, at diagnosis, the patient did not have any high-risk lesions, and the patient did go into a very, very good remission with drop-in BCMA serum levels, after the initial treatment of the patient did relapse a few months later, and patient was attempted to have another BCMA CAR-T infusion, which unfortunately failed. Interestingly, what they found in this particular patient is that the 16p segment of the genome in this particular patient, which is where BCMA resides in the short arm of chromosome 16 was biallelically deleted. So one of the arms was deleted, structural change and the other arm was mutated. So clearly this patient had complete BCMA loss in the plasma cells that were coming through, and therefore BCMA targeting was not effective. It may be sounding like a single patient, but what was concerning is they went back to some of the earlier myeloma genome data that’s available through working with Celgene BMS. And that shows between 4-15% of patients have 16p loss, at diagnosis. And the more concerning bit is actually co-locates with the patients with del 17p, and about 70% of del 17p can have a degree of 16p loss. This is very worrying for, for the very fact that this could be an easy way of myeloma clonally evolving in our patient population. So I think that is something that absolutely concerns me. And what’s more concerning is del 17p has been our biggest concern as a group of patients. And we tend to collect that, but a lot of del 17p patients by about third or fourth relapse about a third of our patients have del 17p. So this is an area for us to watch and this is probably why I liked the fact that we have other targets, like DPRC5D and FCRH5 that we can go after. So I would sum up saying that in the novel agent section, there’s a lot of hope for our patients, but there’s plenty more for us to find out.
Rakesh Popat: Absolutely. And thank you very much Karthik for your insights, that there’s an awful lot of excitement that’s happened at ASH. I think this is one of the most positive years, I think for myeloma at ASH. And actually rather unlike most years where I come back and feel little bit depressed when I was sent back to the UK, I’m actually very encouraged because a lot of the data that I think that we saw is directly applicable to the practice that we’re having in the UK. A number of clinical trials are enrolling with these novel agents, and I would really encourage everyone to send their patients in to be enrolled into these clinical trials so that we can make this progress. So thank you very much, Karthik for your insights and the discussion that we’ve had at ASH, and we look forward to seeing this data as it enrols.