IMF Patient and Family Webinar 

Dr. Brian Durie:
Welcome everyone. We are very pleased that you can participate in this IMF Patient and family webinar today. The webinar will cover understanding the new myeloma landscape and certainly there are so many new advances to discuss that there truly is a new myeloma landscape and we need to all orient ourselves to options that are now available, how this changes the perspective for both the doctors and for the patients. And I'm very, very pleased to welcome guests who will be able to guide us through this new myeloma landscape, starting with Dr. Vincent Rajkumar from the Mayo Clinic in Rochester, Minnesota. So welcome Vincent.

Dr. Vincent Rajkumar:
Thanks, Brian.

Dr. Brian Durie:
Beth Faiman, an esteem member of the IMF Nurse Leadership Board for many years from the Cleveland Clinic in Cleveland, Ohio. So welcome Beth.

Beth Faiman:
Thank you.

Dr. Brian Durie:
And very pleased to welcome Alfred Garfall from the University of Pennsylvania in Philadelphia where a lot of new immune therapies have originated and very, very active in that space. So very, very pleased to have you with us today, Alfred.

Dr. Alfred Garfall:
Thank you Brian.

Dr. Brian Durie:
We are appreciative of our sponsors. So I'd like to thank Amgen, Bristol Myers Squibb, the Binding Site, Genentech, GSK, Janssen, Karyopharm, Sanofi and Takeda Oncology. They are strong supporters and really support this educational effort for patients. You as the audience and participants can ask questions via the chat box. And so if you open the Q and A window, this will allow you to ask questions and we will be monitoring the chat box closely and scrolling through that and we'll do our best to answer as many questions as we can. If not as it says on this slide, you can follow up at the 800 number or via the infoline and at the end we will do a feedback survey and you can click to do that, we will very much appreciate that. And then just to survey the webinar for today, when I finish, I will be inviting Vincent to discuss early disease.

I will follow on with some detailed discussion about frontline therapy. We will then have a Q and A session and a break. There's a little bit of flexibility on time there. We will then have the second part of our session with supportive care led by Beth Faiman and relapse therapy and the very extensive role of the new immune therapies by Dr. Garfall, followed by Q and A and closing remarks. So welcome to you all. I hope this is going to be a productive webinar for you. So just to summarize, the early disease, frontline therapy, supportive care and relapse and immune therapies. And so without further ado, I would like to welcome Dr. Vincent Rajkumar from the Mayo Clinic to discuss early disease. So welcome Vincent. Thank you for taking the time to participate today.

Dr. Vincent Rajkumar:
Thanks so much Brian for having me, and hi everyone. I'm very happy to share some information on how to treat early myeloma as well as newly diagnosed disease, the main options, and then Dr. Durie will get into more details about frontline therapy.

Before I get started, I just want to make sure that everybody recognizes that we have updated the diagnostic criteria for myeloma. Previously patients needed to have end organ damage like hypercalcemia, renal failure, anemia or lytic bone lesions to be even considered as having myeloma and started on therapy. But now we have revised it, so not everyone needs to wait. If patients have 60% or more plasma cells in the bone marrow, that's enough before crab features, those patients can be called myeloma and treated. Similarly, a very, very high free light chain ratio over a hundred or more than one focal lesion, one MRI all qualify as having myeloma. And this was done so that patients don't need to wait to have the end organ damage, but we can prevent that end organ damage by starting treatments early. Clearly, anytime you change the diagnostic criteria for myeloma, it automatically affects the diagnostic criteria for smoldering multiple myeloma. So smoldering myeloma is not just more than 10%, it is 10 to 60%, anything 60 or over becomes myeloma.

Now the second thing that people should keep in mind is what we call myeloma is not really one disease. It is many diseases that we collectively call as myeloma. So within myeloma, about 65, 70% of myeloma patients have what is called standard risk myeloma with either trisomies 11;14 or 6;14 translocation. And those patients have a much better outcome than patients with high risk disease, which is characterized by 4;14 translocation 14;16, 14;20, deletion 17p or 1q gain. What we are trying to do now is to adjust the treatment of newly diagnosed disease so that all patients have similar outcome and patients even with high risk multiple myeloma, can have the same benefits that patients with standard risk disease do. Now when you have two high risk abnormalities that becomes double-hit and three or more is triple-hit. And there again, we will be probably adjusting therapy to make it so that patients can overcome these abnormalities.

Let's start with the initial therapy of newly diagnosed disease. There are two main regimens that we use. One is called VRd and the other is called DRd or daratumumab Len/Dex. The VRd regimen was actually pioneered by Dr. Durie. He led this large randomized trial which looked at VRd versus Rd. And keep in mind with the VRd regimen, we are using the three drug combination only for about six months and after that everyone gets just lenalidomide or Len/Dex. In the study, Dr. Durie found that the time to progression, that is when you start the treatment now, when will the disease progress to the point where you need another treatment change is about four years with VRd and it's longer than with Rd.

Similarly, overall survival is also longer. Dr. Durie has updated these results now with longer follow up and you can see the median survival of patients starting on VRd therapy, both transplant eligible and ineligible with more than 84 months, really outstanding. When you look at more than 65 years of age, the median survival is still quite long, more than 60, 65 months. So very good regimen with a five year survival rate of 69%.

The other regimen that gives very good results in patients for frontline disease is the Daratumumab Len/Dex combination that was studied in patients over the age of 65. Also reported that study has been updated and it shows just like the Vrd, Rd, improvement in both progression-free and overall survival with progression-free survival with DRd regimen more than 65 months. So if you start on DRd today, it'll take five years on average to need the next regimen, which is extremely good with the five year survival rate of 66%. So DRd and Vrd are the backbones right now, one of the two, either one is great, the advantage of VRd is six months triplet, then doublet, whereas with DRd you're talking about continuous triplet therapy.

With all these regimens, we are constantly trying to see if we can improve on them and we have done an ECOG trial looking at KRd or Carfilzomib Len/Dex. We did not find any improvement in either progression-free survival or overall survival. So this is a specialized regimen that some occasional patients may need, but most of the time we can do with VRd or DRd. The field is moving to where we are trying to see whether some patients, particularly the high risk patients I mentioned, could benefit from a four drug regimen that is adding daratumumab to VRd so we have a quadruplet and there we have early results which show that the progression-free survival rate at three years is higher with the four drug regimen. The MRD negative rate that is minimal residue disease negativity occurs in 44% with a quadruplet whereas only 13% with a VRd regimen, and survival is outstanding.

So this is going to be a regimen we will hear more about whether everyone needs quads or not is not clear, but at least young transplant eligible patients who have high risk disease, we are starting to use this regimen.

Now the role of transplantation has been studied recently and has been in the news. I will tell you that the trials that you hear about, the IFM trial and the determination trial are not really evaluating the role of transplant. They're really checking whether we should do the transplant early or late. So it's more a timing question. And in the IFM trial they did the VRd first transplant Len maintenance. The other arm got VRd and maintenance and the transplant was only at relapse. About 75% got the transplant at relapse. What they find is that if you do the transplant early, the progression-free survival is longer.

However, when if you're talking about overall survival at eight years, both were identical. In the determination trial, similarly same design. And they are also reporting that the progression free survival is longer with the early transplant compared to delayed, but the five year survival is identical.

So what is the take home message? Transplant is important, but the timing may be flexible. For many reasons we still prefer early transplant for most patients, particularly high risk patients, patients who are over the age of 65, we really prefer early transplant for many other reasons besides survival. But if patients are really keen on delaying the transplant due to their own life circumstances, if insurance will allow it, we can collect and store and do the transplant later, particularly standard risk disease. All patients even after transplant need maintenance therapy. Studies show that lenalidomide maintenance prolongs overall survival as you can see on the slide.

And this is what we recommend for all patients, whether they finish a transplant or just VRd or DRd initial therapy. So this is my algorithm summary. Standard risk patients can get VRd for core cycles followed by either an early or delayed transplant and Len maintenance after the early therapy. In high risk patients, we prefer early transplant. We prefer a quadruplet if possible. And then for maintenance we do a doublet maintenance with both Bortezomib and Lenalidomide. In transplant ineligible patients, you can use VRd or Drd for the initial therapy followed by maintenance. In high risk patients, you need the doublet maintenance with both Bortezomib and Lenalidomide.

Even prior to the newly diagnosed myeloma stage is the smoldering myeloma stage. And in the smoldering myeloma stage, usually we have just watched patients without any treatment. But now we know that smoldering myeloma is not even one condition. It's a mixture of patients with, some of them have MGUS, some of them have myeloma, and if patients have a high chance of having full blown myeloma except they don't have end organ damage, an easy way of diagnosing them is to use the risk stratification model, which is shown on this slide. This is called the 2-20-20 or the 20-2-20 system where M Spike is more than two bone marrow plasma cells, more than 20 free light chain, ratio, more than 20.

If any two of these are abnormal, that's high risk and those patients have a 50-50 chance of getting end organ damage within two years. That's the group we are really focusing on. Early therapy, the International Myeloma Working Group has confirmed this. So if you take a hundred patients with smoldering myeloma, about one third will have high risk smoldering myeloma. And that one third, the risk of progression is not 10% per year but rather 25% per year. So it's like 50% at two years and that's where we are thinking of early therapy. That's where the trials have shown whether you use Len or Len/Dex, the Spanish trial and the ECOG trial show a 90% reduction in the risk of end organ damage.

So as a result, this is how we approach patients if they have end organ damage or myeloma defining events, as you can see on the left hand side, treat as myeloma, that's basically myeloma. If patients don't have myeloma defining events and they're considered as smoldering, then you risk stratify based on the 20-2-20 system. And if they have high risk smoldering myeloma, consider clinical trials or early therapy with Len or Len/Dex. If you do early therapy, it's a finite duration, two years and stop, not indefinite. Intermediate and low risk patients can be watched every three to four months.

Improving on the 20-2-20 system is the scoring that I've shown here. The IMWG found that if you know the exact values, which we always know, you can actually do a very good scoring system to find out risk of progression even better than the 20-2-20, and this is something we do in practice. It also includes the high risk cytogenetics that we can consider. So this is something we are now encouraging physicians to take into account for deciding on who to give early intervention, who to give early clinical trials and who we can watch.

There is a trial going on in the US, ECOG trial. This is about halfway accrued where the question is if we are talking about early therapy for smoldering, should it be just Len/Dex or should it be myeloma like treatment with Daryl Len/Dex? And this trial will answer that question. And so I'm encouraging patients to go on this trial as well as physicians to consider this for their practice, it's open all over the US. So I'll close with that and Dr. Durie will now get into more details about frontline therapy, which I just gave you an overview of and thank you so much for your attention.

Dr. Brian Durie:
Well thank you so much Vincent for that excellent introduction. Really summarizing the testing and the classification and the standard approach to frontline therapy. I think that in keeping with the title of the webinar today, what I'd like to do is just to introduce the ideas of how will the landscape be changing as we look at the impact of new therapies as they're introduced. What you've just seen is the current standard of care. We have VRd for transplant eligible, we have Daratumumab Rd as a real standard of care for non-transplant eligible patients. But moving forward, how is the landscape going to be changing? And for many patients, how feasible will that new landscape be in terms of access and costs actually?

So you give me the next slide please. For some reason it's not working. Okay, next slide. Sorry about that.

So the main focus of the myeloma treatment paradigm right now is, as I say here, you really have one chance to try to do your best job in understanding how myeloma treatment works.

We know that if you work to achieve your best response as your first response, this really has an impact overall. So for example, in the SWOG 777 trial, which Vincent mentioned, the VRd is given for six months to have that best effort, to have a strong initial response. And the same is true for non-transplant eligible patients. We have shifted from doublets to triplets to try to have that best response. But we have seen, as I'll show you in just a moment, several efforts to try to optimize that induction, see whether maybe intensification is required or is helpful, and how do we maybe fine tune the maintenance.

Next slide.

And so for transplant eligible patients in the US, VRd is the standard of care, Velcade, Revlimid, Len/Dex. However, outside of the US and you'll see a lot of trials with this, Velcade, Thalidomide, Len/Dex is still a strong standard in Europe throughout Asia and Latin America actually.

And they also use Velcade, Cytoxan, Len/Dex as a backup triplet and those are perhaps not quite as good, although we don't have full randomized trial data to compare them. But the big question which we've been focused on these last couple of years, and this will be updated at our ASH meeting which is coming up in December is, what is the impact of a adding Daratumumab or Isatuximab? These are anti CD 38 monoclonal antibodies to these triplets.

Next slide. And so as you just heard from Vincent, adding in autologous stem cell transplant, it does improve the depth of the response, the MRD and it also does improve the progression free survival with VRd. And this is the French study IFM 2009.

Next slide.

However, as he also emphasized, if you look, and this has being updated and updated and is in line with the recent determination trial, the overall survival ultimately is overlapping.

When you look at these curves, the numbers are just the same. And so we do look at transplant as an option versus deferring it. Now what I've put on this slide here is why would we want to continue to look at it up front? Well, as I just showed you, you get deeper MRD and we know that this ultimately does tend to lead to better outcomes. And when you have a chance to do your best, typically it's better to take that chance early versus later.

The other thing which I think is important from a patient perspective is that, that longer first remission is important. You're staying in remission for longer and it's a longer period of time and so you need to be thinking about a next option. It's also cost effective and is also quite good with regards to quality of life where you are in that remission, you're staying in that remission. And so there are a lot of things that if the patient is comfortable to do an autologous stem cell transplant and the doctor feels that it's appropriate for a standard risk or higher risk, then definitely talk about.

Next slide.

Okay, so this is kind of the standard of care, but what we're looking at and focused on right now is how can we improve on this? And there are ways to improve it by changing out the proteasome inhibitor. So what that means is instead of giving Velcade, you could give Carfilzomib or kyprolis as you just heard. Unfortunately, that really didn't seem to make a difference. The key thing seems to be bullet number two out of fourth drug or possibly think of a tandem transplant or improve upon the maintenance approach. Next slide. So I think it's helpful to look at, and these are going to be updated at ASH coming up in just a few weeks. We have four major trials that tell us a lot about how you can improve on VRd with or without a transplant.

The CASSIOPEIA trial, a European based trial led by the French, again looks at Velcade, thalidomide decks along with Daratumumab and autologous stem cell transplant. And as you heard, the Griffin trial, which looks at RVd plus Daratumumab, the 4K trial where the Velcade is replaced with carfilzomib and then a German study in which Isatuximab is used instead of Daratumumab.

Next slide.

And so this is just to give you an idea of what exactly are we achieving with the addition of the Daratumumab in that frontline setting. You can see that initially the curves are really overlapping in terms of the length of their remission, the PFS. Although as you can see, once you get beyond that two to three year timeframe, there is a clear benefit with the addition of Daratumumab with the VRd on the left and the VTd on the right. And so definitely following this notion that it is better to get that best first response, it is clearly something to consider.

Next slide.

So the way that many people are looking at this is to look at if achieving minimal residual disease is the ideal approach. How about the level of minimal residual disease that is produced by these different regimens? And you can see in the red box here, at the bottom here, around 30% with IFM. And then you can see higher levels of MRD and you can see 78% with the Griffin trial. And based on our current understanding, this should reflect that there will ultimately be a better outcome.

Next slide.

Now another trial which has created a lot of interest is the trial called the MASTER trial, which is using Daratumumab KRd. And the intent here is to have a period of treatment free observation once you achieve the MRD negative condition. And so this is another very important concept. If you're trying to achieve MRD negative, to try to conserve the amount of treatment and to achieve your goal, the idea would be to achieve that goal and then to monitor for treatment free observation.

Next slide.

And so if you look from the perspective of the patient and also from the perspective of costs, achieving that best response and then having a period of time off therapy is very attractive, I believe. And so this is also something that we see and I'm sure we'll talk about it later. One advantage of CAR T-cell therapy is that it's a decisive therapy and then the patient is followed off of therapy. And so there is this advantage of having your decisive approach and then being treatment free and able to have a higher quality of life.

Next slide.

Now there are two trials which we've called Cure Trials, and these are linked to the IMFs Black Swan Research Initiative. And both of these trials will be updated and presented at our ASH meeting just in two or three weeks. The CESAR trial is kyprolis, Revlimid and Dar plus autologous stem cell transplant.

And this has produced a little bit more than 70% minimal residual disease negativity. And then the ASCENT trial, which is Daratumumab, KRd, Dr. Shaji Kumar, Vincent's colleague at the Mayo Clinic will be the lead author presenting this at ASH, and this is produced and we will get the results at Ash, but over a 10% higher level of MRD negativity, which is now being tracked obviously at one year, three years, five years and beyond. And so the critical thing is yes, these are achieving high levels of deep responses, but will these be sustained? Because if they are, this is very attractive. For both of these studies here, the treatment is basically two years and then the patients are followed off therapy. So the idea is to have decisive therapy and then see what can be achieved with that.

Next slide.

Now for non-transplant patients, clearly you need to look closely and for patients who are older who have reduced performance status, some other illnesses and maybe have some infection or diabetes or other things that are going on, you need to look at other options.

Next slide.

And so here, obviously you still want to try to get your best response, but you're also focused on controlling symptoms and maintaining good outcomes overall.

Next slide.

Now, one way to do this, and this is something very important to emphasize, is for an older or a frail patient, and this is something studied carefully by an Antonio Palumbo and the Italian group, is that it's very important to doze adjust at the start of therapy so that you can achieve good responses with perhaps even a triple combination, but with less toxicity when you pay attention to reducing the dose of steroids, Mephalan, if that happens to be in a regimen for an older patient, Thalidomide, Lenalidomide, Revlimid, or Bortezomib Velcade. And this is a very important concept.

Next slide.

But as you heard from Vincent, what has made the biggest impact in the frontline setting for the newly diagnosed myeloma patient without stem cell transplant. So if for an older patient who's not going to be wanting to or able to pursue a stem cell transplant, you can see the blue box with the arrows on top. That is the result with the MAIA regimen. Daratumumab Len/Dex, which has really produced remarkably good-

Dr. Brian Durie:
... which has really produced remarkably good remissions and survival, remissions which are out beyond four years, and so, really an excellent, well tolerated regimen even in older and more frail patients, as has been studied by the French. It's not to say that the VRD, which I studied, is not a good regimen, but the Mayo really is excellent compared to the melphalan regimens, the Alcyone, which was worked on by María V Mateos in Spain, and also the Tourmaline regimen. Next slide. This is just to show you that, within this SWOG study, the VRD was impactful versus RD, even in the elderly patients, so that there is... Although it was not a study designed to look at this, VRD can certainly be considered in an elderly patient. However, you do need to be mindful of the doses. And RVD light where you prospectively reduce the doses is very important. Next slide.

And so, the most effective therapies in standard risk patients who are not having transplants certainly or RVD or VRD in Europe using Daratumumab with a melphalan regimen elsewhere or, whenever it's feasible, the Daratumumab, REVLIMID and dex. Next slide. And so, when we look at the treatment paradigm, we really do need to look at, in the frontline transplant and non-transplant, what is the best way to have that best response. But what I want to highlight here is that it does impact what comes next. What comes next is the time to that first relapse and then what might be happening with the subsequent relapses. And we're going to be talking about that a little bit later. Next slide. And so, it's helpful to think about, if a patient is getting three drugs or four drugs up front, how does that impact the future options? And so, if patients have already had bortezomib or Velcade or lenalidomide Revlimid, how does that impact what can we do next?

And it does change the way that you look at things. For a doublet, as you can see on the left, you can use Kyprolis instead of Velcade. You can use pomalidomide instead of lenalidomide. Now, for triplets, you can see what is quite important here. If you look at monoclonal antibody triplets, you can see in that box there that most of the regimens have daratumumab or isatuximab. So, what that means is if we shift and use Daratumumab or isatuximab upfront, that box mostly goes away. And we need to be looking at what else are we going to do? And this is where all these new therapies and immune therapies come into play. And obviously, over on the right, you can see the newer agents that we can move in earlier, the cell mods, melphalan, if that would ever get re-approved, we have to see about that, selinexor obviously in proteasome combinations, and of course the immune therapies that we're going to be hearing about. Next slide.

And so, with Prior Dara or Isa, this means that we just need to look differently at what impact that will have. It will have probably a longer remission upfront, however it will change how we approach what we do next. Kyprolis, pomalidomide, very important in that setting. A variety of combinations can be used. Also, you can still use combinations of drugs that have been used in the past. For example, you can use daratumumab with kyprolis, pomalidomide, and dex. Recently, a study showed that that is really quite good, even although you've previously used some of these drugs before.

But I think the big story is the earlier use of the newer agents and the immune therapies. Next slide. So, I think that there's absolutely no doubt, with these different issues to think about, taking four drugs versus three drugs, thinking about the side effects, thinking about the cost, thinking about what comes next, it really is increasingly important to reach out at least one time to get a consult and to think carefully about how this will impact your total care. And we hope that these kind of webinars will also give you some insight into thinking about how this impacts your own personal choices. Next slide. Yes. So, we've got a lot of questions that have been coming in, so thank you for your close attention. And I think we have quite a bit of time for questions, which is good. And I will start by cycling back through some of these questions. Thank you so much.

Well, I'll just start. The one that just came in, "What is the drug therapy associated with the MAIA regimen?" So, that is Daratumumab, Revlimid and dex, a three drug combination. As Vincent emphasized, this is an ongoing regimen, so the three drugs are actually continued. But let me cycle back up to the top and we can... Hold on a second here... yeah, try to get through some of these questions. So Vincent, I think that we have a number of questions that relate to the earlier diagnosis and evaluation, so let's maybe deal with those first.

Well, the first question, I don't know what to say about this. How do you treat a patient who refuses to get a bone marrow biopsy? I don't know if anyone wants to comment about that. I mean, I think that it's... I mean, a bone marrow biopsy is always difficult. But at the Mayo Clinic, you do them under anesthetic. Is that right Vincent?

Dr. Vincent Rajkumar:
That's right. It's always done with the conscious sedation. Patients don't feel anything when the bone marrow is done. And so, very quick, painless.

Dr. Brian Durie:
Right. Yeah, it's very quick, but it does say something about the patient in terms of... And Beth, I don't know whether you want to comment on that. I mean, I think that we do need to have a certain degree of understanding and cooperation with our patients. Something like a reality check, I don't know what it would be.

Beth Faiman:
Yeah. There have been a handful of patients in my last 20 years that have not had a bone marrow biopsy, but those have been individuals that have had plasmacytomas, which are tumors that affix to bone and maybe invade the bone, primarily. And we have a tissue diagnosis. So, that's what you need is a tissue diagnosis primarily, but you also want to make sure that you understand that there's no other bad things going on in the bone marrow, leukemias, lymphomas and other abnormal cells.

So, having a discussion and offering an option for anesthesia. Also, I will get lorazepam the night before and then maybe during the morning if they don't want to go under anesthesia. So, just really talking through it can help patients cope a little bit better as well.

Dr. Brian Durie:
Yeah, absolutely. I don't know if we want to talk about this or not. Someone's asking here, question number three, the efficacy of the use of psychedelics to manage the anxiety. That's been very much in the news. In fact, there was a recent book out about that, but I don't think that we have access to those, certainly not in my clinic, but yes. Vincent, do some patients stay in MGUS? I guess maybe just emphasizing the percentages could be good.

Dr. Vincent Rajkumar:
Yes. A lot of people in the US and anywhere, if you take five 50 years and older, about four 5% of the population will have an MGUS. But if you follow all patients with MGUS throughout their lifetime, only about 10% or so ever get myeloma. So by and large, most people with MGUS don't progress. What we look at is the size of the M protein and the type and the light chain ratio and identify patients who need to be followed annually. And those patients have a 1% per year risk of progression. We follow them closely, but not everyone with an MGUS will progress to myeloma.

Dr. Brian Durie:
Absolutely, absolutely. Then, there's a question. Is it possible to detect circulating DNA, blood and myeloma samples? The answer to that is yes. There's a group with Andrew Spencer in Australia. They'll be presenting at ASH. They also presented at ASCO, have multiple publications. And so, you can definitely study DNA mutations in the blood. And that is separate from looking at MRD. And it's also separate from looking at mass spectrometry.

So, there are actually three different tests there in blood, which will be coming into play in the next year or two or three probably, as options for assessment and monitoring. Yeah. I'm not sure what to say about that. There's a question here. Well, why is protein in the blood and urine a sign of myeloma? And then, perhaps more importantly, what can be done to prevent smoldering myeloma from changing to full blown myeloma?

Dr. Vincent Rajkumar:
As I mentioned, for smoldering myeloma, if you take all patients, the risk of progression is 10% every year. And we are concerned that rate is very high. And we want to prevent people from getting the end organ damage. And that's why we use these risk stratification models that I mentioned to identify the patients most at risk of progression. And if the risk is high enough, then we recommend early therapy or enrollment in clinical trials. That's what you can do to prevent progression. If the risk is lower, we just watch patients closely. And if there's a change in the M spike or change in the light change ratio, then we act.

Dr. Brian Durie:
Absolutely. Absolutely. And there's a question about maintenance here, one that we could maybe touch on if you want to, Vincent, if we are stopping maintenance if you become M R D negative.

Dr. Vincent Rajkumar:
So, right now, we are not, because the data are all from maintenance until progression. We are waiting for the studies that show us that you can stop the therapy either by a fixed time point or by MRD status. So, there is a trial that was done in the US that's completed, [inaudible 00:44:11] patients got maintenance for two years versus until progression. And Dr. Shaji Kumar let that trial. It's part of the endurance trial second phase that we... I don't know when it'll... the results will come out, but that will inform us. There's also the SWOG and ECOG trials and trials in Europe looking at if patients are MRD negative, whether you can stop it, and whether the outcome is the same as patients who continue. So, those results will help with that.

Dr. Brian Durie:
Absolutely. And then, a gentleman here says, "If you could just go over what are high risk features one more time. It went fast and it's important."

Dr. Vincent Rajkumar:
Yes, absolutely. So, some high risk features are present at the time of diagnosis. That would be like the 414, 1416, 1420 translocations. 17p and Gain 1q can be present at diagnosis, but you can have them show up later on in the course of the disease as well. And so then, whenever you detect them, the myeloma becomes high risk whether at diagnosis or at relapse. So, it's 414, 1420, 1416, 17p deletion and gain 1q. Those are the commonly detected ones you can identify on FISH. If people do mutation analysis-

Dr. Brian Durie:
With multiple extra copies on the 1q.

Dr. Vincent Rajkumar:
Correct. The more copies on 1q, maybe the risk is... the prognosis is... the risk is higher. And if you have more sophisticated testing, like for mutation analysis, you can identify like P 53 mutation as well that can give you clues. And then, two or three high risk abnormalities increases the risk further.

Dr. Brian Durie:
Absolutely, absolutely. And so Beth, maybe you can comment on this. Severe side effects with Revlimid in maintenance, standard risk, how do you handle that?

Beth Faiman:
So, that's an excellent question. And I know Mayo has published data about exceptional responders. So. That might be where we look at MRD and have the discussion. If you've been in remission for 10 years, can we take a drug holiday plan? But that another side of... That's another story. As far as the diarrhea, Cholestyramine is something that I use quite often. Unfortunately, the diarrhea does not usually get better with the drug holiday, but looking at diet and looking at taking antidiarrhea agents is very important.

Fatigue is another side effect that I hear a lot with long term Revlimid maintenance. And so, really ruling out other causes of fatigue... Oftentimes, we as providers don't check for iron studies or vitamin B studies if you don't have significant anemia. And I find that a lot of people have thyroid problems long term that occur on Revlimid as well as other things that are correctable. So, just having that discussion as well and looking at the side effect, and maybe taking plan treatment holidays, or adjusting the dose to keep you on treatment.

Dr. Brian Durie:
Right, absolutely. An interesting point is that, in most studies that we do with Revlimid as maintenance, after the median time that patients in the study stay on Rev, it tends to be around a couple of years because of this, that and the other side effects or blood counts and the like. And so, I don't know how we feel about if a patient's taken Revlimid for a couple of years, maybe has a lot of side effects, it's maybe okay to leave it at that, perhaps. I don't know.

Beth Faiman:
Great. We'll talk more about side effects later on as well.

Dr. Brian Durie:
Right. Okay. Sorry about that. Okay. The one question just to answer Revlimid is lenalidomide, so those are both the same. Okay? Another one for Vincent. Can a person with low risk become high risk or high risk?

Dr. Vincent Rajkumar:
Yes. As I mentioned, anyone with standard risk myeloma like starting off with the trisomies or the 1114 or the 614 translocation, or no abnormalities, later on they can get 1q gain, 1q amplification, extra copies of chromosome one, or they can get a deletion 17 that makes them high risk. So, when we do a bone marrow at relapse, we check for that to see if the patient's myeloma has changed into a more higher risk type.

Dr. Brian Durie:
Right, right, right. There is an important question here that maybe we should touch on. Actually, it's from Jack Aiello, a stalwart on our patient programs. Thank you for being here today Jack. He's asking that, should we still be using overall survival in that frontline setting as the primary endpoint for standard risk myeloma when there are so many options?

So obviously, we have PFS or remission advantages. And do we need to be waiting to see that overall survival advantage? Vincent, do you want to comment on that?

Dr. Vincent Rajkumar:
Yeah. From a regulatory standpoint, clearly the FDA has not been requiring overall survival. There have been five or six regimens approved for newly diagnosed myeloma; Dara-Rd, Rd, Dara-VMP, Dara-VTd, Vel/Dex. All of them were approved without overall survival. They're just based on the PFS endpoint, Vel/Dex based on the response endpoint. So, the FDA is really not requiring us to demonstrate overall survival benefit. All they want to see is whichever arm we are saying is winning on PFS is not doing worse on the overall survival. There's no trend to worse survival. So, they want you to watch for that. But they've been very good about this. And similarly, even in the relapse disease, they've been only interested in making sure that the progression-free survival is longer and the drugs have been approved on PFS, not overall survival. So, I think we are over-emphasizing that from a regulatory standpoint.

They understand the importance of PFS. And that's what they're using not over os. They're just making sure that the survival's not worse., And that's something important for them to do for safety. Now in clinical practice, for certain things, we are looking at overall survival before we make a change in the practice. So for example, if maintenance prolongs PFS, that may not be enough because the patient could get the same drug at relapse and get the same benefits. So, we waited till the survival benefit was shown with lenalidomide maintenance, and same thing with bortezomib plus len. And so, you want to keep in mind that there can be harm to patients if everybody changes practice based on surrogate endpoints. And so, from a clinical practice standpoint, we all make judgment calls on whether an improvement in MRD negativity or PFS really is...

Dr. Brian Durie:
Right, right, right.

Dr. Vincent Rajkumar:
... good enough to change practice or we would rather wait for overall survival.

Dr. Brian Durie:
Yeah. It's definitely, definitely a tricky point. There's a related question a little bit lower down. Since patients can respond to all of the components of a quad, some are on Revlimid, Velcade, Dara. How about individually assessing the best treatment for a patient, determine the minimum best drugs for each patient rather than the full quad? Yeah.

Dr. Vincent Rajkumar:
That's actually the current ECCOG trial.

We are giving triplet to everyone to start with. Dara-Len-Dex, which has given really outstanding results in the MAIO trial, that's how we start. And then, after a few months, then we randomize them to getting the fourth drug or not. And our hypothesis is that, if patients are already MRD negative with the Dara-Rd, they won't benefit from the fourth drug. So, we can spare them the fourth drug. And then, if they're MRD positive, we think they will benefit from the fourth drug. So, that trial is ongoing.

So, tell all your friends and family and anybody else who might have newly diagnosed myeloma that you hear about that there is a trial looking at, whether everybody needs four drugs or many patients can do with just three drugs alone. And that is available all over the US, that trial.

Dr. Brian Durie:
Yeah. I think it's so important Vincent, for so many reasons. So excellent. Another question [inaudible 00:53:27]. We answered that. PFS. What's PFS?

Well, PFS is progression free survival. It's the length of time before a patient shows evidence of progression or relapse. So basically, it's the length of the remission. And so, we look at this period of time in different ways. Another wording that we use is time to next treatment, tnt. And so, there are different ways of looking at the span of time. And PFS is a technical term where it's the time until the criteria for relapse are met. This may be what we call biochemical, where there's been a change in the level of the protein and it may not mandate that a new treatment is required, but it's a technical term that we use all the time to show the impact of the treatment before there's an indication that the myeloma is starting to progress.

Yeah. Let's see if there's any others that we can look at before we close. We're getting close to the witching hour here. Iberdomide. Alfred, will you talk about Iberdomide later? Probably. Yeah? Maybe touch on the cell mods, or a little bit?

Alfred:
I focus on the immunotherapy, so I don't have much [inaudible 00:55:08], yeah, because there's so much recently about them.

Dr. Brian Durie:
Well, we can touch on that later. Okay. Well, we can pick up on some of these later. There's actually a lot of questions. Okay. Oh my goodness, yes. All right, they just keep on coming. This is good I guess. Well, there's a simple one you maybe want to comment on. Vincent, if you have MGUS, can you go straight to myeloma? So obviously, I think the answer to that is yes. You don't need to smolder first, right?

Dr. Vincent Rajkumar:
Correct.

Dr. Brian Durie:
Yeah. And then, there's a question, if the ascent trial is showing 80% MRD negative, when would this become standard therapy? Well, we need a lot of follow up on that. We can talk about that a little bit more later possibly. But these trials, the ascent trial and the seizure trial, those are what are called pilot trials though just a single arm. They're not comparing one treatment with another treatment. What Vincent was talking about, in terms of the very important trials comparing triplets and quadruplets and the like, they're actually comparing so that we can actually really compare the impact of these approaches.

And Vincent, I would assume maybe you can comment on this. What is the MRD testing in those studies? I'm sure you've got a fairly intensive MRD testing protocol, right?

Dr. Vincent Rajkumar:
In the Dara-Len-Dex versus RD trial?

Dr. Brian Durie:
Yeah. Do you have MRD testing in that?

Dr. Vincent Rajkumar:
There is MRD testing. It is not very frequent. The endpoint for that trial is mandated as overall survival, so it'll take a while for that trial to read out. But there is testing and it's done, I think, from after a year of therapy and then at the time patients go off treatment.

Dr. Brian Durie:
Okay. All right. Well, I think that we... Oh, these just... I'm so sorry. There are a lot of questions. So, I think that maybe... Why don't we take a break? And then, we'll try to come back and handle a lot more of these questions moving forward. So, thanks to you all for your contribution so far. We'll take our first break and come back in 15 minutes. So, we'll be 10 minutes past the hour. So, thank you so much. We'll be back with you shortly. Thank you.

Welcome back after the break. Hopefully, that was helpful, a little bit of a stretch, some water. We are very pleased to welcome Beth Faiman, who has been a strong supporter of these programs, and very, very pleased that she's able to present today on supportive care with many of the new therapies, as well as some of the older therapies which we still use for maintenance and a support of our combination. So, please welcome Beth Faiman.

Beth Faiman:
Thank you so much, Dr. Jury. So, I am Beth Faiman, as you know. I'm a founding member of our nurse leadership board. Gosh, 2006. It's been some time and I've been with myeloma all this time as well. And so, thank you for joining me. At this time, we're going to talk about life is a canvas and you are the artis. Many of you know Teresa Maselli, and she helps determine the themes for these each year. And so now, we're going to talk about parts. So, there are a gallery of goals as a myeloma patient, of course, from the myeloma treatment and supportive therapies. And you heard Dr. Durie and Dr. Rajkumar talk about the treatment landscape. And so, I would like to encourage you to take an active role in talking with your providers and your healthcare team.

I've been on many calls this week. And I hear from physicians how busy they are and they wish they had more time to spend with their patients. And that's exactly why you can identify a nurse practitioner like me in your clinic, or a trusted nurse, or a social worker as well. Because the myeloma treatment and supportive therapies provide some rapid and effective disease control, we hope for durable disease control. But you've heard before, drugs don't work if people don't take them. That's C Everett Coop. He used to be the Surgeon General. And so, we need to make sure you stay on the drugs if it's the right answer for you. We want to minimize side effects, allow for good quality of life, and of course prevent further complications. If you weren't able to join on Thursday, Dr. Jens Hill and Gas from Roswell Park, we talked about bone health. And so, that's another webinar that you can tune into. I think it's up on the internet already. But as Dr. Rajkumar and Dr. Durie already shared with us, we think of things in buckets.

So, for most patients, are transplant eligible. So, we heard how transplant is still a good thing in 2022. Future studies will tell us if we could put that on the back burner and maybe go towards the newer therapies. But for right now, have that discussion with your healthcare team. If you're a newly diagnosed myeloma patient or have never had a transplant, we'll give you initial therapy. And then, once you've achieved some sort of remission, four to six cycles, and you're not in a clinical trial, which again, try to look and see if there's a clinical trial that's right for you, we consolidate that with a transplant, usually using melphalan. After that, you'll go onto some sort of maintenance therapy. And then unfortunately, a majority of individuals will need to have a relapse disease treatment. I've mentioned briefly, we are now seeing these-

Beth Faiman:
... this treatment. I had mentioned briefly, we are now seeing these exceptional responders we call people who've been on Revlimid or other therapies for many years, or they went to a MGUS like state after that transplant and they didn't have any maintenance therapy and are still in remission, so there's so much still to learn about the myeloma biology, but at any rate, the supportive care is super important. If you are a myeloma patient, talk to your provider about any antiviral drugs such as acyclovir, should you be on that? If you're on lenalidomide maintenance and you're having side effects such as diarrhea, is there a medication that's right for you? If you're having fatigue from that lenalidomide, should you have your dose reduced? Are you getting your blood counts checked regularly for the disease control? How do you know if you're in remission? We have a discussion tool under the tip cards on the myeloma.org website.

I would urge you to go to that discussion tool and fill out that discussion tool when you go into your provider's office and make sure all these boxes are checked. Patient reported symptoms are really important to share with your provider or healthcare team. They can be physical, psychological, or financial. The physical symptoms can be from the myeloma itself or the treatment for myeloma, so finding the least amount of medication to control the disease is one of the major goals we have in treating myeloma in 2022. Some of the physical symptoms are fatigue, constipation, pain. We still see a lot of peripheral neuropathy. We used to see a lot more earlier on with thalidomide and Velcade when we used to use high doses for long periods of time. But now we have strategies such as holding the drug or reducing the dose that might limit your nerve problems.

Also, looking at other causes of nerve problems or neuropathy such as uncontrolled diabetes, making sure that your B vitamins are sufficient in your blood. Those are strategies that can help reverse some of the neuropathy. There's also other conditions such as amyloidosis and others, that your provider might need to look for if you're having more neuropathy. Impaired physical functioning can be repaired with exercise. Sometimes we get a little deconditioned from an illness or not moving around as much, so talk to your provider and healthcare team about physical therapy exercises and we have some Living Well webinars that you can refer to that might give you some suggested exercises as well.

We had a question early on about, what was it, psychedelics for treating anxiety. There are lots and lots of drugs that are over the counter and by prescription, that can help manage your anxiety. Sometimes just talking through your symptoms. Oftentimes if you're on high doses of dexamethasone, that can cause insomnia, weight gain, and lots of psychological concerns. Talking about this with your healthcare provider might result in a lowering dose of the steroids, so you might not need medications to treat your psychological symptoms, but maybe adjusting the dose of the corticosteroids so that's right for you.

And then financial. Financial toxicity is a big problem. We heard Dr. Rajkumar looking at studies that are layering on drugs that might be quite expensive to see. Does that patient need that particular fourth drug to treat the myeloma, or maybe three drugs are effective. And so ongoing studies are important, so don't forget to go to clinicaltrials.gov. We'll have that later on, to look for if there's a treatment that's right for you.

Now let's jump into CAR T-cell therapy and bispecific therapy. We're so excited. I remember hearing about this in the early 2000s. It sounded like science fiction, taking your own T-cells and engineering them to make fighters that move around in the bloodstream. I thought that was crazy and that was never going to work. But look at where we are here. We have two approved drugs for CAR T-cell therapy, ide-cell or Abecma and we have cilta-cel or Carvykti. Those are two different CAR T-cell products that use different methods to engineer your own T-cells, to target and attack myeloma. We'll talk about how that works in the next few slides.

But the approved therapies are against B-cell maturation antigen or BCMA. Now that's a protein that's found on the surface of multiple myeloma cells that is targeted by these several CAR T-cell products and it's mostly expressed, this BCMA, on the cancer cells and not as much on the healthy cells, which is good news. I love this little cartoon. This woman makes me smile every time I see her and it really emphasizes that age is just a number with these therapies, people might not have been a candidate for stem cell transplant maybe because of organ function. Maybe they weren't fit enough at diagnosis, but now they're fitter, and these therapies are not as toxic in some cases as that high dose Melphalan that we give for stem cell transplant.

At any rate, if you have the discussion with your healthcare team about CAR T-cell therapy and it's decided that it's right for you, then you'll oftentimes go on a list. Now that list can be long because there's a supply issue right now. Hopefully in the next few years that'll be rectified. I'm wishing a few months, but I think it's going to be a little longer than that. I'm just trying to manage expectations. But at any rate, that person that's a candidate for CAR T-cell therapy will consult with the CAR T-Cell Therapy Center. Get on that list, establish that relationship as early on as you can in your treatment. Now you need about at least three prior therapies before you're a candidate for CAR T-cell therapy according to the FDA approved indication.

But start that discussion with the large center early on. Once you have that slot for manufacturing of your cells, we're going to harvest your T-cells through apheresis. That's that same machine if you had a stem cell transplant where they'll take it out through your peripheral blood. They're sent away to a lab that'll engineer your T-cells for four, six or eight weeks sometimes, depending on where you live, your geographic location and what product you're getting. We have this bridging therapy to keep your myeloma under control. We use drugs such as Selinexor and other therapies, in my practice to keep patients nice and quiet. We want to balance the not getting sick from the therapy we give you, towards the being able to give you your cells back. Then we give you this lympho depleting chemotherapy and we give you the CAR T-cells back and then you're at the finish line.

There are some side effects which you'll talk about such as long-term low blood counts, some immune system issues, but it really takes a village with nurses, doctors, social workers, and your physician and pharmacist team. This is a different picture way of looking at it from the patient selection to the pheresis to treatment and then the management after CAR T-cell. I have patients that do so well, they go right about back in their business afterwards. We look for their CD 4 counts and make sure that they're not at risk for certain kind of atypical infections, so you might be on some antibiotics afterwards. But then there are those patients that have the lower blood counts that lasts a little longer. We have to bring them in for blood transfusions or at least check their blood. And then we also put them on other supportive therapies as well.

Let's talk about bispecific antibodies. I'm so excited that we just had a drug approved by the FDA on October 25th, 2022 that was teclistamab. And so there are many different drugs that are currently in clinical trial, so please, find out if there's a clinical trial with a bispecific antibody that you would qualify for. Again, I'm really into clinical trials because we can't move forward if we always do what we've done and that's how we've got all these new approvals. Anyway, what do bispecifics do? Well, this is a very innovative approach and it has more than one arm to attach the cell, so it's like a helping hand. It has this bispecific antibody, has a linker that grabs onto the myeloma cell on one side and then it grabs onto the T-cell on the other side and then it brings them together to cause that cell death.

And so it's given as a shot or an IV depending on the type of drug it is, the product. There are some side effects that we'll talk about such as the cytokine release syndrome and some nerve related side effects. So what is CRS? Cytokine release syndrome occurs when you have that immune process of self killing and all those cytokines are released into your system. It could actually look like people are having an infection because fever and fatigue and headaches are very common side effects. There could be some nausea and vomiting and shortness of breath as well. Because of this cytokine release syndrome, drugs such as teclistamab, which is now FDA approved or those that are in clinical trials will require you to be in a hospital or near a hospital for at least 48 hours. Now the good thing is through clinical research, we know drugs such as tocilizumab or toci we call it, can help lower that risk of severe side effects and that used to be in short supply and now we have much more doses of that drug available.

And so, when you have your bispecific or CAR T, we'll have those drugs on hand to give you to lessen the severity of that CRS. It is common but usually mild and with drugs such as also corticosteroids, we can start with the toci or sometimes we need something called anakinra in some cases, but corticosteroids such as dexamethasone can be given. We try to hold off on giving the dexamethasone with the CAR T and such, because we don't want to weaken that effect but we still can give them safely.

Now neurotoxicity is something that's very frightening for patients. You don't want to have any confusion or headache or altered mindset, but it tends to be temporarily. We have tools that the nurses or the doctors or somebody in the hospital could minister such as asking you your name and date of birth and what time of year and then more sophisticated questions. We also ask you to write your name to see if your handwriting has changed and so those are some early signs that we might be finding this neurotoxicity, again, it is rare but can be serious so you need to be closely monitored.

With these targeted therapies, again we're harnessing your immune system to fight the myeloma cells and so you can have some immune problems so they can be viral or bacterial. Again, acyclovir, many of you have been on for a long period of time for various reasons and you would be on acyclovir as well. It can also cause low immunoglobulin counts. Now many of you have low IgG counts anyhow. Some of you that are getting recurrent infections might have been on intravenous IVIg, but that's something that if you're on Car T or bispecifics, I'm very proactive about checking IgG levels and trying to get that approved through the insurance agencies.

The other thing would be antibiotics. There's something called Bactrim that many people are on or sometimes inhaled pentamidine. Now we don't want to forget to protect your bones during this time. We had the bone health talk on Thursday and I think bone health has kind of fallen out of the way lately, but we also want to make sure that it's right for you to stay on bone strengthening therapies, calcium, vitamin D as appropriate. Again, we worry about high calcium levels, so you should talk with your doctor, and again, looking at antibody levels. All of my patients on bispecifics and CAR Ts, I want to make sure we have the discussion about Evusheld. That's that pre-exposure prophylaxis. You have to have COVID vaccination and negative COVID tests and you get a shot in your behind, in your rear end, once every six months. The data keeps changing but it's still once every six months and we try to give it as soon as possible.

If you have COVID, there are still medications such as that Paxlovid, which is given for five days. We adjust that according to your kidney function and then we make sure you don't have any heart problems or there's antibodies that we can give as well that don't work as well, but still can be quite effective. Again, infections can be quite serious and there is a 7 to 10 fold increased risk of bacterial and viral infections, so make sure you're washing your hands, avoiding people with colds and talking about with your healthcare team if you have signs of an infection. I always like to emphasize in my discussions the importance of healthy living, living well with myeloma. If you don't feel like you're up to exercise, and of course the weather's changing, I'm in the northeast, Midwest forever, Cleveland, Ohio, it's cold today.

But if I can go outside for five minutes and get a breath of fresh air and stretch my legs, it might help me psychologically to feel better. If you're feeling down or stressed out, mindfulness strategies can be done from sitting in your chair. Maintain a healthy weight the best you can and try to think about more of a plant-based diet if you can. Healthy nutrition and talk with your healthcare team if you're worried about types of foods or not having money to buy food. There are lots of resources financially, in many communities to help support people with cancer.

We talked on a previous webinar about financial burden. This was about eight months ago, so that should be on the website as well. Finding financial resources and even people to clean your home if you need it as well. There's a lot of volunteers out there. Protect your bones, tune into our bone health talk if you want, but again, the weight bearing exercise or activity and bone strengthening agents are important.

Let's not forget, and I know I've talked about this throughout the importance of clinical trials, this slide just emphasizes the four phases. When we have the animal studies that first say those are preclinical, that a drug might work, then you have that phase 1 study that will investigate in humans, it looks at this pharmacokinetics or how the drug moves through the body, through blood testing and pharmacodynamics or PD studies and then the maximum tolerated dose or MTD. Once we find the best dose for most patients, you go to this phase 2 study in a specific cancer type or tumor type and then we give that to more patients and that will look at different endpoints such as how long are you staying in remission? And it really focuses on safety as well as the effectiveness.

The phase 3 trial compares a standard of care drug against the newer drug. And as we are moving so fast in the science, these phase 3 studies, we're getting drugs approved before we have randomized trials, which is a nice predicament to be in. But I can talk all day about the design of clinical trials and how they go through, but make sure to find out if there's one right for you by going to clinicaltrials.gov, that's my favorite reference. You just type in the word myeloma, you type in a drug name, you can find out what location that might be closest to you and state and hospital and there's information as to how to find that person, like phone numbers, et cetera, and emails. You can also call the IMF info line at 1-800-452-CURE and you can also call worldwide.

There's so many people there that are willing to answer your questions for sure. And don't forget that knowledge is power. There's so many reputable sources and myeloma.org is the perfect website to go to. I know this sounds like an IMF commercial, but really and truly, they have it in all different languages, free to ship to you, teleconferences and newsletters as well, that you can tune into and opt-in to. And remember, you're not alone. The IMF is there for you to answer your questions and provide resources such as this webinar. At this time I'd like to pause, I can talk all day, but I promise I won't and hopefully answer some questions. Thank you.

Dr. Brian Durie:
Okay, well thank you so much for that Beth. We definitely do have time for a number of questions. Thank you. Just to emphasize on the last point, one question was, do we have a glossary for some of the words? We've used a lot of different words. And so, among the booklets at the back of each booklet, there's a glossary with explaining some of the terminology. And so I'm sorry if we use words which we have not fully explained, but in all of our booklets we do have details to explain the terminology. A couple of questions have come in about Evusheld. One says, "I heard Evusheld was no longer found to be effective." I don't believe that is true. But another question was, "Do we have any clear data of what has been the value of Evusheld, the antibody treatment in myeloma patients?" I don't know if any comments on that. We do use the Evusheld.

Beth Faiman:
Yeah. There are not any good studies. Remember, a lot of this is retrospective, so we're looking back at people that have gotten this drug. And so you need a lot of times, the prospective studies or pre-planned studies to really, really gain insight as to whether or not it makes a difference. In my experience, the Evusheld tends to lessen the chance of people getting hospitalized. So you have the vaccines that lessen the severity, but you can still get COVID. Evusheld, I really think that the data supports the use in immunocompromised individuals. I think one of the criticisms is that it hasn't been tested in patients with cancer, but other immune conditions. And so I don't know if you have any further thoughts, Dr. Garfall or Dr. Durie? Dr. Rajkumar?

Dr. Brian Durie:
No, I think it's good to use it, but I think that the data are not strong. I know this is frustrating for patients. They want to see, well, what is the level of benefit but Alfred, are you aware of any specific data that relate to myeloma? Not yet, I don't think.

Alfred:
Not specifically in myeloma patients. It's a moving target of course too because the virus keeps evolving. And so the variants that were prevalent when Evusheld was initially tested are quite different than the variants that are dominant now. And that is, I think what the question was hinting as if there were some data showing that the FDA released that Evusheld may not have as high an affinity, an ability to bind to the current circulating viruses compared to the prior viruses. But there is still some ability to bind. And considering that Evusheld has so few risks and is very well tolerated, we have been using it in our patients who qualify for it, as just one extra layer of protection.

Dr. Brian Durie:
Yeah. No, I feel the same way. It's probably not perfect as you say with the new variants, but every little bit of extra protection helps.

Dr. Vincent Rajkumar:
Exactly. I agree again, with the discussion, we are also using it and every little bit helps.

Dr. Brian Durie:
Thanks-

Beth Faiman:
Can I ask something? One thing I didn't talk about in detail, I forgot I skipped over, was the flu vaccine. We've been seeing this huge spike in influenza, particularly A in my region. And so I encourage all of my patients to get the flu vaccine. And lately, based on some data, I've been recommending that in a couple of months, maybe January even, to get a second flu vaccine. What are your practice patterns with the flu vaccines?

Dr. Brian Durie:
Yeah, I think it's important to go ahead. I don't know if either you guys want comment on that. If you have set up a routine practice for your patients, that they're coming in.

Alfred:
Yeah, we give everyone the flu vaccine that we can and a lot of patients get it, of course independently, but patients that we're treating at our site, we give it to. And I am actually a little more worried about the flu this year than I have in recent years, that you're started to see some cases earlier in the season than we typically see influenza and influenza's been on a hiatus for a couple years as the whole world was wearing masks. But now that things are opening up, I think we could see a more concerning flu season this year than we have in recent years.

Dr. Brian Durie:
Yeah, I've been starting to see a little bit of that. It's similar to the RSV in children where it was sort of on hiatus, but now we're seeing a lot more of it, which is a concern frankly. Yeah. Maybe Beth, I can ask you, there's been a couple of questions about this. What's kind of the difference between palliative care and supportive care? And I think that in years past, we did talk more about palliative care because there was so little that we could do sometimes for patients, but now there's so much that we can do. We don't typically talk that much about palliative care. We actually integrate psychological care, resilience training, spiritual training, yoga, all kinds of things into supportive care.

Beth Faiman:
Yeah, so palliative care-

Dr. Brian Durie:
Yes.

Beth Faiman:
The definition of palliative care is aggressive control of symptoms. People that need something palliated would be somebody with a new tumor on their spine. They might need palliative radiation to control that pain and control that local tumor spread. That would be an example of that or pain control. You're jumping in when people have symptoms for palliative care. Supportive care should be delivered throughout and just like you described, Dr. Durie that yoga, mindfulness, drugs such as bone strengtheners to prevent bone damage, avoiding supportive care would also be avoiding non-steroidal anti-inflammatories for kidneys and staying well hydrated. And then exercise is also supportive care, going into your primary care, getting your blood pressure checked, making sure your cholesterols are in a good range. Those are all supportive techniques to prevent you from getting to that symptomatic stage. I hope that makes sense.

Dr. Brian Durie:
Yeah, right. There's a few questions coming in about COVID. Here I see one, I'm not aware of this, maybe someone could comment. Is there a connection between myeloma and long COVID. I think we've all seen some myeloma patients who have developed and recovered from COVID. Have you seen any sense of more long COVID? Personally, I'm not sure I've actually been seeing that, but what's your experience, Beth, or any of you?

Beth Faiman:
In my experience, I don't see where the myeloma patients have had any more long COVID. They tend to recover quite well, which is surprising. And maybe it's because majority of my patients are vaccinated and they have supportive environments as well. But there are a couple that have had longer COVID symptoms. I see that less in the vaccinated population though than the non-vaccinated folks. Dr. Rajkumar, you're an expert in this arena as well.

Dr. Brian Durie:
Right. So I don't know Vincent or Alfred, you want to comment? My sense is that with the introduction of the vaccinations and the boosters and the Evusheld and all these different things, that very dangerous impact of COVID that we saw one in two years ago, has really dissipated quite a bit. I don't see so many patients in serious or desperate straits. What's your experience?

Dr. Vincent Rajkumar:
That is true. Clearly because a lot of patients have already had COVID, a lot of people have already had COVID and then so many, many people have been vaccinated. It is certainly less of the severe respiratory failure that we saw before. But just to be careful because you never know how this variant mutates next and the next patient might be more serious, so just keep up to date on all the vaccines. Keep up to date on the flu vaccine, which is also important. I agree with Beth that the rates of long COVID, we don't have any indication its going to be any higher in myeloma patients and wear masks if necessary. And based on your situation in your hospitals and things, because that's another layer of protection and it reduces the viral load, particularly in closed rooms or where there's crowding.

Dr. Brian Durie:
Right. There's a number of questions which I think Alfred, we'll be touching on. There are quite a lot of questions about CAR T-cells, so I think you'll be going over about that. How long do the CAR T-cells last? Which is the best CAR T-cell therapy to get? You have your work card out for you. Does it work in extra medullary disease? You've got quite a few things that you can comment on there.

Alfred:
I'm ready.

Dr. Brian Durie:
Beth, turmeric. This is something that was popular maybe 10 and 15 years ago. I don't know.

Beth Faiman:
I can comment on turmeric because I stay up to date on all of those-

Dr. Brian Durie:
All right.

Beth Faiman:
... all those things. The best study was actually an Australian study that in patients with smoldering myeloma, it did show a decrease in free light chain levels, but it wasn't clear as to whether or not, and again, it wasn't a great study because these studies need funding and not a lot of companies will want to fund studies. At, any rate, there's some anecdotal evidence in other cancers that turmeric can be beneficial to the immune system and maybe help you fight off things.

And so the typical dose is about 500 milligrams. There are some studies that say take it with pepper and so then you'll go to your health food store and it'll already have pepper in it. It can cause some GI distress. In general, I tend to just recommend, because it's found in mustard, just use mustard in your food. Don't spend a lot of extra money on turmeric. The studies are still inconclusive. I do have a lot of patients that are still on it. And you're right, it was probably early 2000s, it was really a hot topic.

Dr. Brian Durie:
Topic, right. Yes. Maybe just one or two more. A lot of the questions relate to what's coming up, so we should maybe move ahead with that. But maybe Vincent, we can comment on this. How often should PET or MRI be repeated if the first one shows no lesions? Obviously costs are an issue in terms of how often you get these different testings done.

Dr. Vincent Rajkumar:
Yeah, cost and reimbursement and things like that. What we recommend is one good skeletal imaging once a year for patients with symptomatic myeloma on therapy.

Dr. Brian Durie:
Right, yeah. If you can get the coverage, I think that's the way to go.

Dr. Vincent Rajkumar:
And at Mayo, the imaging we use is the low dose CT, which is cheaper than PET or MRI and more convenient. That would be for places where their low dose CT is not available and that's the only way they can get the CT.

Dr. Brian Durie:
Right. No, I fully agree. The whole body low dose CT is good. Well, particularly since it identifies what might be a problem, which is the early development of lesions, which is very important. Another very important thing is that obviously you should repeat whatever it was that you had before, so that you can compare.

All right, there's a question about someone healthy over the age of 70 for stem cell transplant. We did go over that very quickly, but I think the main thing to say about age and transplant is that it's not an absolute, it does not preclude transplant if you're over the age of 70, there are many healthy people over the age of 70. And so really, it puts emphasis on what are the things that are negative from a medical standpoint, which would be performance status, how active is the patient. But specific problems like any heart disease, any lung disease, and what we call comorbidities, things that can really have a negative impact is if there's any active infection or hepatitis, other diseases, things like sugar diabetes, that requires insulin...

Dr. Brian Durie:
Things like sugar, diabetes, that requires insulin therapy, some things like that can really make it more medically complicated. And then of course, always, the desire of the patient to go ahead and actually go through a stem cell transplant. So I think that these are some of the main ones that we have coming in right now, in terms of questions. There's another question about psychedelics that seems to be on people's minds, and questions about bispecifics and... Well, maybe a last one. Should I be on somato or xgeva in preparation for a stem cell transplant?

Beth Faiman:
I can comment again on the bone thing.

Dr. Brian Durie:
Yeah.

Beth Faiman:
We did a lot of the bone, great, great bone questions on imaging and the dose, again, the supportive care drugs to prevent you-

Dr. Brian Durie:
Right.

Beth Faiman:
Two main ones that we use nowadays, the zoledronic acid, it's less expensive. The International Myeloma Working Group Bone Committee recommends that that's the first drug based on the grade, taking account the cost, et cetera, monthly for 12 months. And then we can add your discretion of your treating provider. The Denosumab's so good with kidneys. So if you have kidney failure, you're on dialysis et cetera, that's a shot in the arm. It's more expensive. It's a monoclonal antibody though. And we give it a lot for people without myeloma bone disease that maybe have osteoporosis, because it is FDA-approved for osteoporosis as well. So those drugs should be given monthly for at least 12 months. But you can skip around that transplant time. Sometimes you might miss a dose. It's okay just go back on it when you can.

Dr. Brian Durie:
Absolutely. Absolutely. Okay, well I think that clearly there are a lot of questions about the new immune therapies, the bispecifics on the CAR T cells. So I think it will be good to go ahead with our final presentation with Dr. Garfall and very pleased that you can be with us. So please update us about relapse and the role of all these new immune therapies.

Alfred:
Great, thank you. Thank you Brian. And thanks everybody for the invitation to be here. It's an honor to be here with everyone. I'm going to not talk about all of relapsed myeloma, although we can certainly cover that in the Q and A instead. And I actually sort of focus on having a relatively few number of slides that give a general overview of some of these new immune therapies, with a special emphasis on Teclistamab, because that's such a recently approved agent. And one, I think of many agents like it that will be approved in the near future. So talk a little bit about that in more detail, but hopefully we leave lots of time for questions and discussions. Because this is an area that I think a lot of us have been spending a lot of time thinking about.

So I wanted to start with just a broad overview of these different classes of immunotherapies, because these terms get thrown around and I think they can be particularly confusing to patients. So all of these different therapies, so we think about conventional monoclonal antibodies like Daratumumab or Elotuzumab, antibody drug conjugate, bispecific antibodies and CAR T-cells. These all at some level depend on antibodies, and so it's worth just thinking about what an antibody is. And so our immune system can make antibodies against infections. And so we've been talking a lot about antibodies against Covid 19. And so our immune systems and immune systems of all mammals have the ability to create these proteins called antibodies that can recognize particular biologic proteins. And in the laboratory now we can make antibodies for therapeutic purposes against any protein that we want. And so fortunately there are a lot of proteins on the surface of multiple myeloma cells that are not expressed by a lot of other cells in the body or are expressed at lower levels by a lot of other cells in the body.

So we can use those molecules on the surface of myeloma cells as targets for antibody-based therapies. And in doing so, kind of train the immune system against those targets, hopefully sparing normal cells in the body. So you see here I've listed all these different agents that have been approved or are in development and in parenthesis next to them I've listed the target on the myeloma cells that these agents are directed against. And so in the case of Daratumumab it's CD38. And then there's a whole host of therapies that are directed against this molecule BCMA, which stands for B-cell maturation antigen. And that is a molecule that is expressed, pretty restricted in its expression to multiple myeloma cells, and not a lot of other important cells in the body. And so if we think about how a regular or conventional monoclonal antibody works, and so here in the middle is the antibody and the antibody recognizes a target on the multiple myeloma cell. And then the back end of the antibody serves as a beacon for other cells in the immune system.

And when we're talking about a conventional monoclonal antibody, the types of immune system cells that the antibody recruits to kill the myeloma cells are cells like natural killer cells or macrophages. And so these are cells that are part of our innate immune system. And then these cells, these immune system cells have the ability to come in and recognize that the antibody is bound to the myeloma cell, and then kill that myeloma cell just like it were a foreign invader like a virus or bacteria. And there's a few other way, this is a little bit of an oversimplification. There's some other mechanisms by which conventional antibodies work, but I think this is the simplest way to think about it and maybe the main mechanism of action. And these Daratumumab, Isatuximab, Elotuzumab, these have been around for a little longer, and this technology's been around for a little longer.

Antibody drug conjugates, the one that's approved for multiple myeloma is a drug called Belantamab. This is a little bit of a variation on this theme. And so here, with an antibody drug conjugate, we have an antibody that recognizes the target on the multiple myeloma cell, and these antibodies can often recruit natural killer cells and macrophages also. But an added feature of these antibodies is that, attached to the antibody and that's indicated by the red starburst there, is a potent chemotherapy molecule. And this chemotherapy molecule is so potent that if we were just to give this chemotherapy molecule to a patient as a drug, it would be way too toxic.

But we can conjugate very, very small doses of this chemotherapy drug to an antibody, and the antibody serves as a delivery device to recognize the myeloma cell and bring that chemotherapy molecule right to the myeloma cell and avoid exposure of the rest of the body to that potent chemotherapy. So what happens when this antibody drug conjugate binds the target on the myeloma cell, is the myeloma cell internalizes that antibody drug conjugate and the chemotherapy gets released from the antibody, and the chemotherapy can cause death of the myeloma cell. So this is how Belantamab works.

Bispecific antibodies are another variation on this theme. And Beth alluded to this mechanism in her talk also, bispecific antibodies have two targets and that's why they call them bispecific. So one half of the antibody recognizes the target on the myeloma cell, and the other half of the antibody usually recognizes a molecule called CD3, which is a receptor on the surface of T-cells that activates T-cells. And so this antibody grabs a T-cell with one arm, grabs a myeloma cell with the other arm, pulls them together and activates the T-cell in the process so that the T-cell, which is another part of the immune system, can kill the multiple myeloma cell. Now for whatever reason, this effect of a T-cell killing a myeloma cell with a bispecific antibody is a little stronger than the effect you get with a natural killer cell or macrophage being activated by a conventional monoclonal antibody against the myeloma cell.

So with these immunotherapies that engage T-cells, which are just a different part of the immune system that has the ability to kill other cells, the strength of the anti myeloma effect tends to be a little bit stronger with these T-cell engaging immunotherapies. And then to take that one step further, we have CAR T-cells. And so, CAR T-cell are a technique where we, instead of bringing the T-cell and the myeloma cell into the body through this bridge of a bispecific antibody. we take the T cells out of the body genetically engineer them to put on the surface of the T-cells, antibody that can recognize the myeloma cell just the way an antibody with these other techniques can recognize the myeloma cell. And in the process of that genetic engineering, we activate the T cells in the lab and grow them to large numbers and then can reinfuse them back into the body.

And here we're infusing basically a living therapy. So the CAR T-cell that are now armed with this antibody on the surface that can find and recognize a myeloma cell, those cells can actually divide in the body and reproduce themselves and create more of themselves. And so this is a living therapy that can, in its best case scenario, can live for a long time in the body and provide long-term immune surveillance against the myeloma. But at the very least provide an initial wave of anti myeloma immune activity, where these T cells are recognizing the myeloma cell through that antibody express on the surface and the target. And so we have Daratumumab, Isatuximab, and Elotuzumab as conventional antibodies. Belantamab as antibody drug conjugates. Teclistamab was the first bispecific antibody just approved, but there are a couple others coming down the pike. And then we have the two CAR T-cell products, Ide-cel and Cilta-cel that recognize BCMA.

And so I want to make some very rough comparisons between these classes of drugs, and I emphasize that these are rough because I think there are exceptions, and maybe this is a bit of an oversimplification. But we can go from left to right in terms of the potency of the anti myeloma activity provided by these different therapies. But also we can go to left to right in terms of the risk associated with them. And so when we think about risks, we think conventional antibodies increase risk of infection but not in a terribly scary way, usually a very manageable risk, and patients can remain on conventional monoclonal antibodies for years and have only a modestly increased risk of infection. With antibody drug conjugates, the side effects we worry about depend on the chemotherapy molecule that's attached to the antibody. So in the case of Belantamab, there's an eye irritation that antibody can cause, and that we think of that as the main side effect of that medication.

And we heard from Beth earlier about the risks that come with these T-cell activating immunotherapies, bispecific antibodies and CAR T-cells, the cytokine release syndrome, the neurologic toxicity, and these risks are a little bit higher with CAR T-cell than bispecific antibodies. So with bispecific antibodies, because they're a drug that we can dose, we can kind of add in doses very gradually before we get up to the full dose. And that allows us to maybe regulate a little bit better the onset of those cytokine release syndrome and neurologic toxicities. CAR T-cells are a bit unpredictable in that we infuse the full dose and the cells can kind of grow in the body, in some ways they're a little harder to control. And so, I think the risk of the higher grade toxicities are a little bit higher with CAR T-cell. But it's important to emphasize of course, that we haven't conducted studies that directly compare these techniques yet.

And so these are just general senses we get from treating patients about the flavors of toxicity. I would say the risk of infection is a bit higher with these agents as well. And we've seen [inaudible 01:44:52] some patients with bispecific antibodies especially have some opportunistic infections that we typically don't see or only see very rarely in multiple myeloma patients. And prevention of infection and vigilance for infection is a really important aspect of these therapies. And low blood counts we heard. So the inflammation caused by these cells in the body is they activate the immune system can sometimes make blood counts low for a long time, especially with CAR T cells.

These different therapies are given in different ways. And so conventional antibodies of course, many patients have received these for years now. They're generally given indefinitely, even if it's just on a once monthly basis and they can be given intravenously or subcutaneous. Likewise with Belantamab. But we often have to hold treatment with Belantamab due to eye side effects. This is generally a drug that if it's working, we tend to try and continue it, even if it's with infrequent dosing. And this is given intravenously. Bispecific antibodies, as they're currently being studied for the most part are indefinite treatments, but some of them work so well that we really wonder whether it's possible to stop therapy for a long time in patients who have very good responses. And that's something that will be determined with further clinical trials, but these can be given as intravenous or subcutaneous injections.

And then CAR T-cells, as we heard earlier, are a one time therapy, but it is a little bit more complicated to orchestrate. So patients have to have their T-cells collected, their T-cells should be sent off to a company or a laboratory where they're manufactured, and then patients have to receive those cells back through an intravenous infusion often after some chemotherapy. There are some complicated logistics and scheduling issues to consider. And so that is a distinct feature of CAR T-cells compared to these other agents which are kind of conventional pharmaceutical agents that can be pulled off the shelf and started any time.

And so finally, in terms of where these agents are currently used. And so conventional monoclonal antibodies like Daratumumab are used more or less in all settings of myeloma care from first line therapy to therapy of patients who have relapsed. Right now these other agents, at least in their current form, are approved mainly for patients who have had four or more prior lines of therapy. So patients who have been through the conventional multiple myeloma therapies like Lenalidomide, Pomalidomide, Bortezomib, Carfilzomib, et cetera. So I want to spend a few minutes talking about Teclistamab. So this is the first BCMA targeted bispecific antibody, and really the first bispecific antibody the FDA approved for multiple myeloma. And so this is very exciting development because bispecific antibodies offer the same type of T-cell activation against the myeloma that previously you could only get with CAR T-cells. But this offers it in the form of medication that can be given much more easily than CAR T-cells can.

And so just to go over a little bit about the main clinical trial in which Teclistamab has been tested so far, this was a study of 165 patients who had received at least three prior lines of multiple myeloma therapy. And as a single drug, this is a really impressive response rate. So 63% of the patients who received this drug on the clinical trial responded. Except for CAR T-cells, we generally haven't seen a single drug have that high response rate in patients with really advanced multiple myeloma. Most patients in terms of side effects did develop low blood counts as they received this medication, especially neutropenia. There was this risk of cytokine release syndrome that Beth mentioned as this inflammatory syndrome that causes often high fevers and occasionally more severe complications like low blood pressure or difficulty breathing. About 70% or so of patients on this study had cytokine-release syndrome, but in most cases it was low grade and manageable.

About half of the patients who developed cytokine release syndrome required that antibody to kind of calm down the inflammation, the tocilizumab antibody, but fortunately that was very effective in the patients that needed it, and had very few patients progress to higher grade complications of cytokine release syndrome. And then we've also seen neurologic toxicity with Teclistamab. And they're, all of these BCMA directed immunotherapies, the CAR T cells and the bispecific antibodies seem to have some risk of this neurologic toxicity. There's this neurologic toxicity we call ICANS, which stands for Immune effector cell-associated neurotoxicity syndrome, really long word. Basically it means a range of side effects that can happen just as you're starting the medication or just after you've received the CAR T cells, where there can be some confusion, difficulty with motor tasks like handwriting, tremor. Usually this is mild and temporary, but there are occasional patients that can develop high grade ICANS and that's really concerning and even a potentially fatal toxicity.

Fortunately in the study so far with Teclistamab, there was no fatal ICANS, and almost all the cases where low grade. There were a couple other neurologic events to be aware of. So there was one patient who had a seizure on the studies and another patient who developed a neurologic condition called Guillain-Barre syndrome. And this patient unfortunately passed away from that syndrome. That's a syndrome that's called a demyelinating neuropathy, where the nerves can be attacked by the immune system and lead to difficulty with motor function, difficulty with movement basically. That's a condition that can happen on its own, but it seems with a couple of these different BCMA directed immunotherapies, to be a risk with this whole class of medications.

And there was one patient reported that developed this syndrome on Teclistamab. What's impressive for the patients who responded to Teclistamab is that after 12 months, about 70% of the patients who responded to it, the drug was still working. And so these are very durable responses, especially considering that these are patients who had a lot of prior myeloma therapy, for it to have a single drug working that's given as just a subcutaneous injection and can work for that long, is really promising.

So I mentioned that infections are a major problem with this class of medications and Teclistamab in particular seems to have a real risk of suppressing the immune system. And so we see this manifest in patients as very low antibody levels. And so Teclistamab, and I suspect most other BCMA directed bispecific antibodies will kill the normal plasma cells in the body along with the myeloma plasma cells. And so the normal plasma cells are responsible for making your conventional antibodies that help you fight infection. And so the loss of those antibodies puts patients at increased risk of infection. Most patients on the study with Teclistamab had infections and about half of those, a little over half of those were serious infections. And these were mostly pneumonias, but also Covid 19, including a lot of patients who died of Covid 19 while receiving Teclistamab on the clinical trial. Now this was earlier in the pandemic for the most part, and our patients who have been receiving Teclistamab on clinical trials more recently have had an easier time dealing with Covid.

But with some of the earlier variants in the pre vaccine days, COVID 19 was a serious problem. And I think that just speaks to how significantly the immune system is suppressed with Teclistamab. There are also some opportunistic infections that emerge. So a type of pneumonia that we typically only see in immunocompromised patients called pneumocystis pneumonia was seen in several patients on the trial. And a patient who developed a fatal brain infection called PML, that was seen on the trial. And fortunately for pneumocystis pneumonia, we have good preventative medications that we can give to prevent that. And Beth kind of alluded to that also in her talk.

So, just to talk a little bit about the typical patient's journey with bispecific antibodies, since this is a newly approved class of medication. So in order to prevent high grade more serious cytokine release syndrome, these drugs, and this is the schema for Teclistamab, but the other bispecific antibodies that are coming on the pipe will have, I think a similar dosing strategy. Where you get a really small dose at first, wait a couple days, give a medium dose, wait a couple days, give the full dose, and that seems to reduce the risk that the immune system gets over activated all at one time.

And we think that this reduces the risk of severe cytokine release syndrome or neurotoxicity. And cytokine release syndrome or neurotoxicity can happen after any one of these doses. And so while if somebody's doing really well with the first dose and doesn't have any complications, you proceed right with the second dose 48 hours later, if you do develop a fever or have any side effects after the first dose, you delay that second dose until that syndrome has resolved, give the second dose, wait and see what happens and give the third dose that way.

The way it was done on the clinical trials and the way at least we planned to start this medication for now is to give all these doses in the hospital, so that patients can be monitored very carefully for these side effects. We may see over time that it's possible and feasible to give these in the outpatient setting, or at least for patients who are at lower risk of these toxicities. But for now, these initial doses are recommended to be given in the hospital, at least according to the prescribing information provided by the FDA. After patients get these initial doses, they would return to the clinic one week after the first full dose, to start weekly outpatient doses.

And it's pretty rare to have recurrent cytokine release syndrome or neurologic toxicity after you leave the hospital. So these side effects are, for the most part, confined to these initial doses that happen in the hospitals. Patients may have low blood counts during the first couple months of therapy and require supportive care like transfusions or injections of medications to help the white blood cells like Neupogen or Filgrastim. And often, just my personal experience is that patients are often kind of tired in these first couple months of therapy. The way I think about this is that the immune system is really being activated to fight off a bunch of multiple myeloma, that immune activation and inflammation can make people kind of tired.

The response to these medications is usually clear within the first month or two of therapy, and sometimes even those first very small doses, we can see anti myeloma affects kick in very early, which is really impressive. Officially, the dosing for these is once weekly indefinitely, but I suspect we'll be reducing the frequency of the dosing for patients who are responding well, down to every two to four weeks. And what's impressive, while there are a lot of side effects and concerns to be aware of in the first couple months of therapy, in my experience, patients who have been on this medication for a long time, even going on years, feel very well with long term dosing and they don't accumulate side effects the way you do with some other classes of multiple myeloma medications.

So in terms of supportive care for patients receiving bispecific antibodies, I mentioned that we are concerned about infections. We want to make sure that patients who have had prior exposure to hepatitis B take a preventative medication to prevent reactivation of hepatitis B. All patients should receive medication to prevent reactivation of shingles or herpes viruses, and that's acyclovir similar to the way we do with a lot of other multiple myeloma therapies. Antibiotics that prevent pneumocystis pneumonia like Bactrim, prevention against Covid 19 with vaccines, Evusheld, and if patients are infected to receive antivirals like Paxlovid. And most of our patients on Teclistamab are receiving antibody replacement therapy. So we call this intravenous immune globulin. This is just to try and replenish the antibodies that the patient's immune systems cannot make because of the effect of Teclistamab on the normal plasma cells in the body. And then the managing low blood counts, and this is mainly in the early months of therapy, but occasional blood transfusions and then occasional use of Filgrastim for low neutrophil counts.

So just to reiterate again, some of the differences between bispecific antibodies and CAR T-cells, and these are mainly logistical differences. And so bispecifics can be started right away, they're medications as opposed to cellular therapies. And so they can be started without the need to schedule a manufacturing slot or wait for manufacturing like you do with CAR T-cell. Now suddenly this may change with CAR T-cells over time, there's a lot of new technologies to make it easier to manufacture CAR T-cell and to make it faster to manufacture CAR T-cell, so the patients don't have to wait as long. And so these are all, consider all of these moving targets. The availability of bispecifics, we expect to be pretty readily available, and to be available even in not specialized centers. So hospitals that will give bispecifics will be required to have some training in the toxicity management by the FDA, but it's not quite as elaborate as the specialized cellular therapy infrastructure and expertise that's required to give CAR T-cells.

As I mentioned, Bispecifics are mostly being studied as indefinite therapy right now. But it's possible that with time we'll learn that patients may not need to continue treatment forever. CAR T-cells are a one-time therapy and they work for a long while as a one-time therapy. And then bispecifics are perhaps a bit safer but also perhaps a bit less potent than CAR T-cells. And I want to be very careful about being too certain about that, because it's still very early days, whereas CAR T-cells may be higher risk for severe toxicity, but still even with CAR T-cells, most toxicities are manageable and reversible.

So in addition to Teclistamab, there are many other BCMA targeted bispecific antibodies in development. And then in addition, we are going to see, hopefully... I mean we've been getting data for the last couple years on a drug called Talquetamab, which is a bispecific antibody that targets another cell surface molecule on myeloma cells called GPRC5D, and a drug called Cevostamab, that targets a molecule called FCRH5. And it's very exciting to see that, even some data coming out now that patients can move from one of these to the other, if one stops working, the other one can work. On the clinical trials there's been some experience moving between these agents, and that's very encouraging that you don't have to pick one of these necessarily, but you can plan to give all of these at some point in patients multiple myeloma journeys. So in terms of some questions, I would say that we don't quite know how to sequence and choose among these advanced therapies yet.

The way I think about all multiple myeloma therapy is that we try to give every patient a try with every promising therapy. And there's a little bit more art than science to how we pick one versus the other at any given time. And we're still learning about the patterns of response and resistance, and which might be the one, the best for any patient at any given time. And so for sake of time, I'm going to skip over these. And, some of these questions will probably come up in the questions and maybe we can talk about future therapies coming down the pike as they come up in the questions. But I thank you all very much for your attention.

Dr. Brian Durie:
All right, thank you. Actually, I mean, my suggestion... These last couple of slides, it might be worth to comment because we do have some time for questions, just to touch on them. This one and then, yeah.

Alfred:
Yeah.

Dr. Brian Durie:
Just take a moment. It's fine.

Alfred:
Sure, sure, sure. I'm always mindful of the time, but yeah, so just some questions that I think, that I've gotten a lot of from our patients, and from our colleagues as we think about actually using these therapies in the clinic, off clinical trials. So can we start bispecific antibodies outside the hospital? So that is, nobody likes to be hospitalized and hospital beds are precious these days in terms of availability. And so I think in the future we'll learn more that might allow us to start bispecifics without hospitalizing patients, or at least identify patients who are at low risk for those acute complications that require management in the hospital. What we don't like to do is start a therapy though, where we know a patient's going to have to go to the emergency room with a fever sometime in the first week. If that's the case, we'd rather just start it in the hospital, excuse me.

Maybe we can identify patients where the risk of that cytokine release syndrome and neurologic toxicity is lower, and we can maybe start those patients outside the hospital. I mentioned already the question of whether indefinite therapy is really required for bispecific antibodies. There's a real question about whether these therapies can be moved into earlier lines of therapy, and there are lots of clinical trials going on with that. I think in some ways these therapies are the most potent therapies that we've ever had for multiple myeloma. And so it may make sense with time to use them earlier on. On the other hand, it may make sense to save them because they're so potent until later lines of therapy. And it will take a lot of clinical investigation, I think, to figure that out. And everybody has a lot of ideas about this, but I think really this is something that needs to be tested for us to be sure. Should we be combining these medications?

And so, the traditional approach in multiple myeloma therapies has been to find safe therapies and then start combining them. And so much progress has been made for multiple myeloma patients with that approach. I think it is really a question though, whether combining CAR T-cells with other myeloma drugs really add something. Maybe these therapies are so potent on their own that a combination doesn't really add very much except side effects. On the other hand, we've seen transformational effects with prior multiple myeloma therapies by combining them. And I think this is something also that really just needs to be sorted out. And then of course the question with all these medications is their cost and how accessible they're going to be, and the strain they're going to place on our healthcare system. They're all very expensive medications. Of course, all multiple myeloma therapies these days are expensive, but we need to think about how to make these affordable and accessible to all patients with multiple myeloma.

Dr. Brian Durie:
Before you move on, just on that slide, if we go back, you emphasized the occurrence of infection, pneumonias an 18%, problems with COVID an 18%. How frequently did this result in therapy actually being discontinued, because of concerns about the infections that had evolved?

Alfred:
Yeah, not... I don't think patients were generally permanently discontinuing therapy because of infection, certainly interrupting therapy.

Dr. Brian Durie:
Interruptions, but not-

Alfred:
Yeah. Yeah.

Dr. Brian Durie:
Okay.

Alfred:
Exactly. And what's impressive, some patients have... The responses to the bispecifics are so good sometimes that patients can often hold therapy for a very long time, because in some of our patients you had prolonged Covid, courses were off therapy for months and still didn't have the myeloma progress. And then once they recovered from the Covid, they resumed the therapy.

Dr. Brian Durie:
Okay. But mostly there's a intent or a plan to go back on the therapy if possible.

Alfred:
That's how, in most of the clinical trials, that's how they've been studied. Exactly.

Dr. Brian Durie:
Okay, thank you.

Alfred:
Sure. And then in terms of future directions, and so I think as exciting as these medications are, I think in their classes, they're sort of the first out of the gate of this general strategy. And so, I mentioned CAR T-cell and bispecific antibodies against non BCMA targets, those other targets, we already know that...

Alfred:
It's against non-BCMA targets. Those other targets, we already know that those have preliminary evidence from clinical trials that those drugs work and it will just take a time to figure out how well they work and how they would be integrated with the other therapies. In addition to CAR T-cells, there's something called CAR-NK cells that are promising. This is just engineering another type of immune cell to express a CAR as opposed to a T-cell. And some of those are entering clinical trials. And we know from lymphoma that that approach can work in clinical trials at least.

There's something called trispecific antibodies which is adding in another target to the antibody. And so we mentioned that bispecifics grab a T-cell and grab a myeloma cell, but maybe you can grab a T-cell and activate it in just the right way by adding in a third specificity to the antibody. And that's the technique that's making its way into clinical trials. And likewise, just like CAR-NK cells, you can imagine bispecific antibodies that instead of grabbing a T-cell with the other arm, they grab a natural killer cell and that's another way to activate the immune system. So these are all therapies that kind of have these mechanisms that are actually either in early phase clinical trials or making their way there soon.

Dr. Brian Durie:
Very good. I think that was helpful. Just a little more detail there. So really wonderful presentation actually given the current situation. And maybe what I can try to do is to roll you through some of these questions that have been coming in about CAR T-cell and bispecifics. One thing I think may be quite important, why do CAR T-cells die off and disappear from the body? I mean do you want to comment on CAR T-cells, the impact of the initial infusion and then how important is the persistence of the T-cell over time in terms of as you said, immune surveillance and preventing maybe relapse, and what about maybe the longer time toxicities related to that?

Alfred:
Yeah. So this is a really I would say complicated area actually. So if you look at some of the initial patients who were ever treated with CAR T-cell, were patients treated with CAR T-cell targeting CD19 and these were patients with another B-cell lymphoma called chronic lymphocytic leukemia. Some of those patients who got CAR T-cells over 10 years ago, they still have those CAR T-cell in the body and active. So not just floating around but actually still able. And the way we know this is because these patients don't have any normal B cells and so when you target CD19, you're targeting leukemia cells but also targeting normal B cells. And so you can look at these patients and see if they have any normal B cells in their body and they don't, which means the CAR T-cells are still active in the body 10 years down the road. Only some of them though.

And it's really been hard to predict which patients can have that very long lived activity of the T-cells in the body. And I have to say when the CAR T-cell field started, that was the hope that you would be giving this living therapy that would patrol against the malignancy for years and years and years. And that does seem to be the case for a small subset of patients. What we've learned with time though is that the propensity for that long lived CAR T-cell activity in the body probably varies by the disease you're treating with CAR T-cells and by the target and the CAR T-cell design itself. And I think the best evidence we have for multiple myeloma patients and with time even with patients treated with other CAR T-cell is that for most patients what you get with CAR T-cell is a relatively brief wave of T-cell activity in the body that lasts probably a few months and while you might be able to detect some CAR T-cells hanging out in the body years down the road, they are probably not active.

And there's a lot of effort underway to try and understand why that is and how to kind of promote longer lived activity of CAR T-cells in the body. But that's probably especially important for multiple myeloma patients. And so multiple myeloma is a stubborn disease and even if you kill off 99.999% of the multiple myeloma cells, those few that stick around seem to be able to relapse the disease even years later. And so in multiple myeloma especially, it might be nice to have a CAR T-cell that lived in the body and was active for years and years on end to prevent that relapse. But that is not what we have right now with CAR T-cells for most patients. For most patients unfortunately we see, I mean fortunately unfortunately we see tremendous responses but not everybody seems to be able to completely eradicate the disease or patrol against the disease forever and ever. And so we see patients remaining at risk for relapse after CAR T-cell therapy even if it's years down the road.

Dr. Brian Durie:
There is a related question in my mind at least, which is the question about the possibility of second cancers with CAR T-cell or bispecifics, which could be the two edges of the sword. As you said, if you have continued suppression of normal B cell and other activity, that could be a negative in the longer term. Yeah?

Alfred:
It certainly would put you at more risk of infection to have that kind of long lived activity. And in fact we see the infection risk we see with bispecifics against BCMA may be mimicking the effect of long lived CAR T-cell activity because that's what you're getting with bispecifics because you're continuously dosing. It's kind of like a long lived CAR T-cell activity in that way. In terms of risk of second cancers, I don't, in patients treated on the cilta-cel studies, there were a few patients who developed acute leukemias down the road while the myeloma was in remission. I don't know that that is an effect of the CAR T-cells necessarily as opposed to these are patients who had really advanced myeloma that had been treated for years with different therapies and their bone marrows were at risk of developing a leukemia and just Cilta-cel allowed them to have myeloma under control long enough for that to happen.

So I don't know that we have data right now suggesting that long lived CAR T-cell activity put you at risk for other leukemias. In fact some of the long-term follow up studies of those patients who were treated with the early CAR T-cell studies going back 10 plus years ago, the safety of those CAR T-cells have stood up very well. And especially if you consider what the relevant alternative is for those patients, it should be continuous therapy with other therapies that are probably more toxic.

Dr. Brian Durie:
Yeah, so personally, I haven't seen indications of that second cancer problem, although obviously it's a natural concern. There are a lot of questions about, obviously as you emphasized on, Beth, we've all emphasized that these therapies are available later in the disease for or more relapses, but patients want to know, well what about earlier in different phases, maintenance or early relapse, so what's your perspective? In fact, we could all give our perspective on how do we see this evolving over time.

Alfred:
Yeah, this is one of those areas where we can all speculate a lot. I mean I would say that there are trials going on with CAR T-cells and bispecific antibodies in all lines of multiple myeloma therapy. And so again, Beth and Vincent both emphasized the importance of clinical trials. And I agree if you're motivated to do so, I think this is an area where participation in clinical trials can really help us learn and I'll try to avoid kind of speculating on where I think in the years from now where they're have to be most effective.

Dr. Brian Durie:
So Beth or Vincent, do you want to comment on trials or speculate?

Beth Faiman:
My mic is on, so I can go next. I come from the 1990s, like many of you on this call where we had very few effective therapies and I see that with very little therapy, some people could do extremely well for many years. So learning more about the biology of the disease, well-designed clinical trials, those are ways we can figure out when to use these, the bispecifics in CAR T-cell therapies early. Because quite frankly, if I can administer some standard therapies such as the VRD or DARA-RD and then we can have some nice disease-free intervals with just a little bit of maintenance therapy such as the Revlimid or [inaudible 02:12:52], that's probably where I'd still go first. I know there's smoldering trials with bispecifics, right? There's lots of studies open now early on.

Dr. Brian Durie:
Right. Vincent, thoughts about this, how do you see this evolving? Obviously there are a lot of issues from access to toxicities to costs to efficacy benefits, but what do you think? Oh, I think you're on mute maybe.

Dr. Vincent Rajkumar:
Sorry, Brian. Couple of things is many of these new treatments have been approved with single arm trials and that has enabled us to have access to these treatments early rather than wait for the randomized controlled trials, in which case we have to be willing to put up with the fact that these are approved only for the fifth line or higher. And that's because that's where the FDA was confident that the data shows the clear benefit, clinical benefit. Surely as the trials are being done in earlier stages of disease readout, the companies will go and try to get approval for earlier lines of therapy.

We were at an FDA meeting a few days ago and all of us emphasized that in the future, rather than specify the number of lines of therapy like four, five, six, to just specify what classes of drugs the patient should be refractory to and just that because sometimes nowadays you can be refractory to three classes of drugs with one line because of DARA-VRd and if they progress on that and DARA-KPd, CAR T and bispecific are the best option, but you can't get it. And so then people are giving two unnecessary lines just to get the fourth line completed. So we made that case before the FDA and they heard us, we'll see what happens.

Dr. Brian Durie:
Yes. Yeah. But I mean I fully agree is that it's obviously promising, but I mean we need trials and there are just so many issues to think about. I certainly support the idea if a triplet can do the job, why have a quadruplet? Well, I still see patients who are on the 077 trial, they had their triplet and I don't know how long trials normally last, but I still have patients who are logging in on the triplets. It's remarkable and gratifying to see that.

Alfred:
And I would emphasize that when we talk about moving some of these therapies to earlier lines of therapy.

Dr. Brian Durie:
Yes.

Alfred:
Safety is paramount, right? And so for patients because of how effective standard myeloma therapy is, I would feel really bad as a clinician having one of these really bad toxic outcomes in a patient in an early line of myeloma therapy. And so we've seen with CAR T-cells for instance, that there are these occasional severe neurologic toxicities like parkinsonism developing in patients. And those are reasonable risks to take when patients have very few other options. But it may not be a reasonable, it is not a reasonable risk to take when we have such safe and effective early line myeloma therapy right now. Now some people think that as you move those potent immunotherapies to earlier lines of therapy, maybe the risk of those toxicities goes down because there's less myeloma around to excite these cells. But that's really a hypothesis that remains to be tested.

Dr. Brian Durie:
We need to demonstrate that. Yes, for sure. There are a number of questions that relate to CAR T and bispecifics related to higher risk. Those one here right now related to the 11;14, there's about extra majority plasmacytomas, my sense is that patients with high risk have been responding. Do you want to comment on that?

Alfred:
Yeah, so I think high risk patients respond to these therapies and we've seen patients with extramedullary disease respond to therapies. I would say that we talk about risk status, but to me, anybody who got on these clinical trials has high-risk disease because these were all for trial patients who have become refractory to the major multiple myeloma therapies. And so at some point, even somebody who might not have started at high risk but has had myeloma for seven, eight years and made their way through all these therapies has high risk disease at that point just by the way their disease has become resistant. And so we've seen really amazing responses in patients with really advanced myeloma that have been through a lot of therapies.

I suspect that some of the predictors of shorter response and less response that have been the rules for all myeloma therapies will probably apply to these as well. The patients with extramedullary disease might have a tougher time. Patients with some of the high risk cytogenetic abnormalities will have a tougher time. But I still think they're worth trying for all those patients because I think the trials show that those patients can respond also.

Dr. Brian Durie:
Right. Those couple of questions are very heartfelt message coming up, which I think maybe we can comment on. One which is important and we don't pay a lot of attention to this, is are there individual differences in BCMA expression or CD38 expression that could be used to fine tune treatments moving forward?

Alfred:
So as it relates to BCMA expression, at least with a patient's first exposure to anti-BCMA therapy, the studies that have been done so far that are small, they do suggest that some patients have higher or lower BCMA expression, but the patients with high versus low expression seem to have similar responses. And so that's probably not a method for the initial selection of a BCMA directed therapy. We have learned though, and this is really from individual case reports, and so we still don't know how frequently this happens, there is some risk after exposure to a BCMA directed therapy that the myeloma when it progresses might not have BCMA on it anymore.

And you know, you would expect then that those patients might not respond to another therapy that targets BCMA. That's probably a minority of patients though, and we're still really learning about this. And even though it sounds straightforward, even figuring out how to properly assess whether a myeloma has BCMA is not a totally straightforward thing. For example, maybe there's a tiny amount of BCMA there and what tests do you use to detect that BCMA? How sensitive is it? How do you put that into practice is still a work in progress. And so I anticipate in the future that will be as we have more and more therapies to target BCMA that will be asking our pathology friends for help and how to characterize BCMA expression on myeloma. But we haven't figured out exactly what the right tests are for that and what those tests mean.

Dr. Brian Durie:
Right. Circulating BCMA levels or like that.

Alfred:
Yeah, exactly. Yeah.

Dr. Brian Durie:
Yeah. So Beth, there is a heartfelt question here that maybe we should comment on, which is that we talk about we're searching for the cure and we're searching to try to have the best results, but for now, a majority of patients will be coping with relapses and looking for new therapies and that we need to be cognizant and focused on helping patients who are maybe not going to be cured and are facing true palliative care at some point. And this is hard for all of us. I don't know if you want to comment on that.

Beth Faiman:
Right, thank you. That is one of the big challenges is that the majority of patients will relapse. There will be a small percentage, 17-20, sometimes lower depending on the study that you're looking at who will never need another treatment. And so they're functionally cured, which is great news, but you still have to support them through all of this. So that's my plug for making sure you get a second opinion from somebody who specializes in myeloma so you can access the resources of that myeloma center. So a lot of the community practices do a tremendous job and still have lots of resources, but there's no harm or shame in going and accessing the larger center where they might have more well trained palliative specialists, for example, who can find the right medicines to support your symptoms or resources such as social workers or financial coordinators that can help you navigate that process.

So building your team, knowing who's on your team, having that specialty center as well as the community center is really important. And even if you are at a big center and you're not finding that you're getting the answers that you need or the support you need for your neuropathy symptoms, your chronic pain symptoms, et cetera, it's okay to get a second opinion from even within your center if that's something that you feel right. And then finally, the last thing I'll another plug for caregivers and care support. Not everybody has a caregiver and talking to your healthcare team about the lack of a caregiver helping to find some formal or informal caregivers or support you through that as well is really important.

Dr. Brian Durie:
Absolutely. Absolutely. And I mean we never take it for granted. I mean, having myeloma is not the same as not having myeloma. When you have myeloma, that changes your life. And I think that we all are here to try to help our patients cope with that and manage expectations and hopes for the future as best we can. And we certainly are trying to do our best with that. Did I say that 11;14 is high risk? I don't think I said that. I don't think 11;14 and Vincent you might want to comment on this, but we used to say that 11;14 was good risk, I think we've decided that maybe it's not good risk but it's not high risk, right?

Dr. Vincent Rajkumar:
That is correct. I think it's still considered standard risk and let's leave it like that.

Dr. Brian Durie:
Right, exactly. Is a triplet, considered a single line of therapy. Yes. What about accessibility for clinicals in the US for non-US citizens? That is complicated and expensive, unfortunately. Yeah. Vincent, do you have patients in trials, non-US patients in some of your trials?

Dr. Vincent Rajkumar:
Well, it's a very big topic to take on, but in general, it's not whether they are US citizens or not, it's whether they have US insurance or not. Uninsured patients usually pay higher costs, higher dollar amounts for every treatment. And that's because insurance companies get negotiated, rebates, and lower discounts. There are some trials that companies are starting to invest in, which will be called the "All In Trials" where they pay for everything, not just what's standard of care and they will just cover only the whatever's non-standard of care. But to improve accrual and to improve access and to reduce disparities, they are trying to do these All In Trials where they'll cover everything. Those trials would be things that anyone can make use of and they won't incur any costs with that.

Dr. Brian Durie:
Right. I'll just comment that in our Asian Myeloma network trials, one thing we've started is that we have changed the entry requirements so that we can bring into the trials a lot of patients who have previously been excluded from trials. And so that has been a helpful thing to broaden the access to the drugs which are available for free within the trials to more patients who can have benefit from them.

Alfred:
And I think more and more and more we've seen sponsors have explicit commitments to enroll a certain percentage of the trial from populations that are typically underrepresented in trials. I think I would just sort of advocate for all our patients on the line and all the advocates and all the organizations to continue to speak about that whenever you can because it's so important, first of all that these drugs are studied in the population in which they're eventually going to be used. And also that in trials are an important way for patients to access new therapies early, on earlier than they might otherwise have available, and making sure that that access is equitable across the patient population is really, really important. So everybody should, every time they have a chance to talk to somebody in a physician of influence, should advocate for that I think.

Dr. Brian Durie:
Right, right, right. One question, maybe you can just comment on Alfred. Are there studies looking at CAR T re-dosing? I know in the BMS product there was a study with that. Are there any new trials looking at followup dosing at six months or the like?

Alfred:
Yeah, so there's a couple different variations on that theme. And so one is to look at patients who got treated with different CAR T-cell, so progressed on one CAR-T trial, move to another CAR T-cell trial and we have seen some reports of that be successful. I believe the group from Fred Hutch has where they were using a CAR T-cell developed at the Hutch and Memorial Sloan Kettering has presented that they saw very good responses in a handful of patients who had progressed on a prior CAR T-cell, and I think we'll see more and more of that as there are more and more CAR T-cells brought into trials. There's a second question of responding to the same CAR T-cell again. At least our personal experience using our CAR T-cell developed at our institution was that we didn't see really good responses trying to re-treat a patient who had progressed right after that CAR T-cell.

And anecdotally, I've heard similar reports from the other CAR T-cell programs and that's a little bit hard to understand. I think there may be immune responses against the CAR T-cell. So the CAR T-cell all have on their surface these receptors that the patient's immune system could recognize as foreign antigens and mountain immune responses against. And that may mean that when you try to introduce that CAR T-cell again, some monster years down the road, your body has an immune response again, that particular CAR T-cell. But that's just a guess and the mechanism, the reason why patients don't respond to repeat dosing with the same CAR T-cell, I don't think has been fully figured out. But there is a sense that re-dosing with the same CAR T-cell is probably not a winning answer for most patients.

Dr. Brian Durie:
Yeah, I was thinking the same thing. One thing with the questions here about it, cell mods, we didn't talk about it. Vincent, do you want to comment? I mean the cell mods are kind of promoted as sort of the next generation image. We have Revlimid, we have pomalidomide, and then we have a couple of cell mods in trials. And these are active in patients who have previously received Revlimid or pomalidomide. And I mean how do you view those moving forward?

Dr. Vincent Rajkumar:
So the main thing is that they both are active in studies that have been done so far, mostly in combination with dexamethasone.

Dr. Brian Durie:
Right?

Dr. Vincent Rajkumar:
And without any control group. What we don't have is a control group to know how exactly they would work compared to lenalidomide or pomalidomide to get the sense. So the two ones are iberdomide is one and the other one is 92480. Both have shown activity and relapse-refractory myeloma. The trials ongoing will first try to show that they fulfill an unmet need and they're better than standard therapy. But eventually, if and when they come to clinical practice, our goal will be to see do they offer something beyond pomalidomide or lenalidomide earlier on, or do they work in people for whom pomalidomide might have stopped working. So that'll take time, but both are in clinical trials.

Dr. Brian Durie:
Yeah, exactly. Exactly. One other comment I'll just make in closing here is there've been questions about, I'd mentioned biochemical relapse and relapse that might need therapy. Obviously there are two perspectives there. One is that when you treat relapse early before a lot of symptoms emerge, you're likely to have better results. And so we certainly don't want to wait until a patient has a full blown relapse. However, we are also aware that some patients can meet a criteria where the protein level has increased to where they've technically stopped responding or relapsed, but they may or may not need immediate therapy.

And so I guess one important thing for patients to be aware of, even although maybe you come off of a trial because of the protein level, it may be that you don't immediately need to have some aggressive new therapy. So maybe I'll leave it at that for now. So this has been a fantastic webinar. I think a lot of very, very important questions have come up. We obviously thank our sponsors again, whom I identified at the beginning. Very, very good. Any final thoughts from our speakers today? Thank you for the immune therapy updates. Any final words of wisdom from you?

Alfred:
No, thanks very much for having me. It's been fun.

Dr. Brian Durie:
All right. And Beth.

Beth Faiman:
Thank you so much for the honor of being on this panel. I just wanted to say one last thing that I didn't include is the importance of shared decision making. You have a voice in your treatment just like Dr. Durie just mentioned, just because you meet criteria for relapse, have that discussion with your treating team, do you need treatment now? And what are your options? And really have that discussion as soon as you can so you can plan it out so you're not rushing when you do need to change treatment. And don't forget you are not alone. Go to the IMF website myeloma.org. They have lots of good resources.

Dr. Brian Durie:
Thank you so much Beth for that. These are words of wisdom. It's important. Occasionally we need to rush to bring down a calcium level or give radiation to a spinal collapse or something. But mostly, it's good to just think about things a little bit and come up with your best decision, shared decision making. Vincent, final thoughts?

Dr. Vincent Rajkumar:
Oh, thanks again, Brian, for having me. And thanks to Beth and El, beautiful presentations and I'm sure patients have benefited a lot. Thanks to the IMF for continuing to do these patient-family seminars frequently so that we can keep our patients updated. Very few other resources like this exists. So thanks Brian for your leadership.

Dr. Brian Durie:
All right, thank you so much Vincent. So it's obviously our pleasure to try to keep people up to date and answer some of these questions and please reach out by telephone or email and we'll try our best to follow up with some of the questions that we didn't get to specifically. So thanks again to our sponsors. And then if we click forward, we are interested in your feedback and so if you want to give us any thoughts, we appreciate it. Thank you for participating. Enjoy the rest of the day. Enjoy this weekend. Yeah, here is the link where any feedback that you can give us, we very much appreciate it. So thanks to our panel, I'll offer Beth and Vincent for setting aside this part of the day. Have a good day.

Dr. Vincent Rajkumar:
Thank you.

Dr. Brian Durie:
Thank you so much.