Dr. Brian G.M. Durie:
Welcome to the IMWG conference series for ASH 2021. This is a very unusual ASH this year, with a hybrid virtual combination in the face of the emergence of the Omicron COVID-19, which has created quite a bit of consternation. But I'm very, very pleased that our panel have agreed to come together and talk about what important has been presented at ASH this year. So I'm very pleased to welcome Tom Martin from UCSF in San Francisco, Maria V. Mateos from the University of Salamanca in Spain, and Beth Faiman from the Cleveland Clinic in Ohio here in the US. And so I'd like to thank our sponsors this year, Amgen Oncology, Janssen Oncology, Karyopharm, Oncopeptides, and Takeda Oncology.
And so this year in this virtual live hybrid environment, there are 879 myeloma related abstracts were submitted this year. And the interesting thing which is quite different this year is that there are many important reports on the biology and diagnostics and important clinical trial follow-ups. But I would say mostly not a lot of truly new information, more additional follow-up or longer term follow-up for trials that we have seen presented in the past, or even published before.
And so one of the most amazing things this year has been the presentations from the Iceland Project, the iStopMM, Iceland Screens Treats or Prevents Multiple Myeloma. And for full disclosure, I've actually been a part of this project dating back to 2015, 2016. And this year is a very special ASH for the iStop team, led by Sigurdur Kristinsson, in that they submitted six abstracts to ASH. And so I got an email from Sigurdur saying that one of the abstracts had been accepted as an oral. And we were so excited. This was early in the morning. And so as the morning progressed, I got more and more emails saying that another abstract was accepted, and then another, and then another. And it was just incredible morning actually, as we learned that all these different abstracts had been presented for oral, and then also two for poster presentations.
So really quite an extraordinary achievement for the iStopMM team, which now consists of about 20 members, plus quite a number of postdoc fellows and students and the like. And a lot of collaborations in different departments. And so I'm just going to go through not a lot of details, but the overall results presented by Sigurdur indicate data on the screening of over 75,000 individuals over the age of 40. And so the key thing about this is that these patients were randomized into three groups. One with no further contact, a second group with periodic follow-up. And then an intensive group, where very detailed imaging, bone marrow and other testing was performed. And so the main overall goal of this project is to illustrate, or to discover, if the intensive approach provides value.
And so what is presented is that in the second two groups, particularly the third group, many more diagnosis occurred, including smoldering myeloma and even active myeloma, Waldenstrom's, CLL, and lymphoma were picked up, related to the finding of the M component from screening. And so this is the data table. I'm sorry that the numbers are a little bit small at the bottom there. But if you look at the bottom right you'll see the numbers of patients with smoldering myeloma and active myeloma. If you look under arm two and arm three, you'll see under arm two smoldering myeloma SMM 56 and 82 under arm three, and then active myeloma 12 and 16. And so this is really quite remarkable to have this number of cases.
And so there is a separate abstract being presented, which focuses on the unexpectedly high prevalence of a smoldering myeloma picked up in this screening project. So maybe I'll stop there and ask you guys to comment. Maybe Maria V, if you'd like to comment first, because obviously you have a particular interest in early disease. What is your reaction to these initial data?
Dr. María V. Mateos:
Sorry, because my mic was off. So you started, Brian, saying that this AHS 2021 was full of oral presentation based on biology and early precursor of the disease. And I think that this is extremely important, and this puts in context how the early detection, and maybe the early intervention is something critical, if we consider that myeloma has to be a portable disease. And from my point of view, I think that we are able to do the early diagnosis as soon as possible. Definitely the iStop Multiple Myeloma project is very important. As soon as we detect the AM component, and we do the diagnosis of monoclonal gammopathy, patients have to be followed. There is not any doubt.
My question is, how to proceed the between the second and the third arm in the [inaudible] presentation? Because the second group were followed according to the routine. And the third group were followed in a more intensive way. So how to conciliate the routine follow-up versus the intensive follow-up? But definitely there is not any doubt that we have to start with a follow-up. And maybe this will allow us to identify smoldering myeloma, high risk patients, maybe even at the MGUS situation. And if we wanted to cure the disease, definitely we have to plan this early intervention. And the other challenging situation from my point of view, is it prime time for doing screening to the overall population? And honestly, I don't know. And I would like to have the feedback from the other discussants.
Dr. Brian G.M. Durie,:
Right. So Tom, what's your reaction to these findings so far?
Dr. Thomas Martin:
Well, I actually really enjoyed this abstract. I think a couple things, when we talk about screening for cancer, we have a couple really good examples, IE, breast cancer and colon cancer, where screening techniques can lead to early diagnosis. And for those, surgical intervention that can be curative. So you can prevent the disease from progressing. That's the part that we have to fix with MGUS and smoldering myeloma. Right now I don't think we have the tools that we know of to cure the disease. Certainly I agree with Maria V that being able to diagnose it early is going to enhance our chances of getting some curative therapies.
I think today, in this active environment of investigation of immunotherapies, it's going to be the novel immunotherapies, in my mind, activating the T cells in the local environment that may in fact be able to cure some of these patients with early-stage disease. And that is truly the importance of screening, to prevent morbidity and mortality. So that's what we have to show, is that we can prevent the morbidity and mortality. I would say it's a good start with this abstract. Now we got to get the second half going.
Dr. Brian G.M. Durie,:
Right, right. Yes. And so Beth, initial thoughts from you?
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
Absolutely. What I find significant about this first abstract with the iStop initiative is the high prevalence of smoldering myeloma. So I run my own consult clinic for MGUS patients referred, and I'm often diagnosing AL amyloidosis referred from nephrology, et cetera. But I think that the psychological impact, until we get long term data, population screening for all might not be the right avenue to pursue right now. But early recognition of symptomatic patients might be also something to look at. One of the things I'm interested in are the monoclonal gammopathies of renal significance, neurologic significance, dermatologic significance that I see. Will this study look at those different conditions as well? I think it does down the road.
Dr. Brian G.M. Durie,:
Right, right. One point just to mention is that the occurrence of the smoldering myeloma was definitely related to the performance of bone marrow testing.
Dr. Thomas Martin:
Marrow biopsies.
Dr. Brian G.M. Durie,:
So the bone marrow testing had a big impact on whether patients were diagnosed with MGUS or smoldering. So let's continue on just so that we can finish up some of the other findings from Iceland. One, which I think is quite important, is that because of the high level of testing for COVID in Iceland they were able to look at the occurrence of COVID in the MGUS patients. And there was no increased occurrence of COVID in MGUS patients. Which is quite surprising and important, related to what we observed in patients with active myeloma. So I think that this is really quite helpful, especially from the perspective of patients who have been so worried. Does this fit with the experience of you guys in terms of MGUS patients and COVID?
Dr. María V. Mateos:
Yeah, sure. We collected in Spain all patients who required hospitalization when they presented the plasma cell disorders, and majority of the patients were active multiple myeloma. Few patients with monoclonal gammopathy required from hospitalization. This confirms what these ab study is presenting, that patients with monoclonal gammopathy are not a higher risk of becoming infected by COVID-19. But for me, it's much more important to say that the severity is not higher. So I think that MGUS is a very prevalent diseases. And as you commented, I think that this is an important information for the patients.
Dr. Brian G.M. Durie,:
Absolutely. So I think everyone agrees with that. Yes. So then the abstract was the linkage of circulating plasma cells in MGUS smoldering and active myeloma. And we've seen this before, and we'll talk about that a little bit more as we move forward here. And then just to say that, as Beth was saying, there are many, many things that are going to come out of this as this project moves forward, including what is the psychological impact of screening. But many of the other things that can be observed as these patients are observed moving forward. And so the randomized part of the study will probably be seen in 2022, where the outcomes will be better, including survival. There's already a significant trend toward improved survival, particularly for arm three. And so as you were discussing Tom, there will be a question, if there is a improved outcome, how will we adopt this idea of screening?
And then the second thing is that this is just starting to scratch the surface. One key thing for Iceland is that all of these patients have had full DNA sequencing carried out by the deCODE genetics team. And so these correlations are being run right now to look at what is the DNA sequence pattern of those developing MGUS versus the total population of Iceland. I don't know, do you guys think that if the arm three, for example, shows superior outcomes, including survival, that this will really tip the balance towards acceptance of screening? Or what do you think it's going to take?
Dr. Thomas Martin:
Well, I'll start and I'll say yes. I think it's really important to look at survival in this population, and in this study. And so if it does show improved survival, then that's the advantage of screening. That's why you would do screening, is to try to improve overall survival. And so that for me would tip it. And then we'd have to decide what is the screening mechanism, and then what is the follow-up regimen that we're going to undertake? I will also tip my hat to Maria V in the Spanish group, because they actually do very intensive flow cytometry evaluation of these cells, and can actually interrogate the cells to see which MGUS cells are the bad guys and which MGUS cells are not bad.
Dr. Brian G.M. Durie,:
Yes.
Dr. Thomas Martin:
And I think the flow that they're doing is going to be the future of this also. Maybe it's DNA, maybe it's genetic analysis, but I really am a believer of the flow that the Spanish do.
Dr. Brian G.M. Durie,:
Right. So I just clicked forward to the data that is being presented at ASH this year, which we can talk about in a moment. Yeah. So overall, Maria V, for example, in Spain do you see a movement to where screening would be feasible and would be something that would be done?
Dr. María V. Mateos:
Yeah, so I completely agree. And I think that in principle the screening should be done. And it's true that if in the iStop trial the arm three presents overall survival benefit, there is not any doubt that we have to move on that direction. But on the other side, maybe all genomic studies will help us to identify selected patients in which maybe the more intensive follow-up is required. And especially from the additional assessments, like serial bone marrow biopsy or bone marrow aspirates, as well as imaging assessments, because this is definitely to result in a more expensive caring of the patients, definitely.
And also, we are going to generate sometimes psychological impact in the patients. And in this, well, in line with this symptom [inaudible] to this algorithm that will be presented by the Spanish myeloma group in collaboration with other teams. And well, again, the next generation flow, what we can call the MGUS-like profile, utilizing three parameters, the plasma cell, bone marrow, and filtration, the normal and the abnormal plasma cells within the plasma cell bone marrow compartment by flow cytometry can help us to identify this three group of patients.
And maybe those patients with MGUS phenotyping, which the progression rate at five years is going to be zero, maybe we can avoid to do sequential bone marrow aspirate imaging assessment. So I think that we need more time in order to combine this data together with the additional studies that are being conducted in the iStop trial. And I think that we will be able to individualize the follow-up of patients with MGUS. But with a clear objective to early detect the disease that can benefit from an early intervention in order to prevent the myeloma defining events.
Dr. Brian G.M. Durie,:
Absolutely. Absolutely. Yeah. So I do think that this study from the Spanish team ... And they collaborated and looked at different datasets, as you are aware, Maria V.
Dr. María V. Mateos:
Yes.
Dr. Brian G.M. Durie,:
And in the training dataset, it was a very strong identification of the MGUS phenotype. But clearly this is the way forward to try to do a good job in identifying particularly the low risk patients using this technique.
Dr. María V. Mateos:
Yeah, correct.
Dr. Brian G.M. Durie,:
Yeah. So I think that this large number of patients obviously, and then also correlations with other groups. So I do think that this was an important observation. And then just to finish up this kind of a topic, is that we did have the presentation for the first time of the PROMISE data, looking at the black African American population. And looking at, in this case they included patients who would be considered high risk because of family history. And in that population, a very, very high prevalence of MGUS. And so really emphasizes the potential for screening in this higher risk group. Any thoughts about that, Beth? I know at your center, I know that you have a significant black or African American population. How do these results strike you?
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
Absolutely. No, these are very important results that underscore the importance of early identification of patients that might be at risk for MGUS, and identifying early intervention. And just to tack onto the next gen flow that was discussed previously. I think this is wonderful that we have data as personalized our approaches to MGUS. So not all MGUS is the same. I've been saying it for years, those three distinct groups I believe exist. And I'm excited to see in the future more data to support who gets the intensive screening versus just the standard of care screening. And then in the African American population, I have quite a few first degree relatives that I treat in my practice. And I know that this PROMISE study has very important information that's upcoming as well.
Dr. Brian G.M. Durie,:
Right. A lot more details presented actually. So Tom, your reaction to the early PROMISE study data?
Dr. Thomas Martin:
Yeah. Again, these data I think are pushing the field forward. I think what we'll do with identification of this is to look at some of the genetics. And hopefully we can do GWAS studies that we can look at genetic loci that are associated with risk. And so we might be able to figure out why there's a family association of myeloma in 1 to 3% of the cases. And why it's also so prevalent in the African American population. If we can find that genetic loci of risk, that's one thing that we can use also as screening. And hopefully what they find in Iceland is similar to what we find here. Or at least we're able to find some genes that we can look at as increasing people's risk for development of this.
Dr. Brian G.M. Durie,:
Very good. Okay. So moving forward, we were talking about intervening early and trying to have some good results, so I thought it would be good just to show briefly your update for the CESAR trial, Maria V. I don't know if you want to comment. But obviously the results continue to be quite good. What's your assessment at this point?
Dr. María V. Mateos:
Well, I think that progression for survival and overall survival curve look like very good. And the follow-up right now is almost five years. But, well, I have some important comments. If you remember, this CESAR trial included high risk smoldering myeloma, some ultra high risk smoldering. So now myeloma with any one or more of the biomarkers included in the breast center definition. And I would say that higher risk smoldering are closer and closer to multiple myeloma. And in this study, the treatment was fixed for three years, and we had the opportunity to see how some patients lose the MRD negativity once they stop treatment. This is another important observation.
And the third important one is, we have planned an early intervention in case of a biochemical relapse or biochemical progression, including early rescue intervention when the minimal residual disease turned from negative to positive. And it was confirmed twice with pomalidomide, dexamethasone, and daratumumab. And this is the reason why the progression for survival curve looks so good. But this is our final objective, to early treat a high risk smoldering myeloma. And if it would be possible, these patients, well, ideally they would not develop any myeloma defining event. So data are good, but we have to consider some conclusions in order to plan subsequent trials in this population. Unfortunately my main message is high risk smoldering are closer and closer to myeloma.
Dr. Brian G.M. Durie,:
Absolutely. Yes. And we'll see, we're going to be looking at the PFS and overall survival data for myeloma patients, which in some cases look rather similar to this. So Tom, what's your reaction to this? Obviously not the immune modulation that you were talking about, but KRD plus autologous stem cell transplant for high risk smoldering myeloma.
Dr. Thomas Martin:
Yeah, no, I congratulate you, Maria V on this. This is great data. Wonderful. And I believe exactly with Maria V, the high risk smoldering myeloma is myeloma. It's not a lower risk disease that should be treated lower, in my mind, like with lenalidomide or lenalidomide plus dexamethasone. In my mind, that's not the right way to do it. This is the right way to do it, is to treat them aggressively. However, I will say, and I think Maria V would probably vote with me on this one, that our next generation agents are even going to be better than this. So when we-
Dr. María V. Mateos:
Absolutely.
Dr. Thomas Martin:
Yeah, when we add in bispecifics or maybe even a CAR T-cell therapy as consolidation for these high risk smoldering myeloma patients it's going to even be better. So I'm looking forward to the future of this. But certainly somebody with high risk smoldering myeloma needs to be treated aggressively.
Dr. Brian G.M. Durie,:
Right.
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
I agree a hundred percent. And I think that the impressive design in the fixed duration of therapy is what I really like about this study, because we're treating them as they're active myeloma patients. But the sustained negative, it's 12 months, 67%, that's very impressive once you stop therapy. So this is great work. Thank you.
Dr. Brian G.M. Durie,:
[inaudible]. At the bottom you'll see I have a footnote there. There is an abstract percentage using IRD with a CR rate of 21.8%. And so I think that this is the balance. The early outcomes in that study are pretty good actually. But we have to accept that we now see such better outcomes related to MRD negativity. Okay. Oh, this is interesting. Again, Maria V, maybe you just comment on this. This is the first time that I've ever seen a machine learning tool used in this exact way. This can be quite useful. And so in this abstract it's presented that factors that would be linked to whether a patient achieves MRD negativity include the genetic factors, the levels of plasma cells in the bone marrow, and some very interesting immune markers. And so this also could be an interesting application. So Maria V, you want to comment again on this one?
Dr. María V. Mateos:
Yeah, no, I think that this is the future. Because, well, when we have in front of us patients with multiple myeloma we usually say that the deepest response the longest the outcome. But we needed to wait to start a therapy and to see the response, because we don't know if the patient is going to achieve MRD negative or not. And this is sometimes a bit of frustrating for the patient. So we have to develop more and more of these type of tools, utilizing machine learning and artificial intelligence.
And so in order to predict which patients will be able to reach, in this case, MRD negative. And here there are some factors that can help us to identify these patients. And for the starting point it's important for the identification of the patients. But maybe with much more patients and much more data, this will allow us may to do some therapeutic changes based on the prediction model. So I think that these tools have to be incorporated into the myeloma treatment and into the myeloma landscape, not only to predict which patients will reach MRD negative, but also which therapy maybe will be better for each specific patients.
Dr. Brian G.M. Durie,:
Absolutely. Absolutely. So this is just the beginning, I think. So that's what caught my attention. Yes. Okay. So one more thing related to response. And again, this is looking at the impact of mass spectrometry as well as NGF. The mass spectrometry technique, the binding site is now calling this the ascent protocol. And so mass spectrometry positive and negative obviously impacts PFS. The next generation flow impacts PFS. And then the interesting point is that there is a subgroup of patients who are mass spec positive, but NGF negative who seem to do well. The main group that definitely does poorly is the group that are mass spec positive and NGF positive. So this is sort of interesting, where using mass spec, we need to understand what low levels of M component mean when you pick it up with mass spec. It seems that in some cases patients with low level of spike, maybe they're at higher risk for relapse, but at least initially maybe not relapse right away. So any thoughts on these data? Maria V, maybe you can comment again.
Dr. María V. Mateos:
Yeah. From my point of view, I think that mass spectometry, and especially here the utilization of the liquid chromatography in order to purify more the sample has an extremely high negative predictive value. This means that if the liquid chromatography mass spectometry is negative, you can ensure that the next generation flow is going to be negative, with a probability higher than 90%. This is extremely important because, well, I think that the mass spectometry is not going to replace minimal residual disease in the bone marrow. This should be something complementary.
And you alluded to the discrepant cases. And I have to say that these discrepant cases are maybe false positive for next generation flow or false positive for mass spectometry. And there are a few patients in which these discrepancies had been evaluated. And of course, I think that we needed to incorporate the imaging assessment. Because this is basically based on the production from the plasma cells into the peripheral M component. But we are forgetting the extra medullary disease. So maybe if we incorporate PET CT here, the situation will be much more clear, especially for the discrepant cases.
Dr. Brian G.M. Durie,:
Right. I think that's a very, very good point. It's picking up some extra medullary disease not detected by the NGF. Yeah, yeah. Mass spec is not fully rolled out yet, and I think maybe will be in the next year or so, but we're going to have to learn what these low levels mean. Although negative is clearly important. Okay, let's move forward.
The frontline therapy, the key follow-up at ASH this year was the follow-up of the GRIFFIN trial at 24 months. This is the Dara combined with Velcade Rev/Dex versus Velcade Rev/Dex. So for the first time we're seeing with the longer follow-up, 24 months of maintenance, an improvement in the PFS with the four drug combination. So it's eight percentage points difference at this point. And so the additional information, I'll just show the next slide as well, and then we can perhaps discuss. So the additional point is that the level of MRD obtained at the 24 months was obviously significantly higher with the 10th or minus five and the 10th or minus six threshold. So a longer PFS, plus a higher percentage of MRD negativity. So Tom, what's your reaction to this? Does this mean that we are really heading towards four drug combinations frontline?
Dr. Thomas Martin:
So we actually have looked at this data at UCSF, and we decided as a group that, how could we not use this for induction therapy in every newly diagnosed patient with myeloma who are ... For us it's transplant eligible patients. So we are considering this now our current standard of care. However, it's not a guarantee that the insurance is going to approve it. But we're going to try. Based on this, a 90% PFS at three years is quite a high PFS at three years.
Dr. Brian G.M. Durie,:
Yes.
Dr. Thomas Martin:
And after 24 months of maintenance, to have two thirds of people have MRD negative by 10 to the minus fifth, but a third at 10 to the minus sixth is really ... These are amazing data. And the hypothesis is that patients here are going to have remission duration, a median in the order of eight to nine years. That means you start them on line number one of therapy, and eight to nine years later is when you're going to be thinking about what's next. In eight to-
Dr. Brian G.M. Durie,:
Oh, incredible. Incredible.
Dr. Thomas Martin:
Yeah.
Dr. Brian G.M. Durie,:
Yes. So we have a lot of time to work on our immune modulation protocols.
Dr. Thomas Martin:
Yeah, exactly.
Dr. Brian G.M. Durie,:
Yeah. So Maria V and Beth, maybe Beth, how does this strike you? How do you think that will be received in the patient community to use a four drug regimen up front?
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
I've been managing the care of myeloma for about 25 years now, and we go from Thal/Dex to Len/Dex, and now we're looking at four drug inductions, and we're personalizing care with MRD. It's just amazing, mind blowing. When I see patients with newly diagnosed myeloma, if you set the expectation, this is what the data shows, this is what we're recommending as a collaborative effort, I think patients will buy in. As Dr. Martin had alluded to, in many states there are challenges with reimbursement. So we're trying to do KRD or VRD based on their risk. But we have started with VRD, and then added on after cycle one, perhaps Adera, if they hadn't had a deeper response. And that's kind of how we've gone away with that as well. But I think this is impressive data. And the MRD rates speak for itself as a surrogate for progression-free survival. So this is very exciting.
Dr. Brian G.M. Durie,:
And so in Europe and in Spain, will it be feasible to consider a four drug regimen in Spain, Maria V?
Dr. María V. Mateos:
Not yet because the GRIFFIN is a phase two randomized study, and we have to wait to cover the results of the PERSEUS study, the phase three randomized study that will confirm the superiority of Dara plus VRD. I can't imagine that it will be affordable, assuming that bortezomib is generic and lenalidomide is going to be generic in Spain and in Europe at the beginning of 2022. So at the end of the day, the only expensive drug, between brackets, will be daratumumab. And I hope that this will be the new standard of care for this population.
Dr. Thomas Martin:
So Brian, the other randomized study that will first be presented at ASH this year is isatuximab RVD, versus-
Dr. María V. Mateos:
Correct.
Dr. Thomas Martin:
From the German group. And what they're going to show is after induction therapy, six cycles of therapy, they have an MRD negativity rate by next generation flow of 50% with Isa RVD versus 35% with RVD. And that is a phase three randomized trial. So we'll see what happens if it gets part on the NCN guidelines, and if that helps us with insurance approval for CD38 plus RVD as frontline therapy. But I think all the data's pointing us in the direction of quads.
Dr. Brian G.M. Durie,:
Absolutely. Absolutely. Yeah. So I didn't include that abstract, but thank you for bringing it up because that is ... It's equally important with the Isa. And then the other one, which I think I did include, yeah, which is matching. But this is obviously the CASSIOPEIA study with the MRD. And the results for part one and part two clearly trending in the same direction. One comment is that in one arm the every eight week Dara maintenance did not improve the MRD negativity. The only question in this particular study, as you guys know, is the additional value of the ongoing Dara. Any thoughts or comments about this study?
Dr. María V. Mateos:
Yeah. I agree with you. And it is a different study, because in addition, if I can add an additional comment, is the durability of maintenance with the Daratumumab is only two years. So definitely I think that this is going to preclude to see sustained MRD negativity over time in this population.
Dr. Thomas Martin:
And the GRIFFIN was the same, in that it was two years of Dara-
Dr. María V. Mateos:
But ...
Dr. Thomas Martin:
They were on Revlimid, and they could continue lenalidomide by investigator choice. And so all my patients on GRIFFIN are continuing on len maintenance after that two years of Dara. So I think the take away for this, especially did not improve MRD negativity, is that probably Dara works better when you have an IMiD associated with it.
Dr. María V. Mateos:
Absolutely.
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
Agree.
Dr. Brian G.M. Durie,:
Okay. So frontline therapy looking like four drug combos. Some discussion about the maintenance though. All right. So I'm going to move forward. Another important topic this year at ASH was the bispecifics. And I'm going to go through several of the abstracts. There were actually a lot of abstracts on the bispecifics. And I'm just going to show you a little bit of the data. One that I thought was quite interesting was to look at what happens after bispecific therapy. And this was a study from Mount Sinai group looking at, after bispecific therapy it was possible to use other therapies and have significant responses. And one interesting thing that caught my attention was patients transitioning directly to CAR T therapy could actually do quite well. So this was an interesting part of sequencing for me. So I'm going to go forward through a few of these, and then perhaps we can comment together about them all.
So another abstract was kind of the reverse, therapy after patients had been treated with CAR T therapy in the karMMa trial. And this is from [inaudible]. Again, it was possible to get some significant PFS two. And interestingly, that the survival was actually remarkably good in patients, even those who had had progression after this ide-cel CAR T therapy. Then looking at the newer bispecifics, I was interested in the data with the talquetamab, the anti-GPRC5D plus daratumumab. Looking at the way forward to combine a bispecific with Dara. And just a small study indicated that this was tolerable, and with some promising efficacy.
Also at ASH we saw the expanded dataset with the single agent data for 95 patients continuing to look very positive. And then another one interesting was just a new study with the Regeneron 5458 product. It's a BCMA/CD3 bispecific monoclonal antibody. A multicenter trial just starting, with really quite impressive results. The numbers of complete remissions did catch my attention with this particular product. And with acceptable safety and tolerability. So that was quite promising. And so, Tom, I know that you're very interested in the immune therapy space. What is your feeling of the status of the bispecifics at this point?
Dr. Thomas Martin:
I think we all are extremely impressed with the single agent responses based on the early data with bispecifics, towards BCMA, towards GPRC5D, towards FCRH5. And memory lane tells us that lenalidomide, bortezomib, carfilzomib, isatuximab, daratumumab, they all had single agent response rates in the 20 to 30% range. These are single agent response rates in the 55 to 85 rates. Crazy. These are going to change the way we treat myeloma, smoldering myeloma, newly diagnosed, transplant eligible, ineligible, maintenance, you name it, they're going to enter every space because they're so active. I'll leave more fun up to my colleagues, because I could talk all day about this.
Dr. Brian G.M. Durie,:
Right. So Maria V, what do you feel about the bispecifics? I didn't show the teclistamab data, which is also continuing to be strong, several other abstracts. But what's your feeling about the positioning for the bispecifics moving forward?
Dr. María V. Mateos:
Well, the role of bispecific monoclonal antibodies is exciting, especially because they are going to be off-the-shelf therapy. And as Tom mentioned, the efficacy is great, a single agent in heavily treated myeloma patients. And there is some important advantage for the bispecific monoclonal antibodies. They combine very well with the anti-CD30H monoclonal antibodies, and even amongst them. And the data you showed about the combination of talquetamab plus daratumumab are exciting, if we consider that many patients had been previously exposed, not only to anti-BCMA targeted therapy, but also to anti-CD30H monoclonal antibodies. And the overall response rate is over 70%. But this bispecific monoclonal antibodies can be combined also with the immunomodulatory drugs. So I think that this is going to be the great opportunity for the bispecific monoclonal antibodies. And we are going to discuss maybe later on about CAR T single infusion. So advantages and disadvantages. But great opportunity for the bispecific monoclonal antibodies in myeloma.
Dr. Brian G.M. Durie,:
Yes. Yes. I certainly agree. So Beth, what about the role that you see in the clinical setting? The patient acceptance of the toxicities. And obviously the scheduling. This is not the one and done like CAR T, this is ongoing therapy, either IV or subq. What do you see as the positioning for the bispecifics?
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
There is so much excitement right now from patients about the opportunity for different novel therapies. And patients are hungry to move this earlier in the treatment paradigm, especially because the care of these advanced myeloma patients already poses numerous challenges, blood transfusions, antibiotics, cytopenias. And I can see that, as with CAR T and bispecifics, the importance of the multidisciplinary team is going to continue to be critically increasing. The pharmacists, advanced practice providers, nurses, community docs. And seamlessly managing these patients from larger hospital centers to their community practices is going to be a major challenge, especially in the next few years as these drugs become approved and become used more widely available.
Dr. Brian G.M. Durie,:
Right. Yeah. I think definitely there are some challenges in that clinical setting, for sure. Certainly the patients have to come in for those first doses normally. So these are not immediately easy to structure the ongoing therapy. Okay. Now, what about other therapies? There were a lot of other therapies presented. I thought it would be worth just focusing on the updated information on iberdomide presented by [inaudible], abstract number 162. Results for 107 patients. And then he looked at the results, which is important after BCMA therapy. And obviously he was able to show here that the significant activity with iberdomide, this CelMod, is similar to obviously the pomalidomide and Revlimid IMiD drugs, but with some different properties. So how do you see positioning of the CelMods, Tom?
Dr. Thomas Martin:
Yeah, so we made an easy switch, in my mind, from thalidomide to lenalidomide, mostly because of toxicity, less neuropathy. But we've been kind of ... I won't say stuck. Lenalidomide has been a great drug. But since then we now know that the target is cereblon, and cereblon degrades Aiolos and Ikaros, two really important proteins to improve the myeloma cell survival. So we have much better agents, including this, iberdomide, and other next generation degraders, that I think it's time to bring those earlier on in therapy. I do think we have a better drug than lenalidomide. Now we have a better drug than pomalidomide. We have iberdomide. And we have other ones that are being tested in clinical trials. These drugs are all going to pair very nicely with the immune agents, either as maintenance after CAR T-cell therapy together with bispecifics. All these new drugs are going to become the new myeloma therapy in regimens. It's going to be fun in the next five to 10 years to figure out which is the best.
Dr. Brian G.M. Durie,:
That's right. Right. Lots to work on while we're watching our patients in remission with quad therapy. Right? So Maria V, what do you feel as a positioning for the CelMods?
Dr. María V. Mateos:
Yeah, so iberdomide as well as CC480 are definitely the novel CelMods that will replace lenalidomide and pomalidomide. For me, the most interesting data from this abstract, as well as others presented with CC480, majority of the patients were not only refractory to lenalidomide, but also to pomalidomide. And this means that in this case iberdomide plus dexamethasone is able to overcome the resistance to lenalidomide and pomalidomide. And I see this an excellent opportunity to rescue patients after BCMA targeted therapy.
So my feeling is definitely iberdomide is going to move into the first line of therapy, maybe replacing lenalidomide. But this needed to be demonstrated. And there are some clinical priors going on comparing iberdomide with lenalidomide. In the meantime, I think that according to our previous discussion, the BCMA targeted therapy will move to earlier lines of therapy. And maybe the second or the third line of therapy are going to be the ideal places for the BCMA. And after BCMA targeted therapy, if we are not able to cure myeloma patients, why not to utilize these novel CelMods. And indeed, you can see here how iberdomide plus dexamethasone work after BCMA targeted therapy. So again, as [inaudible] with lenalidomide and pomalidomide, they are going to combine very well with the PIs and monoclonal antibodies, and even with the immunotherapy. So great opportunity.
Dr. Brian G.M. Durie,:
Thank you. Yeah, Yeah. And Beth, thoughts about the CelMod?
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
Yeah. The CelMods are generally very well tolerated and can overcome resistance from other IMiDs. And these are not IMiDs, they are so much more sophisticated in their mechanism of action. And patients tolerate them quite well as an oral agent. And so I think that I am looking forward to future studies. I know we have ongoing trials in the post-BMCA therapy at my institution, in combination with Dara and other agents. And so I think it will move further in therapy. I like that it's easily tolerated with very few side effects compared to the CAR T and the aggressive, intensive therapies that we're also discussing.
Dr. Brian G.M. Durie,:
Very good. Very good. Yeah, fully agree. So as we finish up our discussion about this virtual and hybrid ASH, I thought we should just touch a little bit on COVID-19 and the implications for myeloma patients. There were actually were 10 abstracts about COVID at ASH this year, including the one that we discussed with MGUS and COVID from the iStopMM team. One, again from the Spanish team, I thought was important to look at the follow-up. There's a typo on the slide. It's over the past year in Abstract 2719, looking at the pattern of outcomes for 451 patients. And the key points. And again, maybe Maria V, you could comment on this first. The outcomes, particularly with hospitalization and serious outcomes were related to male versus female, older age. And I think probably the most important related to immunosuppression is the presence of active myeloma requiring ongoing therapy, particularly at the moment of new diagnosis or recent relapse. So Maria V, do you want to comment on the follow-up from the Spanish data this year?
Dr. María V. Mateos:
Yeah. So the key factors remain the same at the moment of the first analysis. And as you mentioned, maybe to have active multiple myeloma is the most relevant prognostic factor predicting mortality when a myeloma patient become infected by COVID-19 and required from hospitalization. But for me, what it has been surprising in this second analysis is, while the number of patients infected by COVID-19 required hospitalization reduced because they would control because of the recommendations and so on. But when they require from hospitalization, the mortality rate was comparable, over 30%. This means that, well, this reflects how they are not, in principle, very effective therapies for patients infected by COVID-19.
So we have to emphasize this to our patients in order to prevent the infection by COVID. Of course the vaccination, although we know that maybe prior therapies are not quite effective after vaccination, but the social distancing, the protection measurements, I think that this is something that we have to remark to our patients. Because from my point of view, this is the most effective way in order to prevent infection by COVID-19. And severity. Because if they become a severe disease by COVID-19, the mortality rate is going to be high.
Dr. Brian G.M. Durie,:
Right, right. Very, very important points. So reaction, Tom, what's you're thinking about the COVID status right now? I think that the risk factors continue to be important, and especially in view of the poor antibody responses and the need for boosters.
Dr. Thomas Martin:
Yeah, we've been following antibody responses in patients at UCSF, and our data, just like everyone else's, those patients that have been on an anti-CD38 antibody or a BCMA targeted agent tend to have poorer responses to vaccines, where sometimes they have no response after the second vaccine. With that said, the third, or the booster shot, we've actually had some development of antibodies. We do see some immunity after the booster, where we saw nothing after the first and second. So that's kind of interesting. We're now looking at T-cell responses in those patients to see if they do mount any T-cell responses, which will be interesting. But totally agree with Maria V, it's really about prevention, social distancing, wearing a mask, washing the hands, staying away from risk situation.
Dr. Brian G.M. Durie,:
Definitely.
Dr. Thomas Martin:
It's a preventative thing at the current time. And then we tell patients, "If for whatever reason you do have COVID, we want to know right away, because we want to get you monoclonal antibody-based therapy."
Dr. Brian G.M. Durie,:
Absolutely.
Dr. Thomas Martin:
Yeah. Treat it as early as possible.
Dr. Brian G.M. Durie,:
Very rapid access to treatment. Very, very important.
Dr. Thomas Martin:
Yeah.
Dr. Brian G.M. Durie,:
Yeah. Do you have any sense of, if someone is on anti-BCMA or anti-CD38, if taking a break has any impact on the antibody levels? Obviously I think we all agree that achieving the response that a myeloma patient needs so that they don't have active myeloma, that continues to be the top priority. But do you have any information about what some doctors and patients have been doing, which is to space out the therapy a little bit if patients have responded? Does that have a value or not?
Dr. Thomas Martin:
In practice, everybody does things a little bit different. So at our institution we had a couple docs that would stop daratumumab for eight weeks or 10 weeks, and then give them the booster [inaudible]-
Dr. Brian G.M. Durie,:
Right.
Dr. Thomas Martin:
... check the vaccine. And then we had another group that independently said, "Ah, that doesn't work. We're just going to continue their CD38 antibody." And in fact, when we looked, the booster worked in both scenarios. And so there wasn't enough patients to tell a statistical difference. But I honestly am skeptical that stopping for six or eight weeks makes any difference whatsoever.
Dr. Brian G.M. Durie,:
I have that same sense myself. Beth or Maria V, do you have any experience with this aspect, with the boosters and the therapy?
Dr. María V. Mateos:
So the beginning we do what Tom said, so to wait. Not eight or 10 weeks, because we consider that this is too much, but maybe a couple of weeks or three weeks. But as we were not completely confident about this, now when the patients are asking us, "I've been called for vaccination for the booster." Okay, go ahead and be vaccinated, and we will see what happen.
Dr. Brian G.M. Durie,:
Right, right.
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
I agree. There's not enough time. And look at the rituximab data. And I don't think that there's a big difference. You're still going to have the impaired antibody stimulation after the antigen stimulation. So anyhow, I just say, "Wash your hands and avoid people, wear your mask." The usual.
Dr. Brian G.M. Durie,:
Absolutely. Prevention is key. And also continuing to try to achieve that best response has got to be number one across the board. And then obviously we're all just waiting to see what will be the impact of this new Omicron variant. Fortunately, it does seem that the severity of the disease is less so far. We just have to wait and see if that will be true in the coming months. Unfortunately it seems that COVID-19 will be with us for some time, certainly moving into next year, for sure. Okay. So these are some of the main points that I've chosen to highlight from ASH this year. Are there any major takeaways that any of you three feel was something important for ASH this year that we haven't touched on? This is your moment to jump in with ... Because there are a number of other drugs that we haven't talked about, a number of other biologic studies that I haven't touched on actually.
Dr. Thomas Martin:
The one I'll add for my final one is that MSK is going to present the data on the first CAR T-cell therapy targeting GPRC5D. That's a new target for CAR T-cells. And I think it'll be very exciting to see that. In addition, a second target is going to show very strong responses in patients that have refractory multiple myeloma.
Dr. Brian G.M. Durie,:
Okay. I agree. That's very interesting. And Maria V or Beth, anything else that caught your attention this year?
Dr. María V. Mateos:
No. Just from the BCMA CAR T perspective, only updates, but with a longer follow-up with the data. And you alluded to the rescue therapy. So we are observing more and more data about the optimal sequencing of therapy. And well, I appreciate very much to have this year a lot of biological abstract based on the precursor status of the disease.
Dr. Brian G.M. Durie,:
Right. So Tom, through the IMWG, we're obviously very pleased that we're able to be moving forward with the immune therapy registry, where we will be able to start tracking the immune therapies as they become commercially available, and get a better systematic sense of best sequencing or things that are good or things that are not so good. Beth, any final thoughts from you?
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
No. Thank you so much for this opportunity. We had a great discussion about the iStop initiative. That'll provide some important insight into the significance of monitoring intensive versus non-intensive. Early treatment was discussed here. We had such a rich discussion. And as my colleagues had alluded to, there just wasn't any big groundbreaking. It was more updates, very important updates with drugs. And I'd like to see more of these data to mature. And look forward to the live or virtual component of ASH to hear more opinions from others as well.
Dr. Brian G.M. Durie,:
Right. Thank you so much, Beth. Thank you, Tom. Thank you, Maria V. I know it's moving into the evening for you now, so we appreciate very much you taking the time at the end of the day. So thank you.
Dr. Thomas Martin:
Thanks, Brian.
Dr. Brian G.M. Durie,:
We thank our sponsors once again for supporting this effort. Always good to help us to get this information out. Thanks to you all. And I hope that this is a helpful and an enjoyable program for our listeners. Thank you so much.
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
Thank you.
Dr. María V. Mateos:
Thank you very much.
Dr. Thomas Martin:
Thank you.
Dr. Brian G.M. Durie,:
Thank you.
Beth Faiman, PhD, RN, MSN, APRN-BC, AOCN®, FAAN:
Have a great day.
Dr. Thomas Martin:
Cheers.