What Patients and Caregivers Need to Know About the Newest in Myeloma Care, Side Effect Management, and CAR T-cell Therapies

- Welcome everyone. Thank you for joining this patient and family webinar, New Frontiers in Myeloma Care. We're very very pleased to have so many of you joining us for this session.

So with me today I'm very very pleased to welcome Ann McNeill, a member of our nurse leadership board who's based at the Hackensack University, Hackensack New Jersey. So welcome to Ann. Then we're also joined by Yi Lin from the Mayo Clinic in Rochester Minnesota. I'm very very pleased that she's able to join us. And then the fourth member of our team today is Nikhil Munshi from the the Dana-Farber in Boston. Nikhil is actually attending an important medical meeting in Paris in France, however he has taped his presentation but will be available for the live Q and A session. So we really really appreciate that he's willing to do that.

Thanking our sponsors. Very very happy that we continue to have so many from support us. If we can thank AMGEn, Bristol Myers Squibb, the Binding Site, Genentech, GSK, Janssen, Karyopharm, and Takeda Oncology.

Now, for the audience Q and A you can open the Q and A windows and then we will see questions in the chat box, and we will try our best to answer as many of those as we can. If we don't happen to get to your question there are ways to follow up with us, and we will do our very best to answer especially any kind of an important question. And then we will have a very short feedback survey at the end.

So the agenda for today will be in two major segments. The first segment will be opened by myself with the myeloma 101. Then Ann will talk about side effects and symptom management. And then I'll give a little bit of a newer different presentation about diagnosis, monitoring, and early disease. We'll take a short break. And then Yi Lin will talk about very very exciting latest advances in immune therapies. And with a focus on CAR-T. And then Nikhil Munshi will be talking about what are the current bispecific and novel agents that are available and can be used to treat relapse myeloma. So let's go ahead and get started.

- This first segment, which I call Myeloma 101, is just to give a broad overview for everyone. So where are we with myeloma diagnose and treatment these days? And I think that the important news for every patient and family members is that when you have a diagnoses of myeloma, myeloma is obviously a challenging disease, but over 90% of the patients are likely to respond with the currently available therapies with triple therapies that we would typically use in this early front line setting. And on average now the first remission can be in this range of four years or more.

Now this doesn't mean that there still might not be some patients who present with challenging problems with maybe some more high risk features where we are really pressed hard to achieve that first remission. But the majority of patients can really expect to do remarkably well these days. And in 2022 the average survival is at least seven to 10 years for people starting out with that new diagnosis and front line therapy. We have patients now living out over 15 to 20 years. And so it really is changed days from 20 years ago where the outcome was so much less fortunate. And as you'll learn today, new therapies are continuing to improve this outlook. And so we are just so pleased that we can have this kind of good news to be offering patients as they move through their journey with myeloma.

Now when you're first diagnosed, and actually at every major juncture in the disease course, but particularly when you're first diagnosed, it is important to seek expert consultation at least once so that you have that input to basically come up with that recipe as to what would be recommended in your case. So it's really good to do this early. So talk to your doctor about who might be the most knowledgeable in the area of myeloma in your community. And maybe check out what is that closest largest university center or large center that specializes in myeloma. And especially during COVID what happened is it was more feasible to get a virtual consult. And many of our experts, myeloma experts were offering these virtual consults. And I think it's still a good idea to explore that if need be. It really does set the path for the future and it sets up a recipe, a guide for your local doctor so that you may periodically go back to see that expert. And especially in the relapse setting it's good to have access to new trials through a large local center. So careful testing is definitely required to achieve the diagnosis, but also to make sure the extent of the disease.

So this is called the initial staging to see the extent of the disease. Overall the bone marrow is critical. Typically the diagnosis is made from that bone marrow test which shows the myeloma cells. In this slide here which is slide number nine which we're currently on, those dark kinda purplish cells those are myeloma cells which are filling up the bone marrow which normally would be filled with a whole range of cells producing white cells, red cells, and platelets to produce for your bloodstream. Overall the percentage of those myeloma cells indicates the extent of the disease. Normally they would be less than 5%. Typically for myeloma which is active they're over 30%, but they can be 50%, they can even be 80%. And so they give an idea of the extent of the disease.

Myeloma is called multiple myeloma because there are lesions not just in one spot. So it's a little bit different than having something like breast cancer where you have cancer of the breast. In the case of myeloma you could have lesions in different parts of the body. And myeloma is a disease which affects the bones. And so what we're talking about is lesions. And you'll see here I put a little asterisk there, this is where we start to use words which you wouldn't normally be talking to your family about at breakfast time. These are words that are not part of your day-to-day lingo.

So what is a lesion? So a lesion is an area that has been damaged in the bone by the myeloma. So myeloma is an unusual type of bone marrow problem where as the myeloma grows it damages the bone around the myeloma and produces lesions which show up on an X ray as dark spots. Now typically, Myeloma is diagnosed very early these days. So frequently there are very very few of those kind of lesions. We can look more carefully both at the bone marrow and the bones using additional testing. When you get that bone marrow test the doctor will probably tell you that he will send, he or she will send an extra sample for a special chromosome testing. And these days it's normally done using a test which is called FiSH, which is fluorescent and cito hybridization. And the picture of that is shown on the left there where these chromosomes, each chromosome you got two of each have different colors. And what happens is that one chromosome can get mixed up with another one. And so then you have two colored spots indicating that a yellow chromosome has mixed up with a red chromosome. And then this is how we can tell there are what we call translocations.

And some, a common one is 1114 for example where there could be a mix up of I think it's a green one and a red one I think in this particular picture. These we use and we'll talk about a little bit as we go through discussing how we approach the treatment. As far as the bones, MRI and PET/CT are frequently used, and most of you will probably have had one or maybe both of those. On the PET scan a small amount of sugar is injected, radioactive sugar, and wherever there is an active myeloma lesion it will take up the sugar and where it's taken it up you can image it using different color techniques. In this picture here in one where the sugar has been taken up it shows up as yellow. But you can also use imaging which looks more like an X ray where the spots show up as black spots. On MRI which is in the middle the lesions show up as white spots. And so what we're looking for are spots, which depending on the type of the imaging and the display technique can be different colors. So don't be confused by that. We're looking for these spots to see where are they and how many are they? To try to get a handle on the extent of the disease. So having done all of that and got that baseline established then we assess what's going to be the overall approach. And the overall approach consists of initial therapy for all patients.

Now for younger patients or patients who are in good shape and eligible, on the top of this slide you can see there's an option to consider a autologous stem cell transplant followed by maintenance. For older patients over the age of 65 or those are not able to withstand a possible autologous stem cell transplant there would be some further treatment for the first nine months or so and then maintenance. And along the way there would be supportive treatment which mostly means that there would be treatment to help shut down any bone destruction that is going on. And so basically two approaches. One with the autologous stem cell transplant, one without.

And we're gonna talk a little bit about that, what is the value of having that stem cell transplant. Doctor Vincent Rajkumar does from the Mayo Clinic which is where Doctor Yi Lin is from, Vincent one of her colleagues does a really excellent job every year. Who he summarizes the currently available testing and approach to treatment for myeloma. And so I've referenced his most recent review which I think is a very helpful resource there. Now as you approach treatment, and this is the reason why it's good to talk to your doctor and maybe talk to an expert, is that there are quite a few options. And in the old days meaning like 20 years ago, we had only a limited number of options which are listed across the bottom of this slide. But if you look across the top starting from the left you'll see that there are really relatively few options that we consider standard of care as initial treatment.

We use triple therapy with three medicines joined together. And the common is the one that we would recommend is Velcade, Revlimid, and Dex, VRD. The big discussion that we'll be having now is whether Daratumumab might be added to that to make it a quadruplet. So I've highlighted those. After that there's the option for stem cell transplant and then maintenance. And I've listed the drugs that we frequently would consider for maintenance with Lenalidomide or Revlimid being the normal maintenance but there are a few other options, especially if that FiSH testing shows what we call higher risk chromosomes where we might consider Bortezomib or one of the other agents.

Over in that relapse so you see there's a whole list of drugs which is good. All of these are available for patients who have had the myeloma relapsing, and it's good that we do have so many options. And we keep adding them. And we're going to be talking today about some of the newest ones that are coming on board. I've highlighted Melphalan. Unfortunately this is one that was actually approved but then had been withdrawn. And so now the company is reassessing access for that particular drug. So we just move forward. I think it's helpful, and actually I had the privilege of running this particular trial. This was a southwest oncology group trial which was run starting about 15 years ago now. And this is a trial that tested two drugs Revlimid and Dex which is in the blue is the bottom, Lenolidamide and Dex versus three drugs, Velcade, Lenalidomide, and Dex, To see if taking three drugs is better than two drugs. And so I think the one advantage of this trial is that we now have over 10 years of follow up.

And the key thing that emerged from this trial is that now we normally don't pay a lot of attention to the numbers along the bottom here. But if you look you'll see it goes all the way out to 120 which means that we actually have, that's 120 months. So what that means is the follow up, the real follow up for those patients is over 10 years. And so we are able to say that with a three drug combination you can have a remission which is about three-and-a-half years. And the overall survival you can see even out of four and seven years, actually both of those curves are still looking quite strong. And so this is the reason that I say that with the modern triple therapy, which we're enhancing and improving all the time, we are fortunate to have these kind of baseline possibilities.

And so what to expect with treatment? Well I think that the majority of patients will have a good initial response. And these days we're going to be talking about how if possible we'd like to push the disease with a quadruplet and with transplant to get as deep a first response as possible to get down to that minimal residual disease level, MRD, and you hear us talk about that more and more. Where we try to get down to zero even with that sensitive bone marrow testing. And then following along after that first remission average in the four year range, we want to jump in again quickly and again select a triplet to get a good response. And then keep going from there. And this is how we are achieving these better results these days. So triple therapy certainly a standard option front line. VRD is the common, it's Velcade, Revlimid, and Dex. The D means once a week dexamethasone. RD just two drugs for older or frail patients. If those are not available Thalidomide can still be used and also in patients with high risk disease sometimes we would use Carfilzomib or KYPROLIS instead of Velcade. Autologous stem cell transplant is still considered standard of care. And can certainly be considered to achieve better response after the first three-to-six months of the triplet therapy like VRD.

And just to alert everyone, I think we're all looking forward to ASCO, the American Society of Clinical Oncology meeting which is coming up very soon. At this particular meeting one of our colleagues, doctor Paul Richardson, is going to be presenting the results of a trial called the endurance trial which is a Dana-Farber trial. Which they looked at VRD with or without initial stem cell transplant. So I think that we're all keen to see what is this Dana-Farber study show overall in terms of the added benefit of incorporating that initial transplant as part of primary care? In addition we still recommend bone therapy either with Bisphosphonate or the newer monoclonal antibody the denosumab therapy.

Okay. So treatment strategies for now. Triplets or quadruplets, pushing harder with four drugs to try to get a better response. Use maintenance based upon that FiSH testing information, maybe consider Bortezomib, Velcade, along with Revlimid or instead of Revlimid. As you're moving forward I think more and more we want to stay ahead of the game and introduce and recommend decisive early relapse treatment with a triplet if feasible. And then of course what's so so exciting these days is the early introduction of the newer immune therapies to achieve the best results by using them a little bit earlier in the disease course. And we'll be hearing about trials starting to look at that.

And so the International Myeloma Foundation, we have many publications. We have the "Patient Handbook", we have the "Concise Review". We have a number of these. And of course we have the website where you can go and click through and really find information depending on your particular situation and questions. And so please don't hesitate to do that. And then we also have the info line where you can call to get the help that you might need. We're definitely here for you that's for sure. And you can click across the top there. So I'm just checking through here. Oh yeah we got lots of little arrows for you to take a look at there. So we do try our best to make the information accessible and available. And so I hope that this has been a helpful introduction overview. And we have been getting a few different questions coming in here. So I see the first one which is a good one, the first one is a good one and people can comment on this. Can I provide, can we provide I guess of when we will have a cure for myeloma? I don't know, I mean I'm gonna talk a little bit next segment about what we call cure trials. So Yi Lin, I don't know if you wanna comment on that? Or when do you realistically think that we will be in a position to say we're moving towards trying to cure myeloma? Do you?

- Oh my goodness, I think if we all have a great crystal ball we might be making a lot more money in our job. Certainly something we are all striving towards right as you alluded to some of these clinical trials incorporating these novel treatments. So the hope is that we'll see in some of the current studies are we continuing to move the dial to prolong that progression through survival? And coming up with that rational strategy so that we can have patients really live a good quality life and die from something else while in remission from myeloma. My hope is, I know just the medical conference you just alluded to Doctor Durie in Paris, there's a talk about 2030. That would be great. That would be--

- Right.

- I also want the data to get there, but I do think just in my time from training coming on staff as a licensed practitioner I've seen so much change in myeloma treatment options. So I am definitely very hopeful that in my career time we may see something that we can really say is more of a cure.

- Right right. Ann do you want to comment about that? You've seen I know so much improvement in myeloma therapy during your career.

- Yes. I'm hopeful, I'm very hopeful, put all the new novel agents and the science and the research and the clinical trials. I think we've come a long way. When I started working with myeloma over just about 20 years now I mean it was a very different arena, it was post docs right? And now we have this whole array of treatments. So I'm very hopeful, I am very hopeful that all the research that's being done that the IMF also supports. I'm hopeful, I'm very hopeful.

- Good good good. So a more direct question, and Yi Lin actually you can I think answer this one. When will the first bispecific antibody therapy be FDA approved?

- Yeah so we anticipate the first bispecific antibody is Teclistamab that already have a biologic license application submitted to the FDA. And as far as we know the anticipated reviewed deadline is August of this year and we have not heard any delays at this time. Of course that could happen between now and then. So we're very hopeful that we will have a review by the FDA late this year.

- Right, I think I certainly agree with that. I think we're all optimistic. I think that the trial results were really quite good, and I think we haven't seen any indication of concerns at the FDA level. So I think we're hoping that this will go through smoothly with FDA review. So optimistic about that. I'm just gonna go through quickly, what's extramedullary plasma cytoma? So obviously this is myeloma that might exist outside of the bone. And so actually the PET CT scan that I show, I didn't point it out, but there was some myeloma located in the belly area which is outside of the bones. And so we do want to pay attention to that because it may or may not respond in the exact same way as myeloma which is located within the bone. So sometimes we need to use stronger combination or maybe additional treatment.

And when we're looking at these new therapies like Teclistamab and CAR-T, we're always especially interested to see if it will also maybe do a good good job with that disease which is outside of the bone, extramedullary disease. And the good news is that some of these new therapies like CAR-T and Teclistamab do seem to work with disease, extramedullary disease.

Another thing. Someone's asking about liquid biopsies. I'm gonna talk about that actually in the next segment. I think that if we can use blood testing for precise monitoring versus repeated bone marrows, that's going to be very good. And I'm going to talk about the prospects for that in terms of a precise sort of recommendation. Then. Question here, why does it seem that all multiple myeloma patients seem to have the same treatment plan? Well yeah I think that that is for me that is quite important and interesting. And maybe either one of you might wanna comment on this. We make such a big effort of doing all this special testing and then we give all the patients mostly the same thing. So I think that that's because we do have a standard of care and then we kind of select and give extra treatment later to patients who might need it. But either one of you wanna comment on that?

- No I mean I absolutely agree, because to start off is we wanna say what's the therapy that seems to give everybody a good likelihood of response? Right and then now with all the information we're learning about the genomics, mutations, changes with the myeloma cells but then also with the current novel immunotherapy it's more and more important to understand the patients immune system, what's happening. So if we have a lot of those information put together the hope is that in the future we can become more and more individualized right. So like being the patient that--

- Absolutely.

- Can move the dial a little bit further.

- I think so yeah.

- More tolerable treatment with more response. We're trying to work toward there right now, we're not quite there. We know information.

- Right.

- And I think we need to study how to then rationally pick the treatment.

- Right I think that we're really really keen to have personalized treatment based upon the, not just the FiSH testing but much more detailed genomics, but we're not quite there yet. Now I see on one of the Q and A's and thank you Jack Ielo for always being on top of things. When I was talking about Paul Richardson's trial I misspoke actually, it's not the endurance trial it's actually the determination trial. I'm so sorry. I knew it was one of those very positive approaches but you're absolutely right Jack, it's the determination trial that we're looking for the results. It's actually a plenory presentation. And so that's actually kind of a special honor for myeloma study, so we're really looking forward to that.

Okay so I think that we've covered a number of these opening questions. So I think we could move ahead now Ann with your presentation how do patients manage with these new approaches to therapies in terms of side effects? And how do we kind of proactively manage the symptoms? So, please welcome Ann McNeill from Hackensack.

- Thank you so much doctor Doctor Durie. Good morning or good afternoon depending on where everybody is. With the interest of time I just wanna get started.

As Doctor Durie mentioned I'll be talking about side effect management. And this slide deck has a little analogy as a saying that you are the artist. So life is a canvas. So actually the objective's are looking at the treatments, how to frame your care, and then infection prevention will be the last part of the session. So looking at treatment options, side effects, symptom management, and supportive care, it's a whole look at the wheel, it's a whole different wheel of treatment. So the gallery of goals would be on the left, myeloma treatments what our goals are to rapidly and effectively control your disease. We want not only to control the disease but we want that disease control to last as long as it can, that's the durability of that response. We would like to minimize side effects, of course allow you to have a good quality of life and improved overall survival.

So some of the supportive therapies we have are used to prevent disease and treatment related side effects. We wanna optimize symptom management, and again, allow for a good quality of life. And it's always important to discuss your goals and priorities with your specific healthcare team. And Doctor Lin is going to talk more in detail about CAR-T therapy in a later portion of this program, but it is a newer treatment approach. I'm not gonna go into it in too much detail, but I just wanna talk about potential side effects.

So it is a specific treatment. Patients are selected. There is an apheresis or a collection of cells that are involved. The cells are then sent to a lab and then they are sort of altered to make the cells more likely to kill your myeloma cells. There is sometimes a bridging or sometimes bridging therapy and there's also lymphodepletion chemotherapy. And then the cells are infused. And at that time you are monitored very closely including for sometime after discharge from the CAR-T procedure. So like I said there are some unique side effects for CAR-T therapy and one of them is called CRS. It's cytokine release syndrome, that's the little circle in the middle.

So what does this include? It can include fever, fatigue, headache, some GI symptoms like nausea, vomiting, and diarrhea, shortness of breath, weakness, confusion. It is a common but usually mild side effect with CAR-T therapy. We can also see unfortunately some neurotoxicity. It's rare but a more serious effect of CAR-T. And this would include things like headache, confusion, hallucinations, unsteady gate, facial nerve palsies, tremors, seizures, difficulty in doing some kinds of tasks. So this is a little bit more serious but again not a common side effect of CAR-T therapy. So some of the tips for CAR-T here, and again I'm not gonna go into too much detail about the procedure. But it is taking the patients own, on the left hand side, taking the patient's own T cell and sending it to the lab for kind of manipulation or alterations. And actually we're making the cells, your T cells, more likely to target the malignant myeloma cells. So there are different CAR T's out there, many products out there, and as Doctor Durie mentioned we now have a second one that was approved just this past February. I think it's important to get a referral to a CAR-T cell therapy center as soon as possible.

I think there's a lot of logistics. There's insurance, pre authorization, there's a couple of things that have to be met as far as inclusion criteria even though it's not a study. You have to have sufficient blood counts and organ function to be eligible. Again your own T cells are engineered and grown, it takes a couple of weeks, four to six weeks. You must be able to wait during that time or have bridging therapy, some kind of therapy to keep your disease under control. There is a wait list unfortunately, and we were mentioning that prior to the start of this session. There are certain slots because the lab has to grow your own T cells and engineer them.

So how are these slots allocated? It's a procedure, it's not just something that they can take off a shelf and give you. You need a caregiver, you must stay within proximity of the CAR-T cell therapy center for at least a month after the infusion. There's no driving for eight weeks after CAR-T. But one and done. So this is kind of a one time therapy. But you'd need ongoing monitoring, and some patients will need ongoing transfusion support and other support after CAR-T procedure. Bispecific antibodies. Doctor Durie briefly mentioned this.

This is the newest therapy, the newest treatment option we have for patients with myeloma. If you look on the left, bispecific antibodies, we're actually looking at that T cell again and the myeloma cell. We're looking at two targets on those cells sort of combining the CD3 and the BCMA, getting a molecule that will bring these two together and hopefully lead to more myeloma cell death. There are different bispecific antibodies out there in clinical trials right now. CRS can be a common side effect. These are not yet FDA approved, they are currently available in clinical trials and we are hopeful that one of these will be approved this year. These are off the shelf treatment, these are not a wait kind of treatment where you're waiting for your cells to be engineered like in CAR-T, this is more readily available once it becomes FDA approved. And the infusion is usually every two weeks but can vary depending on the product.

So let's talk about clinical trials. Clinical trials are extraordinarily important. I think this is just important to know what clinical trials are. They are our access to promising treatments, so all the treatments we have out there now that are FDA approved are from all of these patients who are were enrolled in clinical trials and had good outcomes right. So pre clinical studies are usually done in animals. And then we have the phase one which is the first introduction of that new drug, it's called an investigational drug into humans. We're trying to look at the metabolism and identify some of he side effects. Phase two is we look at the evaluation of this medication, how effective it is in a certain tumor type. So again we're gonna look at the side effects, we're gonna closely monitor the patients. Typically it's a smaller group of patients, about 100 and not a very large group enrolled in phase two. And then we get to the phase three trials which is that sort of comparative study where we're looking at that drug or that treatment option or that treatment combination as compared to the standard of care. So placebos may be involved if no standard of care exists. This is usually open to 100 to several thousands of patients, often multiple institutions in multiple countries can be involved. So this is really the phase three is the really the study that tells us is this going to be a promising treatment for myeloma and will it become FDA approved?

So how do you find a clinical trial? You might say well I'm very interested in a clinical trial, I've lived with this disease, my healthcare team is mentioning clinical trials to me. There's some easy ways to do this. You can go on to Clinical Trials dot gov, and the website is listed on this slide. Your healthcare team may actually refer you to an institution that's within a good geographic distance for you that they may know has some clinical trial options available for you and your disease.

There's also the IMF. There is you can go on the web, you can call the hotline, but there is also some help getting access to clinical trials by calling the IMF info line. So there's a lot of myths out there about clinical trials, and I just wanna talk about them briefly and kind of dispel the inaccuracies. So one of the myths is if I participate in a clinical trial I might get a placebo and not get active treatment. So you will always get active treatments, in phase one and two everyone gets active treatment. In phase three it's standard of care versus the new regimen. So you might be randomized to get standard of care but you're still going to get treatment, you're not going to be untreated for your myeloma. If I participate in a clinical trial I can't change my mind. That is not true, you can withdraw that consent for clinical trial participation at any time with no questions asked. And then on a healthcare side there's a myth that patients never participate in clinical trials so I'm not gonna mention it. And that's really a myth because we should mention the option, give the patient the opportunity to participate in a clinical trial.

Some groups may need more information about clinical trials to feel comfortable with the participation and enrollment. But I think we should be as healthcare providers offering it to everyone as a potential option for a treatment. Another myth is clinical trials are dangerous because they have new medicines and new practices. And again, there's some risk involved with every treatment, even our standard of care therapies. Medicines are used in clinical trials with people only after they have gone through some prior testing to indicate that the drug is likely to be safe and effective for human use. So that's something to keep in mind.

Also of course we're all thinking about the financial end of this. And clinical trials are expensive and not covered by insurance. So you should know that research costs are typically covered by the sponsoring company. Standard patient care costs are typically covered by your insurance. But of course checking with the clinical trial team, the research team, they will go over all of this with you as to what kind of out of pocket costs you may have to incur, but most of the time it's minimal and you will get a proper coverage financially.

I think it's very important to have diversity in clinical trials. One of our big road blocks is that people from racial and ethnic minority groups are very underrepresented in clinical research. This is a concern because people of different ages, races, and ethnicities may react differently to certain medical products or treatments. Right so I think it's important for everyone to consider participation or enrollment in clinical trials.

So let's talk about some of the treatments that are out there already. I think we this is a group of a lot of patients out there listening to us. We're all familiar with steroids. There's the bright and dark side to steroids. Steroids have been around for myeloma treatment for decades. They are the backbone to myeloma therapy, and frequently work in combination or synergistically with other treatments to enhance myeloma therapy. I think it's important to manage steroid side effects. Have a consistent schedule. For some of you it might be better to take it in the morning, and some of you it might be better to take it at night depending on your personal reaction to the steroids. Always important to take the steroids with food because it can cause some GI upset. But again we have over the counter or prescription medications to help with these side effects. I think sometimes you also may have to have medications to prevent shingles, thrush, or other infections. So antimicrobials may sometimes be prescribed when you're on steroids. Do not stop or adjust your steroid dosing without discussing it with your healthcare team.

So what are the potential side effects? On the right hand side of this slide you can see there are many, right it affects every body system. And even your emotional state. You can become irritable, have mood swings, suffer from depression, there could be insomnia, fatigue, you get that burst of energy and then you get that let down with fatigue, there's an increased risk of infections, increased risk of heart disease, muscle weakness, cramping, increased blood pressure, fluid retention, blurred vision, cataracts, flushing, sweating, that red face people tend to look like they got slapped. There could be GI side effects like stomach bloating, hiccups, heart burn, ulcers, gas. There could be weight gain, hair thinning, hair loss, skin rashes. And for those of you who are diabetics you know that it can also increase your blood sugar levels. So a big array of symptoms or side effects.

Actually there was a study done that identified the most common patient reported symptoms and the impact on quality of life. And these were present at all stages of the disease. Some of the symptoms resulted from the myeloma disease itself. Some of them resulted from treatment including transplant. And these were the categories. So we have physical symptoms. Fatigue, constipation, pain, neuropathy, impaired physical functioning, sexual dysfunctioning. We also saw some psychological side effects; depression, anxiety, sleep disturbances, decreased cognitive function, decreased role in social function. And then of course financial, we cannot have a discussion about side effects without reporting the side effect on your wallet right. We have the financial burden, the financial toxicity which is an important aspect for myeloma patients and their care givers or family members.

And then when we go to another physical side effect, GI symptoms. I think that looking at prevention and management of GI symptoms is important. Diarrhea can be caused by medications and supplements. I think we have to look at laxatives, antacids with magnesium that can cause diarrhea. A lot of antibiotics, anti depression drugs, and some other prescription drugs can cause diarrhea. Some supplements over the counter be aware that can also cause diarrhea. Milk thistle, aloe, cayenne, saw palmetto, ginseng, sugar substitutes can also cause diarrhea. I think avoiding caffeinated, carbonated, or heavily sugared beverages are advised if you're having diarrhea. You can take with your healthcare team's approval, take Imodium, Lomotil, or Colestid. I think fiber binding agents are sometimes also recommended like Metamucil, Citrucel, or Benefiber. Welchol also if recommended. On the other end, okay we have diarrhea but we can also have patients with constipation complaints right. I think the opioid pain relievers, some also anti depression drugs, heart or blood pressure meds, and some other prescription drugs can cause constipation. Some supplements as well, calcium, iron, can also cause constipation.

I think it's important to look at our diet. Increasing fiber like fruits, vegetables, whole grain foods. And again using those fiber binding agents is also helpful. The important thing with a GI or bowel changes is fluid intake is extraordinarily important to help with both diarrhea and constipation and is very good for your kidneys. A patient with myeloma does not wanna hurt their kidneys. I think we have to discuss these GI issues with our healthcare provider to identify the cause and make adjustments in medications and supplements if necessary, but again keep your fluid level up. Pain prevention and management. Of course we all know that pain can significantly compromise your quality of life.

What is the source of pain in myeloma? It could be bone disease, it could be neuropathy, it could be certain procedures. I think the management is pretty straightforward, we wanna prevent pain whenever possible. Doctor Durie mentioned some bone strengthening agents to decrease skeletal related events or fractures. Antiviral, so prevent shingles. Using proper sedation before procedures. The intervention depends on the source of the pain. We can prescribe medications, we can prescribe activity, there could be surgical intervention, radiation therapy, also complementary therapies. Yoga, supplements, acupuncture, aromatherapy, reiki. There's a lot of things that we can recommend to help with pain management.

Very important to tell your healthcare team about any new bone pain or any chronic pain that is not adequately controlled. Very important, please communicate with us. The most important thing I want to mention that some of these side effects we cannot see on paper, we have to trust that you're going to be leveled with us and tell us what's going on so we can properly manage and help you get through these treatments.

Peripheral neuropathy is damage to nerves, usually in the extremities. It could be the feet, it could be the toes, usually starts at the toes, the feet, and can go up the legs. Could be the hands, the fingertips. So again what is peripheral neuropathy? It's that feeling of numbness or tingling, that pins and needles, sensitivity to touch, could be like a burning sensation or a very cold sensation, could also be a muscle weakness type of a sensation. It's very important to report symptoms of peripheral neuropathy early early on to the healthcare team. Nerve damage from peripheral neuropathy can be permanent if not addressed. So please let us know. This is one of the things we can't see on paper, so please let us know if you're experiencing any of this. And of course if you don't tell us hopefully your husband, wife, brother, sister, son, daughter, your family member, we listen to the family members a lot okay?

So how do we prevent or manage this? Bortezomib or Velcade given at a lower a different schedule once a week as opposed to twice a week. And now we give it sub Q as opposed to IV which lessens the incidence of this neuropathy. There is some anecdotal evidence that massaging the area with cocoa butter can help. Some supplements can help, B complex vitamins, folic acid and or amino acids. If you do use supplements just don't take them on the day of your Bortezomib shot okay? Making sure you have a safe environment.

So if you're having the numbness or funny feelings in your legs you wanna make sure your shoes or your footwear is sturdy. You wanna make sure that the flooring in your home is not slippery or not unsafe okay? If the peripheral neuropathy worsens your healthcare team may change your treatments, they may prescribe oral or topical pain medication to see if it helps, they also may suggest physical therapy, that has been helpful for peripheral neuropathy as well.

So let's talk about fatigue, anxiety, and depression. So all of these things we know can affect your quality of life and your relationships. Fatigue is the most common reported symptom. Look at that percentage there, 98.8%, so basically all of you will have some time in your life during treatment or even during times of remission when you're feeling tired. The source of this fatigue can be anemia, it could be pain, reduced activity being immobile, insomnia not getting the right amount of sleep, some treatment toxicities can cause fatigue, bone marrow suppression. I think also we have not only fatigue but anxiety is reported in about a third of our patients. Depression, nearly a quarter. Financial concerns, disease progression, end of life concerns, change in social and sexual function, were sources of depression in our patients. I think that unfortunately people do not share these symptoms with their provider. I think it's important to talk to any member of your healthcare team. Find somebody that you have a good rapport with. Hopefully it's your doctor, your nurse practitioner, your nurse.

Talk about these symptoms that are not well controlled, especially if yore having thoughts of self harm because there is lots of help available for you. But please we're not gonna know unless you speak to us. Let us know what's on your mind and how we can help. Rest and relaxation contribute to good health right. I think this is very true. I think adequate rest and sleep are essential to a healthy lifestyle. Short and disturbed sleep increases our risk of heart related problems, increases anxiety, it weakens our immune system, it makes pain worse, and it can increase our risk of falls and personal injury if we're not well rested.

So what things can interfere with our sleep? Medications right, steroids, big one cause a lot of insomnia. Other stimulants, some herbal supplements can, just because they're sold over the counter and you don't need a prescription doesn't mean they don't have side effects okay? Some of our psychological issues can interfere with sleep, if we're afraid, anxious, we have a lot of stress, that can interfere with sleep.

And sometimes it's physiological, we have sleep apnea, we have cardiac issues, there's pain, that can also interfere with sleep. But sleep hygiene is very necessary. So we need quality sleep time for day time alertness. So engage in exercise as recommended but not too near your bedtime. Increased daytime natural light exposure. Some tips here, avoid daytime napping, establish a bedtime routine whatever you like to do before bed, maybe have a cup of tea or something before you go to bed. I think associating your bed only with sleep is important, so please don't take your computer and try to fix your checkbook and write all your bills. I mean bedtime is for bedtime right? Try not to do too many other tasks and activities when you're getting ready for bed.

You might need a sleep aid, maybe an over-the-counter one, and truthfully maybe you even need a prescription sleep aid, it could be temporary. I think avoiding these certain things before bedtime like caffeine, nicotine, alcohol, lots of sugar, large meals, especially the large spicy greasy foods, and a lot of computer screen time. And it means not just your PC but your tablet, your phone. Kinda cut it off a little bit when it's getting ready for bed. And I just wanna point out that rest and relaxation is really important for our patients, but I wanna point out too that all you caregivers out there, this is a slide for you as well. So rest relaxation, if you're rested you're relaxed and you're in good health you're gonna be more of an advocate for your patient, for your family member that's a patient.

So again, caregivers also need to take care of themselves. So let's talk a little bit about infection prevention and COVID-19 and people with multiple myeloma. Of course a big topic of conversation over the last two years. In general infection can be very serious for people with myeloma. So if you look at the little palette there it says multiple myeloma and then it says treatment. Both of these conditions can lead to immune dysfunction. Myeloma is a malignancy of the immune system. So you can have a situation of immune suppression. Our treatments frequently can cause immunosuppression. So we have this double whammy right. So there is a seven to tenfold increased risk of bacterial and viral infections for people with myeloma.

With that being said, it's very important for all of you to know what to report, when, and why. So reporting a fever of more than 100.4 degrees fahrenheit, reporting shaking trills even without fever, reporting dizziness, shortness of breath, new cough, low blood pressure, these are things that do warrant that phone call to your healthcare team. Please. And it doesn't mean that if it's a Friday and you're having a fever, oh I have an appointment on Monday, I'll just tell the doctor on Monday. No you really wanna call right when it's happening.

So there's some general infection prevention tips here. I think we're all been inundated with some of these tips right now over the last two years. Good personal hygiene of course, skin as well as dental. Especially for myeloma patients who are going to have bone strengthening agents. Environmental control, wash wash wash your hands. Right you can use the water free alcohol based products. Avoid crowds, avoid sick people. And you might need, depending on your healthcare team, you might need some growth factor support to raise your white count. You might need some medications like antimicrobials to help reduce your risk, some immunizations might be recommended. Of course no live vaccines, but you'll get this recommendation from your healthcare team. So helpful living strategies for prevention. So manage stress okay.

How do we manage stress? Proper rest, relaxation, and the good sleep habits right? That's important. Good mental health, social engagements. I think having a good social support system is critical. Not just your family members, not just your friends, but even doing the things just like you're doing this afternoon and joining this seminar, joining a support group, that is important for helping you live healthfully okay?

Maintain a healthy weight. Nutrition, exercise, activity within reasons and getting your healthcare team's recommendations as well. Preventative healthcare. Health screenings, vaccinations. Health screenings, let's talk about that a little bit. You have myeloma, it doesn't mean that because you're focusing on your myeloma, hopefully you're in remission or maybe you're on maintenance therapy or getting induction therapy, whatever it is, you're still going to want to manage your blood pressure and follow guidelines for mammographic, colonoscopies, PSA levels. We're hopefully helping you live a very long life with myeloma. We can't ignore other things that my happen. Your heart health, your GI health, all of that stuff okay. We do wanna prevent falls, injury and infection. We talked about that a little bit. Please if you're smoking try to stop. There's a lot of facilities, institutions, there's so many resources out there with smoking cessation programs that you can take advantage of.

Dental care is important, again try to see the dentist every six months. Get good dental care so we can see any kind of oral infection before it becomes problematic. Maintaining renal health, that's your kidneys. So again managing myeloma helps your kidneys overall. Hydration, hydration, hydration. Drinking lots of fluids is very important, unless of course you've been told that you have fluid restrictions. Maybe you have cardiac disease or you're on diaplasis. Those patients are separate. But everyone else should really never become dehydrated and should drink drink drink drink drink. Like I said, some patients might have fluid restrictions. Avoid really toxic medications. So some drugs are dose based on your kidney function. So we will look at your kidney function before prescribing antibiotics and things like that. If you are diabetic, good control of your diabetes will help your kidneys because we know that uncontrolled diabetes can also be a traumatic event for your kidneys. I think protecting your bones is very very important in myeloma. So again, the kidneys and the skeleton right, we wanna protect and really be gentle with these two body systems. Good nutrition, calcium and vitamin D supplement with your practitioners recommendations. Weight bearing activity, walking. If you're able to walk, you don't have to be training for a marathon, you don't have to run, you can just walk, get out there and walk. Bone strengthening agents we can give you to help reduce skeletal related events.

Again just using all of these things can help prevent help you live a healthy lifestyle. So I think a couple of more strategies, keep a log or a journal of your activity. I think it's important to don't be immobile, be as active as you can within reason right. Notify your healthcare provider about sudden onset of pain, progressive weakness, headaches, blurred vision, numbness, tingling, basically anything that's not normal for you that you're concerned about okay. Dehydration can lead to low blood pressure and falls. Of course there's some do not's. You don't wanna overdo it. Like I said you wanna walk, you don't have to train for the marathon okay so just walk, go slow at first, don't force the exercise.

Don't try things without discussing with your provider. Okay so really go over your activity plan with your provider. And do not consider weight lifting limits. So you can engage in some of these activities with your healthcare teams recommendations. Movement therapies can reduce stress, promote sleep. Things like yoga, Pilates, Tai chi, these are all great things to help relax you and to actually be good for movement for physical movement. They have been shown to improve sleep and sleep quality and overall improve your quality of life and even your mood okay. Myeloma bone disease may affect your ability to do certain movement activity. So again very important for you to review your activity interest with your healthcare provider. So just because I say you're gonna go see your doctor, Ann said on that program that I should walk walk walk. And I don't want you to do that if you have an impending fracture somewhere. So you have to really discuss anything that you want to do or engage in with your healthcare team okay.

So knowing your team. So you are the central part of your care team, right in the middle, that's you and your caregiver. So who's surrounding that right? You have your myeloma specialist, you have your general hematologist, oncologist, your support network or your family, your primary care team, your allied healthcare team. You need to be empowered. You're going to ask the questions, learn more, participate in decisions. Communicate, communicate, communicate. You need to tell us what's going on. We wanna understand what your goals are, what your needs are. Okay participation in a support network is really important okay. If you're considering telemedicine, it's a Doctor Durie mentioned it, it is an option now. Come prepared. I think you're not physically in the exam room with us, so please have a list of your current medications including the over-the-counter stuff that you're using. Write down your questions and concerns. You're going to forget. So even if you're going to an in person visit I always say jot 'em down and then you can go over them right.

Tell us, has there been any medical or life changes since your last visit? Do you have a new symptom? Is there a change in your symptom? If you have a symptom diary bring it along. Communicate effectively. Again even telemedicine, you're talking to somebody, you're seeing them. Communicate and communicate. Know the next step. When you log off to that telemedicine visit you should know my next appointment is, whenever. Is it a telemedicine? Is it an in person visit? Do I have to get labs before that? Do I have to go on another medication? Right. It's very important to know. Also if we're planning telemedicine, what is the process and what technology do I need? Okay. And again do you need to have labs done in advance okay? Pick a nice quiet well lit location with strong wifi that's always great. Plan yourself, consider if you may need to show a body part or wear accessible clothing. If you have a new skin rash or a lesion that you want shown you may need to plan for that as well. And collect recent vital signs, blood pressure, temperature, heart rate. I think that one good thing has come from the pandemic if we can say that, everybody has a thermometer in their house, many of you have a blood pressure cuff and a pulse ox and it's very easy to get these vital signs right before your telemedicine visit and you can share them with us.

Right. Shared decision making. So this means you're an empowered and crucial part of your team right. So it's if on the right hand side your preference, it's the data from research that plays a role, the healthcare providers clinical experience.

All of that put together, all those circles converge right in the middle that help make the treatment decision okay? But again you might wanna ask for time to consider options if that's appropriate okay. If you wanna understand your options more and you wanna investigate outside of the visit you wanna use reliable sources of information. Please remember that there's a lot of junk out there on the internet. Use caution when considering stories of personal experience. Go on the reputable websites, myeloma dot org is one of them. Please don't. Use caution okay? Consider your goals, your values, and your preferences okay. Again talking about your top priorities, what treatment you think might be best for you. Come to a treatment decision together. And knowledge is power right. Again use the reputable resources.

Myeloma dot org is one of the best right and also there's a lot of printed material available for you, there's a website which is listed here, there's a lot of access to teleconferences, E newsletters, there's a hotline, the 800 number is listed on this slide as well. Again the more empowered you are the more knowledgeable you are the better your outcome is going to be. And if you're not the person that really is into this maybe your caregiver is. I see a lot of patients who they maybe don't wanna investigate too much but they have a caregiver, a family member who's really very empowered to do this. Share this information with them okay. You're not alone, we are here to help you. And doctor Doctor Durie mentioned that as well right. And I think we are now going to turn it back over to Doctor Durie. Thank you so much.

- Well thank you Ann for that really wonderful wonderful presentation. You covered a lot of very very important material and I think extraordinarily helpful, a lot of resources, a lot of tips. And so thank you so much for going over a lot of material in a concise way but also a way in which I think can be well received. So thank you so much. We are back on schedule now. So I think what I'll do is I'll go ahead and give the third presentation in this segment and then there have been a number of questions coming in which Ann you might want to scroll through. Because I think there will be time for answering those when I'm finished. I know there's some questions about steroids I saw coming in and what is financial toxicity. Some quite interesting and important questions coming in.

Okay so let me go through this third segment of this first session today which is a little bit different, but I think there's been a lot of interest in the approach to early diagnosis and disease management. And so I thought it would be worthwhile to have a little bit of a focus on that.

And I think an important thing to emphasize about this is that the approach to early disease, it applies not only to higher smoldering myeloma myeloma at initial diagnosis, but also relapse. We as was mentioned, we want to hear from you, we wanna jump in. If some new treatment is necessary it's good to get that started sooner rather than later. So I think that there is an open road moving forward where looking at the disease across the board, the good news is that we have been making progress across the board. Diagnosis and early monitoring all the way through to later relapse and new drug development which we're gonna talk about quite a bit today.

But what I'm gonna focus on is what we're learning from the study of the earliest stages of the disease. And so one of the sources of this information is a very large study that is going on in Iceland called iStop MM. And so that is Iceland, screens, treats or prevents multiple myeloma. And it's an approach to looking for the earliest form of myeloma which is MGUS which is the presence of a monoclonal protein in the blood for someone who is as far as they know currently normal. And so what Sigurdur Kristinsson at the University of Iceland has been doing is he set up to screen all the people in Iceland over the age of 40. And this amounted to over 85,000 individuals who had their blood tested to see if they had a small spike in their blood. And this allows you to detect potentially the very very earliest stages of the evolution of that spike and progression possibly towards myeloma. And so it allows us to take a look at what's going on early in the disease to maybe understand what's causing those early triggers.

What is triggering myeloma at that earliest point? And we could improve all the outcomes by this kind of a knowledge. And maybe have a chance to usefully intervene early. And so this particular project, it's a randomized study. In fact this 85,000 individuals, that actually represents the largest study that's ever been conducted in one country to evaluate the early stages of myeloma. And so the idea is to see what is the value of screening? And so one group of individuals their screened but nothing further is done. In the middle group we follow along with monitoring. And then in the third group we're set to intervene early and take additional steps so that we can show the maximum value. If we're aware of someone having a very tiny spike, we're ready to jump in and to provide support of care or maybe to provide even early treatment for myeloma if that is appropriate. And so we are getting a glimpse of the origins of myeloma.

And this is one example that actually comes from the Mayo Clinic where Doctor Kyle has been so interested in the early stages of myeloma and monoclonal gammopathy of undetermined significance, M-G-U-S. And so this is a slide of a patient who was diagnosed with M-G-U-S in 2006. Serum was available all the way back to 1997. And using mass spectrometry which is a very very sensitive way of looking at the blood, it was discovered that there was a spike present even back in 1997. And so what we're learning is that these spikes can be persistent and then they start to evolve over time often over many many years. And so there's typically many opportunities to assess things and maybe intervene early. And so this also illustrates another way that is quite important in myeloma research right now is to have a bio bank.

And so if this is part of the options when you are signing up for a trial I would just encourage you to mark that box and sign off and allow if you will agree that some of these samples would be used for special research. Because this allows us to study and understand if you move forward and get a particular treatment we might be able to figure out well why did you do tremendously well with that treatment versus someone else, if we've been able to do special testing on your bone marrow or blood. And so I would just say that this is just a very very helpful aspect. So. By studying early what doctor Kristinsson and his team has discovered is that there are just so many different things that we can look at. And it's kind of like all of the blossoming from a tree.

And so for example, and the IMF and myself in particular, we've been collaborating closely with Sigurdur in Iceland. And in fact I'll be going to Iceland in about a week or so now to get the follow up on this. But one big concern has been if we are finding a tiny small spike early and a patient is informed about that is that a negative in terms of their mental health? Is this something that would be introducing a worry? And should we be concerned about that? And so we'd be doing very very careful sequential mental health evaluations. And the interesting thing is that well certainly in Iceland, the individuals have been so supportive and actually reassured that they're being checked and that someone's aware of it that actually it's quite the opposite. So they're actually quite happy to be engaged with the healthcare team and to be evaluated.

But it is important to be clear that in Iceland there is a healthcare team and then they can go in and work with that healthcare team any time and that's not a problem. I mean there's a universal healthcare. And so they can go in and get checked and do whatever's necessary and there's no implication, financial implication, or other implications to that. But we're also discovering that patients with early disease may be at risk as Ann was just talking about of having risk of infections, a risk of having a variety of other problems. And so there are many ways in which early interventions may turn out to be very very helpful in fact.

What has been noted so far is that when you screen smoldering myeloma is much more common than we had realized. And so what that means is that there is an opportunity to assess patients and see if they might be ideal for early intervention and maybe get the very very best results from myeloma therapy. Because we know that the outcomes overall are better for patients with the earliest disease when the treatment is started.

But to have that intervention you need to be sure that the intervention is necessary so that you need to be able to have a scoring system, which I'll show you in a minute. And better predictors are coming along. And the best management is also evolving. And so. In the last few years we've come up with a risk score to predict progression. And this is a type of scoring system that turns out can be useful not just for patients with very early disease. So smoldering myeloma is one step on from MGUS. And what that means is that the number of plasma cells in the bone marrow has increased.

And so over on the left here you can see that we look at the bone marrow percentage. BMPC. Less than 15%, 15 to 20, 20 to 30, 30 to 40. And then we look at the level of the myeloma protein at 1.5, 1.5 to three, and then three. And then we look at the free light ratio which is low and then maybe higher. And the first thing to note is that the risk of progression is very much linked to the percentage of the plasma cells. So that the higher the percentage of the plasma cells in the bone marrow the higher the risk of the progression and it gives you a higher score. And you can see there at 30 to 40% you get a score of five. And then you can get scores depending on the values for the other numbers. If you look over to the right if you end up getting a score of 12 that means the risk of progression is really quite high within a year-and-a-half or so.

And so this is just using standard lab tests that you can determine that someone maybe needs to have a discussion about some early intervention or to be monitored very closely to try to avoid problems with myeloma and maybe have an opportunity to get the very best results. And so let me just, one other thing about this slide before I move forward. We are looking at simpler and better tests. And there was a question earlier about blood testing. And actually one testing that we are looking at very seriously right now is whether or not there are myeloma cells in the blood. And this is something that we have not really looked at much in the past.

But now we are looking at this as a new blood test where we can determine is there a low level of myeloma cells in the blood? And does this predict that there might be some progression? Either early on or either at the point of relapse? And the answer to that question seems to be yes. And so you're going to be seeing a whole series of papers being published coming out indicating that a new test to add to your list may turn out to be checking your blood to see if there are any myeloma cells in the blood.

Now. As an early approach there was a question about how close are we to curing myeloma? So a study was completed by the Spanish team. Lead by. Doctor Maria V Mateos at the University of Salamanca. And so she conducted this trial called the GEM-CESAR trial. And this consisted of giving patients KYPROLIS which is Carfilzomib, Revlimid and dexamethasone, plus autologous stem cell transplant, if they had a high risk smoldering myeloma. And so what that means is if they fell into this top graph on this previous slide, so there was a higher risk that they were going to get myeloma very very soon. These patients were offered the opportunity to receive KRd plus a transplant. And this was a study of 90 patients. 77 patients completed the whole therapy. And the main thing to notice is that 82% achieved at least a complete remission, and 62% received or achieved MRD negativity which means that when the bone marrow was checked there was no myeloma at a level of zero out of a million or zero out of 10 million.

So really really excellent deep responses. And if you look at this in terms of remission, looking out to five years now, 98%, 95, 98% of the patients are doing extremely well in remission and surviving. And so. Is Marie V offering treatment that may be starting to cure myeloma? We don't know. But these patients are certainly doing very very well. And a number of patients, maybe even some on this call today have participated in the ascent trial which is a U.S. equivalent to this where patients have received KRD plus Daratumumab. And we are out in that three, between three and five years now on that study. And patients are doing extremely well in that study also. And will be reported most likely at ASH this year. And the MRD rate is going to be, it looks like somewhat higher than the 62% indicated with the CESAR trial.

So I think we are definitely making progress to sustained excellent remissions. And we're just excited to see how long these remissions are going to last. Blood testing for monitoring in addition to the myeloma cells in the blood we also have mass spectrometry. And I showed you one picture of that. This is a test that's currently available mostly by sending samples to the Mayo Clinic in Rochester right now. Your doctor can do that and look for low levels of myeloma protein using mass spectrometry.

In a research basis, on a research basis, the immune status can be monitored. For example as part of trials and doctor Lin Yi mentioned this says you can for example you can monitor and see if the CAR-T cells if you have a CAR T treatment, do these engineered T cells continue to be present in the blood? And what is the status of the immune cells in the blood? And so you can look at the MRD status and then you can also look at the immune status. And so we're having more sophisticated ways both before treatment and then after treatment to assess what's happening. Just to show you the evidence for the role of blood testing, quite a number of publications are coming out on that. So this is becoming what I consider to be probably the most important step forward in terms of both precision but also convenience for patients where if we can accurately measure how you're doing with these types of new blood testing this is all the better.

Now in addition to that it's going to be important to get approval so that the FDA accepts the value of this low level monitoring. And so the IMF has been working with a team that we created actually called the I Square Team, where we have been gathering all the data from trials where MRD has been measured. To try to illustrate for the FDA that systematically patients who have excellent MRD where the myeloma is not detected with sensitive testing at a very low level, this indicates that patients are going to do better. And you can see there's a family of curves here where if you're MRD negative, particularly if you're persistently MRD negative, this is really really a good thing. And so we're Nikhil Munshi who is a member of our I Square team along with Jesus San Miguel and myself, we're very optimistic that this package of information with the MRD testing and a large number of clinical trials will be looked upon favorably by the FDA. And so now what is the next phase if we're looking at maybe trying to achieve a cure? Well with these current front line of therapies, VRD, KRD, Dara-Krd, a majority of patients are doing very well but obviously some are still having some residual disease.

And so this is the situation where we can look closely at the particular impact of these newer immune therapies that we're going to be hearing about after the break. And it's gonna be particularly important to see which of these immune therapies can do the best job to sort of mop up any residual disease after what have been our best efforts with therapies thus far. And so there are lots of opportunities, new trials to achieve MRD undetected. Particularly things like CAR-T or biospecifics. Introducing those a little bit earlier and trying to achieve the very very best results. And using what you could call cutting edge disease monitoring where we can look one of our colleagues, doctor Bruno Piva at the University in Pamplona is looking at even more sensitive blood testing down to the level tenth the minus eight believe it or not. Where you can have a very very sensitive monitoring in the blood, and that can indicate patients are likely to do extremely well along with mass spectrometry, immune testing. And then as we touched on earlier, trying to sort out if detailed molecular testing can help us to distinguish groups of patients who might need one therapy versus another to achieve these very very good or best results.

And so this is sort of the way forward. I think we are always aware and we get so many questions as Ann mentioned, these last two years have been very very difficult. Despite that, we were able to continue and actually complete that ascent trial. So patients with high risk smoldering myeloma we were able to continue to treat those and they did extremely well with that therapy. However we need to have ongoing cautions and be very very alert for patients with myeloma. Myeloma patients because of the disease and because of the treatment as Ann mentioned, are a particular risk of infections including COVID. And so it's very very important for you to get your vaccinations, to get your boosters, to get that second booster. If there's a concern maybe after testing that maybe the antibody levels against the COVID are not as good as we would like or we would want, there are options. There is this medicine called EVUSHELD which is an intramuscular double shot.

The FDA had a second look at this and they've actually recommended kind of a double dosing on that which is possible. So I think that considering to get EVUSHELD is something that you consider. If per chance a patient with myeloma does test positive, as Ann was emphasizing, if you have fever or anything that makes you concerned, or if you've been in a crowded setting, get tested. And then if you test positive we do have medicines. You've probably heard of this medicine called PAXLOVID. And there are other approaches that can be used as an early active treatment if you test positive. So it's important to stay in touch and try to be on top of that.

But despite all of the confusions about masks, for me there is no confusion. If you are a myeloma patient and you're out and about and you're in an area where you might be running into people or in a inside space or traveling, wear your mask. Get the best mask that you can and wear it. I mean this will protect you. And I think that this is a personal choice. And I think that it's certainly, and my colleagues can weigh in on this, but certainly this is the way that I view this. And other protections, a lot of them that Ann mentioned, myeloma patients should be very very careful about their personal hygiene. Wash their hands and all those kind of things just to stay as safe as possible.

The IMF has created a special COVID page where we've tried to list all of the CDC recommendations and all of the reliable information about various different situations and options. And so I think we've tried very very hard to make that information as up-to-date as possible and as accessible as possible. So despite all of that about COVID I think the future is indeed very bright, with a high likelihood of continued improve outcomes. And I think we're going to be seeing more and more of early intervention and the value that can be accrued from that early intervention. And so thank you for your attention. I hope that that was helpful to think about the ways forward that we have in 2022.

So I think we do have some time for questions. And I don't know if you want to scroll up for here a mirror. So thank you so much for your attention. And Ann I know there were some questions for you.

- Okay.

- One was a simple one which it was just, so what is financial toxicity?

- Sure. So financial toxicity is sort of a term that describes financial distress. And that could really be unique to your situation. It includes any problems related to the cost of treatment or disease. So that could mean high co pays, consistently high co pays, maybe there's transportation costs, there could be asset depletion, there could be employment issues. Maybe your employer is not that very flexible with time off. Some people have had job changes and stuff like that. So it really means anything related to disease or treatment that is putting stress on your finances. That's what financial toxicity is.

- Absolutely. And then a number of questions about steroids and dexamethasone And I would have to say that that one side where you showed all of the side effect for steroids which was very accurate. But would certainly trigger anyone to say well hmm maybe I should reduce these steroids. Or try to get--

- Right.

- Off these steroids. Do you wanna comment on that? Because I think increasingly we do try to do that yes?

- Yes yes. Steroids still are big players in the field of myeloma treatment. But obviously they're very challenging drugs, they're not benign drugs. So we do try to especially after induction therapy, we do try to reduce the dosage or change the scheduling. They're tough drugs. I mean we will consider like I said dose reduction. Somebody, I saw a question about using steroids--

- Adderall.

- Yeah yeah no I saw a question about different. You have to remember that Decadron or dexamethasone is the most potent steroid. So we have used--

- Right.

- Prednisone in the past. I think there was a question about a Medrol dose pack kinda thing. These are steroids but they're much less potent than dexamethasone, that's why there's more problems with dexamethasone, it's so potent. But as Doctor Durie mentioned, we can definitely work around reducing the doses and working with you to get a good balance of life and steroid use to put it bluntly. Yeah.

- Right right right. I'm just gonna cover some simple ones here.

- Sure.

- What's another name for Bortezomib? That's Velcade, Bortezamib is Velcade. Yeah. Let's see. Another question which would be an interesting one which we can pick up later, Yi Lin just for you to be aware, how long will it take for there to be sufficient data to evaluate CAR-T versus autologous stem cell transplant? And maybe this is something you could maybe touch on later. I think that we're certainly looking at CAR-T as something that may be an aggressive option in a similar category to autologous stem cell transplant. Do you want to comment on that? I mean that's gonna take a little time to work on.

- Absolutely. I have a slide on that actually in my talk--

- [Brian] Oh good. Good.

- There are trials. Of course, as Doctor Durie you mentioned there's currently ongoing trials like in the earlier line setting. But there will also be trials directly comparing CAR-T and transplant in the front line setting that will be opening in the near future.

- Yeah absolutely yeah very good. There was just a simple question, EVUSHELD, it's E-V-U, EVUSHELD it is this intramuscular shot which you can talk to your doctor about, it is available. I mean there was a lot of controversy that you couldn't get it, but actually it does seem to be available. Although your doctor and or you might need to check around to see which pharmacy has it. Ann do you want to comment on that? Has there been difficulty in patients concern about their antibody levels getting the EVUSHELD?

- So we actually have a very, what's the right word, a very strict policy for who gets the EVUSHELD. So we have paperwork to fill out, that patients have to meet certain criteria. Myeloma patients are in a special category where they're prioritized because of the risk of infection. But again I'm not involved in that too much, but I know it is available and there is a policy where we have to fill out paperwork to determine eligibility.

- [Brian] Right.

- But I haven't had too many problems with our myeloma patient population getting access to the medication, that's all I could say.

- Right.

- But it's available for not just myeloma patients.

- Right right.

- So it's just--

- Right I agree. I think that there was a little bit of a lack of awareness and access issues early on, but I think right now I think there is definitely availability. So do talk to your doctor if it seems like it might be a good idea for you. 'Cause most likely you can in fact get it. And it does really reduce the risk by boosting your antibody levels. Okay a question here, will we talk about low risk and high risk? I don't know that we'll talk about that so much more. Despite that FiSH testing where we look to see if you have some of the high risk features which would be 17 P and one Q and some other things like that.

Unfortunately we don't have decisively different treatment for patients who might have high risk disease. And so as I mentioned what we tend to do is give the same treatment, and then if things are not going so well in that high risk setting, at that moment we will pick some alternate therapy that might be able to do a better job in that more high risk setting. Let's see here. Why don't doctors allow sedation during a bone marrow biopsy? It's so barbaric.

Okay Ann do you wanna comment on that?

- Yeah I can--

- How much sedation do you use?

- So I can comment. That's a very big question that we get in our clinic. So we do use of course Lidocaine which is a topical anesthetic. And patients always ask that, "why don't you just put me out? "Why can't I get sedation?" It actually, we do have an option for bone marrows with sedation but not in our clinic. I mean you do need to have a license to give anesthesia, we do not. So.

- Exactly.

- So that's I mean it makes a 10 minute very inexpensive procedure a much longer much more expensive procedure. Again if some patients just will not do it without sedation. I think we try to convince you--

- Right.

- That it's not. Listen it is uncomfortable but I've had people go to work after their bone marrows. So.

- Absolutely.

- Yeah so it's not, again it just makes a very short quick relatively pain free but just a little uncomfortable procedure making it a little bit more involved. But it is an option but not an option we commonly use.

- Right. I think it's very much operator dependent. I suggest a good question is how many of those bone marrow tests have you done?

- Yes that is true Doctor Durie yes. If you have a provider who's done, I mean the people I work with have done thousands upon thousands of these bone marrows.

- Right.

- It takes longer to set up the tray than to do the procedure. So.

- Exactly. Probably not good to have that new student doing it.

- Right. Exactly so I mean you should feel confident that the myeloma experts have done many of these and it's usually not a problem.

- Right right. So Yi Lin, do you have special requirements at Mayo? I know there are special procedures there where patients go over to a whole specialized area where the bone marrows get done. Right?

- Correct, we have a dedicated team that just do this day in and day out. And we do offer the option of anesthesia to our patients. So I would just comment on all the consideration discussed and absolutely true in terms of any concern, prolonged monitoring with anesthesia, increased cost. But I'll say because we do offer that option to our patient I would say it's about 80% on average, 80% of the time the patient do prefer to get the anesthesia despite us explaining some expectations of doing it with and without. And again I explain this a lot, I've never personally had to undergo that, so since we're able to accommodate patient preferences.

- Right right. Yeah in some programs it used to be mandatory for the training doctors to have at least one bone marrow test done yeah.

- I think our trainees do five to 10 before they graduate.

- So I have a question. Doctor Lin you said that 80% of your patients have it with sedation?

- With sedation.

- Really?

- Really.

- I have to say that we have about 90% of our patients that do not get it with sedation.

- Right right.

- Maybe you do a better job explaining the expectations for doing it un-sedated.

- I'll come right to Mayo.

- Right so patients who are listening to this, you have your options.

- Right.

- Okay you know where to go. Okay maybe just a last question before we break.

Someone's saying my M spike has been my key metric. And we talk about that. Yeah well obviously we are very much focused on the level of your myeloma protein, that monoclonal protein. That is the key metric. And so. So we follow that to see if you're responding to treatment and we also follow that to see if you're relapsing. In terms of eligibility for other therapies, in terms of a decision about going ahead to carry out an autologous stem cell transplant, if you've already had an excellent response this is a very good discussion with your doctor.

Overall we still recommend that autologous stem cell transplant would be a standard of care. But if you have had a fantastic response there could be the option to say okay I'm doing great, maybe we could harvest some stem cells and we could save that stem cell for later. At the time of the CAR-T cell therapies at that point, and I think Doctor Lin will probably talk about this, the M component may be quite low and there may be extramedullary disease. There may be other areas of evidence of active myeloma and it can get to be a little more complicated later in the disease to use just the myeloma protein level to assess the entry to the trial and also the monitoring can be a little bit more tricky.

But maybe you can just touch on that later. But okay so I think I've touched on as many as I think we can right now. So let's go ahead and take a short break. And then. We will be excited to move forward with our immune therapies starting with Doctor Yi Lin talking about CAR-T cells. So thank you all and stay tuned. We'll see you back very shortly.

Welcome back everyone. I hope that you had a chance for a good break. We're very excited to go to the second part of our program today. We're especially lucky to have Doctor Yi Lin from the Mayo Clinic available to present. Yi Lin has been very much involved in the trials with the new immune therapies, particularly with the CAR-T cell therapies. And so it's really excellent to have someone who's been directly involved to be able to talk to us today about the latest advances in immune therapies, with a particular focus on these CAR-T cell therapies.

So, welcome Doctor Lin from the Mayo Clinic in Rochester Minnesota.

- Thank you, and it's a pleasure to be here. And thanks all the patient and family for spending the weekend to learn more about what's coming on the horizon for multiple myeloma. So here are my disclosures. And I'll just start with it's certainly very exciting that CAR-T is now FDA approved and available in the U.S. for close to a little over one year now. With Ide-cel or Abecma approved in March of last year. And just til the end of February of this year we have a second CAR-T that was approved, CARVYKTI or Cilta-cel. Both of these CAR-T's are BCMA targeting CAR-T's.

So in the CAR-T world it's also very exciting that for the first time we have approved treatment that is not just targeting CD19 or B cells, so very important proof of concept to move this technology forward. And so in the when we think about the myeloma treatment landscape from the initial diagnosis for symptomatic active myeloma and the treatment options, we've certainly been advancing the treatment overall. From double to triplet and now quadruplet type of therapy, have a monoclonal antibody in addition to proteasome inhibitor and emits all along their sequencing. But in the recent years we've had more advances in terms of other novel treatment. And so these have generally been in the after four lines or more setting.

And now in addition to these off the shelf drug options we also have CAR-T. And I won't go into too much detail here, you can see where we heard some of these in the earlier talks other than BCMA is a very exciting target for multiple myeloma. You can see the example in the bottom right there is a bone marrow biopsy where these cells that are brown in color, the brown is sustaining for BCMA. So in general we can find that the plasma cells or myeloma cells have some level of expressions of BCMA. And this marker is involved in this signaling inside these myeloma cells for survival. So that what makes them such a good target. And I won't go into too much details here, as some of this has been very well covered earlier as well in terms of lots of BCMA targeting option better.

We have some that's approved and some that will be pending approval. And there are some differences in the logistics and side effect options to consider for them. And I'll focus my talk more so on the CAR-T which is very exciting in that it's the currently the only approved treatment that is given as a single dose treatment with no maintenance continuous subsequent treatment thereafter.

However there are still a lot of logistics involved that may limit the accessibility of this treatment at this time for many patients. And so I know that many of you may be on a different time point in your myeloma treatment journey. So just a few background slides. Bear with me if you know some of this already.

What is a CAR-T? And so shown on the left is a schematic diagram of natural T cells signaling. So you kinda see lots of colors and lots of part. So a normal T cell signaling, and the T cell shown here on the bottom, that bottom curve, the surface of a T cell, and the top part of the left diagram is other cells. So it could be a myeloma cell, or it could be another immune cells. And so we typically think normal T cells signaling you need a complex of receptors or markers to come together on a T cell surface to get that T cell to stay active. And so very commonly in immunology we talk about signal one and signal two. And signal one is on the left side of that left diagram which is the T cell needs to get educated on what to recognize, what is that antigen. And that presentation is by this MHC complex. And then there needs to be a signal two which is slightly to the right of that T cell receptor which is should the T cell be activated or be suppressed.

And so myeloma cells like many tumor cells have ways to outsmart this right, ways they try to suppress T cells. One, they decrease the presentation of the antigen, decrease that MHC presentation. And two, they have these increased negative or suppressive signal instead of the activating signal as signal two. So what's shown on the right is the CAR construct, the CAR receptor, chimeric receptor. So this is not a naturally recurring receptor you'll find on any T cell. This is the engineering part. So what this is doing is fusing signal one and signal two. So on the top part of that construct is some portion of an antibody to recognize the antigen.

So now this T cell can bypass the MHC presentation. And if it recognize that antigen or that signal, because it's that chimera or fuse it's automatically going to become activated and hopefully not get the other suppressive signal and start that cascade for the myeloma cell killing. So this is a little video of what that looks like. So the top portion if you think about it is what's happening in the manufacturing process when the CAR-T cells are generated from the patients own T cells. So we need these little viral vector particles to deliver that genetic material inside the T cell, these are now patients own T cells but in the laboratory. And during that manufacturing process the T cells now can express this chimeric receptor on the surface. And you'll notice there's this other purple marks.

So whatever other receptor that is normally on T cells we haven't done anything to them, this is in addition of the CAR receptor. And now this CAR-T product when it's ready and shipped back to the treatment center, and we infuse it back to the patients and it's IV infusion in the body, it would then hopefully travel to the bone marrow microenvironment, plasma cytoma's, and engage, recognize those myeloma cell that express a BCMA and can do direct killing, can secrete a lot of pheto chemokine that activate other parts of the immune system. And so Ann already showed another picture representation too about the journey of the CAR-T treatment.

I'll just comment that if some of you have already gone through stem cell transplant there is a lot of aspects of that journey that's very similar. But in that CAR-T it's currently only available at certified centers that has all the multi-disciplinary expertise for the specific infusion and monitoring, acute monitoring management. So this is not something unfortunately that's available at your local oncology clinic. And so the blue square is part of what needs to be done even with your primary hematologist before you necessarily travel to a CAR-T treatment center. And what's done at the CAR-T treatment center here are the green squares.

And so there's a lot of logistical planning that needs to happen. And this point one to point two is where we really need to try to shorten the journey because we recognize patient have active myeloma that hasn't responded to the previous treatment and we're trying to get them to CAR-T. So a lot of coordination that happens in terms of how to optimize the most recent treatment so the patient can get to the cell collection as quickly as possible without this wash out period so their T cells can be as healthy as possible for that manufacturing process. And then after the cells are collected as I showed you in that little video, there's this manufacturing that happens.

And for the FDA approved product that happens at specialized manufacturing centers in the country, that is not happening at the treatment center. And so that manufacturing process can take on average about a month, from the time that we collect the T cells to when the cells come back and is ready for treatment. So often at that time the patient don't necessarily need to stay at the CAR-T treatment center. They can go home, but there's a lot of coordination that still needs to happen because their myeloma may not just hang out for a month.

And so what's the best way to try to keep the myeloma under control in terms of a treatment plan? If there's any change to the manufacturing schedule, how do we adjust that to keep the patient as healthy as possible so they can still be fit to come back to start the treatment?

So once the cell is ready this is when we tell patients now you are really needing to prepare yourself to come to the CAR-T treatment center and you're staying on average a little over a month. Because of the treatment schedule that needs to happen. There is a chemotherapy portion before your cells are infused. And the intent of that chemotherapy, it's not like stem cell transplant, it is not to try to wipe out all the blood cells including the stem cells in the bone marrow, it is actually just to try to adjust the immune cells in your body to optimize the chance of the infused CAR-T cells to stay around and stay active. So harsher than the treatment you've necessarily had at home but not as harsh as stem cell transplant. And then after the CAR-T cell's infused, because of the immediate reaction that may happen, which typically it's in the first few weeks, at least for the approved product and certainly for most clinical trials, patients will then stay with the CAR-T center for monitoring during that portion. However once you're deemed to be out of that acute window and return home, as I mentioned even though there's no maintenance treatment this is a very very new treatment so we are working very closely with the home hematologist in terms of everything we're learning about evolving needs for survivorship and recovery. Things like immune reconstitution, infection risks, prophylaxis, and so on. So here's the data.

Why go through all these very complex logistics and potentially leave your home clinic and go to a CAR-T center to get this treatment?

So this is the registration study that lead to the approval of Ide-cel or ABECMA the KarMMa-1 study. It was done in the setting of patients who's had at least three prior lines of therapy and all three main classes of myeloma treatments. Proteasome inhibitor and CD38 antibody. And in that patient population as shown on the bottom left bar graph, the response rate, it's quite remarkable for that patient population. Now overall response rates above 70%, CR rates 33%, and particularly paying attention, now majority of the patients, that's a green bar showing there are treated in that 300 to 450 million cell dose. That is the FDA approved dose range.

Now we cannot control the exact dose that the patient will be infused, but any manufacturing that's within that dose can be given. And the final dose may depend on the patients own T cells ability to grow and expand during manufacturing. And what we're seeing, as shown on the right there, is that within the FDA specified dose, so first of all for everybody treated on the study the median progression for survival is about 8.8 months. But then for patients who are able to get that highest dose, the 450 million dose, their median progression for survival it's actually a little over a year. So that's very very encouraging to see.

In addition, this past year at ASCO meeting we also heard some updates and subsets analysis. So we're able to look at patients with known poor prognostic factors like patients who are older, patients who have extramedullary disease, or patients who have already been refractory to that triple class treatment. And for all of these groups the overall survival of the patient treated on Ide-cel were really the same as patients without those risk factors. We are seeing however patients with this revised ISS stage. So that's a known prognostic staging as well for myeloma. So patient with that higher stage, so known higher risk do not do as well as patients who had lower risk.

So there's room for improvement right. Are we able to increase the response rate in patient with those poor prognostic features? What we have seen, so we try to do some comparisons since KarMMa-1 was a single arm study, it was not a randomized study comparing against another treatment. So there were shown on the left is looking at patients who were treated on the KarMMa-1 study versus patients who just received other treatment available in the standard of care practice, so patients who did not get on the study. And as you'll see here that the overall survival is significantly better for patients who received the Ide-cel on KarMMa-1 study. And similarly on the right we try to look at patients who receive another ECMA targeting therapy, the antibody drug that is also now available in clinic.

But this is results from this study dream two, and trying to match characteristics of the patients between those on the KarMMa-1 and dream two study and seeing here again that the overall survival it's better for patients who are treated on the KarMMa-1 study. So suggestion that there are potential benefit for this particular treatment modality. And now we'll look at some of the data for the second FDA approved CAR-T the cilta-cell which is the diagram shown in the middle. Now this is a schematic diagram of the CAR construct. And there's a lot of engineering that can go into the design.

But I'll just comment on one big difference between Ide-cell and Cilta-celll it's in that outer portion or the extracellular portion or that binding domain. So cilta-cell instead of just trying to recognize on area, one region of that BCMA, it's trying to recognize two different areas of the BCMA. The study design was very similar to KarMMa-1 in that it was a single arm study. It is also for patients who needed to have three prior license therapy and exposed to those three major classes of treatment. And we have now seen updates from ASH last year with little over now, two, two-and-a-half year follow-up that the response rate again is quite high in dissipation, with the patients on this study. On this study was an overall response rate of 98%. And encouragingly for the deep response, the CR SCR rate was actually close to 83%.

We have also now seen folks that the progression free survival that's shown on the left, and the overall survival that's shown on the right, for the patient on this CARTITUDE-1 study, the black line is a survival for all patients on the study. And so with two year follow up we still have not achieved that median PFS or OS. So that's also very exciting to see in patients who's already gone through so many prior lines of treatment. And in particular you'll see on the green line, four patients who are able to achieve that deeper response, the PFS is even higher.

And so similarly because CARTITUDE-1 is a single arm study we try to do some comparisons with patients in similar situation in terms of prior lines of therapies and other treatment that are available to them in the real world practice. So that's the LocoMMotion study which is actually an international prospective registry study. And so what you see here with the progression free survival on the left and overall survival on the right, the dark blue line is the survival for patients treated with Cilta-cel on the CARTITUDE-1 study.

And the red lines are either the patients on the LocoMMotion study, or subsets of the patient on a LocoMMotion study that were even further matched to the patient on the Cilta-cel study with additional demographic characteristics. And the gaps you can see between the curves are quite remarkable regardless of just taking patients on other treatment options or further sub stratification, in general CAR-T treatment seemed to perform really really well in this setting in the disease.

Just a few more comments on cytokine release syndrome. Ann certainly covered that as well. It's. A more immuno therapy specific side effects, I've often had patients tell me I've gone through the induction treatment, I've gone through stem cell transplants, I know what to expect, I've gone through that. And we try to explain, it's more like what would you feel if you were going through a really bad flu or really bad pneumonia and less like the strong chemotherapy that you may have had. And so fever often is the first presentation but that can then be associated with my myalgia's athrigias, a number of symptoms. And if left unmanaged just observed, this can progress to cause multi organ system failures. In the very early days of CAR-T investigation people have even died from complications of this.

But we know now how to better manage it both in terms of the potentially the CAR construct design but also just the clinical management of the symptoms. And so for the FDA approved treatment for cytokine release syndrome, Tocilizumab which is an IL6, inter luten 6 receptor blockade, its first line it actually works faster than steroids to shut down some of the side effects of the cytokine release syndrome. And right now this management is based on overall clinical assessment and not on any particular laps. And so I just show representative diagram on the right in terms of number of different cytokines. You can see that come up at the same time that patients feel the symptoms of the fevers and the rigors and the myalgia's, and so on.

Now we do know from CAR-T studies that in general patients coming into treatment with more myeloma disease burden, or have CAR-T cell that expands better in their body can have most of your manifestation of cytokine release syndrome. But I would also caution sometimes we do such a good job warning patients about what to expect from the side effect that they get quite worried if they have absolutely no symptoms. And we can see clinical response even if there is no cytokine release syndrome. So it's not an absolute requirement. So there's a lot of factors at play in terms of their own myeloma disease burden, their CAR-T cell characteristics, so on and so forth.

Little bit more detail about neurologic side effects to expect. I would say the most common neurologic side effect is the one described in the box on the left, the what we call the acute neurologic side effect. And this typically comes on within a few days of the onset of cytokine release syndrome. It's often overlaps with the cytokine release syndrome. And most commonly that initial manifestation could be just some confusion, some difficulty in getting the words right, even some associated tremor. It can progress .where patients can become completely aphasic or not communicating at all, becoming obtunded and so on.

But in general, this set of symptoms can completely resolve, often in days to weeks after the cytokine release syndrome has resolved. One of the reasons why CAR-T is not available yet at your local clinic is the monitoring that's needed for cerebral edema. Now that is uncommon, and I would say even rare in a situation for myeloma CAR-T treatment.

However if it does come on it can very quickly kill the patient. So this is something that all the provider needs to be super vigilant about, on the lookout, and be very proactive in management if there's any concern for this. And the cerebral edema in general, again is typically seen when the cytokine release syndrome really takes off and seems to go into this hyper inflammatory state and the acute neurologic symptom seems to really go into the worst spectrum. But we also know that not everybody get this. So what are some of the specific predictors for this is something that we're still needing to learn. And then in the last neurologic side effect that I do want to highlight because this is something that the particular CARTTITUDE-1, cilta-cel study has been very transparent about sharing the clinical presentations and outcomes of the patient, but it's not unique to that CAR-T is that delayed neurologic side effect. And this can come out weeks to even months after the CAR-T infusion, completely separate from the initial cytokine release syndrome. And it can be limited or it can last a very long time. And some of this may be some mild confusions dysphasia, but the one that we are more cognizant off from, particularly in the myeloma setting, are some of these cranial nerve palsy's, neuropathy, and this parkin parkinsonism.

So patients who have rigid movement, difficulty initiating movement, difficulties with speech and writing. Now on the study what we have at least identified is again patients who seems to have the higher disease burden the more severe presentation of cytokine release syndrome, and initial neuro toxicity seems to be at increased risk for this. And so there's been some additional preventative measures that's been happening. And so we will learn as more study's done in terms of how effective are these measures.

But I think in general, this is still an area we need to learn more about to make this treatment safe for everyone. But just looking at the trial data in terms of that cytokine release syndrome and neurotoxicity that I just covered, the first two columns are the Ide-Cel results both from phase one and the registration KarMMA-1 study. And the right most common column is a cilta-cel and CARTTITUDE-1 study.

And again in general you'll see that it's very common that almost most people would get a fever. Some signs of cytokine release syndrome. But at grades three or higher that second number which we consider grades three as that more severe manifestation where patient may need to go into the intensive care unit for additional monitoring and management. That percent is quite low, less than 10% across the studies. And there are some differences in terms of onset of the fever between the two different CAR-T products.

But then also again that neurologic symptom that I just described, particularly that acute onset one, that number overall is a lot lower than the CRS. So again everybody, for the patients who developed cytokine release syndrome not everybody gets neurologic symptoms. And that grade three where you need more ICU level monitoring, that number is again quite low between the two product.

The other thing that we have now additional data on, because as a provider I've heard certainly anecdotally from patients who's received CAR-T treatment and are in remission, they feel their recovery process has been going so well that they're recalling how good it is to feel like the days before they were diagnosed with multiple myeloma. So that is not trivial, but now we have some data. So this is comparison of the quality of life measures for patients who received Cilta-cel on the CARTTITUDE-1 study versus patient who received real world other treatment options on the LocoMMotion study.

So the higher number is better, so I was trying to show changes from baseline when they started that treatment. So improvement. And you'll see essentially that blue line is for patients who receive cilta-cel. And generally across that time point in that first year there were reporting better improvement in their quality of life compared to other treatment options, which is not surprising if they're on other treatment that has some types of regular dosing and some associated side effects from that. So we get asked this a lot for patient selection consideration.

Is there an age cut off for CAR-T? Certainly for transplant, that's they looked at very rigorously but that age cut off has also changed over the years for transplant. At this time most clinical trials for CAR-T have not restricted an upper age limit. In analysis as I showed a little bit on Ide-cel does not indicate that older patient necessarily have decreased response to CAR-T. So in general we think a patient who is fit to go through the side effect of cytokine release syndrome and neurologic side effects should be considered. And so rather than using a biological age more of a functional fitness.

Of course as we now have CAR-T in the real world there are a number of situations that are not allowed on clinical trials. So we have yet to learn if CAR-T is safe to give in some of these specific situations with myeloma and myeloma associated conditions. And another word of cautions in myeloma unfortunately that can often impact kidney functions and cell understanding of whether or how CAR-T could be safely given in that situation. It's something that we still have to learn. Now we had just a little bit of time left so I will skip over some of the details on the slides other than to comment.

Unfortunately because this treatment has such logistical complex steps that there are some problems with access to commercial CAR-T as well as patients who may have disease that progress through CAR-T manufacturing that could limit the patients who can get it to treatment. I really think about a number of current clinical trials in terms of opportunities to advance access to CAR-T.

This is one study that currently is ongoing where it's using a noon viral vector. So potentially access to different re agents for accessibility for CAR-T. But also the CAR construct enables manufacturing of CAR-T cells that could be potentially even stronger in terms of its ability to attack myeloma cells. And so we're needing to see some emerging data in terms of if that delivers in the clinical trial. There are also platforms in terms of making CAR-T cells faster. So these are two studies where the CAR-T cells could be made literally in under two days as opposed to about a week time frame so the cells could be delivered back to patients a lot faster. And what's interesting to see here, the numbers are really small for you to notice on the Y axis of the graphs. But the dose of the CAR-T cells given on these studies are essentially 10 to 15 fold less than the FDA approved CAR-T product. And so and plus these cells do exhibit a more fit functional phenotype.

So very encouraging early results in terms of their response and potentially a platform that's more immediate access to patients. This is a study that's going on in Spain right now where CAR-T's are being manufactured at the treatment center as opposed to being shipped off and sent back. So again very early results yet, only about 30 patients treated. But clearly seeing a clinical response. So very interesting potential possibility in terms of access for patients on clinical trial. This is a clinical trial looking at allogeneic CAR-T, or CAR-T cell that is off the shelf, meaning these T cells are made from healthy donors, not directly from the patient.

So they could be potentially available right away for a myeloma patient. Now in order to consider this approach there's a lot more engineering that needs to happen with he T cells. Because these T cells being not from the patients, if we infuse them as they are they could try to attack the patients organs, so something we call GDHD graph versus host disease. So there's engineering that happens to remove these T cells, TCR, that's one of the X's that you see on this diagram on the left, to reduce that risk. There's also additional engineering to remove a mark on this CAR-T cells. And then for the on the study for the patients to receive another drug, immune suppressive drug that's targeting that marker to try to remove some of the patients own immune cells from attacking these CAR-T cell's.

So in addition to the CAR engineering, additional strategies to try to make these allogeneic CAR-T cells last longer in patients. We've seen some very early results. So far from this trial what's encouraging is that we are not seeing a severe that graph versus host disease concern, and also not seeing signals for increased more severe cytokine release syndrome and neurologic toxicity. So that's encouraging, but the clinical response so far early in the study doesn't seems to be dramatically better than what we've seen with all of these CAR-T. So there's additional engineering advances that's being done in the next iteration of this platform that's now going into clinical testing. Just comment here. This is as of last month a number of clinical trials available globally. So a lot of activities going on in the U.S. and China actually. And both Ide-cel and Cilta-cel.

So you can think of essentially all the KarMMa study, KarMMa numbers two, here, four, are all the Ide-cel studies. And then the CARTTITUDE, it's CARTTITUDE 245 are all the cilta-cel studies. So these are the same CAR-T product that's now FDA approved in four line setting. And they're moving into earlier line setting was actually not to hear that with a little tude at one of the questions asked earlier, which is is CAR-T used to compare directly against stem cell transplant? Yes it is, that's CARTTITUDE-6. It's not open yet but it will be opening where patients will be randomized to receive either stem cell transplant or CAR-T in the newly diagnosed settings. So these proven strategies in later line settings are now being tested in the earlier line settings. And we should be seeing results from these trials in the coming year.

And I will just finish with just two more slides, I know I may be a little bit over a minute. To comment on CAR-T right now is very individualized. So there are a number of interrelated factors that contribute both to its efficacy and side effects both in terms of what's happening in the patients body, their immune cells, what's happening to their tumor cells. Everything that gets changed from a CAR construct, how we manufacture the cells, and even that preparatory chemotherapy, all of that can impact how the treatment works.

So this is by no means an exhaustive list but a a highlight of a number of those 74 trials that I showed you on the map. In terms of some of their strategies in where they're trying to advance and a component of CAR-T therapy. And I will skip over this particular one as an ongoing study that tries to modify the T cell compositions which is what we think about as next generation of Ide-cel. Other than to see it's encouraging that we are seeing these cells seems to persist longer in patients and seems to work better.

And then I will finish on this clinical trial which is the first time that we're hearing results on a non BCMA targeting CAR-T. And as you'll hear from Doctor Munshi shortly there are so many investigations with BCMA targeting both bispecifics and CAR-T's and ADC options. I think we will want to know what happens once patients' gone through those treatments, what's the next option. And so this is the first time we've heard results from a CAR-T that's targeting GPRC5D, which can also be on plasma cells and myeloma cells. It's really not on many other parts of the body other than skins nail beds and testes. So potential for very limited side effects in terms of on target off tumor.

And so what we've seen so far from this clinical trial, this phase one study, is that we can see clinical response. And in general in terms of cytokine release syndrome, neuro toxicity, that seems to be very comparable to what we've seen so far with the DCMA CAR-T. And as I mentioned because of that target some of the nail changes, skin changes associated with this appears to be at this time in that low grade in terms of severity. And in addition with also encouraging this on the study so far, so that's shown on the bottom right, is that there are a number of patient on that study so far who's had prior BCMA targeted therapies and prior CAR-T therapies. And that we can see clinical response in patients getting this particular CAR-T cell. So I think this is a very important, another target area to watch in the CAR-T strategies in multiple myeloma.

So with that I'll finish. And thank you very much for your time. I'll say this, a very exciting time for immunotherapy in multiple myeloma. CAR-T is an approved treatment, and it's being studied into earlier liens of therapy. And I think all these additional investigating strategies that I try to give you a whirlwind tour of will continue to advance the ability of this treatment to be an option for all of you guys. Thank you very much.

- All right so thank you very much Doctor Lin for that very comprehensive update about CAR-T's, those that are commercially available. And a lot of activity on the research side. So thank you so much for that. We'll have questions at the end. Quite a number have been coming in and so we'll try to get to as many of those as we can. But I'd like to move quickly to welcome Doctor Nikhil Munshi who will talk about approaches to relapse myeloma, what are the current bispecifics and other novel agents. And so thank you Doctor Lin and welcome Doctor Munshi. It's actually a taped presentation although he will be available from Paris for discussion at the end. So please roll the tape as we say here in Hollywood.

- Hello. Thank you Doctor Durie and for having me here. And it's such a pleasure being a part of this very composed symposium discussing all various aspects of new and myeloma and the great hope we have of curing this disease.

So I'm going to focus on basically approaches which are now being utilized for relapse patients, that includes focus on current bispecifics and also various other novel agents and novel treatments that are available and under investigation. These are my disclosures.

Now when we talk about relapse patients the words that you hear and probably want to be cognizant of is one is the relapse disease, which is when myeloma has recurred after response to the most recent treatment. And the second one you will hear called refractory myeloma which is when myeloma is progressing despite the ongoing treatment, that means it is not responding to the treatment that is being given at the moment. And sometimes the relapse refractory patients. So in his group of patients we have to consider various factor in deciding what next treatment to be considered.

One of the factor we call is frailty. We look at persons age, performance status, any other conditions that may be interfering with normal activity what we call comorbidities. The second is that this is status itself, is it a refractory disease? Does patient has a kidney failure or bone disease that we have to keep in mind in assigning drugs and the side effects. Then very importantly we also now look at what is called risk assessment that you heard earlier that patients ISS stage, cyto-genetics and FiSH result.

If myeloma is more aggressive then it is something where we would really become more aggressive in our treatment as well to get better results. The last point is the lifestyle, what patient prefers. Sometimes one wants to travel, prefers oral drug, doesn't like transplant, et cetera. And then the most important component that determines treatment is the history of previous treatment. What did patients get previously? And that will tell us what has more chance of working next.

And all these questions come up because we are at a point where we have a lot of good option for this disease and we just try to pick the best that gives the highest response, least toxicity et cetera. And number of these decisions have been made based on what we know about the disease itself but all sorts of new treatment that has come about. Now there are 11 new agents that have been approved and commercially available in myeloma in last 15 years. It includes proteasome inhibitors, three different immuno modulator, four different antibodies. The specific agents like Selinexor that targets a specific molecule or target in the myeloma cells.

And then there are some of the older agents. And the two of the most exciting choices that you just heard from Doctor Yi Lin is cell therapy. I just sell in Silt-cell and that is really changed how we think and has added what I would call almost a QRT option for this patient population. Now I'm gonna build on this, talk about how we can use some of these drugs, but what new is in pipeline and what new is coming even more than what we have already. So if you look at the therapeutic options, when patients relapses are for certain drugs. So one can relapse after getting Lenalidomide and Bortezomib, one can sufficient is refractory to that. And in that setting the combination can be combined with Carfilzomib, the drug Pomalidomide. That can be the combination we use if the patient is a consent for neuropathy, then doesn't cause neuropathy. A second combination is using an antibody called. Gives very deep responses. This is especially if Daratumumab is not used in the beginning as a fourth drug. And then another antibody, pom dex, very well tolerated regimen. And one of the direct more similar to anti 30 antibody is also. So we have a lot of options for this patient population.

If we go to patients who have progress on just Bortezomib then we have series of option available depending upon patients condition and side effects. And opposite if patient is affected to Lenalidomide then we can give again Carfilzomib, Pomalidomide, Bortezomib and various other combination with allocating agent. So as you see, at a time when patient relapses we end up with many options. And that is the good problem. We have to decide what is the best for this patient. Now how do we decide? I give you a whole list of factors we see, but based on what patient has received we also then come up with potential three drug combination that we use. So if patient has relapsed from Bortezomib we select either Revlimid or Pomalidamide as a next line treatment.

And these are the three four different studies that have been performed. And I don't want you to go through any of this in detail, it's busy slide. What I want you to focus on that this three drug regimen, and you see the numbers in red in the red box, 80 to 90% of the patient responds to these three drug regimens that I'm mentioning in combination with Daratumumab, Carfilzomib. Incredibly high response rate as a second or third line treatment for this patient population. And similarly if you look at patients who have relapsed after Lenalidomide then we have five different combinations mentioned here. Those other combination that is given with Velcade or Bortezomib. And you can see the numbers in red, the response rate anywhere from 75 to 85% again can very high response rate. And what it tells us is that as a next line treatment after the initial line of treatment we have agents and drugs that can be incredibly effective.

And this is what we would build on to give the second line. And if patient does relapse from second line we can go to the third line treatment. Now besides the standard drugs that we have I'm gonna discuss two or three newer agents that we have that are commercially available and have shown also very good responses. These other drugs that have been utilized now even first or third line treatment. So one of one such drug is called Selinexor. It's combined with Bortezomib and dexamethasone so it's called Selinexor-Vd.

And in this particular study that I'm showing it clearly shows that patients who get this three drug regimen SVD, has a significantly better outcome, survival outcome, compared to when they get just the two drugs. And building on that, which patients benefit on the right side you see? Everybody benefits. Older patients benefit, patients who are the cytogeneic risk, high risk it benefits, patients who have previous well kept benefits, and both frail and not frail patients benefit et cetera.

So this is also a good additional drug that we utilize quite extensively now in relapse and later stages of the disease. The next agent again commercially available and of great interest is called Belantamab Mafodotin. This Belamef, it's an immunotoxin that is targeting BCMA. And you heard about BCMA as part of the excursion for CAR-T. This is an antibody unlike the cellular treatment that you heard before. And this drug by itself provides significant benefit. It increases the survival 15 months in this very advanced patient population where it almost everything one can get, the response rates are in one third as a single agent. I'll show you something more in combination it's what's even better.

The point ends up being that a single agent by itself these drugs is very effective. One thing we are to be careful about is drug that you may be aware of is that it can cause some eye toxicity called keratopathy. It's observing around that 30% of the patients. And we modify the dose, hold the drug, and it ends up being a reversible toxicity. And because of this, patients getting this drug are very carefully followed so no significant antibody affect, long lasting affect might persist. And but if that the drug has shown quite good efficacy.

A third drug in this new class of drug that are either available in one or another, Venetoclax is a such drug. It's not yet approved for myeloma, however the data I'm gonna show you is exceedingly interesting and it is available and approved for other lymphoma like condition and CLL. So this drug targets a molecule called BCL2. And in this study, which is a very well known study called Bellini study, although it was given to all the patient, the results in a sub group of patients who were high BCL2, is incredibly good. The response rates are 95%, 90 to 95% patients responding variously from situation conditions with this kind of high BCL2. A group of patients who have high BCL2 are called T-11 14 translocation patient.

And those patients should be considered for this and now studies focusing on that. And as you see in the curve here, patients who have high BCL2, the curve in green, there were much superior outcome compared to the rest of the patient when they do not have a high BCL2. Survivor difference, 30 months versus 10 months. So very big difference with this drug. Overall survival also shows a curve that is not statistically but otherwise higher with the green group.

So in the patients with this category and this specific changes, I've been through a candidate for utilization of Venetoclax. And what's happening is that now we're gonna combine these other drugs with various other sort of molecules. So for example belantamab i being combined with Revlimid, with polyamide with Velcade. And with that we see significantly higher response rate in the range of 60, 70, and 80%. And so those combinations are now effective. Their toxicity is well managed, and it can be given to larger patient proportions. Now this leads to second part of my talk and also something of great interest and significant which is the bispecific antibody.

You heard from doctor Yi about the CAR-T cells targeting BCMA. Now CAR-T cells require preparation. So we have to produce the cells, takes around four to six weeks. During those four weeks time we may give some other treatment because myeloma might be growing. And those are all slight issues, especially if the disease is very fast growing then we have an issue holding the disease et cetera.

So what would be important is that we get similar responses but something from off the shelf, we don't have to wait for its preparation, it can be taken out of a bottle and being instituted. This bispecific antibodies are such products that can come off the shelf. One of the bispecific that has been studied extensively is name is Teclistamab. So what it does, its to just show the concept, that we have antibodies, as you know there are four different antibodies for different targets. There are antibodies targeting BCMA. So this antibody will go and bind to myeloma cells that has BCMA on its surface. There is another antibody called CD3 that targets CD3 molecule. These antibody binds to the immune cells, the T cells. So when if you inject it will go and mine T cells.

So using genetic and other engineering or protein engineering, a hybrid antibodies meet. Well half of the antibody is supposed to bind with CD3, the T cell or the immune cell. Half of the antibody binds to myeloma cells, the BCMA targeting. So when this hybrid molecule, what we call bispecific, it has specificity to two different cells. When those antibodies are mixed or given to patients or mixed in our lab, this antibody one binds to myeloma cell other binds to T cell. And in the process it brings the immune cells closer to the cancer cell or myeloma cells. And this proximity of the two cells leads to interaction between the two that leads to activation of the T cells where immune cells grow on one hand. And number two, they kill the cancer cell because that's what the T cells are supposed to do, affect the cancer cell.

And so this bispecific antibody brings the immune cell and cancer cell together, leads to cancer cell destruction and growth of T cells. Similar in a way to what you saw in CAR-T cell except this happens without having any cells to be produced in with. So this particular bispecific Teclistamab has been show in animal models and various other models to function in such a way and has been utilized in patients. So what has been done in the patient? This was given to patient population, it is off the shelf, so we don't have to produce anything. And it was utilizing patients with advanced disease. They were relapse refractory patients.

The patient population here had six on an average six various prior line of treatment, so very advanced disease in these patients. They had 80% patient had stem cell transplant, majority of them 90% were refractory for the last line treatment, so very advanced patient population as you can see. And these patients were given treatment with this particular antibody.

And so it was given, there was in a step up dose, and then weekly treatment doses just of Teclistamab. And then it was given and continued until progressive disease and the patients were followed for two years. 165 patients have been treated, the first 40 were early phase one study and then phase two study. And what do we see with this treatment? We see very good responses. You wanted a late stage, overall response was 62% with 28, 29% of the patient getting complete remission, 58 getting VGPR. And 42% of the CR patients were MRD negative. So just with one antibody we get incredibly high rate of response in a deep rest of response. So that's important.

You could see in this plot here, so each line is one patient. And it says how long the patients remission lasted. And you could see the number of patients have sustained remission, they are not relapsing. So I think that is very encouraging result here that in this particular study 88% of the patients were alive without subsequent treatment or progressive disease. And that is the power of this treatment that have been in remission for a long period of time.

The arrows, black arrows suggest patients were continuing ongoing treatment. And side effect wise the side effect of this kind of treatment is not very dissimilar than what you saw in CAR-T. What we see is cytokine release syndrome. It was observed in around 72% of the patient, but mostly early grid. Very infrequent what we call a rock toxicity, only 3% of the patients. And then low blood count is observed in 60% or thereabouts. And so toxicities are similar to CAR-T but less severe. And so there is a great excitement about this group of drug showing such a great response. Now this particular bispecific is against BCMA as a target.

Now there are other bispecific. They're targeting another target called GPRC5D. Another name for it is Talquetamab. And this drug, it's given again similarly. This is a very different target than BCMA. And given in weekly or twice every other week dosages Talquetamab at your 60 to 70% overall response rate in late stage disease advanced disease. And now as just as a point, the bispecifics are being combined with other drug, in this particular instance combined with daratumumab where response has reached 75 to 85%, not too dissimilar to what we observed with the CAR-T and other products. And so becoming exceedingly interesting. The process for this particular bispecific is also very similar. One part of the antibody binds a myeloma cell through this GPRC5D, other one binds to CD3, Mix two together to cell killing. So if I summarize the data we have so far there's such an excitement that number of bispecific molecules are under investigation. I'm showing you here six different from different companies and different products.

These are all BCMA targeting bispecific. And you can see, large studies have been done anywhere from 50 to 150 patients have been entered. And if you look at the response rate for all of these bispecific you can see responses anywhere from 40 to 70% to 80% response rate. These are all various stages, some phase one, phase two combine. Bottom line being that these treatments are exceedingly effective as the fifth and the sixth line treatment as you see here between five and six line, that's very advanced. Patients have been treated with lot of things. Each of them has a very similar toxicity profile. They get all CRS but grade three and four CRS is quite infrequent. And the neurotoxicity's infrequent that comes problem I've observed infections are also observed which we have to be aware and careful with. But the point is that these patients do get frequent response and also a deep response. You could say 30% patients in with some of these studies already showing complete remission rate. So that's one exciting part.

The second part is that there are other bispecific. And I'm showing two of the bispecific here's which are gonna be important. Cevostamab is one bispecific that is targeting a molecule called FcRH5 on the myeloma cell. And the other one is Talquetamab which has as I showed earlier target GPRC5D. And so both of them are showing almost 55 to 65% response rate, well tolerated toxicity, not too dissimilar. The point here ends up being that now we are three different targets with this bispecific. If one fails we can consider other one and the third one. So even in immunotherapy we are beginning to have more and more option that can impact the treatment and the outcome quite significantly and quite effectively. So we are keep that in mind as we develop our strategies for future.

So. One more word about GPRC5D BiTE. This combination with Daratumumab, we are to keep in mind I mention it earlier, all these BiTE's we are beginning to combine it with multiple agents. And so the numbers you see with single agent are only gonna get better as we combine using some of the late data and research we do in the lab and findings that suggest what best molecules that can be combined. So we are to keep that in mind. And if that is not enough, just to give the hope we have, there are many new targets that are coming up. And each of these target will have a bispecific we can utilize. So our armament is growing to fight myeloma. And also the CAR-T's, we are making different type of CAR-T's separately. And so the options that are becoming available, you already have very many options that significantly increases their exceedingly effective. And that is the whole excitement right now for this purpose.

Finally the important new other area of research that I would like to highlight is this new immuno moderator drug called CelMods. Now CelMods are help come from our understanding of how when some of the molecules that you're used to, Thalidomide, Lenalidomide, Pomalidomide, how do that work? They work through this pathway called cereblon. And now a newer agents have develop to have even more greater efficacy of cereblon binding and inhibition. And they are providing incredible responses just by itself using this molecule. So one of the molecules that has been evaluated is called Iberdomide. Now so under the name is CC-220. And that was evaluated in combination with Dexamethasone in relapse refractory patients. Again very standard studies that we do.

You may already be aware or familiar with these are all very late stage patients. And in these patient when patients got Iberdomide with and without Dexamethasone, you could see that the patients responses in this advanced disease were around 35 to 30%. And overall BFS was three months or else 12 month. And because of the good tolerance Iberdomide is now being developed for maintenance treatment. It provides good maintenance and we have number of studies utilizing this in that setting. The drug of great interest for treatment is CC-92480. This is again given similar to Iberdomide as a single agent.

But when we went in the right dose which is a light code, and this is still an early phase one study where we are learning to give the best dose with best tolerance. Almost 55% patients respond to this small molecule. The clinical and meaningful effects are observed in 64% of those patients. And I think it is quite heartening to see this agent working so very well. There are other agent in similar class that are also being developed. And I think this would bring up a whole new area of research for us and treatment options for us. These are the molecules which are going to be evaluated and has great promise when they're combined with other immunotherapy. We can combine it with bispecific, we can combine it with CAR-T cells and get better response. And so that's under the area of hope.

And the final thing I would like to say, what is our goal of treatment in relapse disease? In newly diagnosed you have heard what is in that relapses? Our goal now is also to get maximum response, not just give it enough and patients do better. Because even when patient relapses we will have a chance to have the remission even for a long period of time. And that kind of data comes from one of the recent publication where we look at patients getting MRD negativity. And Doctor Durie has put great effort in all of us understanding and learning MRD negativity. And one of this thing in this particular publication what it showed was that the patients who relapse, we normally think well they may not do as well as patients when they're newly diagnosed.

However this data shows that if we get MRD negativity relapse setting those patients, and here they are in this green color at the top, they do almost as well as patients who are newly diagnosed either young or old. And so it suggest that even when patients relapse if you get them into MRD negativity they would have a great outcome. And I think we are to keep that in mind as we develop different strategy. So if I summarize what I just say that we have many options. And all the options need to be tried sequentially, and that's a great news. We have eight options, we can go one after other if one stops working. And there is no clear data which one is better. So we take all these various features I mentioned in synthesize what we do next individually for each patient, there's no general formula for all patients. Toxicities are important from prior therapy because it influences a decision and even for relapse refractory patients we considered patient related factors and prior treatment options as a critically important part knowing the three drug regimens provide better response, more durable response. Coming to the key point for this whole excitement in last two three years, the CAR-T cells in the bispecific, providing incredibly high response rate. Even in refractory patients better than what we do with current treatments. And this is what has brought us to the cusp of achieving long-term history of survival. And a potential cure in multiple myeloma.

After saying this I would still encourage all of you to consider clinical study if offered one. And if appropriate for you. And with this would now be happy to answer question with this great message of hope in curing this disease very soon. Thank you so very much.

- All right well thank you so much Doctor Munshi. And thank you for joining us from Paris. This is tremendous. So we have close to 100 questions that have come in. So there's no way we're going to be able to answer all of those. However let's try to touch on some of these questions. One I think is quite insightful is from a patient who's asking, if CAR-T cells are so dramatically effective, why is it that many patients are not having decisive complete remissions which are sustained? And so basically asking us why, what are the mechanisms of resistance to CAR-T? Which I think is an important question for all of us. And so well I'll have, since he's joining from Paris I'll ask Nikhil first.

- Thank you Brian and thank you everyone. So I think that's a very insightful question. And we are all trying to answer why not all patients get complete response, and number two, why do they relapse? And as we answer those question in the lab and in the clinic that would be the cure for the disease, and there are multiple reason as we know. The myeloma cells change, and so whatever target was may not be the target. Number two, somebody asked that question about microenvironment. It plays a tremendous role.

- [Brian] Right.

- In how myeloma cells behave. And so even when we give CAR-T cells the microenvironment can make CAR-T not work as well or not work completely or may protect some myeloma cells. And that's one of the reason why there may be resistance. In the 30's that CAR-T cells might not persist long enough. CAR-T cells have to stay long enough in the body to clear up everything, and they may not stay long enough. And each of these problems, and there are few more, we're all working on together to find solution so that we can overcome all this inhibitory effects of the microenvironment.

- Absolutely.

- And everything.

- Thank you. So doctor Lin could you comment, maybe at this point that Nikhil was making, what do you think is a relative benefit of the immediate effect with that CRS and cyto reduction versus the impact that might accrue over time from sustained T cells in the blood. Can you comment on that a little bit?

- Absolutely, I'd be happy to. I think. So the immediate cytokine release syndrome that we se we typically think about that as the effect of the CAR-T cells seeing the tumor cell. However much there may be in the body. And so that's related to that immediate response. But can you have durable response? As Doctor Munshi mentioned there's so much we're still trying to learn right. So I think without current CAR-T construct, and given as a treatment without maintenance, knowing what we know about myeloma disease right and everything that Doctor Durie also talked about in terms of CT, DNA, and a lot of further diagnostic testing prognostic tools.

How far can we take when it's a current generation of CAR-T? So I think there's potential for example in future as we understand more about the T cell fitness and can we advance engineering? So can we get there with CAR-T alone? One, that may be a intermediate to long-term goal. And then in terms of the short-term goal, knowing now we're seeing patients with relapse, what does that relapse look like? What do they respond to subsequently? So what is a rational potential combination? And not just everybody let's just get them on maintenance, but can we learn from the type of some MRD signature or their immune signature to say this patient might single current CAR-T, get you two years or more of maintenance free response. But that patient would be concerned should we be investigating adding on something? I see something's in the question about what's the role for Iberdomide or other novel cell mods.

- Right.

- And so on. So I think there's opportunity to use the tools we have but to further advance the tools to get to that.

- Right right.

- Doable remission.

- So could I move you forward to another area of questions which is the neurotoxicity. So doctor Lin you mentioned the neurotoxicity including the delayed neurotoxicity. So one question is the percentage of patients that might get the delayed neurotoxicity. And then also can we identify ahead patients who might be at risk for getting neurotoxicity? And are we modifying or adjusting our protocols to try to reduce that?

- Absolutely yes, thank you for bringing up that question because I don't spend too much details on it in my presentation. So on the CARTTITUDE-1 study for Cilta-cel that initial the registration study there were five patients who had that parkinsonism presentation which came on more in the range of months, one two three months after CAR-T infusion, not in the first few weeks. So that is overall a relatively low percent that puts it about a five percent of the patients on that study who had those symptoms. And you looking in that patient population some of the risk that were identified were patients who came into CAR-T treatment with very high myeloma disease burden, so then who had very quickly after infusion had that cytokine release syndrome and more severe manifestations of that.

In addition, before the patient necessarily developed a full spectrum of all the Parkinsonism symptoms, some of the early symptom that they may have exhibited for example where their handwriting became really small. And so now the ongoing CARTTITUDE study, there's been things that we were able to modify on the trial. So for example we have approval from FDA to allow us to use different what we call bridging treatments or while the CAR-T cells are being made, we can do more things to try to reduce the myeloma burden coming into the treatment. And we're doing addition of very specific monitoring to watch for some of these early symptoms. So so far it seems that since all these intervention there's been just one more case reports in another CARTTITUDE study. So among close to now an additional 200 patients dose. So maybe we are changing--

- Wow.

- The numbers a little bit. But the other thing that we're also still learning is how best to manage this.

- Exactly.

- In a few patients who get them.

- Right right. So maybe I can just switch to another topic just so we can touch on them. So there are a number of questions that relate to obviously we have the CAR-T cell therapies, we have the biospecifics, and then we have the other novel therapies including the cell mods and the like. Can you kinda put these into perspective? Nikhil how do you see us finding a niche for these different new therapies moving forward? What do you foresee there?

- Yeah that's a very loaded question. because there are so many good options. And so I would say and for all the patients in general there would be no one formula that would fit everybody exactly. And but as Doctor Lin showed, CAR-T cells are extremely effective. We are doing studies to compare CAR-T's with transplant. So CAR-T's use would be quite likely be earlier on in the disease. We would not be using hopefully in the near future as a fifth and six line, we would use it earlier on. So that's one aspect.

Number two, the other bispecifics are also appears to be very effective. We still have to understand a little more, but there also might become important component of the regular treatment for myeloma. Maybe as a second line, maybe one as a maintenance treatment. What I don't want our patients to forget is that the currently very effective drug, Revlimid, Bortezomib, Carfilzomib, Daratumumab, they still are extremely important. And any new treatment that starts will start with those treatment where we will use them, bring down myeloma to a very low level, and then use this newer what we would call consolidated treatment to do the trick so that myeloma goes away and not come back. So I think that's a very broad question Brian, but there are so many angles in a good way.

- Right right right right. Absolutely absolutely. Do you foresee the day, I mean you're talking about the very good treatments that we have and then CAR-T. Do you foresee where we might ever switch that where we might say okay well let's try with the CAR-T first?

- I think so. I think the way it is effective works even at a six line it works in 98% and then get 80% CR. And half of them MRD negative. I absolutely foresee this in the near future that that would how we might begin the induction, not induction but newly diagnosed patient treatment.

- Yeah yeah. You foresee that doctor Lin yes?

- I definitely, there's a lot of scientific and clinical rationale that we would anticipate that we would likely see that encouraging clinical response yes.

- All right. So I'm just seeing if there's any other point that maybe we could touch on before we go. I think that there are so many questions. We'll try to get back to people but I think that we really had an excellent discussion period today. And I think the way I'd like to finish is just to get any final comments and words of wisdom from our panelists today. So maybe I'll start with you Nikhil since you are the longest distance. Any final words of wisdom for our patients listening in today?

- I think just two quick comment. One is that even though we have all this wonderful new treatment some of the older treatments are still very effective such as hydro transplant and hydroschematherapy and other drugs. So if they get that.

- Right.

- That is still a very standard treatment and then we would add what we would add. And number two, hearing everything that we all said, there is such a great hope that we will be curing this in a very near future.

- Thank you thank you for that. And doctor Lin?

- I would absolutely echo that. I would say, it's nice to have all these options so the decision on what's the right choice for the patient it's very much that discussion with your myeloma doctor but also with your nurse, with your pharmacist. As I really like the presentation from Ann as well to cover all these aspects, because it's important right to take all of that into consideration in the right treatment choice for you as an individual.

- Absolutely. And Ann? What are your words of wisdom?

- So this was a great session. With all these new treatment options we are going to encounter some new and unique side effects. And again I just think that patients should be knowledgeable and share the decision making process.

- Right.

- And just communicate with us with any side effects they may experience.

- Absolutely. And I obviously echo all of those thoughts. We're moving forward, we have so many great options. And a number of questions have come in about the testing and treatment for early disease. And so certainly I am specially interested in higher risk smoldering myeloma and a number of options including the bispecifics and CAR-T's might end up being considerations even there to see what impact they could have. And so many many options moving forward, but for now as Nikhil mentioned, our current therapies triple therapies or quadruplets really do a fantastically good job.

And so it's fortunate that we have immediately in our hands so many things that can work well and can be managed with careful follow-up. And the mantra is knowledge is power. We want our patients to know what's available and to have access to doctors and caregivers and nurses and the like who can help them get through and have the best outcomes for this disease.

And so I just like to thank our panel on behalf of you the patients and the caregivers and others who are listening. So thanks Nikhil, thanks Doctor Lin, thank you Ann. Appreciate so much of you taking a big chunk of your day on the weekend to help our patients. So thank you all.

- Thank you.

- Thank you.

- Bye bye.

- Thank you bye bye. Have a great weekend.

- Yep bye bye.