IMF Patient and Family Webinar 

- Thank you Robin. Again my name is Donna Catamero, a nurse practitioner at Mount Sinai hospital in New York City. And it's a great honor to be talking to everyone today.

So today I wanna talk about and discuss myeloma therapies, their related side effects, and how we can best manage them. And then we'll talk about how to best frame your care through education and shared decision making, and then finally we'll talk about supportive care measures to really optimize your health and your outcomes.

So with any myeloma treatment the goal of therapy is to achieve a rapid, deep, durable remission, while minimizing the treatment related side effects and allowing for a good quality of life, and we can accomplish this through supportive care therapies to prevent disease related and treatment related side effects.

So as you can see here on this slide we have many, many, many tools in our toolbox. We have different classes of drugs, even newer treatment modalities, such as immunotherapy and cellular therapies, and you can see with each class of drugs there are associated side effects which we will dive deeper into, but I also wanna call your attention to pending FDA approvals. So you can see here that there are several agents that will be available to patients, some in a matter of days but within the next five years, patients will have even more options to choose from, so this is very good news for us, an exciting time. So as you saw on that previous slide, we have many drugs available, and we can mix and match them to really come up with a good combination for an individualized treatment plan. So when we're thinking about what is best for the patient we really look at the patient as a whole. We see how the patient is presenting.

Do they have symptoms from their myeloma? What were their prior therapies and how did they respond to them? Does the patient have any other health issues, such as blood pressure, heart disease, or diabetes? Does the patient have any lingering side effects from prior treatments such as neuropathy? And we take this all into consideration when we're trying to mix and match drugs and come up with the best combination for a patient, so it's really individualized. So you heard me talk about newer treatment approaches, such as immunotherapy and cellular therapy.

So early last year CAR T was approved was approved in multiple myeloma. So Abecma is now indicated for patients who've had at least four prior lines of therapy, and as you can see here on the slide, the process somewhat mimics a stem cell transplant, with some key differences. So once we identify a patient as a good candidate for CAR T we get an apheresis state from the company where we're gonna collect the patient's T cells, so this is unlike a stem cell transplant where we're collecting stem cells, here we're collecting T cells. And there's no prep involved, so patients will come in, get apheresed, we take out their T cells, and we ship them off to be manufactured, and these cells will then be manufactured to target a receptor on the myeloma's cell. So it's really harvesting your own immune system to target against the myeloma cell.

So it typically takes four to six weeks for these cells to be manufactured, and during that time we wanna make sure that we still have good control over our patient's disease, so we will offer patients a bridging therapy to get them through that four to six week process. Once those cells are ready we bring the patients back in for a lymphodepletion chemotherapy for several days, and the goal of this chemotherapy is to kill off the patient's T cells to make room for the new CAR T cells that will be infused. We'll bring the patients into the hospital for that cell infusion, and we'll monitor the patient for up to 14 days in an inpatient setting for any complications from that infusion. Currently we monitor patients on an inpatient basis, but in the future we may be moving to an outpatient setting, but for now we keep the patient in the hospital for up to two weeks monitoring for any complications. And then patients are discharged, where we are still monitoring patients very closely, we wanna make sure we monitor their blood counts, and any signs and symptoms of infection.

So CAR T does have unique and potentially serious side effects. So cytokine release, or CRS, is a cluster of symptoms caused by a rapid release of cytokines into the bloodstream. So cytokines are these immune substances that have various effects on body function. So as you can see here, patients may present with high fever, headaches, shortness of breath, and low blood pressure, and thus this is the rationale of why we monitor patients in a inpatient setting so we can quickly reverse these symptoms.

And overall patients do tolerate CAR T very, very well. So I wanna move on to steroids, 'cause everyone is probably very familiar, they are in the majority of our combination therapies, so they really are the backbone of our combination therapies. They really synergize with other drugs and really enhance the therapeutic effect. With that being said, steroids have a very wide range of side effects. And you see here listed on the slide, and this is only a small, small percentage of what steroid side effects, but these are the more common ones. So patients will often complain of mood swings, changes in their energy level, they'll go from being very hyper to crashing with lots of fatigue, difficulty sleeping, muscle weakness, weight gain is problematic, ulcers, heartburn, patients can develop cataracts, increased blood sugar, so patients who are already diabetic, this is of concern, so we have to monitor those patients very, very closely.

So there are some measures we can use to mitigate some of these side effects. We recommend patients dose their steroids in the morning to limit the effect on their sleep at night. We ask patients to take it with food, so preferably with breakfast to minimize stomach upset and heartburn, we can offer patients over the counter antacids, but we can also prescribe stronger medications if needed. We recommend patients go for their annual eye exams because of that risk for cataracts. Patients who are diabetics we monitor blood sugars on everybody, and we might need to adjust a patient's insulin, or add in an additional insulin to really make sure that patients have adequate control over their blood sugar. So there are other, to really complete the picture of supportive care, we wanna make sure that we have adequate deep vein thrombosis or clot prevention onboard, and this becomes very important with patients who are on either Revlimid, Thalidomide, or Pomalyst 'cause they are at higher risk for clot development.

So we will prescribe all patients at a minimum baby aspirin, and that typically provides good coverage. However patients may be at an increased risk for clot development and we may need to prescribe a stronger medication. Compression stockings are good, especially when traveling or sitting for long periods of time. Bone health is very important, because a majority of patients do have some type of bone disease with myeloma so typically with the initiation, a newly diagnosed patient we'll initiate bone strengthening medications, such as Ometa, or Xgeva, to prevent pathological fractures. We wanna check calcium and vitamin D levels, most patients, believe it or not, are vitamin D deficient, we stay indoors too much, so we can certainly supplement vitamin D and calcium.

Veinal health is very important, we wanna make sure we minimize any harmful agents to the kidneys so we have to avoid NSEBs, and NSEBs are pain medications such as Ibuprofen, or Naproxen, they really can be harmful for the kidneys, so we really should avoid them. And then hydration, make sure you maintain your hydration. So two liters a day on average, but really discuss that with your healthcare team and see what's appropriate for you. Infection prevention, make sure you're up to date on your vaccines, so that's seasonal flu, that's pneumonia, that's COVID with booster, and we'll dive in a little bit deeper about COVID precautions and Dr. Durie will talk more about that at length.

Peripheral neuropathy can be problematic. There are medications that we can prescribe, however peripheral neuropathy tends to be a little bit difficult to treat, so one agent might work for one patient but not another. So there's no silver bullet that we can prescribe that can take the neuropathy away, so early identification is key, and see what medications we can prescribe. GI symptoms we'll talk about a little bit later, but we have great medications for nausea, diarrhea, and constipation. And again maintaining fluid intake will really help those kidneys, especially when patients have diarrhea you don't wanna become dehydrated.

So, there are a lot of symptoms that can really contribute to a patient's overall quality of life. Most common symptoms are fatigue and constipation, pain, psychological depression, and anxiety, and sleep disturbances, but also financial toxicity, which is, myeloma is one of the most expensive cancers to treat, so this can really put a burden on patients and affect their mental health and overall wellbeing, so we'll talk about that in a little bit. So I alluded to some GI symptoms, so there are many drugs that can cause GI symptoms, Velcade, Revlimid, Pomalyst, Xpovio, they can all cause GI distress, so diarrhea or constipation. Antibiotics, opioids, other medications that we give to help supplement can cause these issues. So with diarrhea if it's acute, if it's predictable with treatment, Immodium over the counter works very well, if patient needs something stronger Lomotil is also a good medication.

For patients with chronic diarrhea, especially with Revlimin maintenance Welchol has been very effective for those patients. Constipation, so we talked about opioids can really contribute to that constipation, also supplements like iron can also really worsen constipation, so we wanna make sure that patients are on a good bowel regimen, so laxative or stool softener should be part of that regimen, and increased fiber in a patient's diet, that really will help with constipation, and again fluid intake is very important. Diarrhea and constipation, patients can easily become dehydrated, and again that's not good for your kidneys.

So pain can really significantly compromise a patient's quality of life. Typically the source of pain is from the bone disease which is very common in myeloma. But it can also be from neuropathy or other medical procedures, so we really wanna identify the source of pain, is it something that we can eradiate with radiation therapy? Is it something, is it a compression fracture where we can have a surgical intervention like kyphoplasty? These interventions work really well for patients. So you really need to tell your team about your pain, your location, and any new onset of pain so we can intervene properly. Neuropathy as I said it's usually, this is really the most problematic symptom to treat. Like I said, there's no silver bullet that will help with these symptoms, and neuropathy tends to present as numbness, tingling, sensitivity to cold and heat, in the hands and feet.

And culprits that cause neuropathy are typically Velcade, Revlimid, Thalidomide, Pomalyst, can really affect a patient's neuropathy, so report your symptoms early so we can intervene. We wanna make sure that we don't have any vitamin deficiencies such as vitamin B or folate, 'cause those can easily be replaced with supplementation. There are other ways we can mitigate neuropathy, so Velcade we can move to a once weekly schedule, subcutaneous, so an injection. Back in the day Velcade was given as an IV injection and how it's an injection under the skin, and we saw that moving the route of administration really decreases the incidents of neuropathy. And just make sure you create a safe environment around you, so no scattered rugs, always wear shoes. And report symptoms early, because if you need a dose reduction, or we need to readjust the schedule of how we give medications, because some neuropathy while it can be reversible, neuropathy can be permanent, so we wanna intervene early, we don't want it ever to affect the patient where they're having difficulty walking or buttoning up a shirt.

So report these symptoms early. So fatigue is the most common reported symptom. So you can see here on the slide almost all patients have some level of fatigue, and the source of fatigue can vary, from anemia, to pain, to insomnia, to side effects from medications. Anxiety and depression occurs in almost a third of patients, but I believe that's really under reported, because often patients don't share these symptoms with providers, and I really implore you to really talk to your healthcare team, because there are treatments we can give, there are resources that we can provide to really help you through the most difficult periods of time. So rest and relaxation is always good to an overall sense of wellbeing, so adequate rest and sleep, but we talked about how steroids can interfere with that, so you may need a sleeping aid, and it's okay to ask your team, discuss that with your team.

But also create a good environment for sleep. Try to avoid daytime napping, or vigorous exercise right before bed. And create a bedtime routine for yourself and stick with it. So I talked about financial burden, and myeloma being one of the more expensive cancers to treat, and this can add up. So with premiums, and copayments. Travel expenses, so I practice in New York City, just parking and tolls, it can cost a patient up to a hundred dollars a day to come to our center, so there's that. There's the prescription costs, loss of income, time away from work, to go to treatment visits, to go to followup appointments. You really wanna work closely with a social worker. Most programs have a social worker embedded in their practice, so you really wanna make sure you're tied into those resources. There are many resources available for patients that are underutilized. There's help with copays, help with travel costs, and really we wanna tap into those to lessen the financial burden.

So now I wanna talk about framing your care. So you are really the core member of your healthcare team, so you're part of your team. You wanna be empowered. Education, so knowledge is power. The more you know the more you can really discuss treatment options, so attending seminars such as this, learning about different treatments, learning about side effects and how to best manage them, really, you can add it to the conversation, be part of this conversation with your team. And come prepared to your appointments, so bring a list of medications, both prescribed, over the counter, and supplements. Write your questions down and prioritize them. So we might not be able to address all your questions in one sitting, but I wanna make sure that I answer the questions that are most important to you. Let us know if there's been any medical changes or life changes, and let us know your symptoms. Keep a diary, and show us that diary, share that diary with us. Something you might think is not important might be very important to us, so let us know. And never leave an appointment not knowing what your next steps are gonna be.

When is your next treatment appointment? When is your next followup? Do you have all the refills you need? Telehealth has been really more and more used in this day and age of COVID, so you wanna make sure you get the most out of your telehealth visit, so make sure you have appropriate technology and wifi in place, plan ahead. If your appointment is two weeks from now make sure you get your labs now so you can have a productive conversation, and then try to collect your vital signs, so take your temperature, blood pressure, if you have a cuff, and smart watches can tell you your heart rate and even now your oxygen level, so you wanna provide that information to your team.

And again, you are a central figure in making treatment decisions, so ask, consider all your options, and I know a lot of us are in support groups, so what the experience might be for one patient might not translate into your experience. So share those concerns you have with your healthcare team, let your healthcare team know your goals and your values, and we can really make a decision together what treatment options are best for your.

And there are an abundance of resources through the IMF, through pamphlets and seminars such as this, and newsletters. So I wanna end here with living healthy, supportive care, what we can do to prevent infections, of course in this day and age of COVID-19. So having the diagnosis of myeloma alone, you are immunocompromised, and add an extra layer of treatment, you are now at a almost 10 fold increased risk of infection, so you really need to keep that in mind, that you are immunocompromised, so you need to take precautions. So make sure you have your COVID vaccines and you're boosted. It would be wise to understand did you amount a response to the vaccine? Do you have antibodies?

We're seeing in our center about a third of patients are not amounting a response to vaccines. There are now new FDA approved antibody treatments that we can use a prophylaxis, and I'm sure Dr. Durie will discuss those in his segment, but there are now options for patients who can't amount an immune response to the vaccine. Wear a mask, and I know the CDC guidelines are ever evolving, in fact they were just updated last night, but they still are recommending patients who are immunocompromised to wear a high quality mask, and those high quality masks are those N95 masks. And really try to avoid large crowds and poorly ventilated indoor spaces. So again, just reviewing that, COVID can really easily be spread through person to person, and through the form of respiratory droplets, and that's why high quality masks are very important. So surgical masks are better than cloth masks, but N95 and KN95 are the best type of masks. And this slide really illustrates that.

So if two people and one is infected, but both are wearing N95 masks, you can see they can be together for over a day with adequate protection, so just think about this if you're traveling, or you're getting on an airplane, really you wanna wear that high quality mask, it does provide the best protection.

And then just some other strategies for healthy living, so manage your stress. So relaxation, rest, getting a good night's sleep, maintaining nutrition. I would never say deprive yourself, but things in moderation. Preventative healthcare, so I think patients get so fixated on their myeloma diagnosis that they let everything else fall to the wayside, so make sure you keep up with your annual screenings, your colonoscopies, your mammograms, don't forget about your other screenings, dental care, you wanna make sure you're overall healthy. Veinal health, again, very important for the myeloma patients, so you wanna avoid those medications that can be harmful for the kidneys, and make sure you always maintain adequate hydration. And then remember keep a journal of your activity and of your symptoms and share them with your healthcare team. Don't overdo it, but remain active. Activity can really improve sleep and your overall quality of health.

And so I just wanna, there is a program in the next few weeks, that my colleagues Kevin Riggle and Beth Faymen, about living well with myeloma, and they really will dig deeper into other side effects especially peripheral neuropathy and how we can best manage it, and that is on March 10th at 7 PM eastern standard time.

So with that, I will hand off to Dr. Durie.

- Well, thank you so much Donna for the wonderful presentation, and appreciate you going first, that was great. I think that you covered it very nicely, and there are some questions coming in, and we'll cycle back to those. Actually some of the questions are related to topics that will be coming up later. There's tremendous interest in CAR T and MRD, other different things that we will be taking care of later in the program. So thanks so much, and we'll cycle back around for questions that are coming in, and I'd like to move ahead, what we're gonna do first is what is coming up is myeloma action month, and Robin Tuohy has prepared a presentation which summarizes some of the activities that are very important in myeloma action month, and then after this Robin will be around to take any questions or comments, so if we could go ahead with the myeloma action month video please.

- Thanks Dr. Durie, good morning everyone, it's my pleasure to take a few minutes this morning to share with you some information on an important IMF initiative, and that is March is myeloma action month. So today we are going to take a little walk through the myeloma action month website, which is MAM, M-A-M, dot myeloma dot org. And that's what we're looking at here.

One of the things I wanna bring your attention to is this hashtag right here that I'm circling, and it's myeloma action, my action. So what each of us can do together, and harnessing the power of our myeloma community, how can we increase awareness of myeloma by taking action together. So that's what we're gonna talk about today.

So let's join the movement. Look how easy this can be. One, two, three, four steps. It's all about you taking a photo, an image, anything you'd like to share, about how are you choosing to take an action to bring awareness to multiple myeloma. So upload that image, choose a frame, share that action using the hashtag myeloma action, and then inviting your friends to also join in and do the same with you. And right here is where you can do that. You could click here, upload your image, or choose one of the ones that I'm going to show you, and then simply pick out a beautiful frame, and down here click on this share button, and you can share it to Facebook, or Instagram, or Twitter, any of those social media channels that you feel comfortable choosing to share your action on. I'm gonna scroll back up to the top, and on this navigation bar I'm gonna talk a little bit about other ways and other options that you can join in the fun.

So let's get you inspired. I'm gonna click on that, and we're gonna look at each day for the whole month of March, down below in what we are calling this action advent calendar, everyday we will share a new action that one of you have taken. So in place of all of these questions for each of the 31 days of March, it'll be populated with lots of great actions. And you can see behind each one of these days there's a fact that you could share about myeloma.

Other things you can do, and let me show you on the social media toolkit, if you're not comfortable taking a photo and sharing that yourself, then why not choose one of these beautiful images and then share this image instead. Or better yet, share a fact or a statistic about myeloma; the more people know what the signs and symptoms are of myeloma, the more we can increase the awareness, and again we got 31 facts with beautiful graphics that you can click on, download, and share.

What other ways can you take action? Well, something really important and near and dear to my heart, each year Dr. Durie updates what we call the patient action letter. This letter is geared to be sent to those frontline doctors, the general practitioners and internists that may need a little reminder about what are the signs and symptoms of myeloma, and if my patient is experiencing one of these signs and symptoms of myeloma, what are those initial tests that we should do to get that diagnosis correct early? So right here what you can do is click on this download the patient action letter, and you can simply fill that out and drop it in the mail to your local general practitioners. Under take action, what else can you do to take action? Well we know that multiple myeloma affects you physically, but we also know that it affects you with stress, and psychosocial issues that we all have to live with when we have myeloma.

And on this beautiful wellness website that the IMF is developing and continuously updating, there's lots of good things in here to make you mentally green, and feel better. We have meditations on here, we have yoga exercises that you can click on down here, all very gentle and helpful to you. We also have wellness videos talking about nutrition and diet, and your overall health, and your immune system. So take a stroll through this wellness page and see the things that you could do to nurture yourself. So those were all under take action. Let's look a little bit under educate. It's really important to know what is myeloma. You can click on that tab and share information about that; we know that myeloma is a very diverse disease that affects all kinds of populations, and we know specifically that multiple myeloma is the most common blood cancer in African Americans who have a greater than average risk of developing this disease, and we want to remove any barriers to early diagnosis and treatment for all patients, including African Americans. And here is a flyer, if you would like to download it, or if you would like to order this flyer and maybe hang it up in your local community, to help increase awareness of those facts, and early warning signs. Help us to spread the word. Local press release, under educate.

This local press release is really, really important because this local press release is written for you, and it already talks about what is myeloma, what are the signs and symptoms, who is the IMF and how can we help, and then the bottom section is left for you to fill in about your local support group, or about your story, and then you can send this local press release out to your local newspapers, radio, or TV station, and then we can get more information out there to the public. So that's under educate, and your local press release. Under myeloma publications, we have all of the IMF publications available there for you, and find a support group. If you do not belong to a myeloma support group yet, now is your opportunity to do so. Over 100 myeloma support groups are continuing to virtually, safely meet, throughout this pandemic, and here is where you can scroll down and click to find where is that local support group meeting so I can get involved and virtually join that group to learn what you need to know about multiple myeloma. And to be supported.

Also on here there's always some fun merchandise if you are interested in some fun things that you can purchase, that's where you can click and find a fun fanny pack, those are popular again today, so the fanny pack, the little tote bags to bring your groceries home in, lots of fun things in here for you to look and see what is available there. And then the last thing I'll just show you here, if you'd like to donate to the IMF we're always very grateful and thankful for all that you do, any contribution is an important contribution, and we appreciate each and every one. So remember to take action during March, it is our time to shine and shed light on what is myeloma, what are those signs and symptoms, and where are those local support groups. So I look forward to seeing all of your great actions that you'll be sharing soon. So that's it for now Dr. Durie, if there are any questions I'm happy to field those.

- Okay, thank you so much Robin, and you are right there live, and so excellent, excellent overview of myeloma action month, all the various activities that are happening and really raising awareness across the board among patients, among doctors, the whole myeloma community. And so I'm looking at the chat box here, and there are a lot of questions triggered by Donna and maybe anticipating what we're gonna present in the future, and we will be touching on those. So just to let you know, people who are putting your questions in the chat box, I'm tracking them all as they come in here. But really not anything about what you presented Robin, so I think that was great, and we are looking forward to an exciting myeloma action month.

- Absolutely, I'm looking forward to seeing everyone's actions.

- Right, right, okay, so we'll get back to you as we move through the day, but thank you so much, Robin.

- [Robin] You're welcome, thanks everyone.

- So, we're a little bit out of sync here but what I'm going to do now is in the balance of time in this first segment is cover two presentations, that basically what I'm going to do next is present what is the basic information and approach to myeloma care, which I call 101, and then in the next segment I'll be talking about what has been coming out of new research on myeloma, and the most recent update on that was at the American Society of Hematology meeting, which occurred in December of this past year. And then at the end I'm going to touch on some of the things that Donna already very, very nicely addressed about how myeloma patients should continue to stay safe, and she showed a very nice slide about the impact of wearing masks, which I think is very important.

So let me get started with 101, and I'm gonna move forward here. So, I'm just going to populate this particular slide, back we go, sorry. So, I think the big thing about myeloma in 2022 is that it is very much treatable. If you look at articles and textbooks for the last 20, 30 years, it's saying well myeloma's a very difficult to treat disease, and this, that, and the other, but actually with the introduction of our novel therapies in the last 20 years, particularly the last 15 years, over 90% of patients at the time of diagnosis will have a significant response to our current therapies. And nowadays the average remission will be at least four years, or sometimes many more years, and in 2021 the average overall survival is more like in the seven to 10 years, range.

And so an important aspect to this is that what that means is that if a patient is newly diagnosed right now, and this is very important when maybe a new patient is coming into your group, or you have been introduced or met them, is that chances are that that patient will be able to get their myeloma under control, and that it will be perhaps many years until they need to access some of the novel therapies and newer therapies that are coming forward. So really quite good news in that early disease setting. And we now know that some patients will live over 15 to 20 plus years, and new therapies are constantly improving.

So the big picture is now not as bleak as it used to be, and really remarkably promising, and so we have excellent chance of response, and as you heard from Donna, we're very much focused on handling the side effects and all the different issues related to getting through the various different treatment regiments. Now, to do that in the best fashion, getting a consultation early is good. I think that at diagnosis, or in that early treatment phase I think it really is important to try to get that expert input if you can. So strangely enough during the past two years of the pandemic it has been a lot easier to get virtual consults, so that quite a number of myeloma experts have been doing consultations with patients without the need to travel to a different clinic, or city, or center, and so this has been quite helpful.

However unfortunately it seems like we're going to have to push quite hard to maintain that option because in some places the centers are starting to cut back on those, but I think it's still important to work with your doctor and try to explore if you could get that done. Because it really does set you on a clear path for the future, and guide your local doctor, so that your local doctor can partner with someone who is working with myeloma everyday, and we do list questions that you can ask your doctor, some of the most important ones that will be key to guiding you on that best path. Good to do it early, okay. And to work with your doctor. So, there is increasing interest, and I'm gonna focus a little bit on this today, in early disease, smoldering myeloma, and that's for a number of reasons, is that we are understanding more about the very, very early stages of myeloma, how to diagnose it precisely, so it's obviously very, very important if the myeloma is in early stage, is it important to jump in with early treatment, or is it safe to continue to monitor?

On the one side, early treatment can possibly give fantastically good results, however if you're gonna be stable for a number of years you don't want to jump in with treatment too soon. And so, through the international myeloma working group, the IMF has developed what we call a risk score tool, and this is based on what we call the 2/20/20 model, and it's based upon the level of the myeloma protein, the serum M protein level, if it's greater than two grams, if the free light ratio, FLC, is greater than 20, and the bone marrow plasma cells are greater than 20. And so this model allows you to get a score for each one, and if you look at each one of those, in the red I've marked what happens when you have a higher level, and so one thing that's quite important, for example if you look down at the bottom, if the percentage of plasma cells is above 20, if it's 20 to 30, you get a risk score of three, if it's 30 to 40, it's a score of five, and then it goes up to a score of six with 40, so that the actual percentage of plasma cells is really quite important in indicating the risk that the myeloma will potentially become active.

And so this is a very, very useful tool to guide us in terms of recommending early treatment. And so on the opposite side, those ones with the high plasma cells and high free light ratio are what we would call higher risk with scores up in the 10, 11, 12 range total, but on the opposite end of the scale you can also identify patients who are gonna do absolutely fine in the low risk group. And so this is equally important in my mind where a patient can be quite comfortable that if they have low levels that things are going to go well probably for several years, actually. Okay; so, this has led to what we call a treatment algorithm, where you're looking for those early signs.

Now if there's obvious myeloma, what we call the CRAB features, elevated calcium, renal problems, anemia, or bone disease, CRAB, or plasma cells at 60% or better, or a high free light ratio, a hundred, or more than one focal lesion on MRI, or, actually on CT, then this is myeloma, treat as myeloma. If you don't have those, that's where the 2/20/20 comes into play, and if you have above the 2/20/20 this is high risk, and then you have the option of different treatment to be considered, and I'm gonna talk about that a little bit. And then on the other side, if you're low risk, we would just observe. So this is very, very important, to start off on the right foot. Now, if the testing does show CRAB features or higher levels, then we need to look closely at the numbers to see, okay, what is that percentage of plasma cells, and then also what do the x-rays or scans show?

And so on the x-rays myeloma can sometimes be quite obvious, you can see these holes, these little dark spots in the bone, which are obvious even on an x-ray, and many of you I'm sure have had x-rays or certainly scans, these days, we will often do other types of testing which would be PET or MRI, which is looking at much larger parts of the body. The PET scanning is very good 'cause you can do a whole body scan, and you can pick up F which is focal lesions, or D, which is more diffused disease anywhere in the body and it it indicates where the myeloma is active, and then obviously MRI very sensitive, so both of those techniques show up lesions that would not necessarily be detected by x-ray, and so most all of you have probably had either whole body low dose CT PET or MRI performed.

And then in addition when you have that bone marrow test done over on the left, in addition to looking at the percentage of the plasma cells, you probably had what we call FISH testing, fluorescence in situ hybridization which basically means this special color staining, the colored spots allow us to see if some of the chromosomes have gotten mixed up, where in this case the number 11 has joined up with number four, which is called T, a translocation, and so this has implications which we'll talk about later in terms of whether a treatment such as Venetoclax might work potentially better.

Now, as we are, starting the day here and thinking about therapy, obviously everyone has had that initial diagnosis, and then moved forward into thoughts about initial therapy, and this is in the setting of possibly moving forward into transplant, or for someone who's older, or maybe having some more medical complications, without the consideration of transplant, and then moving forward with maintenance, and so those are what we call the blocks of therapy, and along the way in green we have the supportive care which would include things like Zometa, or some treatment for bone problems, which many of you will have had.

Now, at the bottom there I indicate something that happens every year, Dr. Vincent Rajkumar, one of the board members and advisors for the myeloma foundation, he puts up an article every year which is the update on diagnosis and risk and treatment, and so we post this information for you so that you can, each year you can see this wonderful overview update of where are we with the different testing some of which I've just been showing you, and then some of the options to select if a patient is going to have treatment with the idea of a transplant or maybe without a transplant.

And the good news in addition to the overall likelihood of response, and remissions, is the number of drugs. In the old days at the bottom you can see scattered across the slide there there were just a few treatments up until about 20 years ago, but since then there are just so many different options with very, very active options in the frontline setting which is over on the left, transplant, and then drugs that we use for maintenance, and then over on the right so many that have been approved in this relapse refractory setting with a lot of options for patients where the myeloma has relapsed and is causing new problems. Now unfortunately a couple of the drugs over there, Melflufen, for example, ended up getting withdrawn by the FDA, and actually also Panobinostat which is a little bit above that on the slide there also has been withdrawn from the US market, but all of the other drugs are available, and are options. So, I think that it's important to take a look at what is the basic benefit that you can get with frontline therapy, and I had actually the privilage of conducting this trial SWOG 0777, so it's a trial with the Southwest Oncology Group which started over 10 years ago now, which is quite important in terms of figuring out what is the benefit, where we looked at what is the benefit of three drugs versus two drugs, and so this is a key question because you could take Revlimid and Dex, which is RD, or maybe you could take Velcade in addition, DRD.

And so does that third drug really make a difference in the long term, and so in the big picture this has become important for all of the regiments that we have been looking at in the past 10 to 15 years. Now with this particular trial, with long term followup which was updated at a 10 year time point, we found that consistently the red line is above the blue line, with our remission in the left area 41 months, so a little bit short of four years, and then over on the right side you can see that over half of the patients are continuing to do well at seven years, so this is with three drugs. And so as we'll talk about later, the current question is whether we could be using four drugs, what we call a quadruplet, so this is just the basic type of response that a patient could anticipate these days.

And so then, what is the overall picture that we see? So we anticipate that there will be a good deep response, particularly if a patient moves forward and has an autologous stem cell transplant early on. And then there could be a relapse in that four to five year timeframe, and then we'll talk about it later, increasingly we want top jump in early if the disease is clearly progressing. Now I might emphasize here that sometimes the myeloma protein will pop up a little bit, but it's not rapidly changing, and so we don't necessarily wanna jump in right away every time, if a little bit of protein is coming back or increasing. And then of course later on we have all the different options for relapse that we're gonna focus on in the latter half of the day here. All right, yes. The later relapse, yes. And obviously what I have on the bottom which is left, is if you've been lucky enough to get MRD negative, if you had a fantastic response, and you're MRD negative, so no detectable residual disease, then your remission could be even longer, and we're looking at remissions that could last in excess of 10 years.

Okay, so, triple therapy, VRD pretty common, you can also have options of Velcade with Cytoxan, Kyprolis instead of Velcade, and also Daratumamab Rev Dex, so that Dera Rev Dex is another triple therapy which is really excellent, and has produced really long remissions for patients in the non-transplant setting. So really right now in the triple therapy area we have VRD, or Dera RD, which is called the MIA regimen. And then of course autologous stem cell transplant which should always be discussed with your doctor to see if it's a good idea to maximize your response, and then as a supportive care the bone therapy. Okay, Velcade Rev Dex, yeah, so that really is the standard of care, and autologous stem cell transplant always should be discussed, and bone therapy absolutely if you've had bone lesions to try to maximize the recovery in the bone area. And discuss other options, I mean VRD, maybe something else would be better in your case.

So moving forward, what are the strategies, 2020? Well I think we're looking at are four drugs possibly better than three drugs? Obviously there's gonna be more side effects, and more expense, can we handle that? Is it really that much better that we should be using four drugs instead of three drugs? And then a little bit more sophisticated look at maintenance, what are some different options for maintenance? Revlimid, using Velcade, or using Ninlaro, the oral proteasome inhibitor or even Kyprolis in a high risk situation. But I think we'll focus a lot on this is decisive early relapse treatment where if the myeloma's coming back this is frequently not a desperate situation, it's a situation where you want to have a decisive next benefit. And of course the big, big thing right now is the new immune therapies which are producing such dramatic benefit, and increasingly we're looking to use them much earlier in the disease.

Okay, so this is a basic overview of where we are, and this is the starting point for thinking about what would be ways to treat your myeloma, and then with that baseline we can look at, well, what are the new things that might be introduced to even achieve better testing, or better overall results? And obviously on our website we have access to a lot of different information, text, videos, interviews with researchers that will give you a much richer amount of information about all these different things that I've touched on here.

All right, myeloma.org, yes sir. We're here for you, absolutely. And you can check all these different, these are all clickable, obviously, where you can click and get different types of information. And I'm watching all of these questions coming in and so we will be picking up those questions, we'll try to, it looks like there's going to be plenty of time, and so we will sequence through as many of these questions coming into the chat box as possible. I can see them about different types of testing, different questions about various therapies.

 

Okay, so if we take a deep breath here, and I'm sorry that this is compacted today, I'll go forward now into what are some of the newer things that came out of results presented at the American Society of Hematology that was held in Atlanta this year, 2021, and I'll touch on a few, just a few details about COVID-19, Donna did touch very nicely on that already, actually.

So, for the medical meetings, the meetings for the myeloma experts, we're experiencing the same thing that all of you guys are, is that we've been having virtual meetings and we're waiting, waiting to have live meetings. This year it was a hybrid meeting, which means that there were some people who showed up live in Atlanta, and then there were people who attended virtually. It was about one third live and two thirds virtual. This year there were 879 abstracts, so a lot of information, a little bit lower than in other years, but still a lot of information. The main thing this year is that there was a tremendous focus on the evaluation of early disease, and so I'm gonna go through that with you because I think it will become increasingly important where we try to diagnose that smoldering high risk patient early, and come in with treatment which can do the very best job to have the best longterm benefit.

There were also a lot of important updates of trials, particularly related to CAR T cells and bispecifics, and those are the topics that Tom Martin and Saad Usmani will be talking about after the break, so I'm not gonna talk about those. Those were presented at ASH, but I'm gonna set those aside so that Tom and Saad can focus in on those in more detail. So, this is just to give you the way that it looked like where the hybrid and live, so on the left you can see that was the live attendance, which was 211 people. This was at our Friday symposium, and then we had 647 who participated in a virtual fashion, so 858. And so you can see the way that it worked for both the virtual and the in person activity. And so now what I talk about is that we need to do this in an organized way where we respect and allow each of these audiences to participate.

So like today we really are keen to, that's why I keep emphasizing it, we are very, very keen to take a look at your questions, and we will set aside enough time here to try to get through as many as we can. And then this was for our IMWG breakfast, and very similar where we had 120 live and then we had 230 virtual. The main thing about this was that our breakfast meeting occurs at 6:30, 6:30 in Atlanta, which was 3:30 in the morning here in Los Angeles, so not exactly ideal for hybrid participation, a lot of early coffee.

So, as I said, I'm gonna focus on what was really the first time that there have been many abstracts looking at early disease, looking at monoclonal gommopathy, smoldering myeloma,, and the data was coming out of Iceland, and so this is a project that is actually supported through the Black Swan Research Initiative, which is an IMF supported activity, and this year there were six abstracts that came out of this one project, and four of them with oral presentations, from Dr. Sigurder Christiansen and his team, so really amazing to see what is happening with this information coming out of Iceland. So they presented the overall results.

The interesting thing was that when you screen, and, in Iceland they screened over 85,000 people, 85,000, so a massive screening of people over the age of 40 in Iceland, they found that not only did individuals possibly have MGUS, a small spike, but they found that quite a number had smoldering myeloma, high risk smoldering myeloma, where intervention was probably a good idea. And I believe it was I think 47 patients actually had myeloma, I mean from the screening people were found to actually have myeloma. And so then the other thing is, that was quite interesting, so in the early stages with MGUS there was no increased risk of MGUS or problems with COVID, in patients with MGUS, although obviously with active myeloma we do see increased issues. We also had data on what's the impact of circulating plasma cells, sorry, and also the notion about selection bias. This was completely random screening, which is different than if a patient has gone into the hospital with pneumonia or some other problem and then they're found to have MGUS. So that's obviously different because this is a patient that is already ill with something.

And so in this particular study it was randomized meaning that the patients who were found to have a protein in their blood were divided into three groups. One where there was no further testing, number two where there was what was called standard testing, which meant followup every three to six months, and then arm number three, where we did all kinds of testing to figure out what type of disease these people actually had. And so this just summarizes it, this was what we had published already over 75,000, and those are the three groups, and you can see quite large numbers of people in each of the three groups. But this is what will turn out to be the most important thing; if you look over on the right there, where you did full workup, which means that if there was a small spike discovered you would do a bone marrow, you would do whole body low dose CT, and a variety of other research testing that we're doing, you can see that we found on quite a number of these people had smoldering myeloma and some of them had myeloma.

And so this really supports the idea that screening could end up being the way to go. And you can see over on the left how much different it is where you're not detecting these people who actually do have problems requiring attention. So, quite, quite interesting. Now one of the things that is being studied in, Iceland, is looking at the pattern of disease, and a group in Spain also presented data on that, and found that you can pick up different patterns of disease, but perhaps the most interesting thing that the Spanish team found, and this is the group, well it's combined from both Salamanca and Pamplona, they found that if you look at the number of myeloma cells in the blood, that indicates whether the smoldering myeloma is active or not. And the interesting thing is that the cut off, it may seem like a pretty low number, it's .02%, but with our very, very precise new tools with next generation flow, you can pick this up quite easily, and so this actually might give us a new, very, very good model where it won't be just 2/20, it'll be 2/20 and then .02, where if you do have those plasma cells that could really be a single indicator that there's active disease and that you could benefit from treatment.

So this was quite exciting, and this is quite exciting because Dr. Maria V Mateos from Salamanca presented her update with the CESAR trial, and so this is a study which we call a cure trial, where patients with high risk smoldering myeloma using basically the 2/20/20 criteria, so those are the patients that were in excess of 2/20/20, and then they received Kyprolis, Revlimid, and Dex and an autologous stem cell transplant, so quite decisive, aggressive intervention, and so now, Mary V has followup a little bit short of five years, 55 months, and you can see there PFS, progression free survival, basically means the remission, so 94% of the patients are still in remission close to five years, and the overall survival 95%. And, second bullet, 67% are MRD negative, so really very decisive deep responses which are being sustained, so this gives strong encouragement to the idea that studying people early, coming in early with the best treatment that we have can really give you that best longer term outcome.

Now, just in passing, we've just finished the Assent trial which is the US trial, which is Dara plus KRD and the results look like they're even better, and those will be presented, well they're being submitted to the upcoming ASCAL meeting a little bit later this year. The other testing that is being done in those studies and across the board is mass spectrometry using a testing which is now called EXENT, and then this is something like an MRD test where you look for low, low levels of the myeloma protein in the blood, and you can compare that with MRD testing in the bone marrow which is called NGF, so you can look at the blood and then you can look at the bone marrow.

And so basically what you can see there is that you have the blood on the left, and you have the bone marrow on the right, and you can see you've got your red and you got your blue, very, very similar, and so this is quite encouraging because this means that actually using very, very sensitive testing for the myeloma protein in the blood, with mass spec, with this system called EXENT, which will be rolling out and broadly available, we hope, within the next year, currently available only at the Mayo Clinic, if you send in samples there, but you can see mass spec in the blood could be a really good simple way to assess MRD actually.

Then, since the other speakers won't be talking about the frontline setting but more in the relapse setting I thought I'd just show you what are the results with four drugs versus three drugs. I showed you what are the longterm results with three drugs, VRD or RVD, what happens when you add in Deratumumab, this was presented, actually represented here, and you can see that it does improve the length of that first remission, and you can see here PFS, or length of remission basically, a little short of 90% versus 81.2%, so you can see that, looking at two years and three years, that this is improving that first remission. And so it's tipping towards, now there are other ongoing trials, but this is certainly tipping toward the idea that those four drugs will have an important impact. On the flip side there was a study presented at ASH asking whether Exazamir, which is an oral chrotiasome inhibitor, combined with Revlimid, and Dex, impacts remission at five years, and unfortunately the answer to that was no, it really didn't change the overall outcomes in this particular study. And so, in closing here I'm just going to give one slide to indicate what you're gonna be hearing about after the break, where obviously we have a number of new therapies which are indicated in blue here, but what is so, so exciting right now are the boxes which are in orange and in green.

And these are the new immune therapies Tom Martin and Saad Usmani are gonna talk to you about, what we call the cell therapies, mostly this CAR T, and then the monoclonal antibodies, for example the bispecifics, such as Teclistamab, which is at the top of that green panel, and then over on the right you'll see the different types of CAR T therapies, and so very exciting therapies that will really move us into a whole new era of myeloma therapy, actually, I believe. Okay, so just in closing, just a few comments about COVID, I think that you know we get so much about it in the news, but you could certainly go to these different websites, the CDC, and the World Health Organization, and you can see where the disease is evolving, fortunately things are getting a bit better in the US, the dark blue you can see some parts of Europe, and over in Latin America, over in Chile right now, you can just see where the disease is evolving and getting better some places and then getting worse elsewhere, so it's still pretty active on a global basis.

And then you can track what's happening overall in terms of vaccination and other types of things which is helpful to be aware of. And then you can easily go and, the CDC guidelines now, the IMF has created a COVID webpage and we have tried very, very hard to keep those data updated, and so please consider going to our website, and go to the COVID page where we tried to get all the most recent information for you right there. Now, the things that you know and have been touched upon for myeloma, definitely get vaccinated, get that third dose, and then even now there's the possibility to get what would be a fourth dose.

The other option for patients where the antibody response has been low has been this medicine called Evusheld, which you may have heard about, I've written about it on blogs, and we have it in our COVID page. What we added just the last couple of days is that Evusheld is this antibody treatment where you get two intramuscular shots and that basically these shots give you the antibodies to fight against COVID, and that's obviously very helpful if your antibodies have been low in response to the vaccine. What came out from the FDA is that they have now said that double the dose should really be used to try to improve the antibody levels, and so the dose that had been recommended was basically 150, in each of the shots, and so now they're recommending 300. So people who have had Evusheld, if they can, should go in and get another shot.

Now the other thing that we know too clearly, unfortunately, is that Evusheld has been very, very difficult to access, and so it's kind of challenging to think that even the people who've received it might need to get another shot. But anyway, that's the new information there. I do believe for maximum protection, even as mask mandates come down, that in all situations of risk, myeloma patients included, should continue to mask, and you saw data that, they really do work, and so if you're concerned and you're out, and you may be mixing with people who are, that you don't know, or might be unvaccinated, or you think they're kind of careless, or in a crowded setting, I think wearing your mask is a pretty good idea. The third booster is approved and even another dose beyond that. Just go ahead here. So we leave plenty of time for questions.

Oh this is just, you can also get information about the different variants, obviously these are what we call VOC, it's possibly helpful to be aware of the jargon the World Health Organization classifies based upon variants of concern, VOC, and then obviously, the Delta, which we had earlier last year into this year, was a serious variant, and then mostly end of the year into this year, the Omicron variant. Now there is a newer one, which is BA2, which is being evaluated, it's not yet been classified as a variant of concern, it does seem that it can cause more serious disease than Omicron, but is still at a low level. In the less than 5% range mostly across the US right now, so not so serious. In my blog this week some of you may have noticed that I tried to find out what was the story with Omicron for myeloma patients, and so we did a survey and around 600 people answered the survey, including a mixture of patients and caregivers, and it turned out that among those individuals around 14% did develop a positive COVID infection, despite being vaccinated, mostly, and boosted, and being very careful with their masks.

But the good news is, well for the caregivers, everybody recovered and there was nobody hospitalized. For the patients, also pretty good news, there were only four patients out of the whole group, which is less than 1%, just a fraction of a percent, who actually ended up in the hospital, and then those people also recovered. And so despite all of the concerns with Omicron, our assessment was yes some people have become infected but mostly they have done okay, which is really quite encouraging.

Now nonetheless dealing with all of this nonsense is pretty stressful, and sometimes you're not feeling your best, that's for sure. And sometimes, especially during the surgeries your healthcare team might be pretty preoccupied and not even available, and so there have been a lot of issues in terms to manage, get through this recent COVID world. Yeah, not so easy. And so, it's not so clear how things will move forward, it's clear that vaccination is gonna continue to be essential, I still recommend the best masks possible that K95 or something similar, and definitely caution in the indoor spaces, but the future is still loading. It's still loading, we don't know. But certainly these are key elements moving forward.

I've done a number of videos on this, to answer some very specific questions, and hopefully those are helpful. And then in the meantime, Robin and her team have been doing a lot of virtual support group meetings, and I participated with Suzy on a number of those, and these are clearly great forums for people to communicate and get a lot of information and support each other, really great. And you need to always stay positive despite all these challenges, and nature moves forward, all of these issues cannot cancel spring. The buds are coming, the daffodils are coming, around the world, and so I think that we need to try to keep a positive perspective that we will get through this together despite the many challenges that we face. In terms of COVID but also in getting the best therapy to manage the myeloma on an ongoing basis.

So I'll stop there. And we will have time to cycle through some of these questions. So Donna, I don't know, you've probably seen, so welcome Tom, I didn't see you earlier, hi Tom, and welcome Saad, from New York. Hope things are going well in New York. So, you, I don't know if you can see all of the questions that are coming in, for you guys Tom and Saad, there are a number of questions about CAR T and bispecifics that are coming in, and there are a number about COVID. So Donna I don't know if you notice any that catch your attention that you'd like to jump in and try to answer right away.

- Floating through them all.

- Yeah, I know there's a lot of them, yeah. The ones that are just coming in. At the bottom, should you get a booster with Evusheld? Well that just was a recommendation that came in from the FDA. But, well maybe I can ask you guys, what has been the access to Evusheld? So I think that at least my feeling is that for patients with low antibody levels or across the board it would be good to try to get Evusheld, what's the experience so far?

- So I can speak to Mount Sinai. We didn't have it at first but we do have a good supply now, and we really are prioritizing myeloma patients, so we've had decent luck getting, so we check everyone's antibody levels, and we're seeing that patients who are on BCMA directed therapies, really are mounting a good response to the vaccines, so we put them on the waiting list for Evusheld and we've had quite a few patients been accepted and are getting treated with it.

- Okay, how about in San Francisco, Tom?

- Yeah, so our supply is definitely limited, there's no doubt about that, and there is a waiting list for people to get it. What we've approved is for anybody that's getting active therapy to go ahead and get Evusheld, and we give it to all of our patients post-transplant, post autologous transplant, when they leave the hospital from their autologous transplant we've been giving it to them before they leave. And in our CAR T cell patients we've been doing it essentially at day 30-ish after their CAR T we'll give it, because those patients we won't re-vaccinate until three to six months later. In terms of the 150 versus 300 we've really stuck to 150 only because of supply. And that's where we're at.

- Great, great, and Saad? Saad was there, but I guess, sadly he's not back. Oh there he is. Okay, so, there are a number of other questions here, obviously, one that you guys can, and I can mention, it was interesting, we did this survey, so, one question was whether or not treatment with Darzalex, with Deratumumab seems to put people, patients, at particular risk of problems. And in this survey the percentage was equal, around 30% of the patients were on Darzalex, but being on Darzalex did not increase the risk of getting COVID, which was a little bit of a surprise to me, but I don't know. Is there any perception about that from you guys? People who have had problems more likely to be on Dara or not?

- Yeah, so I think for us, I agree with Donna that the BCMA targeted agents have done kind of the best job of limiting B cell production of antibodies, so response. But Daratumamab, also about probably 10% of our patients, maybe 15%, on active Dara therapy, have also had low antibody levels after getting the vaccines, and so those patients we have been targeting giving Evusheld to.

- Right, right, okay. There's a question here, for patients on BCMA bispecific, how do they do if they contracted COVID? Yeah so another questions about different therapies. Another question that came up, I don't know what you guys thought about this, and it was a question for, in the survey is, where and how did our patients contact COVID? And many of them were a little bit puzzled as to where they picked up the COVID. But another thing that was published recently is that there has been some concern about possible transmission in hospital settings, particularly with Omicron. And so I don't know, have you experienced anything like that?

- I have to say at UCSF we've been quite lucky, we think in our outpatient clinic, in our inpatient setting, we have not had any significant patient to patient, patient to staff, staff to patient, or staff to staff transmission. So we've been pretty rigorous with using masks and face shields, and trying to keep people sequestered and distanced, so we've actually done quite a good job. We've been lucky I think in some ways, but thankfully the Omicron rates are going way down.

- Exactly, exactly, that's the good news. Okay if you could scroll up, let's see if we have any others that might be of interest here. There's an interesting one; is cancer research using the warp speed approach to accelerate the development of new therapies? Yeah, I guess we need to do that, and I guess Biden did launch his new, whatever that was.

- Moonshot.

- Right, right, I'm not sure if going to the moon will help us, but, anyway, we'll see how that works out. I haven't been to a restaurant since March, yeah. Well I think, yeah, I think that that's getting a lot safer to go out and about, frankly, and I think that many patients are, although I would still encourage use of masks. Let me scroll up and see if there's any others that we could usefully talk about. Yeah; so I did say, I did show that data from ASH, where Ninlaro did not add benefit in that maintenance study which was kind of disappointing, I don't know if Tom you wanna talk about that, that was, we were kind of hoping that that would be a positive study, but unfortunately not.

- Yeah, that was definitely unfortunate. And we did a study also that randomized patients to either Lenalidomide or Revlimid, versus Exazamed, and basically it wasn't really our, to show a difference, but that said the Revlimid arm certainly was doing a lot better, and so they closed the Exazamed arm. So, I think the take home message for everybody is Revlimid's probably a better maintenance therapy than Exazamed, there are some people that can't tolerate Revlimid, and then whether or not to use Exazamed as maintenance is something that you should talk to with your doc.

- Exactly, exactly; and then this one, I did, the data out of Iceland is that patients with MGUS seem to react normally with COVID where there was not an increased risk with MGUS, however with smoldering myeloma and active myeloma there was an increased occurrence. So I think that that was, that's kind of helpful information. Next slide, scroll up here, yeah.

- I will also say Brian at UCSF, in December and early January, we had a lot of myeloma patients, I can't give you an exact number, they would call in and said they tested positive for COVID. And if they had symptoms we got them either the other monoclonal antibody or the oral medications. In fact we did not have an increased number of patients admitted to the hospital, or in the ICU, et cetera, so in fact our patients who got the Omicron did actually quite well, in fact, most of them stayed home and just got through the symptoms without having to come to the hospital.

- Right, well that's the outcome of the survey that we just did in the past week. And I think it relates to the cautions of the patients, but also what you're describing is that they were getting therapies to keep them out of the hospital. And monitoring, I think that it's really important to monitor, and if there's some change that you would assess them right away. Let's see what else we have here. We're gonna touch on before we can take a break.

- Hello Brian, this is Saad, I just wanted to let you know that my AV issues have been fixed, so I'm here, and I can hear you.

- I was so sorry that you were not able to jump in and comment, yeah, so it's welcome, and I hope things are going well in New York. For the patients who are possibly familiar with Dr. Usmani he's recently been in, at the Lavine Cancer Center in Charlotte, but is now recently moved to Sloan Kettering in New York. And so I hope things are going well.

- They're going extremely well, and it's been a wonderful move, and I'm really enjoying my time in New York with my new team, thank you for sharing that, Brian.

- Yes, okay, so I don't know if you had anything that you were trying to say, or wanted to say about any of these aspects of COVID, or Evusheld, or other treatments for that, and then we can, gonna move into some of these other questions.

- I don't think I have anything additional to add, I think our experience during the most recent Omicron surge has been very similar to other academic centers, and I think, vaccines work, and so what we have observed is the number of patients who are getting very sick was much less, so the denominator didn't change as much as the numerator, and that was actually a good thing.

- Absolutely, absolutely. A number of questions relate to BCMA CAR T, and then there's one about the different types of bispecifics, so I think it may be good to set those aside for you guys, you're gonna be talking about those, so to reassure the questioners we are gonna be talking about those new immune therapies. If you wanna scroll up and just see if there's any others that we could talk about now. Someone wants to know about tapering off Dex, which is frequently a good idea. Let's see; yeah, so I don't know if maybe someone wants, Donna, you wanna talk about that? I mean that if a patient's during well in general it's good to try to taper off Dex, yes?

- Right, it's always a happy day when we can discontinue steroids, but, so we do have to taper it, because typically patients have been on steroids for an extended period of time, so we take about a month to taper off, but then you're back in the swing of things, and I think the patient's quality of life drastically improves while they're off steroids. So it's a great thing to discontinue steroids.

- Absolutely, and I mean we do have the capacity to monitor and, to reassure patients, I mean sometimes the steroids can be important, and if necessary you can add in that little bit lower dose later, possibly, if necessary, so it's something that is good to try to do, and there's no problem in adding something back in if you really need to. Okay, I'm looking at some of the questions here. Yeah, something that Tom touched upon, taking Revlimid for maintenance but was allergic, and then switched over to Velcade, yeah, so. Yeah so I think that what, Velcade every two weeks, and so I think that that's a reasonable alternative. In that setting of being allergic to Revlimid. And as you were saying Tom, maybe consider and Ninlaro in addition as an option. This particular patient is taking Xgeva rather than bisphosphonates it looks like. So I don't know how many patients, I mean, on my slide I was obviously mostly recommending bisphosphonates, maybe Zometa, I don't know how frequently you're seeing the use of Xgeva, actually, versus a bisphosphonate, is that occurring very frequently in your practice? It's obviously a lot easier.

- Yeah, I think a lot of the local docs actually find it quite easy too, that patients just come in for a subcutaneous injection versus an IV, and that just, the throughput is a lot better.

- Right, right, right. Yeah; Donna, any thoughts on that?

- Yeah.

- Yeah?

- I work with nine physicians, so we have nine different opinions, but we do, but I would say a fair number of our patients are on Xgeva, but we also use a lot of Zometa, so it's really I would say 50 / 50, but we're using more and more Xgeva in our patients, it's an easy in and out for patients, quick injection, so I think it's a good option.

- Good, I'm just scrolling up here to see if there's anything else we should touch on now. 'Cause we'll be focusing mostly on immune therapies later. Yeah, there's a question about, yeah, something other than Revlimid for maintenance. Right, there's a good question. If I'm in remission and MRD negative, do I need to do a stem cell transplant? Okay, so that's like the $64,000 question. So Saad, do you want to touch on that one?

- Yeah, so outside a clinical trial, my answer is yes. I think what we're recognizing about MRD negativity is that one time point is not enough, we actually are aiming for sustained MRD negativity, and if we look at the four day trial and some of the data emerging from the Griffin trial, I think that there is added value to proceeding with an autologous stem cell transplant. If however there are clinical trials that actually give an option to collect stem cells and forgo transplant, and you want to participate, I would encourage you to do that as well. But I think my general advice to patients is go with the strategy that gives you the best chance of having a sustained MRD negativity.

- So really, and my sense is that this still is the standard of care, I mean to go ahead with that autologous stem cell transplant. I think one issue is the standardization and the timing of the MRD testing as well. As you said, is one test enough? And which test was it? And stuff like that. So Tom, what's your perspective on that?

- Yeah, that's a hard one, I don't think there's a right yes or no answer for that one, and that one is really where it's an individual patient level decision. I have some very young patients that get to MRD negative pretransplant, and we decide to do the transplant because hopefully that'll give us the longest remission duration, or some that are really younger and still wanna be fertile, and I say then let's not do the transplant, let's wait and see, we can do a transplant down the road, so it's really I think an individual decision at the current time 'cause we don't have data and randomized trials. I do say pretransplant if you're MRD negative, you have very sensitive disease, hopefully that just bodes good for either way.

- Exactly, exactly; do you have any sense, or do you have multiple opinions in your practice at Mount Sinai, Donna?

- I always say sustained MRD, so one time point, what does it really mean? So, I think the Forte trial again really showed us that sustained MRD is important, so for now just the standard of care.

- Right, exactly, exactly. Let's scroll up and just see if there's anymore before we just take a break here, but these are some important points. Some of these are very individual questions. Oh yeah, here's one, so, which I think is true. Do you recommend taking another drug when you stop Xgeva? And so I think that is a recommendation, right? So have you been doing that if someone comes off Xgeva for some reason? You give them a bisphosphonate?

- Yeah, I mean Zometa is always our go to drug of choice, and again, we consider other bone health, so vitamin D, like I was saying lot of patients especially in metropolitan areas are vitamin D deficient, so we make sure we at least have that supplementation onboard, but yeah, go to standard bisphosphonate is Zometa.

- Right, right; you wanna scroll up and just see if there's anything else here at the top of the list here? Yeah. There's a question about extramedullary plasmacytomas. That's actually a common question. I think probably you guys will talk about that in that, mostly in these immune therapies have been working in patients who have extramedullary disease, plasmacytomas, but maybe you can be sure to touch on that where there are data. I know there are for CAR T, I think also bispecifics. What is the C in CRAB stand for? Calcium, C stands for calcium. But it actually stands for high calcium, so technically it should be an H possibly, but that's not a good acronym. Okay, just see if there's anything else that we can do. Yeah, this is someone who's saying that, what kind of x-rays should be done? In the smoldering stage? Yeah, so that is possibly a good question, if you have a patient with early disease, what's your go to screening? So, whole body? So are you both able to do whole body low dose CT in a smoldering patient where you're not sure if they have early myeloma, so would that be your go to versus PET scan or whole body MRI?

- I'd say it depends, we still do not have codes to get the reimbursement for that whole body CT, I know Brian there has been in the past efforts from Lima, from that end.

- Right, so that alone, just being particularly interested in that, one of your colleagues over there, yeah.

- Yeah, so I think we are able to, we do try, sometimes you can get individual CT orders with bone windows and get them through that way, but if they're unable to because of insurance issues we end up doing PET CTs, I think it's relatively easier to get those than the whole body low dose CTs. I'm wondering if Donna you guys have had similar experience from New York?

- Yeah, so really what we can do is we either do yearly PETs or whole body MRIs, so really the same experience.

- Yeah, which that's kind of sad really 'cause the whole body low dose CT, well the INWG we published a paper saying that that was supposed to be the standard of care, but it's just not day to day feasible. So Tom, what about in San Francisco?

- I think the same as what Saad said, and that is that we kind of have to allow the insurance to help us choose. We do do low dose CTs, whole body CTs as well as whole body MRIs, and we get success with some insurers to do one versus the others, and those are potentially our preference.

- Right, right, it's crazy that imaging has been a chronic problem for reimbursement. 20 years ago I actually went to the FDA, to the CMS, to try to get reimbursement for PET scanning, for myeloma, whole body PET scanning, but it was quite, quite a challenge. I mean we had meetings, myself and Barlowmere, who was so interested in PET scanning. And it's been an amazing challenge to get coverage for the imaging that is necessary for myeloma. All right, there was one question here which was, what's the dose of Dex in these triple regimens or quadruple regimens? And so that is a low dose Dex, what we call low dose Dex, so that is a one day a week 40 milligrams. So maybe we could comment on that. I mean most protocols have that one day a week 40 milligrams, so how frequently do you even cut that down from the 40 to 20, or whatever? Does anyone wanna comment on that?

- I can comment on that. So I think we'd like to dose steroids according to age, so an older patient would be equivalent to 20 Dexamethasone, a younger patient would be 40 weekly, but some patients can't tolerate that once a week dose, so we have other alternatives where we can use Prednisone three times a week. The patients can tolerate that better, so there are a few tricks to the trade that we can, work on us, for better tolerability.

- Right, right, so I think that that's really important. So I think you can glean from that that it's very important to talk to your doctor with that knowledge that you can negotiate to get one of the tricks of the trade, perhaps, yeah. Okay, well I think that we've covered a spectrum of things here so I think that we've had a full first session and we'll take a short break and then we'll come back, and we'll be focused on the exciting immune therapies, so thanks to everyone, and thanks to our three guest speakers today, we're looking forward to the next sessions. So, we'll come back at, 15 minutes, okay, so 15 minutes, so we'll start a clock, so just stay logged in and we'll give you a 15 minute clock and then we'll start promptly right back, okay? Thanks so much guys. Welcome back everyone, I hope that you had a useful break and you're feeling refreshed and ready to learn so much about these exciting new immune therapies.

As you'll see in a moment what Tom Martin calls the new frontier, the new frontier. So I'd like us all to welcome Dr. Tom Martin who's from the Helen Diller Family Comprehensive Cancer Center at UCSF in San Francisco, and obviously is highly focused on myeloma, and doing a lot of important work related to the immune therapies including of course the CAR T cell therapies. So please welcome Tom, and I turn it over to you.

- Thank you very much Brian for the introduction and for the opportunity to talk today, and thanks to everybody who joined. You guys have been quite a lively crowd, we're getting a lot of questions in on the chat which is awesome. I am gonna try to address some of those questions in my talk as we go forward, and I also will have some time at the end so we can answer additional questions for you.

So yeah, I do think we've had a lot of advances in myeloma over the last five to 10 years, but I think the next five to 10 years are gonna be even more substantial and I hope that it allows us to potentially cure a few more patients with multiple myeloma, and thus I call it the next frontier. And I do think immunotherapy is gonna be the direction where we proceed. Now I've given a similar talk to some patient support groups, and what I really wanna do today is I want people to understand what we mean when we talk about CAR T cell therapy.

I'm not gonna show a lot of data slides, but rather I'm gonna talk to you about the process, what we're trying to do with the immune system and how we're trying to renegotiate our fight against the battle with multiple myeloma. And I always tell people that the way we're gonna cure more patients with myeloma is by invoking all of our defenses. The Army, the Navy, Marines, and if I had a larger slide I'd put on the Coast Guard, I'd put on the Secret Service, the CIA, et cetera, I'd put every single dimension on there 'cause we wanna try to attack it from many ways. But I do think using the immune system is gonna be the best way for us to move forward.

Now we already are using immune therapies in myeloma, on the bottom left of this slide I show that there's some naked antibodies, and some, we've had many mention of them in the chat, Daratumamab, or Elotusamab, or Isatuxamab, those antibodies tag the myeloma cell and swing their tail, and in comes the monocytes, or the army, or the macrophages, they see those antibodies on and those actually then go to kill the myeloma cells. Those antibodies use your own immune system to kill the myeloma cell. That is really one of the biggest starts for us for immunotherapy. And it's been a great success over the last five to 10 years. But now we're in the next generation. Dr. Usmani's gonna talk more about bispecific antibodies and some of the other novel therapies. Where these antibodies are more active, where one arm binds to the myeloma cell, and the other arm is activating an immune cell in the area, so those are really actively participating in getting the immune system involved. And then I'm gonna focus on the bottom right, which is cellular therapies, or CAR T cell therapies.

So what really is a CAR T cell therapy? Well it's using the body's own T cells to destroy cancer cells. We're trying to redirect a patient's own T cells against the patient's cancer. Now we all, we have billions of T cells in our body, and in fact in a patient who has myeloma, the percentage of T cells that are actually trying to fight the myeloma is quite low, it's less than .1%, very low levels. And the cancer's smart. The cancer tells that very low level of T cells to say, hey, don't worry about us, we're the good guys, go after some of the bad guys, you can go to sleep. And so in the bone marrow where's there's myeloma cells sitting there, there are T cells sitting there that were supposed to fight myeloma but now they're sleeping and they're not working so well. And so what this T cell therapy is, what the CAR T cell therapy is, to just collect the T cells in the blood, in the peripheral blood, and train them to be professional myeloma killers. They may have in the past been able, trying to fight influenza, or COVID, or something else, but we're taking them out and we're gonna make them myeloma killers, and that's really the gist of CAR T cell therapy, is we're trying to redirect the T cells towards the cancer.

So how do we do that? Well, in fact T cell therapy in cancer it's not a new thing. On the left of this slide, many years ago some of our colleagues that treat solid tumor malignancies, like lung cancer, or GI cancer, they would actually take out biopsies of the tumor, and in those biopsies there would be some T cells in there, again the T cells that went to sleep, 'cause the cancer's smart. And they would take those T cells out and try to activate them in the test tube and then just put back the activated T cells, not do any gene therapy, just put back the active T cells. And those T cells actually would go in and would fight, some patients would have responses to that.

But we wanted to do better. And the way in my mind to do better was to harvest the T cells in the peripheral blood, and to use gene therapy to put a new gene into these T cells to actually activate the T cells when they bind to the cancer cell. Some in the past some of those actually used what we call the native T cell, every T cell has a receptor on it called the T cell receptor, and that T cell receptor gives that T cell its specificity, and so we've done it with doing specific T cell receptors, but CAR T cells actually puts in its own receptor, it doesn't have to work through the regular T cell receptor.

Again it can be a T cell that's against influenza, that we're taking it out and we're putting in a gene that'll make it fight myeloma. And the gene is on the right side of this slide. The gene actually has a binding domain so that it actually will direct the T cell to the myeloma, and then it has an inside the cell, we'll call it intracellular signaling domain. So that you actually, when the cell binds to, when the T cell binds to the myeloma protein, there's a signal on the inside of the T cell that says, yup, that's the guy, go get it. And it activates that T cell. When a T cell gets activated it secretes those growth factors, or those cytokines, or those immune proteins that tell the immune system come over here, here's the bad guys, let's get them. And that's why people get, what Donna said earlier, cytokine storm, we'll talk a little bit more about that in a minute.

So, what I wanna emphasize is that we have a T cell, we have to get that gene into the T cell. The way we get that gene into the T cell, actually, is we use viruses, viral particles, or vectors they call them, and it's actually a hollowed out HIV vector but it can't create or cause HIV but we use it to be able to shuffle the DNA that, the gene of interest that we want, to get to the T cell, and then to get into the nucleus of the T cell, and to put a new gene into the nucleus, and the nucleus will make this new cancer cell binder. And what we focused on initially is BCMA, but there are gonna be CAR T cells, and we heard about it at ASH, targeting a different receptor on the cell surface called GPRC 5D. And at ASH, in the past, there's been some CAR T cells that bind to two things; the BCMA and CD19.

So we can direct these T cells to different surface molecules on the myeloma cell, and I think to cure people with myeloma with CAR T cells, we're probably gonna have to use more than one target. And that's the future of myeloma. Now on the right side you see a CAR T cell will bind to the target antigen on the myeloma cell, it will release cytokines into the area, it will recruit more T cells, and all these T cells will then come in and try to kill the myeloma cell, and they're very effective at killing the myeloma cell. So, there's many components of CAR T cell therapy. So, the first is, patient selection. There was a bunch of questions in the chat about patient selection.

At the current time, the studies that we have, some follow up on, are in patients that have truly refractory disease, they've had all the good therapies, the Pomolidimides, the Carfilzomibs, the Daratumamab, or Isatuxamab, they've had all those therapies and they don't work anymore, and now they're actually using it in the population that have very few options. And so now that we know it works really well in this later line population, we are gonna start moving it earlier and earlier, and some people have asked can I get it as frontline therapy? Can I get it in my first relapse? On a clinical trial? Possibly; and if you wanna participate in a clinical trial, look around, but today no, we can only do it in people that have had four prior lines of therapy, that's on the label of the currently first approved CAR T cell therapy, we'll talk about more of that in a minute.

So, what a patient goes through is a patient puts out their arm, sometimes if the arm veins aren't so good we have to do it in a neck vein, you get hooked up to an apheresis machine, there's no other therapies that we have to give ahead of time, it's not like stem cell collection for autologous transplant, you don't have to receive Neupogen, or GCSF, or anything like that. All you have to do is go there, put your arm out, or we put a catheter in the neck, and we collect the buffy coder, the white blood cells from the blood, we select out those T cells, and those T cells then go for what's called manufacturing. The T cells are sent off to a company, the company expands the number of T cells there, and then they insert the DNA, or the gene, the CAR T cell gene, into those T cells, and expand it into an aliquot, somewhere between 50 million to 450 million CAR T cells that are gonna be later infused into the patient.

That process takes anywhere between three and five weeks. Now some patients who have the T cells collected actually have myeloma that's active, and we have to control the myeloma while the T cells are being produced, and that's called bridging therapy. And so some patients undergo bridging therapy, a chemotherapy regimen to keep their myeloma in check prior to them getting the CAR T cells back at their center to get re-infused. Now when we get ready to re-infuse the T cells, patients have to get another round of chemotherapy, it's called lymphodepleting chemotherapy. It's a lower level of chemotherapy, typically it's two drugs, Cyclophosphamide and Fludarabine, and those are given over a three day period of time with two days of rest, kind of a wash out period, and then the CAR T cells are infused.

Now the lymphodepleting chemotherapy can mostly be done as an outpatient, sometimes we put people inpatient if it's more convenient, but often can be done as an outpatient. And the CAR T cell infusion at UCSF right now we prefer to do that as an inpatient, so we watch you really closely, but some centers may prefer to do it as an outpatient, we'll all just have to see.

Now, I do wanna say that this is a, it's a two person procedure. Everybody, somebody asked in the chat, do I need a caregiver? What kind of help and support do I need? You need somebody 24 / 7, in my mind, for us at UCSF for the first, essentially 30 days after the CAR T cell therapy. We make you stay within at least 60 miles of UCSF. If you live further out you have to stay locally either in an apartment, or a hotel, et cetera, but you have to stay local, and you have to have somebody with you. If you develop side effects from the CAR T cell within the first four weeks we wanna know about them right away, and we want your caregiver to bring you to the hospital as soon as possible. So yes, it takes a village to be able to undergo this just like an autologous transplant.

Now in general when I ask patients, hey, 'cause a lot of the patients who've had CAR T cell in the later lines had an autologous transplant earlier on in their venture, and I say to them, what was harder? The autologous transplant or the CAR T cell therapy? And honestly universally patients say the autologous transplant was much more difficult. I had many more side effects from the chemotherapy than I had from the CAR T cell therapy.

Let's talk more about that. And so, and for a recap of where we are right now, so essentially, steps one for a CAR T cell therapy right now is you have to actually come to a CAR T cell therapy center and get a consult. You gotta get a consult. We will say whether you're an appropriate candidate or not, if you've had four prior lines of therapy and you're relatively fit, you are the person that I think is a perfect candidate for a CAR T cell therapy. The evaluation is actually a little easier than with a transplant. Usually we will want a bone marrow biopsy, we will want some blood tests, we will wanna collect some urine, we often do an echocardiogram, an EKG, to make sure the heart is working fine, and a chest x-ray, make sure you have no signs of infection and everything looks good. And if all that goes smooth, then again, you're a candidate. Then we do the T cell collection, that just takes, it takes two to three hours to do the T cell collection. Again, to get the CAR T cells made it takes about three to five weeks, on average about four weeks.

You may need bridging chemotherapy during that time. When the CARs come back from the center to us, we start the process of CAR T, it starts with lymphodepleting chemotherapy. Three days of chemotherapy, followed by two days rest, followed by an infusion of the CAR T cell. And then most of the time at that point you are in the hospital, and you are being monitored for side effects. Now the big side effects that we're looking for are cytokine release syndrome, or CRS. Now cytokine release syndrome actually happens at different time points depending on which CAR T cell therapeutic that you receive. Currently the only approved one is called Idosel. And Idosel actually has a onset of CRS typically in the first one to three days after the CAR T cell therapy, so for us, we would like to have people in the hospital during their CRS, so we admit them to the hospital at least for their CAR T cell infusion, and then we follow them very closely for the first week to 10 days as an inpatient. And if they have CRS we treat it as appropriate, we'll talk more about CRS in a minute. And then once the CRS is over and there's no toxicities, and the bone marrow has recovered from the chemo and from the side effects with CRS, then we let people go home.

They typically go home day 10 or 14 after the CAR T, and home for us means within 60 miles of UCSF. It could be home to a hotel, it could be home to a apartment that people have rented, but they need a caregiver, and they stay in the San Francisco area for the first 28 to 30 days. And at about day 30, we then give, again I told you we give Evusheld, and we make sure there's no other signs of infection, everything's okay, and then we setup visits, which some of them can be Zoom visits in the next four weeks, and then regular visits, at least every three months.

So, the big toxicity is cytokine release syndrome, and on the right is a picture of what organs are involved. Cytokine release is really a measure of activation of the T cells. The T cells get so active that, and they release all these cytokines, that people feel like they have a bad infection. It's almost like having a really bad flu. Patients can have fevers, chills, headache, fatigue, just general malaise. Also the blood pressure can go a little low, the heart rate can go really high, some people can get a little short of breath, and occasionally there's a need for oxygen. Now we grade CRS depending on what are the associated symptoms, whether the blood pressure goes lower, or whether the oxygen's needed, and we initiate therapy for cytokine release to try to turn down the immune response. We know now that turning down the immune response at that point in time, is not detrimental to the CAR T cell effects.

What we don't want is we don't want the CRS to go out of control, so in fact we have taken an earlier line at treating CRS. Usually we treat it when it's grade one, some people have recurrent fevers, we will give them therapy. Sometimes that therapy is steroids, sometimes that therapy is a medication called Tocilizumab, which is a medicine that really just tries to turn off the cytokine excitement and the milieu from these T cells getting activated. Again the onset of CRS is a little bit different. Idosel it's usually within the first one to two days, one to three days. The second CAR T cell therapy, that I was hoping I could tell you today was approved, I was hoping it was gonna be, I think we were all hoping that it was gonna be approved yesterday, 'cause sometimes the FDA approves yesterday is on target hopefully to get approved Monday, two days from now. And that's Cilta-Cel. We're all keeping our fingers and toes crossed for Cilta-Cel, and Dr. Usmani and I have had a big role in that, and so has Mount Sinai, and we're looking forward to hopefully getting that approved. Cilta-Cel, the onset of CRS, is actually around day seven.

And so our plan for Cilta-Cel is to keep patients in the outpatient setting until about day four. Give them their T cells even as an outpatient, patients get admitted on day four, and then we follow them again for seven to 10 days to get them through that cytokine release, so they're in the hospital for that cytokine release. Dr. Usmani will talk to you more about cytokine release with bispecific T cell engagers, but I think it's a little less severe with bispecific T cell engagers than it is for CAR T cell therapeutics, and Dr. Usmani will talk more about that.

Now the other side effect that can occur is neurotoxicity, and that tends to occur, let me go back and say for CRS, 80 to 90 plus percent of patients get CRS. We kind of see that as a good thing in that we know the T cells are being active, we know the T cells are there, they found the myeloma, they're excited, they're going, they're killing. So essentially almost everybody gets it. 90 plus percent, and then we have good ways to treat it. And we can control it. And we're much, the cytokine, in my mind, the cytokine release syndrome with myeloma is actually sometimes easier to treat than our partners who treat leukemia and lymphoma see, some of those have actually more severe effects. The second one is neurotoxicity.

This actually also can occur anywhere from a couple days after the CAR T into the first month, and that's why we have you stay locally and we want somebody to follow you closely. It typically lasts anywhere between three to seven days, sometimes as much as two weeks. Some, few patients have it longer, but all of these tend to be reversible, a majority of the cases it's very reversible. In terms of symptoms from neurotoxicity, patients can be confused. They can be a little delirious, they don't know where they are, all of a sudden they can't tell you the date. Some people have problems producing words. They have a little trouble talking, actually, and can almost mumble things rather than real words, and those are signs of neurotoxicity, and if there's neurotoxicity we do the same thing, we try to turn off the immune activation, and we tend to do it with steroids. So those patients tend to get Dexamethasone, or Solu Medrol as a therapy for that.

There are some patients on Cilta Cel, and also Idosel, Lisinidosel, that have had delayed neurotoxicity, sometimes a month or two months later, and sometimes it's tremors. Or Parkinson like kind of symptoms, or nerve palsies meaning changes in the way you can move your mouth or open your eyes. And again these tend to be reversible, but if they occur we wanna hear about them and know about them right away. Severe symptoms like seizures or brain swelling, et cetera, extremely rare with myeloma, where it's more common in patients that have leukemia or non-Hodgkins lymphoma. And then the other side effect is cytopenias. The three days of lymphodepleting chemotherapy causes cytopenias, and the CRS, all the cytokines that are secreted in the bone marrow, trying to kill the myeloma, also suppress the normal cells in the bone marrow. And so sometimes even a month later the platelets remain low, or the red cells remain low, or the white cells remain low, and patients may need transfusions even out to that long afterwards. We just follow that and we provide supportive care as needed.

Now, I'm gonna, here's I'm gonna just show you a few data slides for the next two minutes, and then in the final few minutes I'm gonna give you, that was CAR T 101, I'm gonna go up to CAR T 201 and tell you what I think the future looks like, which is really amazing, actually. So Dr. Usmani and I have both presented this data at past meetings, I was lucky enough to present it at, basically this past year's ASH, and I did put at the top of the slide, is it approved? 'Cause I was hoping I can tell you today that it was approved. So this is Cilta-Cel, this is one of the myeloma CAR T cell therapies that targets BCMA, some of the special sauce about this one is at the cell surface of the T cell, they actually have two binding domains for BCMA, so it binds to BCMA in two places, we think that might actually provide a tighter binding of the T cell to the myeloma, and maybe that's why this has a better overall response rate, and a better remission duration. And the intracellular signaling is similar to many CARs. They have two signals on the inside that's telling the T cell to basically get active.

And so this was a study in relapse refractory myeloma, I'll point out a few characteristics. One, very heavily pre-treated, six prior lines of therapy, 100% of them had had prior IMIDs, proteasome inhibitors, and CD38 antibodies, so these, everybody had pretty much a full compliment of therapies. There was a high risk cited genetic profile in almost a quarter of the patients, and in this study we actually had a very high percentage of blacks and African Americans, 17.5%, and everybody responded as well whether, in any one of these categories, everybody responded well, so this was a good sign that this works broadly across patients with multiple myeloma, which is really important that we include everybody in these studies.

And here's the response rate, it was 98%. Amazing, it's like, wow. There was no other therapeutic in these six prior lines of therapy that gives you a response rate of 98%. And if we looked at stringent complete response, so the protein's out of the blood, and the bone marrow, by regular testing, we can't see any myeloma cells there 83% of patients. And of those patients who were evaluable for MRD, the majority of patients actually achieved MRD negativity, which is, again, this is a very potent and amazing study. If we look at progression free survival on the left here, we look at the dark blue line, at 24 months, 60.5% of patients are still in remission, so this is two years after they received their CAR T cell therapy, and the advantage right now of CAR T cell it's one and done, meaning they got one therapy two years ago and they had no therapy since.

And this, 60.5% of the patients still remain in remission, that is amazing. And those patients in the light blue and the orange, we talked about sustained MRD negativity, in blue it was patients who had sustained MRD negativity for six months and orange for hundred months, or sorry, 12 months, you could see, wow, the PFS of 100% if the sustained MRD is more than 12 months, that's pretty amazing. And you can see the overall survival curve on the right, whereas six prior lines of therapy, the old days, with the old drugs, in myeloma patients, we would expect a survival almost of less than a year. And here the majority of patients are doing well and surviving, which is just, again, this is the new frontier with myeloma.

Now, one thing I will say that, our lymphoma and leukemia colleagues, the curves above, show this flattening of the curve, and the flattening of a curve means patients are staying in remission, there's a certain percentage are staying in remission a long time, those patients may be cured. Idosil on the lower left, you can see that curve continues to drop down, we're not sure we're curing many patients with Idosil in the myeloma heavily pre-treated population. The Cartitude, well I just showed you survivals on the bottom right, you have to follow that longer, we're hoping there's a flattening of the curve but we just don't know just yet, we just have to follow them longer, but very exciting data on the PFS. Okay, now, this is just quickly showing you that Cilta-Cel is not the only CAR T cell therapy that has shown really high response rates. I've highlighted in red that there's another CAR T cell from a study called Neumacar that has a 94% response rate, and then the dual CAR BCMA CD19 from China also 95% response rate.

So we have more for more CARs, and as these response rates continue to be quite high we get very excited that this therapy is here to stay, and it's not just gonna be in the refractory patients, we're gonna start doing it in earlier patients. Okay, the only thing I'll say is patients who have CAR T are at higher risk for infection, so they might have prolonged low blood counts, they may actually need infusions of IBID, and we have to follow them over time for secondary cancers. I think the secondary cancers are not coming from the CAR T, I think they're living longer and thus have risk for secondary cancers probably to the chemo that they've been exposed to earlier.

And I hope as we initiate CAR T cell therapy earlier on in the myeloma therapy, that these patients will have less secondary cancers. All right, the last two minutes I'm gonna tell you, myeloma 201, or 202, where are we headed? Well this therapy is brand new. And the nice thing about this therapy is there are many ways for us to make it better. And you guys have asked a lot of questions in the chat. Can I have my stem cells, my T cells made from the stem cells I had created from autologous transplant years ago? That's a maybe, we have to look into that, I think that's a possibility actually, we have to get T cells that are collected earlier on in therapy, maybe are healthier, and maybe will give us a better product. We also need a better binding domains. This, Cilta-Cel is a double binder, but maybe again we have to do dual targeted CAR T cell therapies.

There's a therapy that's coming out, that's on the bottom right, is a universal binder. So that patients can receive an antibody like Daratumamab, or Elatusamab, or Isotuxmab, and then we can give a CAR T that actually is just gonna bind to the backside of that antibody. So the antibody's gonna recognize the myeloma and the CAR's just gonna recognize the bound antibody. And we can use it then with a variety of other antibodies, that would be a great improvement. And there's studies going on to test that.

There is a researcher at UCSF, when we do these therapies where we put the gene into the T cell, the gene randomly goes into all the DNA, we never know where it goes in. In some T cells, it might go in a good place, in other T cells it might not go in such a good place, and it might not work so well. Well we're gonna try to do site specific insertion of the gene, into the T cell receptor, and then it might actually work better. We can show in mice that we can actually cure mice better if we do it, put it in the TCR, but we have to prove it from mice to man, and that's what we're gonna do hopefully for the next, the next level of CAR T cell therapy.

The other thing that one of our researchers, Kole Roybal's working at UCSF, is actually doing a variety of different, what's called switch technology, so it's actually targeting two domains, not just one, so BCMA and say CD19, and if it binds to BCMA it'll make a CAR that'll kill CD19, or if it binds to BCMA, it actually might, they might, sorry, might make in the local environment a bispecific antibody. We can train these T cells to do anything we want. It's pretty amazing, actually.

And then lastly I'm gonna say, these are all the areas on T cell, CAR T cell therapy that are being manipulated and investigated to make it better. Better patient selection, optimizing manufacturing, optimizing lymphodepletion chemotherapy, making the CAR T cell gene better, preparing the patient, selecting better population of patients, making better therapies for CRS and for neurotoxicity. There is so much that we can innovate with CAR T cell therapy, it is in my mind in the future it's gonna replace autologous transplant, we're never gonna use allogeneic transplant anymore. And whether you use a CAR versus a bispecific is a big question, but I think they're gonna work best together.

And with that I'll end and I'll say, we'll answer any other questions you may have, hopefully I answered some of the ones you have asked; thanks Brian.

- Thank you so much Tom, this was a wonderful, wonderful presentation discussing the mechanics of CAR T cell therapy, and then some of the excitement with this product, which as you say we were hoping would get approved on Friday, but hopefully Monday, I've had some emails and things suggesting that Monday might be the day, so to have this very effective CAR T going to be available with a 98% response rate is actually truly amazing. And so, great presentation.

If you don't mind, Tom, if you can take a few minutes now and just, if you can scroll through the chat box, and so when we get to the question period at the end you'll have picked out some of the ones that you think would be the best for us to discuss together, that would be tremendous. But let's move on now to Dr. Saad Usmani who will give the second talk on the immune therapies.

As I was indicating Dr. Usmani is now the chief of the myeloma service at Memorial Sloan Kettering Cancer Center in New York, and has done, as Tom mentioned, quite a bit of work in the immune therapy area, and has been very much involved in bispecifics, specifically Teclistamab, but the whole range of monoclonal antibodies and immune therapies. So please welcome Dr. Usmani.

- Thank you so much Dr. Durie, and as always Dr. Martin did a wonderful job with his presentation and kind of set the stage for me to discuss some of the novel therapies including bispecifics that are coming down the pike in multiple myeloma.

And going on with the same theme, I think the next five to 10 years are going to be very important as we learn how to use these newer therapies, and potentially combine them together in finding curative strategies for a subset of our patients, and this all goes along with that theme of sustained MRD negativity. So having said that, I'll just share my disclosures, and this is what I want to discuss.

I recall many of us presenting data on the frontline treatments in myeloma and how that landscape of first relapse is evolving, and that landscape will now continue to evolve as we get quadruplet therapies in the frontline setting, and two drug maintenance treatments in the post induction post transplant setting. So, as patients are getting to the first and subsequent relapses the options for treatments we have to bear in mind that prior exposure, and so, newer therapies are going to be required, I think there's a lot of promise that the immunotherapies pull from that perspective. So, with that being said, I'm just looking at my clicker here, to see if it cooperates. Here we go.

One of the things that we've been paying attention to is because Lenalidomide has been utilized for maintenance as the standard of care. As patients relapse, the refractoriness to Lenalidomide becomes an important part in our decision making to the therapies that we pick for our patients. So, as patients have subsequent relapses, and have been exposed to the existing treatment choices, we are really relying heavily on investigational options and clinical trials to provide the next best options to our patients. So even this particular slide, so this is taking from the International Myeloma Working Group guidelines for treatment of patients that had relapsed. It's amazing how far we've come with several new options, three drug combinations being utilized for our patients, and a lot of these changes have taken place in the last decade, and there's a lot more work that's being done to even do a better job for out patients based on some of these options.

But when patients do become refractory to three classes of drugs, or triple-class refractory as we like to call it, patients who have had immunomodulatory therapies and have become refractory or resistant, and the disease has become refractory resistant to immunomodulatory drugs and proteosome inhibitors as well as anti-C38 monoclonal antibodies, we don't have many options. And this is where a lot of excitement about Cilta-Cel and some of these other new therapies is coming from, that we need those kind of options for our patients. So it's with those different, those challenges in mind where we have several small molecules that are, that have made their way through clinical developments as well as antibody drug conjugates, as well as bispecific antibodies, and CAR Ts of course, and the CARs, Dr. Martin has covered very nicely but I'm going to touch upon each of these different small molecules, maybe a little bit about the antibody drug conjugates before talking about this bispecific technology a bit more.

So starting off with the small molecules; all right, here we go. So, Selinexor is an oral selective inhibitor of nuclear export, that's a mouth full. But what this oral export inhibitor does is it's able to shut down a receptor, or an export protein in the nucleus of cancer cells, and it helps in overcoming this escape mechanism that cancer cells have, for cell cycle arrest. So all the natural cells in the body have a certain timeframe in which they live, and then they are supposed to either divide or die. And cancer cells can evade that.

And so in myeloma you have this over expression of this protein on the surface of the nucleus that enables the cancer cells to escape that cell arrest and apoptosis and what Selinexor does is block that nuclear export protein and reverses that process, so it inhibits that onco protein from being translated, and then activates, reactivates, the steroid receptor signaling in the presence of Dexamethasone, so that's kind of the mechanism of action of how this molecule works in myeloma.

And even though Selinexor has been FDA approved, as part of myeloma therapy for the triple class refractory patients, when it first came out, one in four of the patients benefited from it, but what we clearly realized is that if you give it too frequently in higher doses, patients don't tolerate it well, and so what we've done since that initial experience is combine Selinexor with proteasome inhibitors like Bortezomib and Carfilzomib, and giving it less frequently in lower doses, and we've found it not just to be tolerable in earlier lines of treatment, but also efficacious. So the Boston trial was a proof of concept study that looked at the combination of weekly Bortezomib being given with Selinexor, and showing that it's active and more efficacious compared to Bortezomib and Dexamethasone, even though Bortezomib and Dexamethasone was being given twice weekly on the control arm of the study.

Now many of us prefer using, and this is, Selinexor is available, it's approved by the FDA for earlier lines of treatment, but many of us utilize Selinexor with Garfilsomeb in our practices for those triple class refractory patients, and some of that early data comes from a paper that was published almost three years ago, where Selinexor was given on a weekly basis, including patients who had prior triple class exposure or refractoriness, showing good clinical activity. And I'd be curious to see, here, when we get to the Q and A portion, of how Mount Sinai and UCSF utilized Cereblon, at Lavine, as well as at MSK, we've utilized more with Carfilzomib. Now the next important class of drugs that's showing good promise is the CELMoDs, so these are the grandchildren of Thalidomide, I guess, because they belong to that same class of drugs as Thalidomide, Lenalidomide, and Pomalidomide, but it appears that the CELMoDs are more specific Cereblon E3 ligase modulators compared to their predecessors, so the two drugs in that class are Iberdomide and CC480.

The way that I explain this to patients is that proteosome is like the garbage disposal system in your kitchen. So things that when you're washing your dishes and getting rid of the food that hasn't been used, it goes down, and the garbage disposal chews it out, well proteosome breaks down unused protein inside any cell, into smaller peptides and amino acids, and those smaller pieces can be then utilized by the cell to manufacture new proteins that the cell makes. Myeloma cells make a lot of protein, so if you block this mechanism of action, you can kill the myeloma cell, and that's where this whole mechanism of proteosome inhibition, as well as Cereblon, E3 ligase that kind of partners with that mechanism, this E3 ligase complex tags the proteins that need to be broken down, by the protein, so if you mess with that process, along with the proteosome, you can effectively kill myeloma cells, so that's kind of the mechanism of action. And so for Iberdomide, these data have been presented in the past by my colleague Dr. Sagilonial as well as Dr. Neilswendinong, at previous ASH and ASFA meetings. Iberdomide has demonstrated good clinical activity in about a third of patients with triple class refractory disease, in combination with Dexamethasone, and now has been combined with Daratumamab as well as with Rotisamab in subsets of patients with advanced relapsed refractory multiple myeloma. Showing that the safety profile is something similar to what we've observed with the predecessor immunomodulatory drugs, so we're not seeing any new safety signals, we expect these patient populations who've had a lot of prior therapies to be more susceptible to infections. Interestingly no incidents of traumatic events were seen, something that we have come to observe with immunomodulatory drugs.

And in terms of activity, we do see higher than expected response rates in heavily exposed and heavily refractory patients, there are patients in the Daratumamab cohort, as an example, who were image refractory, as well as Daratumamab refractory, but with a combination we're seeing a response rate of 42%, including those patients leading time to response being about four weeks, or within a cycle of treatment, in the Bortezomib cohort, again, more than half, more than a third of the patients with IMID refractory, more than half of the patients with proteosome inhibitor refractory, so, despite that fact we've seen an overall response rate of about 61%. So, it doesn't appear as if combining Daratumamab or Bortezomib with Iberdomide show any major issues with the pharmacodynamics of Iberdomide either.

So, we'll hopefully get more data about this particular small molecule of immunomodulatory, or CELMoD in later congresses, in 2022. But these data do look promising for our triple class refractory patients. And then CC480, it is similar in terms of the structural backbone to the immunomodulatory drugs, but it has a higher ability to direct cell kill compared to Lenalidomide, and Pomalidomide, so, its mechanism of action is a bit more direct, and this is where many of us feel that for our more high risk patients, I think, where you have more proliferative disease, the CC480 may actually be a really good drug. And what we've seen in the early phase one clinical trials when combining with Dexamethasone, I'm just going to skip over that design and just go here, is with the recommended phase to those, which is labeled here RP2D, more than half of the patients are responding to CC480 when combined with Dexamethasone. So seven of the 11 patients in that group were triple class refractory, and of these patients we had patients who had CRs, BGBRs, and PRs in this patient population. So early data, small number of patients, but very promising.

Small molecules such as Venetoclax have been shown to be efficacious specifically for translocation, 1114 patients in the relapsed situation, and BCL2 is a pro-apoptotic, or pro, cancer cell death protein, that when over expressed leads to cancer cell survival. So, when you block this protein, you can kill the myeloma cell. So there are about one, one in, I should say 15 to 20 out of a hundred patients who may have this translocal, who may harbor this translocation 1114, and so Venetoclax becomes an important potential option for these subsets of patients. And we have seen good clinical activity of Venetoclax on its own, as well as in combination. So, the single agent data has shown to be active, but then it also combines very well with Bortezomib and Dexamethasone, as well as with Carfilzomib and Dexamethasone. Specifically in Bortezomib combinations, what we've seen in the Bellini trial, is higher percentage of patients getting to a CR and MRD negativity in the translocation 1114 subgroup, compared to the standard of care Bortezomib and Dexamethasone, so again highlighting that the high level of efficacy that we get in this subgroup. And again, compared to the Bortezomib combinations, my clinical experience has been more with the Carfilzomib combinations in more advanced relapse refractory myeloma patients, and I've been very impressed with the activity in our BI IMID Daratumamab refractory patients, either with single agent or Dexamethasone combinations of proteasome inhibitor combinations, and we also now have data with Daratumamab that is showing to be efficacious. All right, so I'm going to switch gears a bit and start talking about some of the BCMA directed bispecifics; so what is BCMA? B cell maturation antigen is what BCMA stands for.

It's a very popular target, Dr. Martin has already given a wonderful explanation of how CAR T cell therapies work and we manage our patients, but then we have a bispecific B cell engagers, and bispecific antibodies, and antibody conjugates, that are being, that are identifying BCMA on myeloma cells, and helping take those cells out. And that's kind of how we're approaching some of these strategies right now. But there are other targets that are under investigation, such as GPRC5D, FCHR5, et cetera. Trying to do similar things for more advanced myeloma patients. I'm sorry I'm struggling a little bit with the clicker here but let's see if I can move this along.

Okay, so Belantamab Mafodotin is an antibody drug conjugate, so it's an antibody that recognizes this surface protein on the myeloma cells called BCMA, but it has this toxic payload called MMAF that it can deliver to the myeloma cell and then that leads to the myeloma cell killed because this toxic payload, or cytotoxic drug can disrupt the microcubials inside the myeloma cell, and that leads to the myeloma cell death. And even though it's active in about a third of the patients who get it, one of the key issues is that patients can get eye side effects with it, which are reversible, but can be a big nuisance. So we tend to, if we're treating patients with Bela-maf we're also having them see an eye professional. And this is where the excitement about the bispecific antibodies, or the bispecific T Cell engagers comes into play. So what these cells are trying, these strategies are trying to do, is something similar. But the bispecific antibodies are full antibodies, as you can see from the structure on the left side of this figure, it's one part of the antibody can recognize the surface protein on the cancer cell, the other part of the antibody can recognize the T cell and brings the T cell to the cancer cell and then the T cell takes the cancer cell out. What the bispecific T cell engager does is the same thing but it's not a full antibody, it's only comprised of portions of antibody, so that's why it's called bispecific T cell engager. 

Essentially both of these strategies are what we call T cell redirection, so we are redirecting the T cells to recognize the cancer cell and go after it. So, there's several bispecific T cell redirecting strategies that are in the clinic, in clinical trials, Teclistamab, Elran, TNB38, and Regeneron are perhaps the ones that are farthest along in their clinical development. In fact Teclistamab has been submitted to the FDA, for potential approval later this year, so all of our, extremely excited about that particular bispecific antibody, Elran is a little bit farther behind but if you look at the clinical activity of each of these therapies, it's in the range of about 60 to 70%, which is extremely, extremely impressive.

Just six or seven years ago, when we were hearing about, or in fact I should say about 10 years ago when we were hearing about the clinical activity and relapse refractory myeloma of some of the newer therapies, such as Carfilzomib and Pomalidomide, the percentages used to be like 20 to 30%, so with some of these therapies, the immunotherapies, it's really impressive to see patients having had multiple lines of treatment and seeing such higher rates of responses. And Dr. Martin had already discussed that as we're redirecting these T cells, just like with CAR T cell therapy, we do see cytokine release syndrome, in these patients.

In fact, the Regeneron product, it's early data but it's probably seen the less amount of CRS, but unlike the CAR T data, all the cytokine release syndrome that we see is only grade one and two, and it's managed very nicely with supportive care measures, sometimes using Tocilizumab and steroids, but grade three, or more serious CRS, is quite negligible across each of these different bispecific T cell redirection strategies. And ICANS, which is neurologic side effects that Dr. Martin touched upon with CAR T cell therapy is essentially negligible, grade one or two, but we're not seeing any grade three or four kind of side effects here. So, really encouraging data with each of these four, and while we are super excited about Cilta-Cel potentially getting a nod from the FDA for approval, again I feel that several of these bispecifics will not be far behind in regulatory approval. In fact again I'm really excited about Teclistamab as well.

All right, I think that was my last slide, I'd like to thank my team at MSK, my service members as well as our transplant and cellular therapy program, and I'm going to hand things over to Dr. Durie, and we thank all of you for your attention and for your support, and for the chase for the cure for multiple myeloma. Thank you so much.

- Thank you so, thank you so much Saad for this wonderful update of the range of relapse therapies that we have right now, from the small molecules to the different types of antibodies, and so, great, great update, very exciting, and so we have possibility for CAR T approval on Monday, and maybe Teclistabmab later in the year, but with many more following on behind.

So, we have quite a bit of time for Q and A, and a lot of questions have been coming in, so perhaps we can start with the CAR T Tom, have you had a chance to scroll through? There's a number of different types of questions. One type maybe that you can answer is obviously CAR T is going to be approved in the relapse refractory setting, but we keep saying, well it's gonna be great to use it earlier, but actually how do you see that evolving? We won't be able to give Cilta-Cel to the earlier patients yet, but number one we certainly do think it's gonna work better earlier, although it works pretty well in the relapse setting, are there trials coming along where a patient could potentially get it earlier?

- Yeah, thanks Brian for the questions, and for all the, for the audience, you guys have put in quite a few questions, and they're really great questions, so that's awesome.

- [Brian] Yeah so feel free to go through them, Tom.

- Yeah, so I'll go over a few, and that is some people asked about which line of therapy in our patients cured, and we can't really say anybody's cured yet from CAR T cell therapy, we have to follow them over time. I have patients that received Idasel more than three years ago and still remain in remission, and this is without maintenance, no maintenance based therapy, and the Cilta-Cel study happened later so I have patients that are now over two years after Cilta-Cel and remain in remission, so again it's promising whether they're cured we'll just have to follow a time, but when something works so well in the relapse refractory setting, we do wanna bring it into earlier lines of therapy, and there was data at ASH in patients receiving one to three prior lines of therapy, and the overall, there's only 20 patients reported and 19 out of the 20 had response, so the response was 95%. And when you do it in earlier lines of therapy, again, it's not just about the response, but how long does that response last? And so we just need to follow those patients longer to see if they can get a single CAR T cell therapy, and then after that be without maintenance, without any other therapy, and stay in remission for years and years, which is what we hope.

There's a lot of questions also about maintenance, why no maintenance after CAR? It's a great question. CAR T cell therapy does have some cytopenias associated with it afterwards, so we've been a little reluctant to start maintenance when patients have some cytopenias, but you will see data, and you will see in the future patients receiving maintenance therapy after CAR, and it might be with some of the new agents Dr. Usmani just talked about, some of the cell mods, Iberdomide, everybody thinks potentially could be a great maintenance therapy 'cause it might continue to activate the CAR cell. And I think we all wanna combine these therapies together, like we can give a BCMA targeted CAR T cell therapy, and then after that as maintenance maybe we give a different target, a GPRC5D bispecific antibody as maintenance, so I think that'd be kind of interesting, but we have to do the studies.

Some person asked, well said, the FDA can't dictate medicine, why can't we just give it to everybody newly diagnosed? Well the truth is, is we have to prove that it works in that space, and then the FDA gives us approval to use in the space, and then insurance will pay for it. These are gonna be very expensive therapies, and so we have to wait for the FDA to give us the okay, and we also have to wait for insurance to say that they are gonna approve it.

The other question was about grading of CRS and some neurotoxicity questions; the majority of people at CRS had grade one to two CRS, that's 90%, so either low levels of oxygen needed or mildly low blood pressure, and again those patients essentially resolved, there was only 5% of patients that had more severe therapy, but in the Cilta-Cel study, 99% of the patients responded to their therapy, and then the CRS resolved. In terms of neurotoxicity about 10% of it was grade three, or greater, which is serious, where patients have serious side effects. And one patient as somebody pointed out in the chat, one patient actually died in the Cilta-Cel data from, at Mount Sinai, from neurotoxicity from Cilta-Cel. And what they found in Mount Sinai is that there might be BCMA expression in the brain.

And was that really the reason why that person had neurotoxicity? I would say we need more data before we can conclude that, but I think honestly earlier treatment of any of these side effects hopefully is gonna preclude the more severe side effects from happening. I think that was, that was the gist of it, Brian, I don't know if you have any others, or Donna wanna add to?

- Well, one thing maybe you can touch on, which is, the access issue. I think that there's been concern that with Abecma, there have been access issues, and now we have a second CAR T getting approved, so what's your best guess about access moving forward?

- Yeah, that is the million dollar question.

- Oh you moved up the dollar amount now.

- Yeah, exactly, I suspect that Sinai, and MSK even have longer wait lists than we have. We have many patients on a quote unquote a wait list for CAR T and we're just not getting a lot of slots, because manufacturing is a big issue, it takes space, it takes time, and it also takes that vector, that HIV vector to insert the gene into the T cells, that vector's in short supply. And so the more CARs that are approved for use in myeloma the more slots we're gonna have available. So we have hopefully two approved by Monday, and hopefully we'll have three or four within the next couple years so that we have better access. Access I completely agree is an issue.

- Saad do you have any, Saad or Donna, do you have any comments about that so far? I know everyone I talk to the access for Abecma has been so tricky, allotments of one patient a month, things like that.

- I agree, I think that those challenges are shared across all the centers in the US, and I think, Janssen, with this second product, have been a bit more proactive in engaging the sites and having realistic expectations on what to expect, and so, I think for many of us, when, Idosel had rolled out, we were thinking that we'd be able to get slots right away, and we had these long wait lists. I think that expectation management is hopefully going to be better, but the antiviral supply chain issue I think is not going to get better right away, so it will still be, it will still require logistic management on the Cilta-Cel commercial team's part, I guess. Yeah, but, they're much more engaged than the Idosel, rollout, I would say.

- Right, right, right. And I guess we don't wanna get into it too much, but the new data, the Cartitude data presented at ASH by Tom, with a 98% response rate, and the excellent results with the two year followup indicate that this product is doing a great job, and potentially it is a little better than the Idosel, I don't know, I mean, what's your guys' sense of that? I mean it may be too early to know, but it certainly is quite promising for these new data.

- Yeah I think Dr. Ninashad calls it the secret sauce, right Tom?

- Sorry?

- Yeah, so, again, for Cilta-Cel data, I mean all of us are very impressed with what we're seeing, and we can hypothesize the scientific rationale of why we're seeing it. Dr. Ninashad calls it the secret sauce, that maybe Cilta-Cel has the secret sauce.

- Okay, maybe we can leave it at that for now, the secret sauce factor is maybe adding in a little bit.

- Yeah, I do think, so, hopefully we are gonna be able to tell early after CAR T cell therapy who seems to be the best, the good responder, and who may not be the best responder. And maybe it's in the patients that are not the best responder, in short period, within a month or two months after the CAR that we could then add maintenance to those patients to try to make those CARs better and work, work better and live longer, et cetera. But yeah that's, it's hard to know, 'cause I do have patients that got Idosel and are more than three years out, and remained in remission, haven't had any therapy since.

- Yeah so, likewise, yeah, so I think that time will tell. So then in the bispecific area, so that we can get, and also the other agents that you discussed Saad, so, if we touch on the bispecifics first, there was one question, just a basic question, is there a preference between an engager and just a bispecific? It's a slightly different molecule. Is either one of these mechanisms preferred? Or are they just kind of equivalent?

- They appear to be equivalent, in terms of efficacy as well as the safety profile, that's what we're seeing in all the experience so far. So I don't think there is benefit of one over the other. I think the route of administration would be an important piece, and many of these other, now being actually developed as subcutaneous.

- Right, right, right. Okay, and then, some of the other agents, the CELMoDs, the 480 product data, that seems to be especially promising, so, in that category, how do you see, it's interesting you got the two CELMoDs, the Iberdomide and 480 moving forward together, but the 480 it looked quite good, I have to say. Do you have a preference there, or what's your thinking?

- I'm thinking, I like, I think the way that they're being developed, it's a little bit of a staggered development, I am very impressed with what I'm seeing with 480, especially with some of the combination data that was shared at ASH. And knowing that high risk patients still don't have a good standard of care, I do feel that evaluating 480 in some of the higher risk subset patients who have extramedullary myeloma circulating plasma cells would be a very important clinical investigation that we need to do. I'm impressed with both, but I think 480 will probably play a more significant role for the high risk patients.

- Thank you; yeah, actually maybe we could touch on that, that was a question earlier about the management of extramedullary disease, and I do think that all of those agents have shown activity, I know CAR T and bispecifics have shown activity for extramedullary disease, right? Tom, you wanna comment on that? I mean I think that the number of patients I know have had great responses in that category.

- Yeah, absolutely, there were a fair percentage, 15 plus percentage of patients on Cilta-Cel that had EMD, and again the response rate was 98%, so most of those patients actually had a response in their extramedullary disease. I think, we've had a little bit of a bias that the CARs are better at EMD than the bispecific antibodies, although I do have quite a few patients now on a bispecific antibody therapeutic and are basically having nice responses in their EMD sites. So I think more data's needed, those are the type of patients in my mind that we might eventually do a combined approach, so maybe they get a CAR and then followed by a bispecific to a different antigen.

- Right, right; so the difference between some of these antibodies like the bispecific and CAR T is the CAR T is that you have the one and done, and then obviously with the bispecifics you have ongoing therapy, and Teclistamab, as you said Saad, is already moving forward for approval, but that will be in an open ended setting, there won't be like six months of therapy or something like that?

- You're right, I mean that's how the approval will come in, but we're already thinking about less frequent dosing, and even potentially stopping therapy in some of the patients who've had sustained response. And I've brought few of anecdotal experiences in other patient seminars, and I'll share one with you here. So, I had a patient who was on Teclistamab, they had responded very nicely for a few cycles and then the pandemic hit, and they had a prior history of getting pneumonias, and upper respiratory track infections, and treatment was interrupted, and the patient decided not to continue Teclistamab. And they were already nearing a CR, they got to CR and we checked MRD negativity and they were MRD negative at 10 to the minus six, at that time. And that was almost two years ago. And they're still off treatment, they're still off treatment and this was their 15th line of treatment.

So, I'm sharing this anecdote as an example of how T cell redirection can work, and if you get to a good response, there might be patients where you can discontinue bispecifics, so I think, just like Tom mentioned earlier in a response to a question, can we deescalate treatment if someone gets to MRD negativity, post induction? I think the same kind of things will apply to immunotherapies in the relapse setting, so. Sorry about the long answer I just wanted to give an example.

- Yeah, so it would be, that's very interesting and helpful, so I think it would be cool if a more limited course of therapy, especially if you achieve an MRD negative, or excellent response, then you could stop and then maybe retreat. And I guess that's become more of an issue when ongoing therapy predisposes you to COVID infection, or having a low antibody responses to vaccines and the like. So, ongoing therapy does put you in a little bit higher risk category, so it's become an extra consideration. There is a question here that someone wants you to explain how the bispecifics are given, so maybe you could just touch on how that's evolved with the IV and the subcue, Saad.

- Certainly, so initially the bispecifics were being utilized, or being developed in the IV formulation, but the bispecifics are concentrated enough and have a smaller dose than some of the naked antibodies and can be formulated into the subcutaneous formulation, fairly easily, so the administration is much better, it's faster, there are no, additional ingredients to the subcue formulation, like with Daratumamab we had to combine it with the recumbanant high lude onadase, that's not the case with the bispecifics. So Teclistamab, Delkeetamab, I think Elran, as well as ABV383, all of those are being developed in the subcutaneous formulation. It's, I think that, in terms of infusion related reactions or rather epostration reactions, that's not a major concern, and it's very convenient. That's been my experience, Tom, what do you think?

- Yeah, I do think, the bispecifics are gonna get more and more, I'd say convenient for dosing. Right now with the trials they vary between IV or subcue weekly to every three weeks, but like you said, Saad, we're gonna go to every four weeks, every six weeks, maybe every eight weeks, or sometimes, maybe we just do it four times a year, every three months. Or people who achieve MRD, sustain MRD negativity for six months, 12 months, or longer, we stop. I totally agree, we need to get to a point where we could take people off therapy.

- Yeah, I think it's gonna be an important, an increasingly important consideration, both in terms of myeloma benefit, but also having an ability to reconstitute the immune system, in fact there's actually a, one question is does autologous stem cell transplant suppress the immune system for several months? And Tom you really already addressed that in saying that you give Evusheld to patients, right? After autologous stem cell, as well as CAR T, right?

- Yeah, absolutely, and somebody's asked can you give CAR then an auto? Or an auto then CAR? And there's gonna be study in high risk patients where they get an auto followed by a CAR, we'll see what happens there. My hope is that we won't have to use the auto transplant, we don't have to use the high dose Melphalan, I think high dose Melphalan is the association with secondary cancers, and I think we have to hopefully get to a point where we don't have to use high dose Melphalan anymore.

- Right, right, I would agree with that. Okay so we've actually reached the witching half hour, so maybe what I can do is ask each of you for any final comments, I think that we're pretty excited about the future for myeloma, and it's a new frontier as Tom mentioned for his talk. Actually maybe before, just, one last question just came in which is what is MRD negativity? Which is obviously quite important, so minimal residual disease, so we have testing right now of the bone marrow to see if any myeloma is left behind. You can use this with an immune flow method looking for myeloma cells, or you can use a molecular technique, and we talk about 10 to the minus five, 10 to the minus six, and this is saying if you check a million cells is there one myeloma cell there or not? But basically it's looking for very, very low levels of disease which is incredibly important with these much, much better therapies, and it's really good news that we have to be doing this because we're having such great success with many deeper responses. So Donna, any closing thoughts from you? For our listeners, for the patients, and caregivers? Oh, you're muted.

- Okay, sorry; so I know CAR Ts and bispecifics are very exciting, and I know there's a lot of frustration around availability with CAR Ts, but I think bispecifics might be an answer for some patients who can't get access. And also I wanna just close with clinical trials, the reason these drugs can come to market is because of clinical trials, so really the clinical trial is offered, it's a good option for patients to get access to these novel therapeutics.

- Right, I mean I love that point, Donna, I mean it does give early access to that patient, but also it allows us to learn and understand the efficacy and possible side effects, so clinical trials are so important, and we've been so fortunate in the myeloma community is that there's been such enthusiasm and motivation to jump in and participate, yes, so thank you for that. And so Tom, some final words of wisdom?

- Yeah, I will hop on that same bandwagon with the clinical trials, and there's been a lot of questions in the chat. We, honestly, we do the clinical trials because we think we can do better than what's standard practice at the current time, and most of the, almost all trials, or no trial right now is randomizing patients to a placebo where you have a chance of being harmed, that does not happen whatsoever. And these trials, when to participate, whether you're on your fifth line, sixth line, 10th line of therapy, or whether you're newly diagnosed or on your first relapsed line, we have trials for every patient and every scenario, including smoldering myeloma.

Your participation in these trials really makes it important to bring these therapeutics to everybody faster, and that's all that we wanna do. And I will also say, if you're getting a blood test, or if you're getting a bone marrow, and they ask you to donate, if you feel up for it, that also helps us to really define better targets for myeloma, or better ways for us to go at the myeloma and try to kill the myeloma. And lastly, if you're uncomfortable with your doctor or with your, the care that you're getting, seek an opinion at one of the major centers across the country, and the IMF can hook you up with all those centers across the country. There's plenty of them and there's great myeloma doctors.

- Thank you, thank you so much for that, and that one thing you touched on I think is terribly important, and Tom is actually leading an effort which we are calling the virtual tissue bank, where we're encouraging all of our researchers to do the research at their own institutions and try to have the samples that we can use to study and learn for the future, and that's important, rather than sending samples to somebody else, but then what you can do is you can collect and analyze the results of the testing, and so this is what we call a virtual tissue bank, which we think can be very powerful to collectively study the processing of these tissue samples. There was a question about can we tell which patient's going to be responding by looking at the surface receptors? Well that's the sort of thing we could learn from this analysis, so thanks for that Tom. And so Saad, final thoughts?

- I think both Donna and Tom have shared a very important point, we keep on talking about how the next five to 10 years are going to be extremely important for us to find a cure, the first patients who get to a cure are going to be the ones on a clinical trial. So, again, harping on the same message that this is a partnership, these clinical trials are there for our patients, and if it wasn't for the patients who participated in clinical trials previously we wouldn't have these wonderful options available for the population at large, so, yeah.

- Thank you for that, yes, and it just reminded me and Tom touched on it, we have trials also for patients with high risk smoldering myeloma and I actually did a podcast with the first patient who went into the Ascent trial, which is the high risk trial in the United States which is Daratumamab KRD, and this gentleman is 15, 16 months off therapy, so he completed his two years of therapy, and is now 15, 16 months off, and is MRD negative. And so, doing extremely well.

And so very promising; how long will he stay in remission? These are early days, but we have promising information and these are the kind of patients, some of whom will be the beneficiaries of that exciting new approach which turns out to work really well. But we're seeing that it's effective, and this patient experience where they're in remission and off therapy for 15, 16 months, this is especially attractive, and this particular gentlemen was almost giddy with excitement, because it was the first time that he'd been off therapy for that long for all these different years of treatment, so that is a very excellent aspect of this.

So, anyway, this has been a great session, covering a lot of ground, a lot of good questions, and we are happy and keen to follow up with everyone. Thanks to, excellent, excellent panel today, you learned so much clear and important information. We thank our sponsors that you have on the screen here, Amgen, Bristol Myers Squibb, Genentech, GSK, Takeda Oncology, and Janssen, that we are partners together, they are developing agents and we are so keen to try to move forward quickly towards these approvals that we've been touching on.

So, thanks to everyone for joining us today, thanks to our speakers, and we look forward to your continued participation and involvement in myeloma action month that we talked about, here again, and many other activities of the myeloma community.

We are so blessed that the myeloma community is an active community, and so we are very proactive and, we're a noisy community, and it makes it easier to get action and move forward strongly together. So thanks to everyone, have a great rest of your day.