IMF Patient and Family Webinar 

- Well, good morning and good afternoon, everyone. Thank you for joining us for the International Myeloma Foundation's patient and family webinar on Back to Basics: From Testing to Tailored Therapy. I'm Robin Tuohy, Vice President of Support Groups. Today, we'll hear from IMF chairman of the board and scientific chief, scientific officer, Dr. Brian Durie, discuss myeloma 101 recommended testing and monitoring algorithms for 2022. And Dr. Durie, if you would like to start this off, we'd love to hear from you.

- Okay. Well, thank you Robin for that brief intro. Obviously, we're very pleased to have you all joining us today. And as Robin said, this webinar is Back to Basics. We've had a number of webinars in the last 2, 3, 4 months, and many of these have been highly technical. Actually, the last couple of webinars, one was from ASCO and EHAK, where we reviewed all of the scientific abstracts that were presented, which I think are very, very good and very informative, but maybe taking us away from what's required for data daycare of myeloma. So we're going to try to bring it back to some of that basic information about testing and monitoring, basic care, initial therapy and relapse therapy.

So joining us today, very, very pleased that Dr. Paul Richardson will be joining us from the Dana-Farber, and he will be talking about approaches to frontline therapy. Mary Steinbach will be joining us. Very, very pleased to have her coming from Huntsman Cancer Institute in Salt Lake City. And she will be talking about myeloma, managing myeloma care, particularly from the perspective of the Nurse Leadership Board. And especially pleased to have Saad Usmani from now Memorial Sloan Kettering in New York, cancer center in New York, who will be talking about relapse therapy and with a particular focus on some of the newer immune therapies.

So, thanks to our panelists for taking time out of the weekend, very, very busy times for all of us. So, I'd like to obviously thank our sponsors. We are very grateful always to our sponsors, especially when we have in-person meetings that we're hoping to get back to soon, but even supporting these webinars. We very much appreciate the support of Amgen, Bristol Myers Squibb, the Binding Site, Genentech, GSK, Janssen, Karyopharm, Sanofi and Takeda Oncology. And then moving forward, perhaps I'll talk to you, Robin, for a moment, if you want to go through with the audience, the Q&A, and the survey information.

- Yeah, sure, Dr. Durie. This is so important and we definitely want to hear from you. It's going to be a very interactive program. So you can see on this slide here, there are some instructions on how to participate. You simply open up that Q&A window, allowing you to ask those questions to us. And don't forget, if you don't get your question answered, we do have the IMF info line available to you. You could see the number right there, 1-800-452-CURE, or you could email them at [email protected]. And another important part of this program is we always wanna hear from you. So at the end of the program today, we're going to have a survey. It's a very short survey, and it's gonna help us to make sure that we're always responding to those things that you feel are most important, so we can bring you most valued programs. So please at the end, take a moment to participate in the survey. And Dr. Durie back to you on the program today.

- Well, thanks Robin. Yes. So the overview of the agenda is here on slide number five. I will be speaking first, the Myeloma 101 Back to Basics. And then as indicated here throughout the webinar today, there is plenty of time for questions. After those first questions, Dr. Paul Richardson will talk about frontline therapy and then we'll have a break of 15 minutes, and then come back with Mary Steinbach, talking about managing myeloma care, and then Saad Usmani, who will talk about relapse options. Looking at agents that have been FDA-approved on clinical trials for quite a number of exciting agents that are moving forward toward approval. Okay. So, with that said, I will go ahead with the first presentation, Myeloma 101 Back to Basics. As I said, this is to focus on some of the basic testing and monitoring that's required to assess, first of all, the diagnosis and then the monitoring of response to treatment. So again, these are just the topics for today, moving forward into frontline, managing care and choosing and sequencing therapy. Okay.

So, what are the most important tests that are needed for diagnosis and monitoring? And it's rather straightforward, actually, the basic testing that you need to keep track of. And we do have rather a good area on the myeloma.org website under what is myeloma, which indicates a lot of the information that I'm going to be presenting to you in the next few slides. You can look and see, for example, there's a very nice segment about interpreting your lab tests. You know, what is the importance of your hemoglobin? What is the importance of your white blood cell count, your platelet count, your kidney function test, all of these different things. And so I just referenced that so that you can go in more detail and check some of those things out.

But the routine blood counts are very important. One of them being that one of the ways that myeloma can be diagnosed is if you develop some anemia, so where the hemoglobin is low. And so that may have been the case for a number of you where you were being tracked along, perhaps by your medical doctor, your internist, and were found to have some reduction in the hemoglobin develop some anemia, or possibly some reduction in the white blood cell count, or the platelet count, the other two main blood count test results that come back on what's called the CBC, the complete blood count, which you would normally have done at each of your monthly or every three week or so visits. Then of course, the chemistry panel is also done routinely. And we are particularly interested in the serum creatinine test, which is the test for kidney function and also the blood calcium test. Although for most patients under treatment, the serum calcium is typically normal. And initially, we do carefully test the urine to see if any myeloma protein, particularly light chains, which flow over into the urine are present in the urine. But the key testing for myeloma that is done initially and periodically to keep track of the myeloma is SPEP, the serum protein electrophoresis, and IFE, immuno fixation. So on the SPEP, what that shows you, if I could just go forward here. Oh, no, I'm sorry. I thought I had a picture of it.

So, on the SPEP, the spike protein is present, and you can see what is the amount of the myeloma protein. And so myeloma cells, which are present in the bone marrow, they produce this protein, which we call the monoclonal protein, the M protein, or the spike protein. And on the electrophoresis, the SPEP, you can see the amount of the protein. And that is very, very crucial at the time of diagnosis. And then also with each visit to see if you are responding to treatment, or if there has been some change, whether the myeloma is increasing again. On the immunofixation, the IFE, this is especially important at the beginning, because this tells you the type of the myeloma protein. And so, the commonest is that the myeloma protein would be, IGG, which can be CAPA or Lambda light chain type.

The next most common is IGA and it can also be CAPA or Lambda. And the next most common is where it would just be light chain alone, where it might be just CAPA or Lambda, in which case this would be picked up by the light chains being in the urine, or with an elevated free light chain level in the blood, which is under bullet number three, where the light chains are increased CAPA or Lambda. And then the ratio of the abnormal to the normal, the let's say, CAPA over Lambda, if it's a CAPA myeloma would be increased. And so these are the fundamental tests that tell you the amount of the myeloma at the time of diagnosis.

And then at each of your checkups, you can see whether the amount of the protein is going down, which will be reflecting the reduction of the myeloma in the bone marrow. So at the top of the slide on the right, you can see the bone marrow is packed with all of those blue and purple cells, the myeloma cells. As the myeloma protein comes down, that is telling us that the number of those myeloma cells is being reduced. And so fortunately, we don't need to be rechecking that bone marrow all the time because the blood and the urine give us an indication that the myeloma is responding.

Now, when we do that initial bone marrow, it's also important to do this test, which is called the FISH analysis, which is Fluorescence In-Situ Hybridization. And so this is a test where the chromosomes are light up in different colors. And you can tell if there has been a switching of chromosomes to give abnormalities, some of which may indicate a pattern, which we would call a higher risk, which I'll talk about in just a moment. A majority of patients with myeloma have some problems with the bones. And this is something that shows up on x-rays or some type of imaging.

Now on the bottom right, you can see a picture of an arm, a forearm, which has lots of dark spots on it, which indicates areas, which have been damaged by the myeloma. And so basically, when the myeloma is growing, it triggers the destruction of the bone around where the myeloma is located and growing. And this is what we call a lesion. So you may hear some discussion that there are lesions in the bone, and that means it would be like one of those dark spots that you see right there. Now, when it shows up on an x-ray, that is fairly advanced. Many times these days, we pick up changes, which are much, much less than this, which show up on an MRI or a CT-scan or a PET CT-scan. And so this next slide just shows you some more details.

Over on the left here, you can see a picture of the FISH testing in the bone marrow, and it shows the bone marrow chromosomes. This is the chromosomes of the myeloma. So we're interested in what are the chromosome abnormalities of the myeloma cells themselves. And so if you have two color spots, like one is red, and one is yellow, which come together, that means that these two chromosomes have switched and come together, which is what we call translocation. And so this particular slide shows translocation 11;14 coming together as a red and yellow there. And so this is something which is linked with a particular pattern of myeloma. And we'll talk a little bit about how that might indicate a need for different treatment. Then over on the right, you can see how using MRI or PET CT scanning, you can see details of myeloma in the bones in a much more precise way. And you can see F, where there are focal lesions, and D, where there is more diffuse involvement, for example, in the spine.

The PET imaging is one positive emission tomography. This is where a small amount of radioactive sugar is injected and where the myeloma is active, it takes up the sugar. And so on the PET scan, it's very, very useful to see, not just where is the myeloma, but is the myeloma active. And that is particularly useful for follow-up monitoring where you can see is the myeloma still active in the spine or elsewhere where there may have been a focal or diffuse lesion. So at the time of initial diagnosis, we have for many, many years used what we call the CRAB criteria, which indicate that myeloma is active and is causing some problem, which can be increasing the blood calcium, causing kidney damage or renal damage. As I mentioned, causing anemia or causing damage to the bones, which could be picked up on x-rays or now more frequently on MRI or whole body, low dose CT, which is available in many centers now, and can be used as a screening for all the bones. Now, five, six years ago now, we introduced a new category, which is a PRE-CRAB. It's a earlier diagnosis for myeloma before the onset of any of these CRAB features. And so there are three indicators of that.

One is where the percentage of plasma cells in the bone marrow reaches a level of 60% or higher without actually causing bone damage where the serum free light ratio is at least 100 on, and where at least two or more lesions are found on MRI. This is an indication that treatment is indicated, and this gives the opportunity to get myeloma under control before bone damage and other problems like kidney problems have emerged. And so this is the way forward for myeloma treatment to try to introduce therapy as early as possible to achieve the best results. And so, we're looking at that in the same way with what's called high-risk smoldering myeloma, where the cutoffs for that, where the bone marrow plasma cells have to be at least 20% free light 20, and the serum protein tresis level, at least two grams, and then a new testing, which is 0.02% that is circulating plasma cells in the bone marrow. And so this can be a situation where some type of therapy could be offered either lenalidomide or something more intensive or something to be discussed carefully with your doctor. So if the treatment is working just to refresh these different words that we are using, so PR, partial response, this means that that SPEP, the spike, the monoclonal protein has dropped by half. And so with serial monitoring, we've seen that level of improvement.

With the therapies that we are currently using, things like Velcade, Revlimid index, or daratumumab, Revlimid index, these kinds of things, the improvement occurs rather quickly. And so within the first two or three months, you would certainly be seeing or want to be seeing that this 50% improvement is occurring down to 75%, which would be very good partial response, or we would be keen to see even a complete response where there's no spike evident on SPEP, and the bone marrow percentage of myeloma cells is less than 5%. Stringent CR is where even with immune testing, you can't find any myeloma in the bone marrow, and also the serum-free light ratio is normal. You've probably heard a lot about the deepest level of response, which is called minimal residual disease, where a bone marrow test is done. And we look very, very carefully to see if we can find any evidence of myeloma cells in the bone marrow. And this can be done using sequencing techniques, which are called next generation sequencing or flow techniques, which means that you pass the bone marrow cells through a flow cytometer.

So the cells are passed through, and using different antibodies with next generation flow, you actually use a combination of eight antibodies to see if there's any indication of myeloma cells in the bone marrow. And so, if that testing is negative, if for example, you test a million cells and you don't find any myeloma, then this would be what's called negative at 10 to the minus six or zero out of a million. So that would be, and then 10 to the minus five is a next step lower than that. And so we know that if we can get to that level, this indicates excellent response and definitely improved outcome. And so these are things to be aware of. And so in the big picture to try to achieve those kinds of response, what we're gonna be talking about, and initially Dr. Richardson will be talking about what options do we consider for transplant eligible patients and transplant ineligible patients, obviously initial therapy.

If you're transplant eligible, you will have a transplant and then followed by maintenance transplant, ineligible, some intensification, and some maintenance, and then along the way, supportive care. And Mary will be talking quite a bit about that. Down at the bottom on this slide, Dr. Vincent Rajkumar from the Mayo Clinic, he does a very, very nice update every year of myeloma management for diagnosis, stratification and treatment. And I've added here his most recent 22 link. So these are really, really excellent updates to be aware of. So, in addition to the website under "What is Myeloma?", you can see a lot of information. This is a very good resource.

So what we're gonna be talking about is, and this slide, I've updated it so much over the years, that at the top on the right, I've got so many treatments. Now it's running outta space over on the right. I need to start having a new slide format, but in the old days we had, and this was up until really, the late 1990s. So up until basically 20 years ago or so, we had very limited options. We had old-style chemotherapy. We did have stem cell transplantation. We could use steroids or thalidomide for maintenance, and we really didn't have a lot of relapse options, but now we are so lucky that we do have a lot of frontline options that Paul is going to be talking about. And the big question, as far as initial therapy is, should we use three drugs, which is called a triplet like VRD or a quadruplet, which would be normally either daratumumab or isatuximab plus three drugs.

But then over on the right, you can see I've got two columns of therapy that can be used in relapse setting. And frankly, I think it's quite challenging for Saad to cover all of the permutations and combinations of these different drugs as to what would be recommended if you failed on one, and then you can switch over to the other one. And so this is definitely a situation where you want to have a discussion with your doctor, and possibly, consultation with an expert to review what could be good things to consider. 

You'll see, I've listed over on the bottom of the right, the very exciting CAR T cell therapies with the two, which are commercially available now, Abecma and Carvykti. And then a drug which was approved and then might get to be approved again, which is Melflufen, which was recently re-approved by the EMA, and then a bispecific monoclonal antibody, Teclistamab, where Dr. Usmani has been very, very much involved with the trials and the development of this. And we're waiting, hopefully this is something that will be approved in the U.S. by the FDA in these coming months, rather soon, we hope. Okay. So just broadly so that we have a sort of framework for the rest of the discussions today into the early afternoon, we'll talk about frontline therapy, transplant eligible, as I said, triplet or a quadruplet, non-transplant really, as we'll hear the daratumumab Rev-Dex has produced such good results that really, that has become a significant standard of care in the frontline setting for non-transplant patients, which actually is a majority of myeloma patients.

Then we'll talk about the relapse therapies and the new agents. And so just to summarize the way that we are going to be looking at your response to treatment and your management throughout the course of the disease, I think it is helpful to have kind of a big picture concept. The first one is that with the options that we have, that you're gonna be hearing about from Dr. Richardson, a deep first response can be highly expected. We are expecting you to respond, and you probably will have a great response. We're expecting that. And it could even get down to that level where the MRD, the minimal residual disease is not detected. And if you get down into that good response range, the first remission is going to be at least in the 3, 4, 5 year range. And so this is so much different than it used to be in the past is that we have a high expectation that patients, a majority of patients will do well for those first years.

The next step with close monitoring. And actually a question came in ahead of time asking if you're in this kind of first remission, how frequently should you be checked? So let's say you had a stem cell transplant and everything looks great, how detailed should the testing be? And this person was getting testing done every six months. I think that we certainly want to check your blood, your SPEP and your blood counts and things monthly. We want to keep doing that. If there's any indication at all, then we will do more extensive testing, mostly related to what your problems were when you were first diagnosed, possibly getting new imaging, maybe a whole body low to CT, or a PET CT or something to make sure that everything is continuing to be in remission. And then increasingly, we are ready to jump in with some decisive first relapse therapy.

And this is what Dr. Usmani is gonna be talking about, where we focus on triplets in this setting right now. And we're also looking very much at some of the exciting new immune therapies and in this kind of setting to achieve the very best, second response that we can achieve, which again, can give in many instances now, remission for several years. And so the main thing I want to convey to all the patients today is that you are looking at, for a majority of patients, a significant number of years through the first remission and through into that second phase, which is a much better expectation than we ever did have in the past. And so just to summarize, we're going to be talking about the treatment options, the triple options, sorry, just so we got it clear, and then the Autologous Stem Cell Transplant.

And just to summarize that we use ASCT, Autologous Stem Cell Transplant. And Dr. Richardson's gonna be telling you quite a bit about the pros and cons and the impact of that. And then you'll hear about the supportive care using Zometa/Aredia or denosumab. And so the big picture is get that frontline treatment, look at what's best for maintenance, more and more looking at decisive, early relapse management. And then also, the earlier use of new immune therapies. And as I said, we have a lot of publications online, "The Patient Handbook", "The Concise Review", a number of things where you can search and get your questions answered.

So I'll stop there. And we have a number of questions that have been coming in. I touched on the first question that came in ahead of time. So basically some extra testing, if any of the tests show some changes. All right, so...

- Dr. Durie, I see a couple that could be combined. I see that there's a question about how often would you do PET CT scans and then speaking of PET CT or PET MRI?

- Right. I mean both of those are possible. So maybe I can ask my guests as well, but in general, those are tests that we might do once a year. We don't do those too frequently. Mostly, we're focused on doing them if we had some concern that some of the other numbers like the aspect or the like were changing. And a part of that relates to reimbursement. Plus, you know, we don't want to be doing those things too frequently. So, Saad, maybe you wanna comment, how often would you get a PET CT scan?

- So thank you, Brian. It's a pleasure to be here with you and other colleagues. I agree with your stance. You know, I think early on during the monitoring period, we've put out the International Myeloma working group guidelines on imaging.

- Right, right.

- Few years back. And what we suggest is maybe annual imaging for the first two years, just to see if things are evolving, but then base that decision off of labs and clinical symptoms and really looking at clinical picture. So I agree with your comments.

- Right, right. Yeah. And I see Paul has joined us now, so welcome. Do you have any thoughts about monitoring with imaging? What's your protocol at the Dana-Farber on that?

- Well, good morning, Brian. Good afternoon and good evening to everyone. I just wanna echo Saad's very kind comment. I mean, it's a pleasure to be with you, and thank you so much for bearing with me. Just sort jumping on the call with a few little glitches earlier on there, but suffice to say, I'm very much in line with what you're saying, Brian. I use PET CT skeletal survey and MRIs.

You see, I'm a little old fashioned. I do actually like the skeletal survey. I use it really to get a sense of bone loss because bone mineral density testing tends to be limited really just to the pelvic girdle. And you can use your skeletal imaging liberally in that context to get a better idea. But I love PET CTS, particularly I totally agree with Saad that MRI used judiciously makes sense, but just like you said, Brian, I think imaging has to be used appropriately because of course, as you point out, it's expensive and it's not, you know, we certainly, as patients now are living 10, 15, 20 years with their disease. One has to be thoughtful about quantitative effects of imaging over time. So I do think those are all important considerations, but I'm very much agreeing with what you said.

- Right, right. Yeah, I guess the only small comment about that is that we have had some questions over the years that some patients with myeloma could have second cancers. And so one advantage of PET CT is that if there was something like that going on, it does show up actually, and I have found it useful in that fashion.

- I agree.

- Yeah, yeah.

- So I see, I'm just looking at all these different questions here. Can you determine MRD status without doing a bone marrow? Well currently, no. Although the Spanish team, particularly Bruno Paiva is doing some really wonderful work now where he's looking at using the next generation flow technique in the blood. And he's actually even developed an enhanced technique using an magnetic V approach where you can get sensitivity down to as low as 10th or minus eight in the blood. And so, I think that we might be seeing something related to that coming up at Ash as a matter of fact. And so I am optimistic that maybe in the blood, we can get away from the bone marrow. So perhaps start off, do MRD testing in the bone marrow, but then instead of doing lots of bone marrows, monitor in the blood, looking for myeloma cells in the blood in a very sensitive way.

And then the other thing is to use mass spectrometry, looking at the level of the myeloma protein, using a very, very sensitive mass spectrometry technique, which again, will be available in a more broad way in maybe by next year. This is something that will be more accessible for patients to have this kind of a mass spectrometry. So I think more to come on that. I don't know if Paul or Saad, you want to comment on that or Mary, obviously it would be great to get away from all a lot of different bone marrows. Yeah. All right.

- Dr. Durie, I see that when you were talking about MRI.

- Right?

- And PET CT, I saw a comment that could be important to non-secretory patients and how often it may be important for non-secretory.

- Right? Right. And so that is a good point that if you do not have a detectable myeloma protein in the blood or the urine or very, very low levels, then the imaging does become more important. And so then you rely on that either with more extended MRI, the spine and pelvis and affected areas, or a whole body PET CT. The imaging does become much more important. Plus those more sensitive tests that we're talking about, if you use mass spectrometry, the notion of non-secretory mostly goes away in that using mass spectrometry, you do find a low level of protein so that this new mass spectrometry technique is gonna be very important for that group of patients. And right now in that case, samples can actually be sent to the Mayo Clinic, clinical samples and results can be obtained. And so in that setting, that might be something to consider.

- Yeah. Brian, if I may, I was looking to Mary to Mary to comment on that perhaps and of course, Saad as well.

- Exactly. Yeah, yeah.

- About the MRD question because I think it's such an important one for our patients and yes, I think it's an invaluable research tool. I think in clinical practice, we're using it increasingly, but there's that lovely old saying quote /unquote, "A fool with a new tool is still a fool." You have to use it very carefully and thoughtfully, right. Because we try and get as much information as possible. And I think it really matters in the research setting for sure. But when we assess it in the clinic, we use it with everything else that we can possibly master. So I love your comment about peripheral blood, 'cause I do agree with you. I think if we can get away from having to do marrows to obtain MRD information, that would be wonderful. But what we are doing at the moment with that peripheral blood testing question, as an important new research area, when we do our marrow testing, we do as much as we can in terms of next generation and flow and try and get as much information 'cause you'll be surprised how many, and I'm sure Saad, you've seen this and Mary, I'm sure you've come across it too, where you can get surprisingly dissonant results or you can get MRD negativity on the one hand, but yet under the microscope, couple of us, my colleagues and I have seen tumor cells, even when next generation say sequencing is negative. Rare, but we've even seen that. I love comments from Saad and Mary on this.

- Right.

- Right, absolutely.

- No, I agree with you, Paul. I think developing peripheral blood techniques, I think mass spectrometry probably has the most, potential in terms of disease monitoring, but when it comes to disease biology, I think, Paul highlighted a very important point. Not all myeloma cells secrete monoclonal proteins. And one of the patients in fact raised this question about the non-secretory nature of myeloma as well. And we know that under the rest of therapy, you know, myeloma cells do evolve and don't produce monoclonal protein. So that's where I think we may not be able to get away from bone marrow aspirates, and biopsies all together, but may be able to minimize them in monitoring disease. That would be my opinion. I wish there was an easier way, but the cells are so ingrained into the bone marrow micro environment that I think that's where we get the most biologic information. So it will probably have to be a mix of both.

- Right, right. Right. One comment about the MRD testing and Paul touched on it is I think that we still have quite a bit to learn and part of it is standardization. And so one piece of good news is that for the next generation flow, the company Becton Dickinson now owns the rights to all of the antibodies that are required for that test. And so they are now ready to market next generation flow in a much more standardized way. And so they're submitting their data to the FDA, which includes the kit. The kit will include the eight antibodies in a kit, but also a software package so that there is a standardized readout of the next generation flow. And so with this focus on standardization, it might be, we'll be able to get a little bit more reproducible results. So's something to look forward to.

- Can I jump in here, guys 'cause-

- Absolutely.

- All your comments have been so brilliant. And I always learn from these webinars myself, but I think an important kind of umbrella approach for the individual patient is them and their care team understanding their disease and the correct, perhaps diagnostics that occur and then how to survey their disease going forward, right? So some patients might need a PET CT at relapse.

- Right.

- Maybe a different patient. You could get away with lesser imaging, maybe their insurance forces your hand and you get lesser imaging, but for kind of the myeloma expert and the patient to help become their own expert, understanding the kinetics of their disease, what their primary markers are and how to monitor them going forward is really important.

- Absolutely. We are gonna have to move on here in a minute. I want to be sure that Paul has his full allotment of time here. Someone says, should you have FISH testing with every bone marrow? No, we tend to do that at the beginning. And then if relapse has occurred, we might repeat the FISH testing. So we don't do that on every marrow. You must scroll up just to see if with any others that we should touch on before we move on.

- Dr. Durie maybe one on when we have transplant ineligible patients.

- Right.

- But are we gonna talk about those that are transplant eligible, but choose not to. So delay, this is a big question. Maybe even Dr. Richardson will touch on with the determining trial.

- Right. Okay. So the question is, yeah. So with the therapies in the past, it was more important to decide if you want to have a transplant or not initially, but now with the therapies that we use, that option remains open, you know? And so you could be deciding about that along the way, and I'm sure Paul, you can touch on that.

- Yes, I think we'll come to it and give datas as supportive. But I think that you'll see that clearly in certain patients, Melflufen clearly matters. We really identify that. And obviously, Brian, you touched very nicely on Melflufen as a next gen, a new way of delivering the value of that particular agent, because there's no question Melflufen matters. I think the issue is there's one size fit all. And what we've learned is with the advent of new therapies, we really have options for patients. And clearly for some patients, it's very important to take advantage of the benefit that autologous stem cell transplant can provide. But at the same time to recognize it in others, on the one hand, it may not be needed certainly immediately, it can be kept in reserve. And moreover in certain patients, there may actually be certain disadvantages to be aware of 'cause the data show us. Having said that, you know, we'll obviously go into detail rather than to your point as we go through the frontline options. And it's so fortunate to have Saad with us and of course, Mary, to provide their perspectives as well.

- Right. So maybe just one last comment before we move to your formal presentation, Paul. So there's a question here about, would we recommend starting a patient on treatment related to the flow light, a free light ratio of 150 and 30% plasma cells? I think that one thing that came out was presented in our recent meetings is that you do need to be a little bit cautious just about the free light ratio. There was a presentation that just having the free light ratio elevated was not necessarily always an indicator of immediately progressive myeloma. And so, certainly I would be hesitant to treat a patient just based on a free light ratio without some maybe serial monitoring and the like. So good, good question. To be cautious in this sort of PRE CRAB, high risk motoring category, we don't want to be giving treatment to patients who could maybe be safely monitored for some time.

Okay. Well perhaps we should just move on. We can maybe come back to some of these questions. So Paul, very, very pleased. Thank you so much for setting time on a Saturday to join us. The patients will really appreciate it and benefit from your knowledge and insights, especially related to your recent determination trial results, but also your perspective about frontline therapy overall.

So, please welcome Dr. Richardson, obviously from the Dana-Farber Cancer Institute in Boston. Thank you.

- Thank you, Brian. Well, it's just my pleasure to be with you. And I'm so grateful to Robin and your whole team. It's such a wonderful team you have, and above all to the patients and families taking time from their Saturday afternoon to be with us. And I'm delighted to be with Mary and Saad. I think this is a wonderful panel, and looking forward to lots of conversation. A very good afternoon morning and evening for folks overseas, basically, and a warm welcome to this particular part of the session.

Brian had asked me to touch on frontline options and to cover this fairly comprehensively. So very much hoping that will be the case, and the technology obliging, I think this will work. I just pressed my advancer. Megan, I may have to ask you to help me here and just to move to the next slide, thank you. That's great, thank you, Megan. I'm not sure if that was you or me, but I'll keep pressing mine. Anyway, basically, so what I will do is talk about current standards of care and then perhaps give us a look into the future, 'cause I think that's critical, and I think it'll dovetail very nicely with what you'll hear a little bit later from Saad, about how many exciting things there are in the pipeline, in the relapse space that are gonna come into the frontline space. Now again, if this works, hopefully it will. Oh yes it is, it's great. Here are my disclosures, my relevant relationships and just for everyone's attention and I'll move out to my next one. Lovely, great.

So in terms of treatment for patients with newly diagnosed myeloma, I show this graphic adapted from a presentation that we did at Brian's IMWG summit that he and Vincent co-chaired this summer and particularly it was an outstanding meeting, Brian again, and thank you. But suffice to say, as we think about transplant-eligible patients, obviously as some of the questions were already asked, can we go up front immediately? Should we in every patient, or can we defer in selected patients depending on their course and is tripled induction already now outdated with the outstanding success of the quadruplets, which has really been amazing to see perform as well as they have. And then at the same time, what about the impact of MRD-guided therapy?

And this, I think will be a very important part of this afternoon's discussion. In the very important population, which is after all almost two thirds of myeloma patients in whom transplant may be not something that's appropriate or safe to use, is the same thing applied? Can we use quadruplets here and what special considerations should we have? And indeed does MRD have a role here and understanding what kind of maintenance we should use? And then I think what's so exciting to share with our audience is the impact of next generation therapies for newly diagnosed myeloma and in particular, the really amazing advances that have been made in the space of novel targeted treatments on the one hand, but above all, immune based strategies.

And that's why I think it's particularly good. And it's terrific to have Saad with us today, who's been one of the leaders with the development of Teclistamab which is one of the most exciting bispecifics that I think is gonna be, in my opinion, fundamentally change the therapeutic landscape. And similarly, of course, CAR Ts and others potentially for those selected patients would potentially do the same. So with that in mind, my next slide, I hope as it comes up assuming the connection loss, okay. Next slide, please. If I may just 'cause we lost connection on my advance. Sorry about that. Yeah, so we're gonna touch on recommended approaches and considerations for treatment selection. Next slide, please.

So treatment landscape and newly diagnosed myeloma clearly evolving. I just wanna show you a little bit of the past. In the past, it's amazing to say today that we have lenalidomide or bortezomib based treatment as something of old and now as we go forward, we can think not only about what's now, but in the future are these remarkable array of quadruplet regimens that we have. And I specifically want to bring your attention to the impact of daratumumab in this space, whether it's combined with RVD or with the very powerful platform of KRd, and in that same context, we can adjust these treatments to make them less intensive for selected patients, such as the use of RVd lite or the use of Ixazomib based approaches upfront, which have the big advantage of course, of being oral, albeit a lot gentler.

And then in that same context in terms of the future, what's I think important to note is that MRD is clearly emerging as a vital research tool. I'm sorry, this pointer is giving a little bit of trouble here. I'm so sorry about that. The timing of transplant is clearly important be it early versus delay versus other strategies and the positioning of next generation agents and CAR T cell therapies, for example, recognizing some of the logistic challenges with that, which we have to be, I think very practical about that these of course are changing the landscape. Now I think the point is working quite well now. So hopefully this will do the trick. Yep, were we are, great!

So let's talk a little bit about NCCN guidelines. These are the most recent just published by our colleague Natalie Callandar and her team. And as you can see, the current standard by the NCCN guidelines, which are very good guidepost for American practice, you can see that for transplant eligible patients, we recommend RVd, RVD Dara, which in our practice is a mainstay. Similarly, in the appropriate patient RVd Dara is sometimes better used as KRd-Dara, where we bring in carfilzomib And then as I've mentioned, ixazomib can be also an important consideration in the frailer patient. Now in the non-transplant setting, I think our options are a little bit more broad. And in this regard, we have of course, other options to exploit such as the RBD light regimen we can talk about in the European context, the use of bortezomib with melphalan prednisone is a viable option, particularly in certain healthcare systems and healthcare jurisdictions as they're called. So that's one to bear in mind.

One very important combination to bear in mind is CyBorD-Dara. This is a combination of cyclophosphamide, bortezomib, and dexamethasone with daratumumab and we will use that in the appropriate transplant eligible patient as well, particularly if they have renal disease. And then maintenance consists of lenalidomide as a backbone. Ixazomib may be useful typically in combination with lenalidomide. We rarely use it on its own and above all we, of course, think about how we can incorporate bortezomib carfilzomib as part of maintenance. Now a new kid on the block for lack of a better word is daratumumab maintenance and that's becoming and be typically lenalidomide.

Again, I'm hoping this pointer is gonna oblige. See if that's gonna go forward. Megan, I might go to, just asking for next slide. I think that might be wiser just 'cause it's gonna be a little bit quicker perhaps. I just show here the European guidelines because they compliment what we currently have. And I just bring them to your attention simply because for members of the audience today who are from overseas, just to bring that to your attention. So in terms of considerations for frontline therapy, this is what I call the build of a slide, but it helps move things along nicely to sort of give you an idea of some of the considerations that we like to bring into play when we consider treatment options for any patient.

For example, in terms of the disease itself, it's a very heterogeneous disease. And so as a heterogeneous disease, we have to bear in mind long term views and strategic considerations and understand also that immune dysfunction is fundamental to disease pathobiology and it's diverse. And also what we have to recognize. And this is an important consideration in the era of how now biologically derived therapies, as opposed to our older classical chemotherapeutics, which are of course Genotoxic. We have so many choices. This generates the concept that we have opportunities to exploit certain agents at certain times in a patient's disease. And at the same point also, keep in reserve very effective options that may be inherently genotoxic, and therefore perhaps better kept in reserve for if they're needed. So going to the next slide, next slide, please Megan, 'cause I think this thing is saying connection lost, I'm afraid. Yep, no problem.

That basically not only of course is the disease diverse, but our patients are diverse and that means we're looking at both younger transplant eligible patients or frailer patients who are also maybe older or maybe even younger frailer patients in who whom transplants should be kept in reserve, and above all, we now have treatment options for patients where different needs for a patient in terms of their family, their work and so on can be addressed to tailor their treatment accordingly. And then a very important consideration is to bear in mind, long-term toxicities. Now this doesn't just mean fatigue and some of the chronic type effects that we see from our treatment combinations, but also much longer term consequences, such as secondary cancers, which we have to now be very careful about then in a sense because our patients, thank goodness are living longer, but at the same time that certain therapies may be more associated with these types of complications than others. Next slide please, Megan.

And so in that context, the final point to build on this particular slide, when it pops up, it should do I think, sorry Megan, is it coming through? It's a bit of a slow build here. Oh, here we are real world considerations. And I put this in because obviously personalizing treatment is absolutely essential. I'm sorry, it looks like we've lost a little bit of the flow in those slides, but not to worry. We don't have to go back, Megan, we'll just keep going. 'Cause I think it makes sense that you have to personalize decisions and also as we've been facing the huge challenges of the pandemic, for example, our ability to keep certain options in reserve and keep hospitalizations to a minimum clearly makes a difference. So onto this next slide.

Basically, as we think about transplant eligible patients and upfront deferred triplet or quadruple induction MRD-guided, we can think then about this following study, which Brian was so kind to acknowledge our determination work, which was a long time in the making. This was basically a trial looking at the option of RVd with early transplant versus RVd with transplant kept in reserve. And to give you an idea of the progress that's been made in terms of treatment options for our patients. I remember, and this dates me of course, but newly diagnosed trials could be reported within three to five years and it's taken us much, much longer to report this one, which is a great news. We started this study in fact in 2010, and we were not able to report results until 12 years later. And I think that tells you in itself a lot about the strength of the results. Megan, I'm not sure if you can do the next slide, please, just to help move things along. Here we go.

So we move through this relatively quickly, please, Megan, if we can. The primary endpoint was really not nicely met. We were very pleased to see that if you used early transplant with maintenance, until progression a key point, we were able to generate a progression free survival median of over 67 months. Now, if you kept transplant in reserve and didn't go straight to transplant and you held it back, that medium was lower at 46.2 months. So about a 20-month difference. So quite significant and important from a patient perspective, obviously. But let me show you a little bit more data to make sense of that. Next slide, please.

When we looked at the key secondary endpoint though, of overall survival. In other words, if you kept your transplant in reserve, did this mean that you lost later? Well, from what we can tell at least so far, no. And I think that's a critical point and very consistent with other studies. Now I wanna be careful here because the maturity of follow up here is very important. So with that in mind, nonetheless, what was so interesting to us and will come to it in a minute, is that in our French partner trial, the so-called IFMDFCI 2009, which read results much sooner than ours because in their study, maintenance was only given for one year, not until progression, which made these results substantially better. In their study, too, they showed the same exact thing that you improved progression free survival, but you didn't improve overall survival if you used transplant early. In contrast in their study, however, most of their patients got transplant late. In other words, about 70 to 80% of them got their transplant later in their course. In contrast so far in our study, only 28% of patients have got transplant later because we're very fortunate the U.S. healthcare system that we have access obviously to newer drugs, monoclonal antibodies in particular, pomalidomide and so forth. And we'll come to that in a moment. Next slide, please, Megan.

Now I show you this two next slides, just because these are key endpoints. When you look at overall response rates in the study, they were remarkably similar over time. What you can see here is that the response rate for the RVd alone over was 95%, and for the transplant early group, 97.5%. So very similar. What was higher, however, was the rate of complete responses you can see at 47% for transplant early versus 42%. Interestingly, that was not statistically, significantly different. But where things did become a little different is in the next slide, please. This is the MRD data. And here you can see that the rates of MRD negativity were higher for early transplant at 54% for the early transplant group and actually 40% for the delayed transplant group. Now the numbers here in the first 200 patients. So what was really interesting is that this trends to significance, but actually doesn't quite make it yet, but I suspect it will as we do more MRD. But the bottom line here is what's so important I think is at the top end of this slide.

As you can see if you're MRD negative, whether you get RVd alone or RVd with transplant, and if you're MRD negative and get RVd alone, your five-year progression free survival estimate is almost 60%. And if you get RVd and transplant, your five year progression, free survival estimate so far on this is 54%, and that's not statistically significantly different in favor of one or the other, but just shows you if you're MRD negative, the results are very good. In contrast, if you're MRD positive, additional strategies are probably important, as you can see with the RVd alone group in particular, enjoying a median progression free survival of around 34 months or so, but the transplant group doing much better at 51 months. Next slide, please.

Now what we also did was what's called a additional analysis for sensitivity. As I mentioned, this is the progression free survival. Next slide, please. Now tied to progression is another type of endpoint, but what is showing is this difference in a progression estimate is very strong. Next slide, please.

But then if you look at event free survival, the curves dramatically narrow. And in fact, at certain points, crossover. Why I show this is to give you the importance of randomized trial and the importance of really going deep into what the data tell you as opposed to necessary just a high level kinda headline approach. And why this last slide's important is that it explains something that we saw in trial, which was a lot of patients. If you took away the hard end point of progression and looked at event free survival, you can see that the actual difference between the two arms is surprisingly smaller. If you look at the event free survival, you can see here that it's only about 15 months as opposed to around the 20 months or 21 months or so for progression. So that tells you other things are going on. And this may help explain a little bit as to why the overall survival is so far, at least identical. Next slide, please.

So with that in mind, let's talk a little bit about second primaries and acute toxicities. The good news is that the treatment related mortality for both groups was very low. It was 0.3% for the RVd alone arm and 1.6% for the RVd with transplant. So again, very low rates of treatment related mortality, which was incredibly important. As you can see from the rates of significant toxicities, though very much as you might expect, there were higher acute rates across transplant. We expect that. The good news is they were by and large wholly reversible. And that's obviously very, very important. One, however, late toxicity that I touched on earlier, which is very important to bear in mind is that of second primaries. Next slide, please.

Now we know that lenalidomide can cause second cancers, and we know that melphalan most certainly can. But understanding the differences between the two is very important. And what we saw was that overall, the five year cumulative incidence of second primaries was reassuringly similar. And the rates of what we call invasive cancers were fortunately quite low and hematologic cancers even lower. But as you can see, they were marginally higher for invasive cancers in the melphalan and a little bit higher in the hematologic group. This did not achieve statistical significance, but you can see one is 1.6% and the other is 3.5%. And I think it's important just to bear in mind that follow-up remains relatively early. However, what did stand out in us was the difference of AML and MDS. And these are important second cancers. The good news here is they're rare. That's the most important thing, but what's also important to note, however, is that we saw 10 cases in the transplant early on versus none in the transplant delayed group. So this is an important thing as we go forward in better understanding who might benefit from what and trying to better understand who the patients are, who are vulnerable to this key tolerable toxicity problem in the long term, and hopefully protect them from this potential risk. Next slide, please.

Thanks, sorry, Megan, this a bit slow, there's something off with our technology, I'm afraid at our end. If we look at quality of life, this is tremendously important and the determination trial. Oh, and I'm sorry, can we go back one, Megan? I think it advanced too fast cause the quality of life key. Thank you, Megan. This is basically the quality of life. Now the really good important message is that across both arms of the trial, compared to the start of treatment, quality of life improved. What's also important to note though, is that for those patients who underwent early transplant, there was a significant drop in the quality of life across the transplant period. The good news is that it recovered, but I think these are very important things to share with patients and families so they understand exactly what each approach entails. And this particular piece of data was comprehensively assessed across all 720 patients. So I think this is a very kind of reliable data set because it also mirrors what our French partners showed in their trial. Very similar results there. Next slide, please.

So where does this all leave us? Well, I think where it leaves us now is in the context of a three drug combination, clearly early transplant met the primary endpoint and exceeded our expectations. However, the absence of a survival gain is a critical point to better understand. So going forward, we're thinking, well, look, if we can achieve this with triplets based on MRD results, for example, and I've highlighted the transplant delayed studies in red and the transplant early studies in blue, you can see that MRD rates on the one hand are increasing with each study. If you go down to 40, for example, they're going up. What you can also see is that transplant does consistently appear to improve progression-free survival, but what's so interesting is the overall survival differences are not different between the two approaches consistently across studies. Next slide, please.

And then if one looks to the right of this slide, this is now what we call the quadruplets, where we've combined. And I use this metaphor with my patients, so I hope it helps, the Army, Navy and Air Force, the proteasome inhibitor, the IMiD and the steroid with the Marines, the monoclonal antibody. When you put those four together, you see things go up a notch. And as you can see, the MRD rates go higher. For example, the German study, the GMMG-HD7 goes up to 50%. The IFM 2018 study with Dara-KRd up to 62%. And then our own work with Griffin, which we'll come to in a minute incorporating transplant, going up to 64%. And then the Manhattan study led by Ola Landgren and the Memorial team, Saad's team going up to 71%. Now, this is really interesting because these MRD rates are actually, the ones in red are without transplant. The ones in blue are with transplant.

And as you can see, the progression-free survival data remain relatively immature. So we have to be a little careful here. But as you can see from the MRD negative rates, they appear to be improving regardless of whether you do transplant or not. And very, very importantly, we're getting up to rates of MRD that are really impressive, 71% in the Manhattan trial, for one example, in the master trial up to 80%. And as you can see, really in both of those studies at the bottom of this slide, outstanding progression free survival, 98% for the Manhattan trial one year survival at 100%, two year progression free survival for master at 87%, and two year overall survival at 94%. So these are really striking results and extremely encouraging. Next slide, please.

So these are sort of my conclusions, high rates of MRD negativity, promising outcomes either with or without transplant. And an exciting point is that their quadruplets clearly are proving tolerable. And then when we integrate immune therapy based maintenance, we are seeing MRD negative rates that have been unprecedented. Next slide, please.

So I just wanna do a quick drill down on our Griffin study. This is a study launched through what's called the Alliance Foundation for Clinical Trials. And I especially want to acknowledge my colleague, Peter Vorhees who's led this study, and also my other colleague, Jacob Laubach, who's been a key co-investigator in this trial, as well as all the other members of the Griffin study team. And what you can see here is that this has been where we chose to build on RVd with daratumumab and transplant. This is not without transplant. This is building on RVd transplant, adding Dara or not, and seeing what happens. And we are very pleased to report that clearly the Dara RVd has dramatically improved not only rates of MRD, but also progression free survival.

And then of course, the next question is what then does transplant add compared to keeping it in reserve? And obviously, these are being addressed by some of the studies I just touched on, but it's my privilege to be working with Saad and other colleagues on the Myeloma Alliance Committee to build what we call determination, too. And I noticed that on our Zoom today, we have no less than Jim Omal from our patient advocacy group. And Jim is helping us with the design of this study as well. So determination too is gonna be understanding, what now happens with the quadruplets and the newer therapies as we go forward. Next slide, please. Great.

And this just gives you an idea of some of the studies that are trying to compare the RVd versus Rvd-Dara, the Isa-KRd just, I think there was a question in the audience. What does KRd mean? It means carfilzomib, lenalidomide, and dexamethasone and the name in the Manhattan trial is not about whether it's carfilzomib or not. It's just because the study was led by Memorial and of course, they're based in Manhattan. And then there is also a study looking at elotuzumab, which we think may be helpful in certain settings. Saad, in fact, led our work with RVd ELO versus RVd in higher risk patients. And whilst we didn't see a big difference in that particular study, I personally, I'm a fan of elotuzumab. I think it does have some really exciting properties and above all, as well tolerated. So this is another interesting and important study. Next slide, please, Megan.

Yeah, this is just simply to build on the slide, just making some key points to give you an idea of the newer directions. And I understand from Megan that we will make these slides available to the audience by Adobe PDF. So please don't worry too much about the details 'cause they'll be available to you down after our presentations today. Next slide, please. Good.

So this is just touching on the details of the Manhattan trial, just to give a little bit more granularity to that. And as you can see, the results were really exciting with the overall response rate of 100%. The CL or VGPR rate of 95% of the MRD negative rate of 71%. One caveat, and why I wanted to show this slide was to stress that this is a single arm study. So whilst there's been great excitement around the results, understandably so as a single arm Phase 2, you know, great results, but we have to understand what that means. We have to be careful about over-interpreting information from this, but clearly a very promising start. Next slide, please. Excellent.

So this is just a quick look at MRD negativity for prognostic long-term benefit and as a surrogate for progression free survival, as I mentioned, it can be independent treatment, certainly in newly diagnosed patients. It's a little less clear that that independence is there in the relapse setting. MRD negativity, for example, can be quite unstable in the setting of CAR T therapy for complex reasons, but I simply want to make, bring to attention that MRD is a research tool appears to be key for treatment decision making. And increasingly, we're trying to use it thoughtfully in the clinical setting. Next slide, please. Lovely.

So just to let you know that there are some trials looking at MRD adapted therapeutic approaches. This is one example led by our French partners, specifically by Fe Morro and his team. This is the so-called MIDAS trial. It's got the acronym IFM 2020-02, and this in uses KRd plus a new CD-38 antibody called isatuximab, very similar to daratumumab, but may have some properties that have important differences. We don't know exactly, but from clinical studies, but we have some clues from the preclinical setting. Suffice to say, just like Dara, an outstanding antibody, Isa KRd six cycles, MRD testing. Next slide, please.

And here we look at low risk definition as by virtue of genetics and so forth. And if the MRD negative, there's a second randomization, next slide, please. And this shows that if you're higher risk and MRD positive, you get transplantation and more Isa KRd. In Europe, there is still a strong appetite for double transplant. I think it's fair to say in the U.S. based on our own results from the stamina trial, we're a lot more cautious, I think probably rightly so. In any event, what I love particularly about this trial is that it's bringing into it a new, what we call CELMoDs, Isa+Iberdomide, which may have important advantages over lenalidomide. It doesn't appear to cause second cancers, pre-clinically in the way that lenalidomide may do. And it may be that much more powerful. And this has been combined with isatuximab. As I mentioned, daratumumab has become an antibody used extensively in maintenance now, and isatuximab is also being tested in that same setting. So this study, I think very attractive because it's offering a risk adapted approach with the integration of a new so-called CELMoDs into maintenance. In the top slide, I don't know the next slide, please, Megan. I hope it builds. Yes, absolutely.

If you are lower risk and MRD negative, they're looking at transplant. Next slide, please. And conversely, they're gonna keep the opportunity to keep it in reserve for others. So the top part of this slide, I think answers a key question. If you have MRD negative disease and low risk, do you need the transplant? I think the one thing that would be a little different in the U.S. is this interest in the double transplant. Flicking across to the maintenance, however, in Europe, there is much more caution around maintenance until progression. And as a result of that, these maintenance strategies are curtailed at three years. Certainly in the U.S. from our trials, both CLGB 10104, which is an alliance study led by our colleague, Phil McCarthy, we've been very convinced that lenalidomide and until progression makes a big difference and determination certainly supports that. Next slide, please.

So we're now moving into the transplant ineligible group and I promise my colleagues, my faculty will get this wrapped up as quick as we can. And I'm sorry, it's taking a little bit of a while. Now, let's quickly talk about the transplant ineligible, triplets or quadruplets and special considerations in the elderly and frail. Next slide, please. Basically, standards of care quickly evolve. We now have Dara RD and RVd standards of care for transplant ineligible patients. The MAIA trial really led this showing remarkably higher response rates, incorporating daratumumab and high quality responses as well. Next slide, please. And in that context, we were able to show that MRD negativity was dramatically better.

For example, for Dara-Rd/RVd, you've got 30% MRD negative base rates in patients versus under 10% for Revlimid and dexamethasone alone. So clearly daratumumab making a very big difference. Next slide, please. And then in terms of Brian's study, which is a very important trial comparing RVd to RD critical phase three, and this was a SWOG study in which Saad was also part of this trial. And what this trial showed very nicely was that clearly the triplet outperformed the doublet. Next slide, please. And this allowed us to assess progression free survival and overall survival. What's very interesting in this trial, in contrast to what we've seen with the transplant studies is that you clearly show survival difference relatively early in these studies. So I think there are a number of factors that may be at play here, but nonetheless, be that as it may a clear evidence of the benefit of the three over the two. Next slide, please. Wonderful.

So then how is these being built on? So the addition of quadruplets to this platform has become very important. And as I mentioned, these focus on daratumumab based approaches and also now isatuximab coming up front. So we will have a plethora of information for you regarding these studies, hopefully fairly soon, although some will take a few years from now to report. But the good news for patients across the world, actually, 'cause these are international trials. Some of these, they will be providing access to these quadruplets in the upfront setting. And then of course, we have some of our own studies such as the qua trial, Dara RVD versus Dara RD. And these of course also are based out of what we call the U.S. mechanism, hence the constructs there as well as other studies. Now there are a number of other trials listed there just simply for your information. Next slide, please. Yeah. So these are sort of summary points that simply the addition of Dara or Isotuximab to either carfilzomib or bortezomib containing platforms is key. And basically, MRD negativity may be acute goal of therapy in this setting. And some studies restricted to younger patients without to transplant or fit patients are also becoming quite popular. Next slide, please.

So, in the last part of my presentation this afternoon, I'm gonna focus on some special considerations in elderly and frail patients at the same time, also touch then on some of the newer directions. So obviously as we show on the left side of this slide, patients may not be able to tolerate standard quadruplet regimens. Obviously, CAR T therapy, exciting as that is , it's a relatively selective platform. And therefore, there may be very important gentler combinations that could be extremely effective. And the so-called gentler quadruplets in our practice do exist. Next slide, please.

And so in that context, reduced intensity of regimens is obviously a very popular direction to go in there's so-called RVd light. And then basically there are a number of other strategies, the build on this that hope we believe create not only results that are outstanding, but also show excellent tolerability. Next slide, please. So very quickly just to touch on RVd light that was led by my colleague Betsy O'Donnell. What Betsy and the team showed very nicely was to this very extended regimen of RVd across 35 days, and we were able to generate no overall response rate of 86% with the VGR rate approaching 70%. And at the same time, we were able to use much lower doses of lenalidomide at 15 milligrams. And bortezomib just on days one and 15. Next slide, please.

And with this less frequent dosing, we had excellent progression free survival, which was basically at almost over 35 months. So a very nice regimen for the frailer holder patient. Next slide, please. Oh, I'm sorry. Just the media not built, reached. And next slide, please. Megan, I'm sorry, these are builT slides. So a little bit tricky to move forward through the safety. Just 62% of two thirds of patients getting some form of neuropathy, but manageable, but only in 2% was it considered grade three and reversible in all actually and the median treatment duration was 15 cycles, so, and only four, two patients, 4% discontinued due to side effects. Next slide, please. This is just very quick.

There are multiple dose adjusted regimens of RVd. Simply just to share with you, this was just published in the British Journal of Hematology by Dr. Georgia McCaughan. And basically, this is just the various different regimens that you can use on a slightly funny note since it's a Saturday, they do have kind catchy names, Rvd-classic, Rvd-lite, Rvd-premium-lite, and Rvd-ultra-lite. But just to share these with you, because they do generate a little bit of humor for those who amongst us, who like to have a glass of beer every now and again. And as you can see, these are all very practical. They're all very active and they're all very patient friendly. So hopefully, they're useful to our audience. Next slide, please. Excellent. Next slide, please. Lovely. So I'm gonna finish up now, but just talking about the future. The real excitement here, novel immune based approaches and novel targeted therapies. Next slide, please, Megan.

Now this is a schema that you're gonna hear a lot more about from Saad. So I just want you to give an idea that what's in the relapse setting as novel mechanisms, action is coming up to the upfront setting, and there's some very important ones that could be making a very big difference. And in the interest of time, I'm simply gonna move straight into the next slide, please.

And this I think is one of the most important sort of scientific slides to bear in mind that as we think about targeting novel myeloma cell antigens with monoclonal antibodies, we also need to think about restoring host immune surveillance. And at the same context, we can also potentially even be considering some vaccination based strategies recognizing that these have not necessarily been on the forefront of our research to date. I mean, obviously they have been in the context of COVID, but in the context of vaccines against myeloma, this is a relatively new space. And then at the bottom here, the immunological effects of anti myeloma agents mustn't be underestimated. And these include not only those of the established immunomodulatory drugs, such as the image, but also the cell ones, these degraders, which are coming in a very, very exciting.

And then also this third mechanism, if you will, immunogenic cell death or other, I should say fifth, if you look at all the mechanisms outlined here, but these are very important to understand because they deliver a mechanism of delivery of a targeted warhead to a tumor cell and then create immunogenicity around it. And we've recognized that immunogenic cell death is not just unique simply to certain antibodies, one that Saad and I have worked together on belantamab mafodotin being one obvious example, but another immunogenic mechanism that we've not appreciated until recently actually is in proteasome inhibitors. They trigger immunogenic cell death. So under the waterline, as it were, there are many immunogenic mechanisms at play in myeloma therapy. Next slide, please. And this is simply to emphasize that point in the BCMA tech category. And again, you're gonna beautifully in a moment from Saad, in the interest of time, I'm just straight through this next slide, please.

And belantamab again, you're gonna hear more from Saad. So we'll just move through super fast. Just if you could click, click, click, please, Megan, 'cause this is taking time to get through. And these are just simply to illustrate that in the upfront setting, we have a number of belantamab studies ongoing, as you're gonna hear more about bela from Saad. Next slide, please.

And then CAR T therapies, obviously very exciting. I just wanna emphasize the important point of the practical realities of CAR T over the hope and promise of the trials. But having said that, I see progress coming, and in that spirit, we're gonna see these studies coming up front and they already are as listed here. So you'll see here, the opportunity for CAR T participation for fit, healthy patients in whom this would be an appropriate approach, recognizing that there are some side effect profiles to be aware of. But having said that the results are simply outstanding. And you'll hear more about that from Saad in a moment. Next slide, please.

By specifics again, the same story. Next slide, please. Perfect. Thank you, Megan. This is simply to illustrate the point. Oops, if you just go back one, if that's okay. Lovely. Just to illustrate that in addition to teclistamab have a whole array of bispecifics coming, not only targeting BCMA, but also targeting GPRC5D and 5FCRH 5. And my simple point here is that this is gonna be so exciting for the future and the upfront space. Next slide, please.

And to that point, there are studies that are ongoing exactly in that looking for endpoint results in newly diagnosed patients. So this is incredibly exciting in my view. This is truly off the shelf. CAR T obviously is not it a cellular approach bi-specifics are off the shelf and as Saad very kindly explained to me, real differences in practical terms, which I do think make a big difference in terms of applicability. This could literally have application in the community setting, whereas arguably CAR T more challenging. That being said, the promise of all of these approaches, I think is dramatic. Next slide, please.

And now in the last sort of 30 seconds, I wanna click close on what we call CELMoDs. These, I think are gonna come upfront in ways that you may not necessarily be aware of. Iberdomide is clearly gonna be upfront early. There is in fact, some work being done with a CC92480, which we've christened mezigdomide or mezzi for short. but mezzi is probably gonna be our in reserves CELMoDs. That's used for relapse. We're gonna focus on Iberdomide. Next slide please, Megan.

And what you can hear see here is that already Iberdomide is moving up front dramatically. Very exciting trials in this area, especially wanna acknowledge the leadership in the Iberdomide space of Dr. in particular and Mils Vanda Don from Holland and really an amazing team effort going forward in this space. Next slide, please.

And then this is just a number of novel agents in the relapse space that are gonna come forward. These include selinexor, melflufen which Brian touched on a sort of Trojan horse that delivers the melpholan and warhead without toxicity to other areas, and is specifically designed to hit the myeloma cell, overcoming 17P deletion without alopecia and without mucositis, which is fascinating. So a lot work to do, but we're hopeful that will provide a real difference. And then Venetoclax, you're gonna hear more about from Saad, but that to me is a really important drug to be having coming up front in patients with 11;14. Next slide, please. So these are my conclusions. I think, as you've heard from Brian and myself, PIs, IMiDs, monoclonal antibodies have dramatically improved outcome for our newly diagnosed patients. Brian, in that excellent slide showed how we can expect 100% now of patients to respond.

And at the same time, we've seen that translate into meaningful differences in progression free and overall survival. An important thing is high risk disease and high risk disease in particular remains a great challenge, especially patients with 17P and other types of genetic change that can be challenging. For these patients, innovative ideas are clearly needed. We have immune therapies to meet that challenge, including bispecifics, which I've touched on an antibody drug that you're gonna hear much more from Saad, and of course, CAR T therapy, which represent truly new directions in going forward. And then I think it's very important to emphasize the convenience and the value as well as the true potential therapeutics of next generation, small molecules.

And I've listed them here, selinexor, CELMoDs, Iberdomide and so forth and other drugs targeting myeloma stemness such as for example, melflufen. But I think beyond all of that, new insights into mechanisms of drug action and the use of tools like MRD will be absolutely vital in better understanding who benefits from what, and to embrace this concept that not only does one size not fit all, but we have the tools in the toolbox now to truly tailor therapy for our patients. And I think I'll stop there, Brian, thank you very much for your patience. And I apologize for the slowness of the technology, but I think we've done our best here. Thank you very much to everyone.

- Okay. Thank you so much, Paul. Yeah, very, very comprehensive presentation. And I think that some of these summary slides, well, I think be tremendously interesting and helpful for our audience. We have actually run over into our break time, but there have been some quite important questions coming in. One question asked, but I think is pretty important. So what is event free for survival? So what is an event then?

- That's a great question, Brian. Event means anything that happens that interrupts therapy or is important in a patient's course. So it includes not only a progression event, but also a toxicity. It includes a hospital admission. It includes something that leads to treatment discontinuation or another problem. So from a patient and family perspective, event-free survival really matters. That's kind of how you're doing, you know, and progression obviously is critical because that reflects disease control. But if you then start to look in the events and that's why we thought that sensitivity analysis was so important. And so do the FDA actually. Rightly so then, you know, that becomes important in understanding the value of the therapy.

- Right? Absolutely. And then there's another series of questions here related obviously to stem cell transplant. Do any factors make it more recommended in the frontline setting, for example, high risk cytogenetics, is that a situation where we might expect to see more benefit with transplant?

- That's a great question. And I'm really glad for the question you're asking it because high risk and in the interest of time, I didn't dive into that. But what we're seeing is that risks does matter and higher risk patients clearly may get benefit of progression free survival advantage from using transplant earlier. I will stress however that we've not seen a big difference in overall survival yet, but I suspect that's got a lot to do with maturity of follow up. I think in the same context, standard risk do very well. However, what's so interesting is this MRD interaction with risk. In other words, if you're MRD negative, you know, it seems to be very relevant to overcoming the impact of risk.

What we've also learned is that high risk is a very, you know, we tend to basket things as you know, Brian. And what we've learned from determination is that 17P and transplant behave very differently to say 414, which transplant really makes a difference to. So, you know, it's kind of a complex question. And my last comment would be that one of the proudest things of the determination trial is that we were able to enroll almost 20% African American patients and took a great concerted effort to do that. But we were so pleased to see that. And very interestingly, we did analyses by ethnicity and interestingly in patients of African American heritage, the progression free survival benefit, and they all get the same treatment.

So this is nothing to do with access or anything like that. Everyone gets the same treatment and the same access to free medicines, which is very important in the trial for everyone. What we were able to show was actually the PFS benefit from transplant for African American patients was actually very modest. And in that contest, it means they were getting more or as much just from the simplicity of the less intensive approach and keeping transplant in reserve. So for important subgroups who may get more benefit from transplant and other subgroups who may not have to rush to it.

- All right. Thank you so much for that. Just a final comment before we close out, there's question about how long could you stay on maintenance? And I think that one very positive thing is that there are patients now who've been on lenalidomide maintenance since the earliest trials started, you know, so 15 years and more patients are on lenalidomide.

- Absolutely.

- And so this is something that can be long lasting and beneficial for many patients, but so we'll come, come back as much as we can to some of these questions, but thank you so much. Let's take a break. I suggest that perhaps we take a 10-minute break and come back a little bit after quarter of the hour. So, well maybe why don't we come back at 10 minutes to the hour. Okay.

- Perfect. Thank you everyone. And again, my apologies for running over time with the slides and really appreciate Megan's help, too. Thank you very much.

- So welcome back after the break and thanks to everyone to helping us try to make these as smooth as possible, despite some different issues along the way. We'll try to pick up a little bit of time on this last segment. So, I'm very pleased to be able to introduce Mary Steinbach from the Huntsman cancer Institute in Salt Lake City, who will take us through managing myeloma care. So, please welcome Mary.

- Thank you. It's an honor to be here with this panel of physician experts. On behalf of the Nurse Leadership Board, the Nurse Leadership Board at the IMF works hard for patient advocacy education. Along with education of our nursing colleagues, we work really closely with all the physician experts. And so I look forward to speaking today to everyone about symptom management and as Dr. Richardson suggested, patients are living a lot longer, sometimes on multiple therapies for long periods of time. And so symptom management becomes an important piece. This is our reminder that you patients are the artists, and so really in charge and supposed to work along with all of us providers to help maximize your quality of life.

We're gonna go over the color wheel of treatment. So the spectrum of symptoms that patients can experience. And then we'll spend a little bit of time talking about infection prevention, particularly with COVID-19 and for myeloma patients in general, we all know that staying infection free is an important point. So myeloma treatment as has been suggested that the main goal of getting patients started on treatment and remaining on treatment is disease control. And that means limiting symptoms related to the disease.

And in that, patients can have a improved quality of life and then improved overall survival. There's a number of supportive therapies out there for patients optimizing bone health, staying free from infection and managing the common symptoms that we know are gonna happen with our certain treatment strategies. As patients, we really appreciate when you guys talk to us about your symptoms and really have open lines of communications as we start therapies and you're on your treatment journey. So that's an important piece for sure.

Stem cell transplant has been touched upon and will remain a important part of treatment and conversations amongst patients and providers. As we heard earlier, there's really no black or white answers to this picture about transplant, and patient-specific understanding the physicality of it. The social support structure for patients is an important part of the conversation. Care partners are critical for interventions such as the auto stem cell transplant and for CAR T therapy and some of our newer interventions. So as a patient, being able to understand the process of transplant and all that, that goes along with it in terms of supportive care and care partner management is important. The newer treatment approach that we have, which can be compared to the stem cell transplant, just in terms of logistics early on and the importance of support from whoever your care providers are, is really important.

And this picture here just depicts sort of in a beautiful way, the complexity of the logistics of CAR T, and Dr. Richardson touched on how it's an important intervention, but it's not one that's available in all places, right? And it's not one that most patients are gonna be able to see, especially more recently with some of the logistical concerns around it. But an important part to this whole CAR T process is patient selection.

And then patients move on to apheresis and then you often have a bridging therapy or some sort of treatment while you're waiting for the CAR T product to be made. And then you receive some chemotherapy and it gets reinfused, and then there's long term monitoring after that. So it certainly has made a big difference for patients who have been able to receive it thus far. And it will continue to make a difference in our patients upfront and still at relapse. But I think an important piece from the patient perspective, it just is understanding the complexity of it. And it's more logistical complexity, but of course, it does have some medical complexity associated with it as well. And side effects that we haven't seen with some of our other therapies. And one of these side effects is called CRS or cytokine release syndrome. It's depicted here on this slide.

There's a multitude of symptoms that can occur for patients. So fever, fatigue, headache, nausea, and vomiting, diarrhea, confusion. This is something that affects patients early on after their CAR T infusion and depending on the product, that can kind of help us predict what day this might occur for people. The major all patients at this point in time are in the hospital when this is likely to occur. So this is a hospital-based management occurs. A more long term side effect of CAR T is something called neurotoxicity.

And so this also does happen more in the acute phase after CAR T. And again, often patients are in the hospital when symptoms may initially present, but we're learning more that even one month or in well beyond one month from CAR T, some patients are experiencing degrees of neurotoxicity. So it's important for nurses in the outpatient setting, certainly care partners and patients to understand that difficulty walking or confusion, difficulty with word finding. These can be symptoms of a long term side effect from CAR T.

And part of an effort by the Nurse Leadership Board going forward will be helping community-based nurses, clinic-based nurses, patients in their care partners, kind of understand, and be able to identify what these symptoms are, so that then they can be managed appropriately. I mentioned this term care partner support. So this is when I am speaking to patients about this. I often say like, this is your person, or these are your people, who's gonna be with you at appointments, who's the second or third set of ears. Oftentimes, it is more than just one person and that can be helpful too. For the autologous stem cell transplant CAR T process and really, really life, I think it's important not to have a good emphasis on who your support is. Getting to and from appointments can be challenging for some people, again, understanding the medications, the side effects, and what was said at provider appointments is really important. A large meta-analysis was done a number of years ago to look at patient reported symptoms in multiple myeloma.

And so these symptoms can be defined into three different categories, physical symptoms, psychological symptoms, and financial symptoms. And I think at certain time points in the myeloma journey, some of these are more present than others, depending on a patient's social structure and what's going on, you know, certainly the financial might play more of a role than the physical. So these are all points that are important to touch base with your healthcare team about, and just recognize that no myeloma patient is alone and experiencing some of these toxicities. And we will break down these categories here, going forward. So kind of the big, easy thing to start talking about, in terms of especially physical symptoms are the steroids that we use. You all know, we use dexamethasone and often high dose dexamethasone at various time points, especially upfront when treatment starts, that dexamethasone plays a really important role.

There are a lot of side effects, both good and bad that can happen to patients with this. And so recognizing that if you're having difficulty sleeping, you have really a day with really good energy or two days with really good energy. And then kind of these crash days, that's probably related to your steroids. There can be GI side effects, bone side effects, and this can really affect the care partner in your whole social system. I believe too, depending on what you are experiencing. So it's important to talk to your healthcare providers about any of these symptoms that come up. There are some kind of tricks to the trade in terms of helping patients manage steroid side effects.

And as I mentioned, sometimes during treatment, the steroid is critical, and sometimes it may be less critical. And so just having that continual conversation with your healthcare team about your doses, how you're taking it when you're taking it, and often things, the steroid doses can be reduced depending on tolerance. Another really common physical symptoms are everything that falls under GI. So nausea, vomiting, diarrhea, constipation, abdominal cramping, bloating. Sometimes these are caused by the medications we're prescribing to help manage your myeloma. Sometimes it's part of the supportive care meds that maybe causing some problems or just medications that you take to manage your hypertension or to help with depression. These can all have GI side effects. So when I'm talking to patients about these, I usually like to try to establish a pattern. So when are you experiencing diarrhea? When do you experience constipation?

A lot of people experience both these symptoms, and sometimes during the same week, which can make it confusing and challenging to know what other types of medications or supplements or foods to take to try to help this. Some general guidelines are having a high fiber diet can help with both constipation and diarrhea. Trying to avoid the laxative cycle of becoming severely constipated, and then having diarrhea, there are foods that may trigger some people that don't trigger others. So food diaries can be an important part of understanding these symptoms. And then hydration is really an important piece when we're talking about GI symptoms. And good hydration as you guys know, helps with renal management too, so helps protect your kidneys. And so it's important for patients to drink. I usually recommend like up to two liters of liquid a day, if that's possible.

Another common physical symptom is the pain that patients live with. And sometimes this pain gets better over time. It might be pretty severe at diagnosis, depending on any type of bone damage that occurs. There are surgical interventions or interventions that radiation can help with that help patients with their pain. But a lot of myeloma patients live with some form of pain. So understanding what's causing your pain, what your healthcare team or you can do to help maximize your pain and then always treating pain when you do have it, I think is an important piece of it.

And treating that pain sometimes takes opioids or narcotic medications. And I think being okay with using those appropriately is an important piece for patients. For a lot of good reasons, there's stigma around using opioid and narcotic pain medications, but when it comes to cancer-related pain and pain that's related to your bone lesions or fractures, sometimes it's necessary to use these medications and better to treat pain than to live in constant pain, because that affects all other parts of your lives. Bone health can be, as I mentioned, radiation oncology can help with that in interventions, such as a kyphoplasty can help with vertebral compression fractures and then exercise and figuring out what type of exercise works for you can really help with pain management. And I think whenever we can use a non-medication based strategy, that's good for everybody. Peripheral neuropathy. So numbness or tingling in your extremities, feet or toes. This is certainly part of the pain spectrum for a lot of patients. It isn't necessarily painful for people.

So if you experience a symptom like this, it's important- With your healthcare team, to identify exactly what you're experiencing, and there's certain testing that can be done for sensory purposes to see what the extent of your numbness might be, and then understanding maybe where this is coming from. So sometimes it's the medications we use such as Bortezomib that certainly early on when it was given IV was associated with a lot more peripheral neuropathy. I think since as a group, we've reduced the use of Velcade more to once weekly, instead of twice weekly. That's something that can help with the potential for peripheral neuropathy. There are dose reductions that can be done. In terms of supplements, using some of the B vitamins or folic acid can be helpful for peripheral neuropathy management. Again, you just wanna consider what other medications you're on when you start these and talk to your healthcare team about it. Acupuncture works really well for a lot of people, and that's something that can help with peripheral neuropathy and also some GI side effects.

So I think the take home on this is a lot of patients experience it, especially patients who have had multiple myeloma for longer periods of time, probably based on the medications that we have used. And this is something that should be spoken to your healthcare team probably every time you're in the office, someone should asking you a question about this. Fatigue, anxiety and depression are extremely important. And I think they actually fall under the category of both physical and psychological symptoms. And they're so closely intertwined with our physicality and the way our brains work that often you can't separate it out and you can have fatigue as a symptom that affects what you're able to do. You can certainly have anxiety and depression that worsen your pain or are worse because of your pain. And so these things can really, they're all connected to each other.

This is a really under reported symptom and that's something we're learning more and more about. I think, as a nation, certainly since the pandemic, we have been working more towards maximizing people's mental health. The cancer community has been a little bit better at this overall, I think, but this is still doesn't mean these things go away, right? So figuring out how to talk to your care partner or friends or family or your healthcare provider about these symptoms when you're experiencing them.

Sometimes medications help, sometimes therapeutic interventions group support groups can be really helpful with this, but I think the important point is just not taking this stuff on and doing it alone. That's important. Let's see. Okay. And then the financial toxicity of having multiple myeloma certainly is more and more at the forefront, I think is we have more medications and therapeutic interventions to offer patients. And in a variety, you know, some are oral, some are IV, some are subcutaneous and insurance drives choices sometimes, and that can be limiting for patients recognizing kind of what is possible in terms of your medications and pain for them. And then I think utilizing support groups or programs, a lot of times there can be pharmaceutical support from companies who have these medications. There's federal programs. If you're at a open enrollment time period with your insurance, kind of understanding choices you can make during those times to help maybe make copays less, can be important.

There's the number of nonprofit organizations that can be helpful for patients in terms of these financial burdens in the cost of care. As an example, the Leukemia Lymphoma Society has a number of grants that are offered to patients to help with prescription costs and recognizing that this financial burden obviously changes over the lifetime. And with patients living on more continuous therapies for longer and longer, I think it's become more to the forefront of our minds as providers, nurses, pharmacists, who are all committed to taking care of myeloma patients. And, you know, perhaps historically we didn't have the privilege or opportunity to make different treatment decisions based on finances for a patient. But I think certainly we're at that time point. And so it's important to let your team know.

Moving along to infection prevention and especially COVID-19. So with the immune dysfunction that exists with multiple myeloma patients, as you guys know, is partly disease driven, partly treatment driven and kind of finding the balance of how to have a quality of life and be social with people, but doing it in a way that keeps you protected is important. And as you guys know, we've learned a lot through this COVID-19 pandemic. I don't think we can give a presentation any longer without touching on some of these things though. So, the COVID-19 vaccine and boosters are recommended. Wearing a mask, especially if you're depending on what type of treatment you're currently receiving or where you're at during the autologous stem cell transplant period or CAR T, intervention is certainly important.

And then these are, you know, I think these are still very important for myeloma patients to avoid crowds and poorly ventilated indoor spaces and do your best to just stay away from people who are sick. Washing hands with soap and water, well, that will never go away. It happens to be like one of the most important things anyone can do to prevent infection. This slide is really important, I think, especially as we continue to ask you guys to wear masks. It's just a reminder of what the difference is in terms of becoming infected if you're near someone with COVID 19, and more and more recently, where you're gonna be around people who have it and may not even know they have it.

And so this just highlights the importance of as a patient, you wearing a mask in particular situations. There are a lot of strategies, some easy, some not so easy to just help you guys and help all of us, even non-patients live like full lives with the best of health, managing stress, maintaining a healthy weight, doing all the preventative healthcare that's possible. Some of these things are really easy to talk about and to recommend. I fully understand that the execution of 'em are not always so easy. So again, this is another important place where care partners and being part of a myeloma community, maybe what helps you guys overcome some of the barriers to living healthy lives, especially as it comes to relaxation and social engagement activity, daily activity is one of the number one things to help prevent and overcome cancer related fatigue. And it's not easy when you have very little energy, but sometimes just getting up and taking a five minute walk, makes all the difference. Protecting your kidneys over your life course is very important. That allows us to continue to use different therapeutic strategies to help treat your multiple myeloma and then also bone protection.

So calcium and vitamin D supplement, we mentioned briefly before the bone strategies such as using Zometa, denosumab or Aredia, and kind of the choice between those medications is gonna depend on some of the factors around what your kidney function is like, and then again, how often you're coming in for treatment or what type of intervention is best for you. So it's important to talk to your healthcare team about that. Benjamin Franklin, such a brilliant man did tell us, "Amounts of prevention is worth a pound of cure." The IMF has a number of resources as you guys hopefully are aware of, and we continue to help make you aware of. And so we break down in these pamphlets here, the different medications strategies and supportive care. So if you have any questions, this is always a good place to go. And I think that is it. Our final reminder of you are not alone. We're here with you and for you. And so open the floor to any questions. Where's it hiding?

- Thank you so much. Yeah. So you went through some very important points there. We do have just a few moments for questions. Some have been coming in here. So Robin, I don't know if any caught your particular attention. We did touch a little bit on dexamethasone. One of the questions maybe for Saad or Paul, is that linked to daratumumab maintenance. How much dexamethasone is used? Do you use linked to that? I guess it seemed like someone was continuing to get decks along with the Dara.

- Yeah, it's a great question. I am minimal. I mean essentially, one of the beautiful things about Dara is after the initial dosing and safety and especially with the use of singular and other pre-medications in my experience, you know, Dex dosing can be absolutely minimal to zero, especially with the . And I love Saad's comments, but you know, again, it can be minimized.

- Right, right, right.

- [Dr. Brian] Yeah, go ahead, Saad.

- I was going to say, you know, typically after the first cycle or two, we can actually eliminate Dex for majority of patients, if we're just continuing the daratumumab on its own.

- Okay, that's great. That's what I was thinking. Mary, maybe you can comment. There was a comment here about diarrhea linked to Revlimid and the body and the value of taking colestipol. Do you wanna comment on that side effect?

- Yes, thank you. I just saw that. So Revlimid-related diarrhea is a real symptom and a lot of patients live with it on a daily basis. I think anecdotally we see it sometimes later on. So as we talked about patients who are on Revlimid maintenance, three to 10 years, you may develop this diarrhea symptom, you know, five years after being on Revlimid. Beth Famin, one of the Nurse Leadership Board members did a wonderful presentation a couple years ago on the use of bile acid sequestrants for Revlimid-related diarrhea. And it does help. It's certainly an intervention that may not be harmful. So it's probably worth trying. And I often talk to patients about using fiber, maybe modifying their diet, trying to find some triggers. And if those things don't work, then I usually try a bile acid sequestrant and see if that can help. And sometimes it's just about limiting the urgency related to the stool pattern, or just limiting the number of times a person has to go in a day, which allows you obviously to live a better quality of life. So I think it's worth trying. It's something you should talk to your myeloma providers about though, too.

- Right, right, right.

- Mary, I've heard a lot of myeloma patients, so it's either colestipol or Welchol, or colesevelam hydrochloride for the generic version of it. And a lot of patients say they're finally able to get out of the house by using this. And it's really a cholesterol drug, right. But so maybe it'll even help your cholesterol.

- Well, Robin, yes, indeed. I mean, it's actually all based on a thing called bio acid malabsorption diarrhea, and we have the rather appropriate acronym of BAMDR because it sort of does summarize how unpleasant it is. It's incredibly challenging when it occurs. And I think Mary, when you described in your patient that can occur later, we completely agree with you because when you're on steroids, interestingly, it's much less likely to occur because it's an inflammatory response, especially to the bile acidic exposure. So counseling the patient as to exactly when to take the colestipol half now, before meals is essential. Minimizing the fat content of food is important.

And also to differ to your point, Robin, different preparations of the bile acid sequestrants can be tailored to a patient's need. Colestipol capsule is a big, big tablet. It's big. And I sometimes counsel my patients, if it's too difficult to take one thing, just chop it up. And then other patients have gone for the powders and so on. And some folks have found that the powders work better than colestipol and vice versa.

- All right. Okay, so I'm gonna suggest that we move on to our final segment. So thank you so much, Mary. And there are actually quite a few questions and we may be getting back to people with answers to those online or later. Okay. But I'm very, very pleased to be able to invite Saad Usmani from Memorial Sloan Kettering in New York to talk about relapse therapy options and where do some of the newer immune therapies come into play. So, please welcome Dr. Usmani.
 

- Thank you so much, Brian. It's again, a privilege to be here. And, you know, we've had two wonderful talks and some really important questions that have already been addressed. And I'm tasked with covering our typical approach to relapse patients right now, as well as the plethora of options that we've been able to bring up for our patients through the regulatory approvals and others that are coming down the pike, and I'm going to try to do justice to the time and, and the content that that I have, but really welcome, you know, comments after my presentation from my esteemed colleagues as well, because this area is changing quite drastically. I still recall, you know, giving a presentation a few years back where we only had the PIs and IMIDS and data was just coming into the picture, and now we have so many options and combination for relapsing patients. So, it speaks to how quickly the field is changing. And I'm pretty sure this evolution will continue to change, how we manage our patients.

So I'm going to move through the disclosure slides and as well as the learning objectives to go to the frontline approach that Paul has already highlighted. So, you know, we do think about patients in terms of transplant eligibility, a patient who's presenting at the age of 50 versus someone who's 75. We obviously you are thinking about, you know, treatment strategies in a different way, but for the most part, like Paul highlighted in his presentation, the quadruplets, with data RVd is something that we do consider as a frontline regimen for most transplant eligible patients. And at MSK, we typically do collect stem cells, post induction, and then for eligible patients who move on to their stem cell transplantation.

The only difference is in terms of their maintenance strategy for standard risk patients, we, we utilize Len as maintenance and it's an IMID and PI based maintenance strategy for high risk patients. And then, based on the forte data, there's a strong rationale to consider KRd as induction and KR as maintenance for certain subsets of patients. So we actually have that informed discussion with our patients before we pick that optimal frontline strategy for patients. For transplant and ineligible patients, just as Paul highlighted, looks like I do have a bit of a delay in moving the slide. So my apologies, I'm gonna give this another shot. All right, here we go. So, you know, oops, now it's moving it way too fast. So let's move back a couple of slides. Here we go. All right.

So transplant ineligible patients, you know, Rvd-lite or ultra lite or premium lite as Paul highlighted are various renditions of the PI/IMID combination that we utilize for our transplant ineligible patients. And then the MAIA data highlighted the use of DRDs as frontline regimen, and then patients who are receiving RVd light. Again, you know, we do want to distinguish high risk versus standard risk maintenance strategies and try to keep a PI on a dose attenuated schedule for our high risk patients and for patients who are receiving DRD, they can continue that regimen in a dose attenuated fashion until relapse progression or intolerance. And many times if patients are in a good response after they've had a response plateau, we may be able to peel off one of the drugs in that combination. So that's the typical approach that we take. And the reason why I'm highlighting that is with that approach, Paul has very nicely highlighted how long it's taking for our patients to actually, you know, for the disease to come back. And that's great.

I mean, we've made strong progress, but the fact is, that our patients do relapse. And when they do, we kind of bucket our considerations into three categories. We look at patient specific factors, disease specific factors, and treatment specific factors. And I think of all these, I think the disease specific factors are probably, you know, are relevant to the pace of the disease, as well as the high risk nature of the disease. And whether patients are developing any phenotypic features of high risk, like extramedullary myeloma, circulating plasma cells. And myeloma is a disease of older patients. So, you know, patients do have competing comorbidities that arise during the course of their myeloma journey. So we have to pay attention to those when the patients are relapsing and also pay attention to the treatment related factors like side effects, neuropathy, and Mary has really nicely highlighted some of the challenges that our patients face, as part of going through myeloma treatment.

So all of those factors need to be considered when you're thinking about treatment for that first relapse. And this is what we are looking at. So we have all these options, and patients are getting either three or four drug regimens with, or without stem cell transplantation. We still have some patients who are frail and elderly, who might be just getting two drug regimens. And so, they're expecting median progression-free survival will depend on the treatments that they receive. And these numbers are based off of all the trials that Dr. Richardson has presented. And so patients are presenting with all of that, you know, previous therapy, different PFS expectations, different drug exposures into that first relapse. And this is what makes the field very interesting.

This is where the one-size-fit-all does not work. And this is what makes our job very interesting. So let's talk about some of the options in the context of various combinations. So we were very excited about five years ago, we had, you know, these four tries that would report being reported out one after the other, looking at combinations of Lenalidomide and dexamethasone with a third partner. So it was either a proteasome inhibitor or a monoclonal antibody.

In terms of proteasome inhibitors, we had the Aspire trial that combined car with carfilzomib with Len-Dex comparing it Len-Dex in patients who had early relapse disease. In the Tourmaline Trial, it was exacermate with Len-Dex. in the Eloquent-2 trial, it was the monoclonal antibody elotuzumab. And then Pollux study looked at daratumumab with Len-Dex. All of these studies were positive studies, you know, highlighting the fact that we need combination chemotherapies for better outcomes for our patients. But perhaps the most impressive results, in the PI or the proteasome inhibitor category was the carfilzomib combination. And in the antibody combination, it was the daratumumab Len-Dex combination.

And those two regimens became more popular because of the results we were seeing, as well as the safety profile and administration ease we were seeing. But the matter of the fact is that in our clinical practice, majority of patients are lenalidomide refractory patients stay on lenalidomide either on its own or in combination with a proteasome inhibitive. And what we were starting to see in different clinical trials is the outcome of patients who were on lenalidomide and progressing.

So the lenalidomide refractory relapse myeloma patients was not as good as someone who had been lenalidomide exposed or had been lenalidomide naive. So we had to do something different for these patients. And this is where, you know, the pomalidomide based combinations and the carfilzomib based combinations came into play. So there were clinical trials that combined pomalidomide and dexamethasone with anti C38 monoclonal antibodies like daratumumab and isatuximab, then elotuzumab was combined with pomalidomide and dexamethasone. And then Pom-Dex was also combined with bortezomib in the Optimism trial that esteemed colleague, Dr. Paul Richardson actually led. We also had some data from the carfilzomib combinations that was originally presented by Dr. Jason back in the mid-2010s.

The bottom line is that each of these combinations, even though the prior regimen number of, or media lines of regimen was different, had a relatively high proportion of Len refractory patients. And I think there is a mistake on this slide. If I recall Dr. Richardson in the Optimism trial, almost all the patients were Len refractory to my knowledge. So I think that there's an error on this slide that I just want to voice over right now, but the bottom line is for Len pit refractory patients, we were getting somewhere between 11 to 12 and a half months of PFS benefit with each of these three drug combinations.

So our job is still, we still need to do a better job for that particular patient population. This is where it was very interesting to see the anti CD 38 carfilzomib dexamethasone data in the Candor Trial, as well as in the Ikema Study. Both of these studies looked at the anti C-38 Kd combination compared to Kd. The studies designs were a bit different, but the percentage of patients who were Len refractory and some of the other statistical assumptions were similar, and what we saw is the PFS benefit that the delta was really similar across these two studies.

So, you know, proof of concept, that interestingly, the anti C 38 carfilzomib-dexamethasone combination fairs very well for relapse myeloma patients in general, but for Len refractory patients, the PFS benefit was quite profound. A third study that I do want to mention here is one that was presented by Dr. MV Mateos looking at the carfilzomib combination with cyclophosphamide and dexamethasone. This was a smaller randomized Phase 2 study, but showing interesting results for the Len refractory patient population, where, you know, if in economically challenged or emerging economies, as we like to say, in the year 2022, where some of the more expensive medicines may not be as feasible for patients utilizing cyclophosphamide with carfilzomib may be a reasonable approach for that land refractory patient population. But these results, kind of highlighted the carfilzomib based combinations can be a good option for lenalidomide refractory patients. In fact, for patients, you know, who were getting the Anti C-38 Kd combination.

So this is the Candor Trial data, the overall response rates for patient such patients that first relapse was very high. It was 90% overall response rate, and 16.5% of the patients were MRD negative, in negative CRs. So, you know, good option for this kind of patient population based on the available data. The International Myeloma Working Group guidelines, this is the scientific arm of the International Myeloma Foundation, which many of us are part of published this approach. This is like the global approach to that first relapse patients. We do identify patients to either not being Len refractory versus Len refractory in that first relapse. And you can see the preferred regimens based on the data that I've shared with you. As patients progress to subsequent lines of treatment, some of the basic principles that we do utilize is utilizing therapies that patients have not seen before, ideally, you know, two new drugs, but at least one new drug, and we always like to put patients on clinical trials if possible especially at the academic centers.

And then, going back to the point that Dr. Richards had made in his presentation, for those patients who did have their stem cell collection early on, and did not pick that option, high dose Melflufen with stem cell rescue may be an option for those patients. And this also becomes important as many of our patients as they're having subsequent relapses may have low blood counts. And if we want to replenish their counts to get them eligible for clinical trials, that may also be a potential option for them.

So similar to the International Myeloma Working Group criteria at Memorial Sloan, we have a very similar kind of an approach where we think about patients in terms of Len sensitivity, or refractors proteasome inhibitor sensitivity or refractoriness, or in case of high risk patients. But, you know, we can have PI/IMID refractory patients, even at that first relapse. So thinking about clinical trials, thinking about the various options that we have for that patient population. And similarly, as patients get into their second relapse, now we are talking about whether they're sensitive to pomalidomide carfilzomib or to both, and think about those options. And this is where I think Dr. Richardson had alluded to the translocation 11;14 patients, they might actually benefit from a Venetoclax based combination in that setting. And I'm going to talk a little bit more about that because we have several options coming down the pike. So we have small molecules, novel antibody drug conjugate combinations. We have the bispecifics and CAR Ts that are making their way into the clinic. And I'm going to, you know, just voice over the FDA-approved options as I go through the next few slides before handing things over to Dr. Durie for discussion.

I think within the small molecules, both Iberdomide and Mezzi, which is the CC-92480 have been very exciting. So Dr. Sagolonia has kind of led the Iberdomide development program and presented some of the early single agent as well as dexamethasone combination data. But we now have data with Iberdomide being combined with daratumumab, as well as in bortezomib in subsequent cohorts of the same study, showing very comparable kind of safety profile as we one would expect from an immuno laboratory drug being combined with either daratumumab or with bortezomib and dexamethasone. Interestingly, overall response rates, even in patients who are daratumumab or bortezomib exposed and refractory being, being quite high. So very encouraging results, early results with di-iberdomide combinations and safety profile, being very comparable to what we would expect with other immunomodulatory drugs. And the CC-480 program, You know, again, Paul has kind of led that early drug development with 480.

This is a very unique kind of a CELMoD with a more rapid protein degradation. And interestingly could be something to utilize for our more proliferative high risk patients, hypothetically, but showing very good early response in patients who are PI/IMOD as well as triple class refractory with high overall response rates and the recommended Phase 2 dose with this particular CELMoD And hopefully, Paul, we are going to be seeing some combination data coming later this year, as well as the year after. So, really excited about the prospects of seeing these new CELMoDs. Then Venetoclax is already FDA-approved actually for other indications, but, it has shown good, within the malignancies I would call, you know, I should qualify. But we are already familiar with its activity and relapse refractory myeloma specifically in translocation 11;14, and DCL to over-expressing myelomas. And this initial data came from, you know, single agent activity of about 40 odd percent in relapse refractory setting.

But then, you know, Venetoclax is also active in combination with bortezomib dexamethasone and our colleague Philip Mero had presented some of the early combination data that led to the randomized phase. These three study called Bellini. The Bellini Trial was actually quite controversial a couple of years ago, in fact, three years ago when it was placed on hold by the FDA, because this was an all commerce clinical trial, which was showing PFS benefit. But then it did show higher rates of deaths in the Venetoclax exam. And it turns out that was being primarily driven by some cardiac and infection issues in the non transplant, you know, translocation 11;14 group. Looking at the translocation 11;14 group specifically, which made up a smaller subset of the BELLINI trial, there were very high overall response rates of the key message from their experience was that, you know, therapies like Venetoclax benefit a biomarker driven patient population, and that's where they will likely have to be utilized.

So, very important data, very impressive data for that particular patient population. And then Venetoclax is also active with carfilzomib dexamethasone. So there are studies that are looking at combinations with other proteasome inhibitors that even with daratumumab, for that translocation 11;14 patient population. Then, you know, belantamab mafodotin or Bela-maf is an FD approved therapy for patients with four or more prior lines of treatment and triple class exposed or refractory myeloma. This is a BCMA directed antibody drug conjugate. And I've had the privilege along with Dr. Richardson and the Dr. Loneal to have been involved with the clinical development of this BCMA directed antibody drug conjugate.

The essential concept here is this antibody has a toxic payload that gets delivered to BCMA positive cells. So these antibodies can recognize BCMA on the surface of the malignant plasma cells and delivers this toxic payload that leads to cell death. And the overall response rates, were about 32% with the two different doses utilized in the Dream 2 Trial that led to the FDA approval of this therapy about two years ago. But the key issue that was, you know, in terms of safety that was observed was this keratopathy or ocular side effect. And that keratopathy occurred in about a third of the two thirds of the patients, and it was reversible for the most part, but then it sent us back to the drawing board in trying to figure out what is the optimal dose, what's the optimal schedule. And what we are recognizing is that you can give this antibody drug conjugate less frequently to patients and still get the bang for your buck.

So new strategies giving this drug less frequently in combination with other therapies are being utilized in clinical trials. You know, our colleague, Dr. Susan Trudel from Toronto has presented some of these data with pomalidomide and dexamethasone. And so I think that there's a good future for this particular BCMA directed antibody drug conjugate. Then for that triple class refractory patient population, we had the approval of selinexor along with dexamethasone, based on the Phase 2 Storm Clinical Trial data for triple class refractory or more advanced myeloma patients. This therapy's oral, but was not the easiest drug to give on the original schedule that was approved by the FDA. And more recently what we've recognized in combination with proteasome inhibitors and Dex like your bortezomib and dexamethasone is that you can give it less frequently in lower doses. And there is a synergy.

So the Boston Trial actually reported out, this was a randomized Phase 3 study looking at one to three prior lines of treatment, comparing Selinexor, bortezomib, dexamethasone with bortezomib dexamethasone, showing a PFS benefit in favor of the three drug combination. And this was a proof of concept. This is an image free regimen. And the significant portion of this population was lenalidomide refractory and the responses and the PFS benefit seen in that subset of patients was certainly higher. And there was a signal in favor of high-risk cyto specifically deletion 17-T in this study as well. That certainly needs to be validated, but an important signal, indeed. More importantly, I think, selinexor combination with carfilzomib and dexamethasone was quite impressive. And we are hoping to see more with this dataset. I think there's a randomized study that's been planned with the selinexor, carfilzomib and dexamethasone combination. So a lot to come on the small molecule front, but that's not it.

I think we have some T-cell redirecting strategies that are making their way into the clinic. On the left side of this figure, you see the CAR T cell therapies, and CAR T cell therapies, a fancy way of of saying that we take the patient's T cells, teach the T cells, know, or genetically modify them to recognize certain surface markers on the myeloma cell. And then infuse those cells back to the patient, and then those genetically modified immune T cells without the cancer cells. And that's essentially the process. Now you can do a similar kind of an approach with what we call bispecific antibodies or bispecific T-cell engagers. You know, those two terms are essentially a function of the structure of the molecule that does the job. So both these approaches by specific antibodies or bispecific T-cell engager one part of that molecular structure recognizes the patient's T cell, the other part recognizes the myeloma cell and brings them together. And then the patient's T cell kills the cancer cell. That's the real concept.

And the difference between bispecific antibody and T-cell engage is really that structure that bispecific antibody is a full antibody, that T-cell engager is only a fragment of that antibody. But they're doing the same job and they're doing a darn good job at that. So my specific antibodies are showing very high response rates of well over 60% while Teclistamab is the farthest along in clinical development. And fingers crossed, we might hear some good news later this year, or very shortly about an FDA approval for that particular bispecific antibody and Ranotamab and the as well as the bispecifics are showing very good clinical activity.

I think that it's good for us to have all these options, the dosing schedule, the cytokine release syndrome patterns and percentages and management is probably going to be different for some of these, but showing very good promise indeed. And then, the BCMA directed CAR T-cell therapies, there's several constructs, but two that are already in the clinics. We have FDA approved if we had the FDA approval of Ide-cel showing a little over 70% response rate in relapse, refractory, multiple myeloma. And that approval came about two years ago.

And then Cilta-cel, which is the second BCMA CAR T. It was approved last year with an overall response rate of about 98%, both highly active, but we can talk about some of the logistics challenges that all the centers have had in trying to get patients to CAR T-cell therapies. And this is where I think, you know, the bispecifics will become very important, in managing myeloma patients at large, you know, because of some of the logistic challenges we have with the CAR T-cell therapies. But very exciting strategies for our patient population. And then something that's still coming down the pike is allogenic CAR Ts. I do want to briefly mention this because one of the issues with CAR T cell therapies is the manufacturing process can take up to four to six weeks. And many of our myeloma patients have aggressive disease and they require treatment right away.

Well, you know, with an allogenic CAR T-cell therapy, you can take, T-cells from one donor and make hundred products. And you can essentially give that allogenic CAR T cell therapy to a patient within a week. And that's the advantage of this strategy. And my colleague Shamal and Cody from Sloan had shared some of these early data last year. So, I think when we are thinking about these immune therapies, we have to weigh the efficacy, safety pace of disease relapse. All of those things are going to be key in how we are picking each of these treatment strategies. And this is again an opportunity of how we can utilize each of these modalities to fit the patient's need.

You know, there are going to be patients who are 200 miles away from the closest transplant center or an academic center. And so you'll have to think about picking therapies that give a good efficacy to patients without compromising their social situation, or logistic challenges. So we have to kind of bear all of those things in mind. These CAR T and bispecific studies are now moving into earlier lines of treatment. So there are clinical trials and there are comparing, both bispecifics in CAR Ts in one to three prior lines of treatment. And some of these trials have already accrued, I mean they're getting close to accrual and should be reading out soon. In fact, I think, Dr. Durie, we actually had BMS announced maybe a week or two ago that the KarMMA 3 Trial has read out in favor of Ide-cels. So, we might be hearing some more good news about that CAR T cell therapy sooner than later for our relapse patients. So I believe, you know, I only have maybe one more slide left here, and this talks about fixed duration treatment with bispecific antibodies.

So this is one of my patients who has had a lot of treatment over the years. In fact, Dr. Durie, I believe his wife has periodically actually reached out to you for advice over the years as well. And the bottom line is that this patient, got a BCMA directed bispecific therapy in the summer of 2019. And the patient had to come off after eight cycles because they had a history of recurrent infections. And COVID was just around the corner. So the patient and the spouse decided to come off of the bispecific antibody study, but they have been off of therapy since then, and they're still MRD negative. For the first time ever in their whole course of treatment, they're MRD negative by NGSN flow. And that was well over two years ago. So, the point I'm trying to make is with some of these new immunotherapies, we may be able to give a longer reprieve to patients if they're getting to optimal responses. All right, with that being said, I quickly acknowledge, the myeloma service members at my center, as well as our transplant cell therapy team. And I will hand things back over to you, Brian, thank you so much.

- Well, thank you so much Saad for that, again, a comprehensive overview, but I think excellent summary of the approach to relapse therapy. We do have quite a lot of questions that have come in and I'll try... We've got 10, 15 minutes left, so we'll try to cover as many as we can. Okay. So let's try to keep our answer short. Over the time, there have been several questions related to high risk myeloma, and I know, Saad that you particularly have an interest in high risk. And so question about how do we change the treatment for a patient with 17P minus, and then a more recent question is how do we look at patients that have 1Q plus addition? So do you wanna comment broadly about high risk patients?

- Certainly, I can. So, the one broad comment I'll make about high risk disease is the high risk of relapse is really a function of treatments that we have at hand, and that high risk definition will likely change in the future because we have better therapies at our disposal. I think for Deletion 17P patients, my preference is to use combination chemotherapies to change treatment at biochemical relapse before patients get symptomatic disease, because we know that when patients get systematic disease and higher burden of disease, it becomes more challenging to treat those patients. So those are some of my general comments around that particular subset.

- So that's very, very helpful. Another question, which I think is quite important is how do you select between a couple of relapse options, for example, the Candor regimen. So Dara Kd versus Dar Pd with Pom? Somebody would like to, how do you select between those two regimens?

- So it depends on, you know, I'd welcome comments from Paul as well, but I'll keep my comments brief. So it depends on what the previous treatment that the patient had if they were Len refractory or not. And also you have to factor in patient preferences of oral versus IV therapies. And then the cardiac history also plays an important in picking between, you know, the Pom versus the carfilzomib combination.

- Right.

- Yeah.

- I would completely agree with Saad, Brian. I would make one other comment, which I thought was very nicely framed in Saad's presentation, which was really, dealing with Len refractions. But now the new challenge is Dara refractions. If you've got patients in whom they've had Dara maintenance and they progress as part of their maintenance regimen, what do you reach for? And I think that's changing the way we're thinking. And for example, reaching for a BCMA targeted approach in that setting after CD 38 has failed the patient makes sense. But again, at the same time, Dara maintenance can take many flavors. And if it's very intermittent say even every two monthly or monthly, a re-challenge could be reasonable. And what's so interesting, Brian, is the impact of isatuximab and that's kind of changing the playing field even again. So, lots of things to think about.

- All right. Very good. There's a simple question here. So what's the difference between Ida-cel and Cilta-cel? So you wanna tell us that one, Saad.

- Certainly. So, these are two different constructs or different kind of CAR T cells. One is manufactured by BMS, the other, Cilta-cel is manufactured by Janssen. You know, I think the key difference is Cilta-cel has two binding domains for BCMA compared to Ida-cel having one. And that's the one functional difference between the two, but the results we are seeing with both of them are a bit different, too, as well as the pattern of side effects.

- Right. Right. Absolutely. But the response rate does seem to be a little bit higher with the Cilta-cel, which may relate to the two double-headed approach. Yeah.

- And I think Brian, it's worth making point for patients that I completely agree with with Saad. I think Cilta-cel is clearly more potent. Yeah. But the co-binding with BCMA for this rare, but important toxicity, this late onset neurotoxicity, that seems something we've really gotta get a handle on actually, 'cause when it occurs , having one of my patients, very sadly having passed from it. I think one just has to be very, very thoughtful about this because the BCMA is expressed in the brain.

- Right. Right. Maybe just to switch topics at Mary, there'd been a few questions about neuropathy. One of them is quite important. I mean, what do we do about neuropathy? I mean, are there treatments that we can give patients who've developed neuropathy? You know, it's obviously a challenging problem.

- Yeah. It definitely is a challenging problem. I think one of the first important things to do is identify what's causing it. And if it's possible, you know, stop the offending agent or make a dose reduction, take a break from it. In terms of managing the symptoms of it, it's gonna depend on what the most bothersome symptoms are. Some people have pain and some of the atypical pain medication such as Gabapentin, which is also called Neurotin can be helpful for peripheral neuropathy pain. Some tricyclic antidepressants can be helpful for neuropathy pain. And then I think there's a lot of supportive stuff that we probably don't do a great job of talking about such as like compounded creams that can help with pain.

- [Dr. Brian] Yes, yes.

- I've had patients have experience, good experience with acupuncture as I mentioned, but also certain light therapies that can be helpful for neuropathy. So-

- Good. Yeah, yeah. So, Paul or Saad, any magic words for the neuropathy, which is challenging for a number of our patients?

- Right. A couple of little vignettes. I think I'd love Saad's thoughts on these as well. We partner steroid on the day of bortezomib administration the day after and the effect of this concomitant administration's important for reducing the inflammatory component of the bortezomib mediated neuropathy. In that same spirit, we have always embraced the use of intravenous normal saline, even when you're giving the drug subq. Let me explain why. You literally, as you draw your CBC chem profile, you leave your butterfly in the vein and you pop up your half a liter of normal. The patient can then get their subq shot and there's not extra time spent necessarily in infusion area. And why this rationale. The rationale is that perfusing in the small vessels that feed the tiny small fibers in the skin. The so vasorum is very important to getting free radicals away from the nerves at the time of exposure to bortezomib which is relatively rapid actually. And we have a cohort study led by my colleague, Jacob Laak and Peter Gorman from Ireland. And we showed in two cohorts in this group, we sort of made this observation, that's published to the American Journal of Hematology that with the use of intravenous normal saline, we were able to see a reduction in grade three neuropathy.

It was very interesting. It's preliminary, but there is a science behind it. And then my final comment would be to build on Mary's really nice comments about emollients and emollients can really make a difference. And we love a cocktail. I'm sorry for the beers. We're now getting into really great areas. We use cocoa butter, coconut oil and shea butter and we mix them all together. So Saad, over to you.

- Love those. Both those commentaries are so important. I think the only thing that I can add is early recognition.

- Is important.

- Is extremely important. And I think this is so important for patients to hear as well as for our community colleagues to pay attention to. And the other piece is early intervention with functional physical therapy as well as acupuncture can actually help. You know? So I think those would be that additional comments to what you've already said.

- All right. Another series of questions. One was, if a patient is MRD negative and then becomes MRD positive, what do you do? Would you immediately treat the patient? The answer'S probably no, but what do you do in that circumstance? Maybe you'd repeat the test.

- So I would, you know, get up. I don't act on that information, and I'd be surprised why one would be checking MRD after, unless you're thinking about checking for sustained MRD negativity. I think, you know, yeah. One situation where, where I would be worried, Brian is the high risk patients.

- [Dr. Brian] Yes. So, high risk patients getting MRD positivity would worry me. I would probably keep a closer eye on that patient for biochemical relapse so that I can get them

- Very, very important point. Now there's a question about experience with the Bela-maf, but I'm wondering maybe for all of you, for patients who are interested in accessing CAR T as we know, there has been quite a difficulty in accessing CAR T. For patients who are interested in that, what could you recommend right now? What's your current experience in terms of getting access. it's been, you know, like maybe one patient a month or what's your current experience?

- Yeah, so this is actually a big logistic as well as ethical issue. And every institution is managing this a bit differently. And, you know, at MSK, we actually have a weekly meeting amongst the myeloma, service providers and all of the patients. We have like a list of 60, but we have only a finite number of three or four slots for either Ida-cel or Cilta-cel on a monthly basis. We actually have our ethics committee, institutional ethics committee join the call as we go through the process of discussing patients where they are in their disease process and who needs it more, you know, and where it fits off from a logistics standpoint in their care. So it's a major challenge. And this is where I think, you know, if we do get a bispecific approved, which is giving 60% on response, that will change the landscape of, you know-

- Yeah. Gives you a safety valve, an alternate therapy.

- I so agree, Brian. I mean, my comment here would be to really echo. I so agree with you Saad. I think bispecific will decompress dramatically. And in fact, potentially there will be an array of them. We have exactly the same challenge as you saw. We, and our team are fantastic. We meet every week and prioritization is given. We don't actually necessarily have an ethics committee involvement, but we definitely go through sort of prioritization. But even with that being the case, I'm very lucky because I have partners with NGH. And so, you know, some of my patients for example, will go across to MGH if we don't have availability.

- Over there example.

- And that that works. But I think this brings a key point, Brian, to share with the audience. Myeloma is always a matter of all hands to the pumps. This is not a disease where one particular modality beats the other, we need all of them. And for example, you touched earlier on the importance of some of the newer approvals. For example, I think Venetoclax hopefully will be FDA approved early next year, based on Canova. We've cristamab approval coming pretty soon, I think, and we also got willing, we'll have Melflufen back on the books, because at the end of the day, we need all of these drugs. For example, colleagues of mine were using Melflufen as a bridging strategy to get to CAR T and other things, very successfully actually. So I think we need all of these approaches because at the end of the day, we can't do the impossible. There is a limited amount of CAR T availability.

- Right, right. So we've reached the end of our time, but I think these are excellent final comments. I'll just say one question. Albushel, which is the antibody treatment, I think we do recommend that for patients who may have had very poor response to COVID vaccination. So I think that this is a very helpful therapy, but for those of you, we haven't gotten around to all the questions. I think we've actually covered quite a lot.

And in closing, I would like to thank all of our speakers, Paul getting us off to an excellent start with frontline, Mary, with how to manage the patient through the course of their disease, and Saad, really excellent approaches to relapse therapies and the exciting new therapies, which are gonna make such a big difference. So Robin, I'll turn it over to you for final thoughts and comments.

- Sure. So, thank you so much. Each one of you presenting something so important for patients and caregivers to be aware of. And even though this was titled "Back to Basics", I think it covered a lot more than just the basics.

- Yes.

- So the good news is we did record this. It will be available next week on the IMF website for replay. And I would suggest while you're on the IMF website, there are so many really good, important places that you can go to. We talked a lot about FDA-approved drugs, and there's a section on the website that you could click on and look at all those different options there. And where does that fit in when you have your conversation with your healthcare team and then the clinical trials that Dr. Usmani and Dr. Richardson talked about today.

Those trials are our future, and some of them are getting approved faster. You know, maybe aSH, we're gonna hear some more information coming from there. So all the questions were excellent questions. If it wasn't answered, don't forget we've got the info line and that's 1-800-452-CURE, which is the best cure, 2873. That's a really good info line number.

And as always, we always thank our sponsors for these educational programs and this time, that's Amgen and the Binding Site and Bristol Myers Squibb, and Genentech, Roche, GSK, Janssen, Karyopharm, Sanofi, and Takeda Oncology. So, thank you all. And before you go, next slide, please. We wanna remind you that you do have that questionnaire at the end of the program, and we really want to hear your opinion so we can continue to bring you really good information to help you feel hopeful and have good conversations with your doctors. So that's it for me, Dr. Durie.

- Well, thank you so much. And then in closing, I also want to thank obviously our IMF team members who've helped to put today's webinar together and our partners that organize the technology and the logistics. We would not be able to do it without them. So thanks to them for helping to make all of this happen. So, thanks to you for participating. Thanks again to our faculty and the very best for a wonderful weekend. Thank you all.