Brian G.M. Durie, MD:

Welcome everyone to the IMWG Conference Series, a program that attempts to make sense of treatment by summarizing the outcome from three very important recent meetings which just happened over the past couple of weeks, ASCO, the IMWG summit, and EHA, the latter two occurring in Frankfurt, Germany. I'm very privileged and pleased to be joined today with two very special myeloma investigators, Dr. Maria V. Mateos from the University of Salamanca in Spain. Welcome, Maria V and-

Maria-Victoria Mateos, MD, PhD:

Hello, Brian.

Brian G.M. Durie, MD:

And Dr. Thomas Martin from UCSF in San Francisco. So welcome, Tom.

Thomas Martin, MD:

Thanks, Brian.

Brian G.M. Durie, MD:

As usual, we're very pleased that this program is sponsored. In this case, Janssen Oncology, Karyopharm, Sanofi, and Takeda. So thank you so much to our sponsors. There will be a video replay available and you can see the details there. You can search and find it on the IMF website. And we do want to hear from you. There will be a feedback survey, whatever you have as a reaction to this program, which we hope you enjoy, but please let us know. We are going to be talking about these meetings, as I mentioned, ASCO 2023, the annual meeting, which occurred in Chicago June 2nd to 6th, the IMWG summit, which occurred June 7 and 8 in Frankfurt and the EHA Hybrid Congress June 9 to 12 in Frankfurt.

I have to say one of the most notable events was an event which occurred at the IMWG summit, which has an awards ceremony. And this year, it was a really a special evening where the whole myeloma community was so thrilled to honor Maria V. Mateos as the awardee for the Kyle Award this year, a very prestigious award. And Tom Martin as the winner of the... the awardee for the Durie award. And so, congratulations, you guys, richly deserved and greatly, greatly appreciated by the myeloma community, the members of the IMWG summit this year. So very, very pleased to have you today to comment on these meetings. So I think that there was little doubt that the top abstract that everyone was talking about, both at ASCO and at EHA where this particular abstract was a plenary presentation and Maria V is obviously a co-author on this.

The abstract concerns the CAR T, the cilta-cel product which was compared with standard of care in early relapse and it was presented at ASCO during a special CAR T session. Really impressive results with 74% reduction in the risk of progression versus pomalidomide, Velcade, dex, or daratumumab, pomalidomide, and dex. So some standard regimens which are used, standard of care regimens which are used in the early relapse setting. So very, very prominent abstract. And I think that to set the stage for the discussion of this CAR T, as well as the rest of the abstracts which focused a lot on the immune therapies, it's helpful to look at the impact of these immune therapies compared to all of the other therapies which are standard of care up to now.

And on this slide here with the blue bars, you can see that the cilta-cel is actually the tallest blue bar over on the right with a very, very high response rate in the relapse refractory setting with the ide-cel, the other product, a little bit lower. And teclistamab, the bispecific monoclonal antibody coming in strongly as a third immune therapy. All of these having already been approved by the FDA. Obviously, the CAR T cells are genetically modified patient T-cell, so the T-cells are obviously harvested and then redirected to attack the myeloma. And the bispecific monoclonal antibody is a type of antibody which links both to the myeloma cell and to the immune T-cell in the immediate microenvironment to enhance the myeloma killing effect.

And so, the CAR T cell therapy in early relapse has been studied in phase-3 trials. The one that was prominently presented both at ASCO and EHA is the Cartitude-4 in patients with one to three prior lines of therapy. And you can see the overall response rates in that study and also compared to the other CAR T product in the KarMMa-3 trial. But over on the right, you can see the progression-free survival, and so, this is the length of time that the patients are staying in remission. The PFS with the cilta-cel versus the standard of care, and the median PFS has not been reached with the cilta-cel and is 11.8 months with the DVd or DPd.

And if you compare the outcomes of the Cartitude-4, so giving the CAR T cells in this early relapse setting versus Cartitude-1, which was in the relapse refractory setting, you can see the cartitude-4 is numerically better at the 18-month follow-up. And so, I'll be interested in the comments from my myeloma expert colleagues. I think, clearly excellent results giving the CAR T cells in this early disease setting. But I would comment that, I think, maybe a little disappointing that there doesn't seem to be any plateau in that curve, either on this one or on the prior one which I showed you. In other words, obviously, patients are doing well and they're doing better, but without any flattening of the curve thus far. And so, I'll turn to you guys... Perhaps, ladies first. So maybe Maria V. since you are involved with this study, what is your take on how we should interpret these results?

Maria-Victoria Mateos, MD, PhD:

Well, thank you very much, Brian. I think these data are great, both the update of the cartitude-1 with a median progression-free survival of approximately three years for triple-class refractory myeloma patients after a median of six prior lines of therapy. I think that this is maybe the longest median progression-free survival we can offer to a triple-class refractory myeloma, and there is not any doubt. And as we do usually see in myeloma when we use the therapy earlier on, the benefit is more evident. And in the Cartitude-4, for me, the most relevant situation is a phase-3 clinical study in which cilta-cel showed to be better than the standard of care for relapse in refractory myeloma patients after one to three prior lines of therapy. This means that cilta-cel is going to be the standard of care in some patients just after one prior line of therapy, if they are refractory to lenalidomide, that I think that this is the main feature for all patients treated in the Cartitude-4.

And we know that we utilize always lenalidomide as part of the first line of therapy as continued therapy. So this means that all patients are going to be len-refractory. And I would like also to do, if I can, a brief comment about the slide in which you showed the Cartitude-1 and the Cartitude-4, and in principle, it seems that there are not major differences. I would like to focus on the minimal residual disease negativity rate because it is much more higher in the Cartitude-4 72% versus Cartitude-1. We know that MRD negativity rate is an important, maybe the most powerful surrogate marker for PFS. So maybe, we need longer follow-up in order to see how this high proportion of patients in MRD negative will translate into a better, into a longer progression-free survival applicable to more patients. And this is basically my main message, but definitely optimal data for heavily pretreated myeloma patients but also for myeloma patients in early relapses.

Brian G.M. Durie, MD:

Right, right. Thank you for that. Yeah, thank you for emphasizing. Yeah, these are patients who were refractory to lenalidomide. So Tom, what is your take on this? It's obviously excellent results.

Thomas Martin, MD:

Yeah, really amazing results. And with your first slide, when you showed ide-cel and cilta-cel and teclistamab, you're showing that these new immunotherapies in the latest line in the most refractory patients having response rates over 60% with the CAR T over 90%, really amazing. So it is a natural progression for us in the myeloma spaces to take those really active therapeutics in the later line setting and move them forward. And so I agree with Maria V that it just showed that it works dramatically well, even in the earlier line patient population. I will just add two things, and that is, the way these studies are reported, it is intent to treat. So you see the overall response rate for the cilta-cel was only about 84% compared to 98% when it was done in late line. But those are the... Not everybody received the CAR T. It includes some patients that actually did not get the CAR T.

If you just look at the patients that had the CAR T, the overall response rate was just as high. But as Maria V said, the MRD negativity rate in that earlier line patient was better. And so, that's really an amazing result. We have to see over time, does the curve become flat, Like Dr. Durie was saying, meaning are some patients 10 years later not going to need any therapy? That is really the amazing result, hopefully that I will be able to see in time.

And the only other thing I'll add is, this is standard therapy, which as I think everybody knows triplets. So you get on a combination of dara, pomalidomide, dexamethasone, but you take it until progression, so you're on it for a long period of time. Whereas this CAR T-cell therapy is a one, we call it one and done-

Brian G.M. Durie, MD:

Absolutely.

Thomas Martin, MD:

... yeah, you get the therapy and there's no maintenance. And so, there's a difference in my mind in quality of life. Quality of life a year after a CAR T cell being off therapy versus the quality of life of somebody on a year of triplet therapy is a big difference. And so, the CAR T seems to win, in my mind, in terms of the overall response rate and the MRD negativity rates. And I suspect, when we get the data, it's going to also win dramatically in the quality-of-life domain.

Brian G.M. Durie, MD:

Absolutely, absolutely. And this is a topic that will pick up as we go through the other immune therapies. This one treatment approach versus... Right now, at least the bispecifics, which are an ongoing therapy is a big difference. But on the other hand, the access to the CAR T is an issue which needs to be addressed so that there can be true wider access to the CAR T programs. Okay. Just to summarize a little bit for the main oral session that occurred at ASCO on Saturday, June 3rd, this is a list of that main session with a lot of actually very important abstracts that we can't discuss all of them in detail. We will spend some time on the teclistamab plus talquetamab, the RedirecTT-1 study. We'll do that in just a moment. Of the others, clearly interesting and helpful to see new data with KRD, KRD plus elotuzumab, KPD as maintenance in high risk myeloma, which was beneficial. A new phase-1 CAR T from the Dana-Farber group.

I was specially interested to see results with the rapid CAR T, the dual-targeted CAR T that has been developed in China and has been used in the treatment of high risk myeloma frontline. And then, a couple of the newer bispecifics, the Regeneron 5458, the LINKER-MM1 study, and the MagnetisMM trials, the bispecific elranatamab. Very interesting to see those early results. And of course, continuing follow-up results with the various DREAMM trials. Particularly, there was the DREAMM-3 where the belantamab was compared with pomalidomide and dex. Excuse me. At ASCO and at all of these meetings, just for everyone to be aware, there are many additional special presentations this year. At ASCO, there were presentations on special populations related to age and disparities and renal failure. There was also a very nice session with Philippe Moreau and Dr. Garfall from UPenn talking about the bispecifics, the promise, the toxicities related to the bispecifics and really a wide range of orals and posters.

And at EHA, Maria V, you're very much involved with this and the program. It was impressive to see over 200 abstracts this year related to myeloma with many unique presentations, really impossible to summarize them, but I've made a list here just to touch on the different topics, the range of topics, CAR T and the bispecifics, a lot about real-world findings, patient preferences, an increasing focus on infections, especially related to side effects from bispecifics, as well as CAR Ts. A follow-up on the MASTER trial, which is the Dara-KRd frontline with MRD testing selinexor combinations. An interesting study, we haven't seen much in the way of studies on Zometa, but a study looking at four years versus two years, which seemed to be beneficial and tolerated outcomes for young patients. Studies on extramedullary disease, interesting research looking at arginine deprivation and Bruno Paiva presented abstract on MRD surrogacy.

And so, just to give you guys an opportunity... I mean, we can't focus on all of these. Maybe I'll go to you first, Tom, among all these different abstracts at ASCO and EHA, whether there any that you felt were specifically important that we should comment on that were striking?

Thomas Martin, MD:

Well, yeah, so... Probably, the one I like the most, and we'll talk about it a little bit more later is the teclistamab plus talquetamab is basically combining two different biospecifics targeting two different cell surface proteins. And I do think that that's the wave of the future. And also, so that everybody is thinking the same right now, these are single agent studies that we've talked about, meaning using just one drug, a living drug, the CAR T cells or the [inaudible 00:18:32] antibody. But you know, in myeloma, we always like to combine with other... Take our best and put them together to combine forces, the Army, Navy, and the Marines. And that's been our best defense is when we combine. So I do think the future is in the combinations and also hoping that we can give a really aggressive therapy for a shorter period of time, not forever, a shorter period of time, fixed duration therapy to try to get a deep remission and then give people quality of life off of therapy.

The only thing I'll mention about the frontline studies, I think we are all gravitating to a quadruplet regimen for frontline therapy and the KRD Elo did show a benefit for the four-drug versus the three-drug. I think that's really the take home point. But we're probably not going to be using Elo KRD as the frontline. Right now, it is dara RVd or there's other studies using also isatuximab in RVd and it's going to be a CD38 plus those three drugs as our frontline depending on some studies that are going to happen in the next 6 to 12 months. So I do think we do quadruplets and then, what we're going to do for maintenance and on onward is really going to depend on the research we do in the next two to five years, which is exciting.

Brian G.M. Durie, MD:

Right, right, right. So any overall thoughts, Maria V, of importance of some of these abstracts?

Maria-Victoria Mateos, MD, PhD:

Well, I think that I agree with what Tom said basically based on the combination of teclistamab and talquetamab, and I would like to focus on the fact that this combination seems to be very effective in patients with extramedullary disease. Indeed in this study, 35 patients were included with pure plasmacytomas and the efficacy is great. The data are preliminary, but I think it's important to know that a new cohort of patient is going to be included only with extramedullary disease. And from my point of view, it's relevant because we know how extramedullary disease is a challenging situation in myeloma. And if this combination would be very effective, this can be maybe the first choice for patients with extramedullary disease. And also, I would like to move towards the combinations of the bispecific monoclonal antibodies. And we have some data of teclistamab plus daratumumab not reported at ASCO and EHA, but talquetamab plus daratumumab.

And from my point of view, this combination resulted also in great results because the median progression-free survival for patient receiving this combination was almost 20 months. For me, I think the combination with the anti-CD38 monoclonal antibody, based on the immune effect that daratumumab can have, I think that will result in an optimal combination from my point of view. And for the rest of bispecific monoclonal antibodies, I think that more or less I would say that all of them targeting BCMA are quite similar in terms of efficacy, in terms of overall response rate, as well as progression-free survival. And for me, the challenging situation in which we have to discuss, but we have to work more and more in the future is the optimal sequencing because we are having already how in some of these studies evaluating the role of bispecific monoclonal antibodies targeting either BCMA or GPRC5D patients previously exposed to BCMA-targeted therapy were included.

So I think that we need to dissect more and more of the results. Because at the end of the day, we are going to have in front of us patients and we have to decide what is their first option and what is going to be the second one. And I think that we have to consider the target, but also the fitness of the T-lymphocytes.

Brian G.M. Durie, MD:

Yes, yes. A lot of really key important points, the duration of the therapy, very important, the toxicities, the quality of life in addition to the benefit, the efficacy. Absolutely.

So I think that... Tom had a couple of slides that he presented at the IMWG summit and I have to say that the immunotherapy working team, the IMWG summit, such a active group, such a productive group, and that out of that came, I think, is this really excellent timeline summary, which allows the audience to see kind of where we are. And then, perhaps, you guys can comment a little bit on the green and the brown arrows over on the right. But for everyone, obviously, up to now, we have the approval of the belantamab, the ide-cel, [inaudible 00:23:58], cilta-cel that we've just been talking about. And then, obviously, the teclistamab, the BCMA CD3 bispecific, all of those are approved and we are using those.

For the CAR T cells, there are quite a number in development and on the horizon, and there are even homegrown CAR T cells at UCSF, Tom Martin... The team there actually are developing CAR T cells for themselves. And obviously, we're used to BCMA as the target for CAR T cells, but as you can see here, using the GPRC5D as a target, which is the same as the talquetamab bispecific, it is definitely going to be interesting to see the potential impact of that as a CAR T product. And we do have a little bit of data on that. And then, for all of the bispecifics and we had results on most of those presented, it's, I would say, quite challenging to think about how this will move forward for the future with so many different products and so many potential options.

I don't know if you can maybe comment on the differential points between CAR T and the bispecifics that maybe will indicate that one is going to be a winner or might be better than some of the others. Tom, do you want to comment on that? How do you see this plethora of CAR T and bispecifics or even trispecifics playing out over time?

Thomas Martin, MD:

Yeah, that's where the fun of this is going to be over the next five to 10 years. Specifically, from CARs, I think you have already mentioned it, Brian, that right now, we don't have as much access to CAR T cell therapeutics globally worldwide that we really want. There's more patients I think that need it than we have the availability to produce the autologous CARs. So that leaves room for much more development in CARs. So in the green, on top of this slide, the first is an allogeneic CAR. Can we just take donor T cells and make a CAR T cell and then give it to patients? And that's going to... we're going to see over the next few years if that's going to be really an advance in this space. The advantages obviously is if it's made from a donor, it's on the shelf, well, you can just take it off the shelf and give it to people.

The problem right now is there are immune differences between an autologous and an allogeneic CAR, and so the body tries to fight off those allogeneic CARs. So we'll see if those can reach as good as the autologous. I'm not sure about that. The PHE885 is one that can be... It's a fast manufacturing. So right now, the cells remain in culture for a few weeks and then we have to do some studies. They're called release criteria where we check them for various bacteria, viruses, and fungus so that they're not going to give an infection when they're infused. And at the end of the day, it's four to eight weeks later that we get the cells. Well, this is a way in which we can actually manufacture the cells within 24 to 48 hours and then get them back to patients with less than three weeks. So we can get them really quick. So it's almost... It's close to off the shelf.

And then, the GPRC5D is a different target, right? Are we going to actually be better at different target? And then the CAR from China, that you mentioned earlier, was a dual-targeted for CD19 and BCMA. So we do think that we're going to have to go to dual-targeted CARs. The mechanism resistance to some of these things are that cells that grow out or they don't have the cell surface antigen anymore, and so probably going at two different antigens is going to be a better strategy. But we have room to have all of these be approved in the next whatever, one to five years to hopefully increase our armamentarium so we can get these therapeutics to patients who need it. Right now, the late-line patients is a small number of patients. As we go to earlier lines, one to three lines of therapy previously, that's a big population of myeloma patients. So we have to be able to produce a lot of CARs to get to all those people.

Brian G.M. Durie, MD:

Absolutely.

Thomas Martin, MD:

I think I'll stop there.

Brian G.M. Durie, MD:

Yeah. So thank you. Thank you, Tom. So maybe Maria V, you could comment on the range of the bispecifics. We have all of these bispecifics moving forward. Obviously, we will talk in a moment about the [inaudible 00:29:08], but what do you think about this whole range of bispecifics that we have moving forward right now?

Maria-Victoria Mateos, MD, PhD:

Yeah, so I think that, again, the [inaudible 00:29:18]. For me, well, we have to consider that teclistamab is the BCMA bispecific monoclonal antibody approved targeting BCMA. Elranatamab targets also BCMA, linvoseltamab targets as well BCMA, and the same is applicable to alnuctamab, is to that not all these bispecific monoclonal antibodies are exactly identical from the structure point of view. We need a longer follower in order to see efficacy, but with the data we have right now is to that they seem quite similar in overall response rate as well as in durability, the response and progression-free survival. And maybe, the only way we have right now in order to distinguish them is because of the root of administration, subcutaneous versus IV, as well as the schedule of administration.

Because at the beginning, majority of them were given every week, and now it's true that new schedules are emerging in order to convert the administration of the bispecific monoclonal antibodies in something much more convenient, and I would say safer than when we give this bispecific monoclonal antibodies as continuous therapy. And beyond BCMA, we have here talquetamab targeting GPRC5D, so a different antigen expression, the surface of the plasma cells and cevostamab, that it does target FcRH5, another new antigen expression, the surface of the plasma cell. The common characteristic to all bispecific monoclonal antibodies is they are of the shell drugs. So in comparison with what Tom said about CAR T, the bispecific monoclonal antibodies are going to be broadly available because they will be at the pharmacy of the different hospitals and they can be utilized right now without waiting for the manufacturing process.

Brian G.M. Durie, MD:

Right, right. The next question that I have is that there are a whole range of trials that are in place, either current or planned, to evaluate the bispecifics, in particular. Do you feel that these will really establish some new standards of care? What we're looking for is, how can the bispecifics... And you mentioned this already related to the teclistamab/talquetamab combo, Maria V, that this maybe could become a standard where we use a combination. Do you think that we have enough or the correct trials in place that will really move us toward positioning bispecific in some type of standard of care or what do you think? I mean, these trials will certainly have the chance to lead to approval of one or more of those in the different disease settings.

Maria-Victoria Mateos, MD, PhD:

Yeah. What do we see here in this slide, there are many different phase-3 clinical studies with the bispecific monoclonal antibodies and basically in combination with anti-CD38 monoclonal antibodies and also in combination with immunomodulatory drugs. And honestly, we have to wait in order to see the outcomes because this clinical development plan was planned maybe some years ago, and now we are having more information about the efficacy as well as the safety profile for the bispecific monoclonal antibodies.

So this is a personal opinion maybe, but honestly I don't see the bispecific monoclonal antibodies as continuous therapy, as we did with other drugs in multiple myeloma. Why because we know that infections are... The main issue we have to face when we treat the patients with bispecific monoclonal antibodies, especially those targeting BCMA. So maybe we have not to reconsider but to evaluate what is the optimal schedule of therapy for the bispecific monoclonal antibodies. I think that they can consolidate very well the bulky regimes in order to increase the number of patients in MRD negativity rate as consolidation, as part of the maintenance. But my feeling are, my thought is maybe the bispecific monoclonal antibody should be given for fixed duration of therapy. But we'll see because the trials are ongoing.

Brian G.M. Durie, MD:

Yeah. Do we have trials that are really sufficiently addressing that fixed duration of therapy aspect, which would look at both efficacy and tolerability and quality of life for the patient? Do we have sufficient trials in place to really address that?

Maria-Victoria Mateos, MD, PhD:

Yes, yes. Sure. And indeed at the beginning, all trials were planned for giving the bispecific monoclonal antibodies, anti-progression disease. But as soon as the clinical trials move earlier on, I think that majority of the trials are potentially planning fixed duration of therapy. And we'll see how the results will be coming up.

Brian G.M. Durie, MD:

Right, right. So any particular comments about the trial menu, Tom? Obviously, a lot here, very challenging, frankly.

Thomas Martin, MD:

And this is not an exhaustive list either.

Brian G.M. Durie, MD:

Right.

Thomas Martin, MD:

And I think the take home note is that there's so much interest and there's so much excitement with these, and there's many companies developing a BCMA therapeutic, like Maria V just went over, that they're launching studies in many parts of the paradigm, the treatment paradigm for myeloma. So we're going to learn data much faster. This data's going to come really fast to us, which is great. I do think fixed duration is where it's at. And the original cevostamab study which did fixed duration, and this is the FcRH5 bispecific. When people came off at the end of that therapy, the majority of people continue to be in remission for a durable period of time. And that I think has rung true with many companies that, wow, we can actually probably stop at a certain point of time and still have maintained remission-

Brian G.M. Durie, MD:

Yeah, that's a good one.

Thomas Martin, MD:

... with the possibility of restarting down the road. So I'm very excited about all this. I think we are going to incorporate these drugs into the entire myeloma treatment paradigm.

Brian G.M. Durie, MD:

Okay. Let's go forward and then just take a closer look at the TT1 study. Obviously, as we've referenced a few times, the combination of teclistamab which is bispecific directed against BCMA and talquetamab which is bispecific directed against GPRC5D. So two different targets, two different bispecifics, a lot of the optimism that this could be very effective. Important for doctors and patients to be aware, 32% of the patients in this study, extra medullary disease 33% with high risk genetics, no unexpected toxicities and really so the infection and other toxicities pretty much, as we would expect, a low level of higher toxicities.

The overall efficacy remarkably good for all patients. And obviously, this was a dose finding study, so looking at the efficacy with different doses. And as Maria V already mentioned, really quite exciting that there was a high overall response rate in patients with extramedullary disease, which is really an important challenge for relapsed, refractory [inaudible 00:37:58] resistant patients. And so, as she mentioned, and I feel the same way that these results in extra medullary disease, quite impressive. And then, also led to this idea that in some of these trials now incorporating these patients, we're also looking at whole body scanning, whole body PET/CT scanning to evaluate the quantity and the quality of the response because obviously, the M component can drop, but the M component may be low to start with or may be switching over to light chains. And so, a little bit of a focus on the role and the function of scanning to evaluate the extra medullary disease.

So we've already talked about it a little bit, but Maria V, you mentioned that this really could be sort of a pilot for a future standard of care in some setting, right?

Maria-Victoria Mateos, MD, PhD:

Yeah. In principle, I think that the efficacy is superior to that [inaudible 00:39:11] teclistamab and talquetamab as single agent. Important to remark that the safety profile is comparable to teclistamab and talquetamab as single agent, so there is no additive toxicity. And this is extremely important because we are using two bispecific monoclonal antibodies, no more infections than with teclistamab as single agent. And in addition, the efficacy in patients with extramedullary disease.

So this is the focus, this is the population in which a specific cohort is going to be expanded. And if the data will be good, I think that this combination can represent an important choice for patients with extramedullary disease. And this cohort of patient is going to be activated very soon. So I think that new information will be coming in the upcoming months.

Brian G.M. Durie, MD:

Yeah. Thank you. So Tom, additional comments from you? I think, obviously, we were just excited that this combination was manageable and pretty effective.

Thomas Martin, MD:

Maybe, even just one word, "Wow."

Brian G.M. Durie, MD:

Okay. All right, we can go with that. Yes. I think people were pretty excited to see these data, and it's sort of a plan for the future. In that very first slide that I showed where we have the efficacy of the immune therapies as single agents, one can really only imagine the potential bringing some of these together. And so, this is just the first example of probably many where we can see some remarkable synergy or additive or combination benefit.

Thomas Martin, MD:

I was able to talk with one of the investigators at EHA-

Brian G.M. Durie, MD:

Yes.

Thomas Martin, MD:

... and privately what she said is, she had a couple patients who actually were on therapy had a great response, but then had to stop because they got COVID-19. And when you get COVID, that's always a big problem with these. You have to stop the therapy and watch them. And they actually had a pretty significant bout of COVID, so they had to be off therapy for quite some time, but they survived and got better and everything okay. But meanwhile, while they're off therapy, they remained in remission, their disease remained stable. That was... For me that's... And for her, she was like, "I was quite amazed that these really high risk patients, even off therapy just continued to be in remission." So another...

Brian G.M. Durie, MD:

Yeah. So I think just over emphasizes the need for these fixed duration trials. And Dr. Saad Usmani, he's always commenting about a similar thing that he had in the teclistamab trial where a patient had to come off and stayed in remission for at least a couple of years where it does seem that there is some durability with some level of fixed duration, induction or early maintenance.

Maria-Victoria Mateos, MD, PhD:

Yeah, it's true or at least at the beginning to prolong the intervals between the administration of the bispecific monoclonal antibodies. Because until now majority were given every week, and now we have patients receiving the bispecific monoclonal antibody monthly, every other month, I think that the response is sustained. So we have to move towards more convenient schedules of administration.

Brian G.M. Durie, MD:

Right, right. We're going to be looking at these kind of innovative new strategies. And this slide put together by Tom actually, looks at where are we headed in the future? And we already touched upon, we may be looking at four drug combinations or minimum triplets. Then in the second block look, looking at the early introduction of CAR T cells or a bispecific combination that we've just been discussing. And then, looking at some of the newer agents like CELMoDs or some sort of antibody therapy, as you've mentioned, Maria V right there, instead of Revlimid. Although I do think that maybe, we can just comment on this right now. I do think Revlimid as a maintenance will be around for a while. How do you guys feel about that?

Maria-Victoria Mateos, MD, PhD:

Well, I think that maintenance with lenalidomide that continue being the standard of care. There are some phase-3 clinical trials ongoing evaluating the role of the anti-CD38 monoclonal antibodies plus lenalidomide. One of them is the AURIGA study conducted in the US, the other one is the [inaudible 00:44:11] study conducted in Europe. And we need to have the data of these trials in order to consider, from my point of view, lenalidomide plus daratumumab as the newest standard of care. But in parallel is to that there are new CELMoDs, and you referred to them, Brian, iberdomide is more potent and better tolerated than lenalidomide, and it is also ongoing being compared with lenalidomide in a phase-3 clinical study.

And in addition, we have some other new trials in which the bispecific monoclonal antibodies are being evaluated as part of the maintenance after autologous stem cell transplantation, single agents or some in combination with lenalidomide. And so, in principle, we have a plenty of options as Tom is putting here in the slide. For me, the challenging situation is, well, we need maybe many years before we can have some data about all these trials. This is good because the progression-free survival with maintenance therapy in the first line of therapy is becoming longer and longer. But the problem is to have access to all these new combinations in the clinical practice. But I think that the clinical research is exciting also in terms of maintenance.

Brian G.M. Durie, MD:

Right, right, right. And just for timing, I'm going to move ahead, Tom, just so that we have time to cover some of the IMWG summit key discussions. Obviously, just like ASCO and EHA, we can't possibly cover all the presentations that occurred at the IMWG summit covering from early disease all the way to relapse and immune therapies. But I thought it would be interesting and helpful for our audience to talk about, where are we with smoldering myeloma? There has been a lot of interest in smoldering myeloma, diagnosing smoldering myeloma and high risk smoldering myeloma, and using treatment that could produce excellent results. And so, I think it may be of interest to the audience to see what was the discussion with Maria V and Shaji Kumar as the leads in the area of smoldering myeloma.

I think that the different bullet points here are worth commenting is that... The second bullet point is probably an important one that back in 2014, we already classified patients who have an 80% risk of progression in two years as active myeloma. And so, that is kind of a target. And with the new risk stratification that we used, one developed by Shaji and Maria V and [inaudible 00:47:15] myself, actually, we developed the 2-20-20 system, the 2 g of protein, 20% plasma cells, and 20 as a free light ratio, did a pretty good job with a 72% risk of progression at the highest level. But Maria V can comment on this. I think we still feel like we need to do a little bit better job there with that.

But I think that the big picture for those listening to take away is that if there's a high level of likelihood of progression at the 80% level, I think there is an agreement that it's reasonable to treat like active myeloma. If it's between 50% and 80%, then there's an option for lesser therapy. And then, obviously, below that, we would not be so keen to offer therapy. But there was a lot of input on this, Maria V, including on the second day when you were not able to be there for all of the discussion. But when you're evaluating treatment for a patient with smoldering myeloma with high risk smoldering myeloma, how do you evaluate the benefit? Is it enough to stop progression? Obviously, the survival is so long in these patients, is sustained MRD negative the way to go? And what about quality of life? And so, maybe, you could comment on this first as to if we're trying to intervene early with high risk smoldering, with a good definition, what should be our best endpoints?

Maria-Victoria Mateos, MD, PhD:

Yeah, so Brian, you know that there are a lot of discussion. But from the patient's perspective, for me, I think it's important to recognize that when we plan an early treatment in a good selected population, so high risk smoldering myeloma, our main objective is at least to delay the progression to myeloma or to maintain these patients without any end-organ damage. And if we can manage these patients for many years or even forever without anemia, without lytic lesions, without hypercalcemia, without renal impairment throughout continuous therapy or maybe only fixed duration, I think that for me, this will be the optimal objective and how to translate this into clinical trials. So we have to try to generate consensus about the endpoints. And of course, the ideal one will be sustained MRD negativity over time as surrogate marker for cure. But if this is not the case for all patients, I think that it would be also fine to generate strategies of therapy just in order to delay the progression to multiple myeloma and to maintain, if possible, forever these patients without any end-organ damage.

Brian G.M. Durie, MD:

Right, right. So Tom, what's your thinking about high-risk smoldering, smoldering myeloma with a high risk of progression? Are you comfortable treating those patients like myeloma? Or how do you view this patient population?

Thomas Martin, MD:

Yeah, this is, I think, one of the trickiest questions for us as myeloma doctors is when to treat, when to pull the trigger. I do like... I tell everybody, I don't like to just take the numbers at one point and say, "Okay, you looks like you're high risk, let's get going." I'm more of the evolving phenotype persons that you have to look at the movie over three to six to 12 months-

Brian G.M. Durie, MD:

See what's happening.

Thomas Martin, MD:

Correct. And see the M proteins. And if the M protein's going up or the hemoglobin's going down, we kind of know what's going to happen.

Brian G.M. Durie, MD:

Right.

Thomas Martin, MD:

And if they have high the otherwise high risk characteristics, like bad cytogenetics or bad FISH testing, I think they often need to be treated like myeloma, like active myeloma. We're just catching them with their active myeloma at a better time point at a really low burden of disease. So I treat them like active myeloma.

Brian G.M. Durie, MD:

Right, right. Okay. Yeah, I'm going to skip over that. And then, the other committee that I thought had some interesting commentary was, this year a combined committee report on mass spectrometry and MRD and Dr. David Murray from the Mayo Clinic provided an update on mass spectrometry where they have huge experience. As it says here: Mayo update: Over 200,000 tests by mass spec performed at the Mayo Clinic. So they do have quite a bit of experience with mass spectrometry. And then, he reviewed the literature and he discussed the fact that the mass spec technique will be commercialized, rolling out this year and then into next year. For our patient listeners, this is a very simple technology, which is a very, very sensitive way to measure the myeloma protein.

And so, the importance of this and the reason to bring this up is that mass spectrometry looks like it's going to be the way that the labs will be measuring your myeloma protein levels. And so, you will need to become aware of what does a mass spec test result mean? And this is going to be an educational process for doctors, for labs, and patients. And so, the importance is that it's an automated technique and it really increases the workflow in the lab and it's also very cost-efficient. Now, the expense is the equipment, which is a big issue, but once you have the test set up, processing the tests is very cost-efficient. And also mass spec can be used to detect and monitor other kinds of diseases as well, particularly the glycosylation, which is a type of light chain, which is predisposed to creating amyloid.

But another issue that was discussed a lot is that there are two methods for mass spec. There is a routine method and then there's a high resolution method for mass spec at Mayo Clinic. They call that Mass Fix. There's going to have to be some thought and processing about how this will actually move forward. The lower sensitivity is the standard method. The high resolution could be done for patients where there's a question about lower level disease perhaps. At the Mayo Clinic, they have looked at the cross correlation between mass spec, the low sensitivity, the high sensitivity, and also next generation flow.

And Maria V, this is the sort of thing that Noemi Puig has also done in Salamanca, and so, you have some experience with this. I think that the bottom line summary is that these two testing systems where you would be doing mass spectrometry to measure low levels of myeloma protein in the blood and next generation flow measuring myeloma cells in the bone marrow or the blood. These are complimentary techniques and it's going to take some time to sort out how we best use those. So a lot of work to be done in this area, actually. So perhaps, we could just stop for a moment and talk about the mass spectrometry piece. Tom, how do you envisage the role of mass spectrometry moving forward now?

Thomas Martin, MD:

I do agree that as a community, we will switch over to using mass spec. When do we get a test that's better and cost less, that's amazing just in that regard. But it also will be able to... Typically, when we get normalization of all the proteins in the blood, that's when we consider doing a bone marrow biopsy to look at MRD negativity. But if we can detect a protein with this method at even a lower amount, we would be less likely to do the bone marrow at that point in time. It would save us from doing a bone marrow biopsy at that time, which I think is great. And so, when you get to that really low point by mass spec or mass spec negative, that's when we would have to do the bone marrow in my mind, and they would be complimentary test to prove that somebody's MRD negative. I think this is a win-win for us. But I'm curious what Maria V says because nobody that's done more than this, than Maria V in the Spanish group.

Brian G.M. Durie, MD:

Right, right.

Maria-Victoria Mateos, MD, PhD:

I completely agree. And I think that mass spectrometry today does complement next generation flow. For me, the most important information today, and it is possible to see in this slide, is the negative predictive value. If you see when mass spectrometry is negative, in majority of the cases, next generation flow is going to be negative. So this can save many bone marrow... And in addition, in order to monitor the minimal residual disease in peripheral blood in order to detect the early reappearance of the M component, I think that this is going to be the ideal technique.

Brian G.M. Durie, MD:

Right, right. Absolutely. But in evolution, I think we're still learning and we'll be rolling out over the next one or two years and probably beyond that. And then, just an interesting point presented by Dr. Bruno Paiva from Pamplona, he presented this at EHA, looking at the cross correlation between MRD negative and PFS, and he did an aggregate analysis of the datasets that actually have been submitted to the FDA. And so, this was a very helpful aggregated analysis indicating that if you look overall at the randomized clinical trials, there is a pretty good correlation with NGF and NGS, despite a lot of different variables in the system. And one thing that came out of this analysis is that if there is an MRD difference of at least 10%, this has a clinical significance. In other words, patients with 10% more MRD negative can have an outcome which is improved by at least 12 to 18 months.

And so, Bruno Paiva presented something that you guys were talking about where we could, maybe, combine bone marrow and blood testing where we could use mass spec. And then, Bruno actually has a new method that he's developed for high sensitivity next generation flow in the blood. And so, we are going to be seeing evolving different combinations of blood and bone marrow testing moving forward. But the recurring question, and maybe we could end with this one as we come to the end of our time here, is people are constantly focused on, "Okay, MRD is great. We should be doing it in clinical practice. Why are we not doing it more and what do we need to have effective MRD testing in clinical practice?" And Bruno is certainly leading the way along with Alberto Orfao, saying that we need to look at different patients, we need to look at the time points, the frequency, the sampling methods, all different things to try to have a reliable outcome in clinical practice. So Maria V, first, what about MRD in clinical practice?

Maria-Victoria Mateos, MD, PhD:

Yeah, the guidelines are absolutely necessary. And honestly, I don't know if the guidelines will be enough because... But at least the guidelines are going to be critical and very useful in order to select the patients, the time points, the frequency sampling, concerning the methodology. Well, we will see because different approaches are possible and the reporting and interpretation. So I think that these guidelines are maybe necessary for majority of the physicians. Because we see some patients coming to our clinic with MRD negative, but the sensitivity level is 10 to the minus 2, so this means that-

Brian G.M. Durie, MD:

So you can't [inaudible 01:01:14], right?

Maria-Victoria Mateos, MD, PhD:

... this MRD is not valid. And I think that this should be clearly stating these guidelines because when we say this patient is in MRD negative, we have to understand all of us the same message.

Brian G.M. Durie, MD:

Right, right. Just because of time, Tom, I think we need to move forward. But I think it's pretty urgent that we have the guidelines that would allow us to use this in clinical practice. But I want to have time to just... Well, the final takeaways, obviously, just to summarize quickly, there were many new projects coming out of the summit. And obviously, Tom, coming out of the immunotherapy group, the Registry, tremendous excitement about that as well as the virtual Biobank, a lot of publications are pending and planned, some new areas of focus including infections triggered by the infections that have been occurring with teclistamab, quality of life, and patient perspectives. Very, very important in trying to sort through all of these new therapies and looking at follow-up at our ASH breakfast meeting for sure.

But I wanted to have time just to show this final picture. And at the IMWG Summit Awards evening, there is a musical group that performs. And at the evening this year, they named themselves the plasma cells. This is coming from Philippe Moreau who is playing at the keyboard at the back on the right there along with Vincent Rajkumar and the ladies who are the singing group. And I would say Maria V, that their favorite piece is their music for the Dancing Queen. And so, [inaudible 01:03:18] for everyone to be aware that Maria V is the dancing queen for the IMWG Plasma Cell band. And you see that they also have a lot of paperwork there where they have little stories that they tell along with the music about the winners of the award or the awardees rather, including for Tom and a number of the past winners that they did this year. And so, this group is really established now and really a lot of fun for the evening.

Maria-Victoria Mateos, MD, PhD:

We have to take care in order to see if they abandon the myeloma and they convert into an official band.

Brian G.M. Durie, MD:

That's right. That's right. We need to watch out. We don't want to lose them. Yes, that would be the worst for us, although they could be a big success. I don't know about the broad success, but the technique is good.

Thomas Martin, MD:

You need to get them to do a virtual performance, Brian. A virtual performance would be amazing.

Brian G.M. Durie, MD:

Yes, actually it could be very, very good. So I want to close by thanking both of you at a very, very, very busy time for commenting on the output from ASCO, EHA, and also from the summit. I'm sure it has been very, very helpful for the audience to hear your thinking potentially for now and well into the future with the exciting new therapies and approaches which are emerging. So thanks to you both. Enjoy the rest of your day everyone, and we are very interested in your feedback. And this survey right there. And once again, thank you to our sponsors, Janssen, Karyopharm, Sanofi, and Takeda. And with that, I will close and really appreciate it. And thanks to everyone for joining us today.