A roundtable discussion with experts Noopur Raje, Nina Shah, Katja Weisel & Yi Lin as they review the key updates in the treatment and management of multiple myeloma from the ASCO & EHA 2021 virtual meetings.

Welcome to The Myeloma Sessions brought to you by the Video Journal of Hematological Oncology (VJHemOnc)! This exclusive roundtable session features world-renowned experts Noopur Raje, Nina Shah, Katja Weisel & Yi Lin, who discuss the latest research in the treatment of patients with multiple myeloma following the EHA and ASCO 2021 virtual meetings.

This session features updates and discussion around key clinical trials including the MAIA trial, the FORTE trial, the Cassiopeia trial and the TOURMALINE trial, the latest news on novel agents and CAR-T therapies, and insights into the optimal sequencing of multiple myeloma therapies.

Newly-diagnosed & transplant-ineligible

“For me, and now with the ability to give dara subq in most of the countries, [dara-len-dex] is the clear and undoubtable standard for most of the transplant-ineligible patients.”
– Katja Weisel

“The MAIA data, first of all, when it was initially presented, was actually practice-moving, and most recently has been practice-changing. And I think this data with the overall survival makes a lot of us feel like we’ll move in that direction for transplant-ineligible.”
– Nina Shah

Transplant-eligible

“I do think that the data from the FORTE trial is speaking to the conventional practice, in that with these patients with these risk features, although yes, you can define mutational risk features versus certain biologic risk features, but to intensify the treatment upfront, use the most effective regimen upfront, we do see differences in response rate between the arms on this study.”
– Yi Lin

“I think once you start using combinations like we do, in addition to the efficacy – and we’re seeing really high efficacy where we are seeing MRD-negative disease – I do think we have to pay attention to toxicity. And the Cassiopeia data certainly informs us of the possibility of us being able to attenuate treatment, at least in this subset of patients.”
– Noopur Raje

Maintenance strategies & MRD

“The standard-risk patients do very well with a number of treatments that we already have. And so, for this patient population, I think more about tolerability of the maintenance treatment, toxicity and quality of life.”
– Yi Lin

“I think what was nicely shown at this year’s meetings was also sort of long follow-up. In this case it was on the TOURMALINE trials where they used ixazomib maintenance, and we may have a tool in the future wherein we are using minimal residual disease testing. And what that trial essentially showed was that if you were able to have sustained MRD negativity, that the outcomes of that was really better, and that it didn’t matter how you got to that point.”
– Noopur Raje

Novel agents and CAR-T

“I think we have now entered there also a new generation of immunomodulation. We are more specific, and we have less toxicity. And this is what we want to have. And it seems that we can even more specifically target what we want to target.”
– Katja Weisel

“I think in the early days of CAR T-cells, all of us were concerned about even giving a single dose of dexamethasone. And we’ve learnt along the way, as we do with all drug products. You know, we are still learning how best to give for example, selinexor and were doing weekly dosing. Bortezomib was approved in 1993, but we still went to weekly more recently. So, I think the beauty is we have all of these, then over the course of our practice, we start adapting and adopting different ways of giving our treatment.”
– Nina Shah

Watch the full session
Full transcript

Noopur Raje:
Welcome to the Myeloma Session from VJHemOnc. It is my great pleasure to welcome a fantastic panel for a discussion on the recently concluded ASCO and EHA meetings. We’re going to be talking all myeloma, from new diagnosis to some of the new and exciting things we have in the myeloma space. And to discuss all of this, I have the pleasure of inviting Dr Katja Weisel, she is the Deputy Director of HemOnc at the Comprehensive Cancer Center in the University Medical Center in Hamburg. I’m also joined by Professor Nina Shah, who is from UCSF. And we are very fortunate to have Dr Yi Lin from the Mayo Clinic, who is a superstar when it comes to CAR T-cell therapy and some of our new immune oncology strategies. So, with that, welcome, ladies.

Nina Shah:
Thank you.

Yi Lin:
Thank you.

Katja Weisel:
Thank you.

Noopur Raje:
Again, I think it’s fantastic that we have an all-women powerhouse out here. So, let’s get started. You know, we had sort of interesting presentations at ASCO as well as at EHA. We started out by, you know, there was, I’m going to go because I want to try and do it in some sort of an order. So, we want to talk about the newly diagnosed, so I’m going to jump between ASCO and EHA if that’s okay with you, ladies? But I did want to start out by talking about MAIA, because MAIA is a clinical trial which is going to be practice-changing and it was a late-breaker at EHA and Professor Thierry Facon presented the updated results of MAIA, which is the triplet of lenalidomide-dexamethasone with daratumumab when compared to lenalidomide-dexamethasone, and we saw an overall survival data which was presented at this EHA meeting. So, you know, I just wanted to get thoughts around this clinical trial. And I’m going to start out with you, Katja, you want to talk a little bit about this? Because it is really going to impact how you take care of folks, certainly in the EU areas.

Katja Weisel:
Yeah, I think MAIA is a fantastic trial and is continuing the series of plenary talks. Thierry had, was starting with len-dex, establishing as a standard treatment with a first trial which was huge with more than 1,600 patients. And now MAIA again, a large Phase III trial investigating daratumumab in combination with lenalidomide and dexamethasone. Then the first standard as serving here as a standard, it’s len-dex. And patients were really included as an all-comer trial when they were newly diagnosed and transplant-ineligible. And how I think investigators trust in this tolerability of this regimen, showed that nearly half of the patients were 75 years and older. So, representing a true elderly population and we saw those outstanding PFS data. But this year, then the overall survival data. And what was for me very surprising, that the median PFS for dara-len-dex was still not great and is estimated beyond 55 months somewhere, and that there was, despite all the innovation we have in myeloma, a clear and significant overall survival benefit. So, for me, and now with the ability to give dara sub-Q in most of the countries, this is the clear and undoubtable standard for most of the transplant-ineligible patients.

Noopur Raje:
Yeah, no, I think you bring up such a good point. Specifically with the subcutaneous dara now which is available to us, Katja, this is sort of our go-to regimen. I know in the EU you are using our RVd in the upfront setting for this patient population. Does this MAIA trial now mean that you will be transitioning to a dara-Rd-based regimen, certainly in the non-transplant-eligible patients?

Katja Weisel:
Absolutely, I think we switch in the majority of patients. There might remain some patients with renal impairment or at high risk where you consider to put the proteasome inhibitor in. However, with this data, I think the majority of patients will switch to the standard, absolutely.

Noopur Raje:
Thank you for that. So, Nina, I’m just going to switch gears and come to you here. You know, we’ve clearly made a lot of progress in the non-transplant-eligible patients. The MAIA data is obviously unprecedented data that we’ve seen with survivals as high, where we haven’t yet reached the medians. We in the US have been using RVd-lite in this patient population, would you have any preferences between RVd-lite versus going to dara-Rd based on what you’re seeing with MAIA?

Nina Shah:
Yeah, I think is a great question and that thank you for having me on this panel. I really actually think the MAIA data, first of all when it was initially presented, was actually practice-moving, and most recently has been practice-changing. And I think this data with the overall survival makes a lot of us feel like we’ll move in that direction for transplant-ineligible. I’ll speak for myself, but I have really moved to that as a regimen for the transplant-ineligible, because I was actually very happy to see that many of the patients were above 75. And I think that’s truly, some of those patients were probably transplant-ineligible, which has mirrored some of our practice.

Nina Shah:
And in addition, I think that I worry about neuropathy. Although weekly bortezomib does decrease that, I worry about any neuropathy in these patients who are older with comorbidities and also may be having decreased performance status. So, I like to avoid that as much as possible, and certainly subcutaneous daratumumab has made this easier and then when the schedule gets monthly, it’s easier. So, that’s also a quality of life issue. So, I’m excited to see this data. I do like to see things that change practice in myeloma, because we always want to do better for our patients.

Noopur Raje:
So, talking about changing practice, we’re going to move now to the transplant-eligible patient population. And I’m not sure that this is necessarily going to change practice, but it’s certainly a lot of the, you know, we are going to be talking about this. We saw in the transplant-eligible patient population updated data from FORTE. And what the data there showed was the trial in itself was KCd versus KRd, continuous versus KRd with a transplant. And the interesting thing to me in this transplant-eligible patient population was a high proportion of these patients were high-risk, albeit they had been defined in a slightly different way, it’s not the conventional way which you and I are used to defining high-risk disease, and what was interesting to me also was the second randomization, wherein they randomized patients to what we refer to as standard of care, which is lenalidomide maintenance, versus the combination of lenalidomide and carfilzomib maintenance in that second randomization.

Noopur Raje:
So, Yi, do you want to speak a little bit about some of the advances we’ve made and what you think about using a triplet such as KRd specifically in the high-risk patient population which is transplant-eligible?

Yi Lin:
Absolutely. So, I think, you know, this is still an area of unmet needs, where we’re seeing that these patients can blow through treatments very quickly. They may have initial response, but very short duration of response or a short PFS. And we’re quickly going through the backbones of myeloma therapies, if you will. And so, I do think that the data from the FORTE trial is speaking to the conventional practice, in that with these patients with these risk features, although yes, you can define, you know, mutational risk features versus let’s say certain biologic risk features, but to intensify the treatment upfront use the most effective regimen upfront, we do see differences in response rate between the arms on this study.

Yi Lin:
Now, I think we, I would like to see longer follow-up as well, to see if, what is the exact right triplet combination to truly make a difference in the long-term in terms of, you know, keeping that PFS. And I think there’s, with the emerging data towards a quadruplet that may also make us think, “Well, what’s the effective proteasome inhibitor?” Plus let’s say the IMiDs, or maybe CELMoD’s coming down, but plus an antibody therapy. I think this is where the data is pushing for high-risk, upfront in multiple myeloma patients.

Noopur Raje:
So, it’s almost like you’re reading my mind out here. Perfect segue into the Cassiopeia trial, which essentially is a four-drug combination. And what the Cassiopeia data, again, is something we saw for the first time here, this is obviously a combination of dara with VTd. So, bortezomib-thalidomide-dexamethasone with daratumumab upfront compared to VTd alone. There was a crossover allowed and you saw a longer follow-up of this dataset and it kind of speaks to a little bit of what we do in the maintenance setting as well. So Katja, I’m going to come to you, because in the US, we don’t necessarily use VTd the way it’s used in the Cassiopeia trial. But just your thoughts on what Philippe Moreau presented at this year’s ASCO and EHA, and then we can talk about how it really impacts practice as well going forward.

Katja Weisel:
Yeah, thank you. I think Cassiopeia is a very special trial, that it gives us in many aspects a lot of insight we can translate, even if we don’t use it in daily clinical practice like it was exactly in the trial. For us in Europe, dara-VTd is now the only possibility to give a quadruplet in the approved label. So, we have no other chance to applicate the quadruplet in transplant-eligible patients. And what we now saw, to my opinion was very interesting how important the anti-CD38 strategy is to add right upfront in the initial cycle and combining it with a PI-IMiD combination. Because when we saw that in the VTd arm, a significant proportion of patients didn’t make it to the second randomization in the Cassiopeia trial, randomizing them dara maintenance versus no maintenance, and saw the poorer outcome of those patients, we again see confirmed how important it is to go very broad in right from the beginning.

Katja Weisel:
The other thing I found personally very interesting was that those patients having had dara in the induction and consolidation for six cycles and did not have a maintenance, had in this follow-up a comparable outcome to those who had dara in front and in maintenance. That might separate when we have a longer follow-up, absolutely. However, and for me, it showed again, you need it right from upfront, and then you can discuss what you do later. And so, for me this was the clear confirmation towards quadruplet in front, especially for patients at risk.

Katja Weisel:
For maintenance, I think we have to say those patients received in this trial only 12 dara administrations in maintenance, so every eight weeks for two years. Looking on the FORTE study we just saw, combining maintenance len and carfilzomib, I think here for the impact of daratumumab in maintenance we have to see the data of the combination trials, of len-dara combinations. And they will come out next year, I’m sure.

Noopur Raje:
No, I think you bring about so many important points. Whether or not the Cassiopeia data can really be looked at upon as a maintenance data set is something we have to really wait on. You talked about the dose intensity, Katja, which is so important and sort of gets forgotten about, so thank you for bringing that to everybody’s attention. But just pushing you a little bit, Nina, because we’ve all joined the bandwagon of using quadruplets now, more is, you know the way things are panning out is more seems to be always better. But in your mind, has the Cassiopeia trial taught us anything specifically with what Katja referred to? You know, you are seeing four drugs, and do we need to continue them or is there room to kind of tailor therapy a little bit?

Nina Shah:
Yeah, I think there were some important points that we learned from Cassiopeia. One, that if you’re going to have nothing go on after transplant, that’s not a good idea. As people need something, so some kind of maintenance is better than nothing. And I think we knew that we tend to give maintenance. But I think that as far as what, it made me feel better because a lot of people are doing the dara-RVd. For example, induction therapy in the US, but they’re not continuing the daratumumab in the maintenance setting. Instead, they’re doing lenalidomide maintenance alone, which is standard of care. And in a way that’s good, because you’re not giving dara for 32 cycles like we did in GRIFFIN. And I felt better about that after seeing the Cassiopeia data, that the benefit of the daratumumab was fine, if you just gave it up front and didn’t necessarily give it afterwards. And I get that the control arm is not the same, you know, it’s not lenalidomide, but it’s observation. But I think this does give a little justification if we have to sort of slice trials and take parts of it, to help us in practical management, that we can give daratumumab upfront as a quad and not necessarily continue it for all 32 cycles. Which then allows us to use it later because the person would technically not be daratumumab-refractory.

Noopur Raje:
Absolutely. I think once you start using combinations like we do, in addition to the efficacy, and we’re seeing really high efficacy where we are seeing MRD-negative disease. I do think we have to pay attention to toxicity. And the Cassiopeia data certainly informs us of the possibility of us being able to attenuate treatment, at least in the subset of patients, which is again a nice way of leading into maintenance strategies for myeloma. You’ve alluded to that Nina right now, in terms of talking about len maintenance. Katja, you’ve talked about some of the new trials which are coming down the pipe, where we are comparing lenalidomide to lenalidomide and daratumumab for example, and we’ll see who are the ones who are going to benefit from the doublet.

Noopur Raje:
Having said that, I just want to go back to the FORTE trial, because the second randomization did include carfilzomib and lenalidomide, and what you found in the different risk categories is that everybody benefits. And in fact, this is something which I really have been saying for a long time, is, you know, we focus in on the high-risk patients, but it’s the standard-risk patients who actually do the best with whatever is the best option out there. So, based on some of the data, which was presented in FORTE, do you all think you will adopt the use of a dual maintenance here? Would you consider using a proteasome inhibitor and lenalidomide as your maintenance in everybody or should we be reserving it for mostly the high-risk patients, as of right now?

Yi Lin:
So, in my mind, as you already pointed out, Noopur, is that the standard-risk patient do very well with a number of treatments that we already have. And so, for this patient population, I think more about tolerability of the maintenance treatment, toxicity, as that’s already been brought up, quality of life. So, this is not necessarily the population, until I see more convincing data, let’s say from a large randomized trial with sufficient follow-up. I’m not anxious to, right now in my standard of care clinic, to add anything beyond, let’s say, lenalidomide. But the high-risk population is definitely a space where we say, “Gosh, what we’ve been doing clearly hasn’t made a difference.” We know proteasome inhibitor makes a difference, and so that is something, you know, even in my own practice that a proteasome-based maintenance is what I’m using. I am also thinking in that space, you know, is there room to add daratumumab in that setting? But for sure, you know, some type of doublet in this space. And I think, you know, this is for me, the space where I’m looking at these data very carefully and probably more readily to make a change to the practice.

Noopur Raje:
Yeah, I think most of us would agree, Yi, that we are all using lenalidomide maintenance. I think what was nicely shown at this year’s meetings was also sort of long follow-up. In this case it was on the TOURMALINE trials where they used ixazomib maintenance, and we may have a tool in the future wherein we are using minimal residual disease testing. And what that trial essentially showed was that if you were able to have sustained MRD negativity, that the outcomes of that was really better, and that it didn’t matter how you got to that point. There were patients who did not even get maintenance and were MRD-negative over a sustained period which was at one year apart, your outcomes were good. So, rather than, like you said, jumping on the bandwagon of treating everybody with two and three drugs, I do think we’re going to have tools to better identify this.

Noopur Raje:
And just speaking to some of the tools, Nina, you know, there’s a lot of data which was presented on, this time we obviously have next-gen sequencing. We have the next-gen flow, a mass spec was presented a little bit at this year’s meetings and even single-cell sort of follow-up for looking for MRD was presented using peripheral blood samples. So, in your mind, just, you know, forget the type of test here, but talk about MRD in general terms, where do you think it sits? And do you use it in practice? And if you do, well, which patients would you consider using MRD testing in?

Nina Shah:
Yeah, I think MRD is probably one of the most controversial topics that myeloma doctors talk about. Because we all love to know data, right? We all love ourselves some data. So, in my mind, MRD is another piece of data. It’s another piece of data on disease burden. And even if you told me a person was MRD-negative 10 to the minus nine, I would still think that that person has disease somewhere. I just can’t find it. And so, what that helps me to do is understand how the patient’s going to do. In almost every trial that’s been reported in MRD analyses therein, all the people that are MRD-negative at whatever measure it is do better than the ones who are MRD-positive. For that reason, I like to get the MRD test, so I kind of know where people are amongst most my practice. But I’m not ready to make clinical decisions on it, yet.

Nina Shah:
Although, getting more information in our practice, putting our data together, sharing data amongst institutions actually helps us to understand the value of it better, so that we can do clinical trials which have MRD-based decision-making and study this, and also so that we can go to the authorities and say, “Maybe sustained MRD-negativity is the way to go to power a clinical trial, to get an answer sooner than five years,” which is too long for me to wait.

Noopur Raje:
Absolutely. I think the other piece which you didn’t touch on is testing MRD on everybody, it’s the anxiety management that you have to do with all of your patients. You will have a separate clinic for that, but that’s for a different discussion altogether. I do think MRD testing is going to be a huge tool in the future. Specifically, when we have so many options, and allowing, that’s going to allow us to tailor therapy. We’re not quite there yet, as you pointed out Nina.

Noopur Raje:
So, I want to move quickly to the more exciting parts. This is all exciting, this is fantastic. It’s really changed the landscape of myeloma. We are beginning to see our first relapsed patient four and five years down the road, which is absolutely remarkable, and we found that there was exciting data in the relapse/refractory space as well. I’m going to leave the immunotherapies for a little bit later and I’m going to talk about some of the newer things which were presented, and I would love to get your insights. So, I’m going to start with you, Katja, on iberdomide. It is sort of an immune-based strategy. It’s a new, novel CELMoD, and we saw some combinations. Dr Lonial presented this at this year’s EHA. Your thoughts, your ideas? Do you know where it’s going to fit in the lenalidomide, pomalidomide paradigm?

Katja Weisel:
Yeah, this is an absolutely interesting drug and I think we have now entered there also a new generation of immunomodulation. We are more specific, and we have less toxicity. And this is what we want to have. And it seems that we can even more specifically target that what we want to target. And for me, those data and the combination data were very strong, they were very consistent. And, for us, it’s also important to have easy-to-applicate regimens, easy to use regimens with a low toxicity. So, seeing in parallel the emerging data from CC480, I personally think that those may substitute len and pom. I wouldn’t mind probably len and CC480, probably pom, if it turns out that they are more potent and potentially even better to tolerate. So, I think very important results for our future.

Noopur Raje:
Yeah, it’s early data, but it’s promise nonetheless and, you know, more options for our patients. And like you pointed out, Katja, these are drugs which are easy to combine with some of our backbone drugs. So that obviously we’re already familiar with years’ worth of experience of using these immunomodulatory drugs, so certainly a great addition.

Noopur Raje:
Well, obviously the excitement over the last several years has been everything BCMA. You know that. We all saw really great data with ide-cel, we now have ide-cel which is FDA approved. And I just heard this morning, it’s actually approved in the EU as well and you guys have a better indication than even we do in the EU, where you have three lines of treatment and your last line has refractory, you don’t even need four lines. But what was exciting and interesting at this year’s ASCO and EHA meetings was the cilta-cel data. So, cilta-cel is the other CAR T-cell drug product, which was presented by Dr Usmani. Yi, can you speak to CARTITUDE-1, the efficacy we’ve seen and what you think of the data thus far?

Yi Lin:
Absolutely, I’d be happy to do that. I think, you know, it’s interesting in multiple myeloma that we have a lot of BCMA-targeting CAR-T trials. And unlike what started with CD19 CAR-T in the lymphoma/leukemia space where the external portion of the CAR, the epitope that’s targeting CD19 was pretty much the same for a lot of the product. Here, we do have differences across the design of the CAR, and that may play into, you know, what we could be seeing both with these more mature products and what’s coming down the pike for investigation. But I’m certainly very, very excited about the cilta-cel updated results presented from CARTITUDE-1. This is again a very heavily pretreated patient population, median prior lines of therapy is six, high numbers of triple-, even penta-refractory patient, extramedullary disease.

Yi Lin:
And what we’ve seen so far, overall, just generally in the CAR-T how we think about CAR-T toxicity too, that this is in the milder spectrum of toxicity. The more severe type of cytokine release syndrome or neurotoxicity associated with cytokine release syndrome, the type where we think patient may need to go to ICU level monitoring and care, that is down in single-digit percentage. So, that’s very encouraging to see, especially as we think about this as a patient population who are older by the time they’re in that relapse/refractory setting.

Yi Lin:
And what’s really exciting to see is that this stringent CR rate with cilta-cel in CARTITUDE-1 is 80%. I mean that is really, really impressive. Including MRD-negative rate as we were touching on. But, although, I think we have a lot to learn about how to interpret MRD as well in the immunotherapy space. But what’s also really exciting is we now have slightly longer follow-up as well on the study at 18 months, and you know we’re seeing really encouraging PFS rate, 66%, overall survival rate also, you know, very high median. The PFS and OS not yet reached on the study. So, I’m very, very excited to see this product. I know the BLA’s been submitted for regulatory review.

Noopur Raje:
Absolutely, I think we saw fantastic data, we’ve seen a 22-month PFS now with the cilta-cel drug product. We’ve never seen such fantastic results in such a heavily pretreated patient population, so a lot of room for excitement. But along with that, you know, there was a cautionary tale with CARTITUDE-1 as well. And we did see some sort of delayed neurotoxicity, so not the classic ICANS that we think about or the CRS we think about, they reported, I think, somewhere between 10% and 12% of a delayed neurotoxicity. And based on that, they had another presentation on CARTITUDE-2 with some of their patient management strategies to try and address the sort of delayed neurotoxicity which was seen with CARTITUDE-1.

Noopur Raje:
So Nina, you’ve seen that data. The follow-up is pretty, not that short, you know, they have a five-and-a-half-month follow-up, it’s a smaller patient population. But do you want to speak a little bit to what was seen in CARTITUDE-1 with neurotoxicity and what the potential sort of mitigation strategies, so to speak, are for this cilta-cel drug product?

Nina Shah:
Yeah, I think that this analysis of toxicity is important. Because these are, this is going to help us decide to give what product to whom. In the CARTITUDE-1 data they had 20% of patients have some sort of neurotoxicity, of which 16 and a half percent had ICANS. But 12 and a half percent, and there was some overlap there, had this alternative neurotoxicity. This delayed, sometimes neurocognitive or peripheral neuropathy of which one patient did pass away. So, this was a small signal. But it was a signal that was there, and I think there are some subtle differences between the BCMA products. And there may, we think it’s possible there’s some BCMA-like or BCMA expression in some of the neuro tissues. Potentially basal ganglia, we don’t know.

Nina Shah:
But, what was very reassuring was that based on the CARTITUDE-2 data that was presented and Dr Usmani’s subsequent discussion about the CARTITUDE-1 data, there have been no additional scary neuro signals in the CARTITUDE-1 patients. So, nothing else new, and nothing really that is irreversible or detrimental in the rest of the CARTITUDE program, which is as you know, they’re studying this in other disease times.

Nina Shah:
So, this was actually reassuring to me, and one of the things they may be able to pull out as a potential factor in this is disease burden. So, if we know that, and it’s hard to know because when you have 12 patients having this out of 100, you really can’t tell exactly what the disease factor was. But it may be that the disease burden maybe allowed the T-cell expansion to be more potentially and have this off-target effect, we don’t know. But that does inform me. Because if we decide to take this to standard of care and we’re choosing, I might want to have a disease reduction step before I take the person to get this particular cilta-cel product, just to decrease the chance of this alternative neurotoxicity if you will.

Noopur Raje:
So, key to bridging therapy like you pointed out, Nina, also early treatment of CRS and neurotoxicity is important, so we don’t allow that to progress. I think in the early days of CAR T-cells, all of us were concerned about even giving a single dose of dexamethasone. And we’ve learnt along the way, as we do with all drug products. You know, we are still learning how best to give for example, selinexor and were doing weekly dosing. Bortezomib was approved in 1993, but we still went to weekly more recently. So, I think the beauty is we have all of these, then over the course of our practice, we start adapting and adopting different ways of giving our treatment.

Noopur Raje:
Similarly, you know, I just want to quickly touch on some of the other exciting immunomodulatory approaches, and these are bispecific T-cell engagers. We saw a lot of great data. We saw data on elranatamab, I should know how to say that. And we also saw data on teclistamab. Both of these are bispecific T-cell engagers, both of them targeting the same BCMA target that we’ve seen with CAR T-cells. So Katja, just your early impressions on bispecific T-cell engagers and a little bit on where do you think they fit in the whole treatment paradigm?

Katja Weisel:
Yeah, thank you. This is an exciting question, and I think it’s a bit mirroring what we saw with CAR-T. So, we have different constructs targeting BCMA, and we also learned that they have different, slightly different, toxicities. The elranatamab trials were shortly on hold due to an unclear neurotoxicity, which was not described for teclistamab for example, but are now moving on again. I think both constructs showed exciting data, solid data on response. Cross-trial comparisons are very, very complicated and one should not do it. But it seems that the depth of response and the overall response rate might be slightly less than with CAR-T, especially in cilta-cel where the response were deepened over time. However, for example, teclistamab is very, kind of, easy to use with its sub-Q application, so after the step-up dosing every two weeks.

Katja Weisel:
So, I think this might absolutely enrich our armamentarium. And those are again potentially drugs where you can combine or where you perhaps in the future perspective could go in, in patients turning MRD-positive like we do in acute leukemia. So, I think they will have to find their role, their place, and they are different, but they are a great gift also to move forward in myeloma.

Noopur Raje:
You’re absolutely right you know. We have something which is off-the-shelf as you pointed out with, you’re providing really deep responses. We have this wherein there is no waiting time to actually give it to patients, we don’t have the four to five weeks of a turnaround time. So, if I, if you had all of these tools in your toolkit, Yi. You were allowed to use a bispecific, you were allowed to use CAR T-cells, can you imagine a scenario where if it was your choice, what would you want to do? Would you want to sequence them, would you want to combine them? One, which one, before? This is just hypothetical, but what would you think about doing here?

Yi Lin:
I think sequencing is definitely a trickier question that we will learn more of having BCMA, ADC and CAR-T already in practice and more that will come. And that we anticipate also bispecific in the space as well. We’re seeing some emerging data, very limited early data on trials that are now allowing prior BCMA exposures of maybe a different modality of treatments. And, you know, we can see response there sometimes, but not enough of a sample size to really understand the impact. Particularly if we’re thinking about immediate sequencing, we know a little bit about BCMA expressions, amount of expression that can change at the time of progression. And we need to understand how that may impact the selection of subsequent therapy.

Yi Lin:
But at least in terms of right now where we may still have patients that are, let’s say, BCMA therapy-naïve, how I would think about the therapy selection for patients, certainly CAR-T right now is limited to centers that have to go through a certification and accreditation process in order to give it. And so, travel logistics having, requiring higher level of caretaker support may potentially be restrictive to some patients. CAR-T for the most part are given with some type of lymphodepletion chemotherapy. And with the myeloma one, a CAR-T investigation more commonly with cyclophosphamide and fludarabine. And that can have impact too in terms of recovery, cytopenias, risk for infection on top of just the CAR-T alone. So that, the patient’s performance status, comorbidities, may come into consideration in terms of that CAR-T consideration.

Yi Lin:
However, the eligibility for CAR-T isn’t necessarily the same for stem cell transplant. So, there may be some patients that I typically wouldn’t think about for transplant, granted I know we’ve typically used that a little bit earlier than the FDA approved indication for CAR-T. But just strictly thinking about patient selection criteria, that I may consider that they could tolerate the toxicities of cytokine release syndrome, neurotoxicity. I can support them through count recovery, and I would consider them for a CAR-T. And for those types of patients, are the ones where I think about, those that could benefit from the one-and-done, right?

Yi Lin:
Right now, the CAR-Ts are investigated as a one-time dosing, no maintenance therapy. Granted, I know we have the investigation where we talk about, is there value, you know, to adding that? But currently it’s one time done. And for the patients who do respond to CAR-T, the quality of life of not, now not being tied to any chemotherapy unit for any maintenance therapies is huge. It’s huge, right? Even though they know it’s an outpatient thing that they can do, but they notice, I’ve had patient that tell me once they’re done with CAR-T and are, you know, in that recovery phase, not on maintenance therapy of any kind, that it’s the best they’ve felt. They felt almost like before they even had the myeloma diagnosis. So, I think that is not a trivial factor in considering which patient might benefit from CAR-T.

Noopur Raje:
Absolutely. You know, this has been such a fantastic discussion. And I think it’s such an exciting time to be in myeloma research and to be able to have all of these things available to our patients. We can really start beginning to see the light at the end of the tunnel. You know, in the old days, you used to be worried about saying we do have a curative platform. I think now we are bolder and braver, because it’s around the corner. It’s a question of time, how long we follow. So, I want to thank all of you for joining me in this panel discussion, this was a really fantastic discussion. Thank you so much for being there, and thank you all for listening in.

Disclosures

Noopur Raje – Advisory role: BMS, Janssen, GSK, Amgen, Karyopharm, Immuneel Therapeutics, Caribou

Nina Shah – Research Funding: Celgene/BMS, Janssen, Bluebird Bio, Sutro Biopharma, TeneoBio, Poseida Therapeutics, Nektar, Precision Biosciences; Advisory role GSK, Amgen, Indapta Therapeutics, Sanofi, CareDx, Kite, Karyopharm, Oncopeptides, CSL Behring

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