Dr. Brian Durie:
Thanks so much, Meghan. And just to say that we have had some questions that came in ahead, and there are two or three questions that have come in before we've said anything here actually. So, there will be an active discussion, I believe. And so it's my pleasure to try to set forth what one could call the big picture for myeloma. In other words, what is the expectation for a patient with myeloma in 2023? And to do that, I will touch on the subjects that you'll hear about later from Ann and from Rafat and Saad. Welcome to Saad. Sorry, you weren't here when I introduced you earlier. So glad you can join us.

So, I will be just touching on what we can expect with frontline therapy in a big picture way, what we can expect in terms of outcomes, what are the big picture expectations for all of the new therapies, and perhaps most importantly, how to really track and follow how all these various treatments are working as you proceed through the myeloma journey. So, what can we say about myeloma in 2023? What we could say in California, if you're very lucky, you have lots of fantastic sunsets here out over the ocean. And so when you're doing well, there is a lot to enjoy out here in California.

But not only that is a good outlook, but really in the big picture, I think that for patients, certainly newly diagnosed patients, it's pretty clear that long remission is really an expectation these days rather than what used to be something that was rare. With the frontline therapies you're going to be hearing about and then all of the backup therapies, that first remission is likely or could well be a very long one, meaning four, five, six years or longer. And even with some aggressive approaches and combinations, it may be that even a cure is on the horizon, which is getting closer and closer to reality.

And so the other important thing is that we are approaching the treatment for myeloma much earlier than we ever did in the past. Diagnosis tends to occur early and even screening can lead to diagnosis, which is a part of a number of research projects now. And so we start the discussion, what should we be doing even earlier than we used to do in the past if someone has high-risk smoldering myeloma? And this means smoldering myeloma where we think there's a chance that it could progress within one to two years, this is what's called high-risk smoldering myeloma, and we talk about whether or not we should watch or perhaps intervene early.

And so we start with this, what we call an algorithm for patients with potential new myeloma or smoldering myeloma. This is where discussions begin these days in 2023. We're looking to see obviously if there are what we call the CRAB features. And these are the traditional features of myeloma, where the blood calcium could be elevated, where there could be renal or kidney problems, where there might be some anemia because of the buildup of myeloma in the bone marrow, and actual bone damage because the myeloma growing in the bone marrow can damage the surrounding bone. So, these are the CRAB features, and certainly in the past many patients had one or more of these features. However, these days we will consider starting treatment earlier if the percentage of plasma cells is higher, in that 60% range as you can see in that box on the left there. If the free light ratio in the blood, which is the level of light chains in the blood, if that's elevated, or if an MRI or some other type of imaging shows more than one lesion in the bones.

And so these are early things which can be myeloma defining events. And as I was saying, even earlier, if someone has high-risk smoldering myeloma, there could be an idea to intervene and really try to achieve the best outcome. And so it's important to realize that things have changed so much in the last 15 years, and it's clear will change even more dramatically probably in the next five to 10 years. And so 15 years ago we still talked about chemotherapy. And actually one of the questions that came in is, "When you start treatment, does it always mean chemo?" Well, actually, chemo in the traditional sense, the old sense of chemotherapy that made you lose your hair and have all different kinds of side effects, is mostly a thing of the past for myeloma patients now.

It's still used in other kinds of cancer like breast cancer, lung cancer, and the like. But for myeloma, we've really moved from what was a relapse therapy 15 years ago using Velcade, bortezomib, and Revlimid, which is lenalidomide, that has moved up into the frontline setting and that is not a chemotherapy. And this is actually based on the 777 SWOG trial, which Dr. Abonour will talk about in a little more detail later. And this was a trial in which the Velcade/Revlimid index was compared with Revlimid index to see if three drugs were better than two drugs. And so let me just say that we'll be trying to touch on what all these different drugs are as we go through. Next slide.

And so with this particular study, the most important finding was that the length of the remission, which is in the left graph here, the PFS, this is what's called progression free survival in terms of the number of months, and that is the length of the remission. And if you look at the red one, you can see the top one there is for patients who are under the age of 65 and the length of that first remission is 48 months. It's four years with that first remission. In fact, this may be one of the longest lasting trials ever in myeloma, because you can see these lines are still continuing off to the right and patients are still actually on this trial and continuing to be monitored, with an overall survival which is remarkably good, with you can see over half of the patients in these groups doing well beyond 72 months. So, remarkably good results with what is not chemotherapy.

And so the big picture is that we've moved from chemotherapy to using something like that therapy. And there are a lot of options you are going to be hearing about. That VRd, Velcade Revlimid index could be given with a new medicine called Daratumumab, you'll hear about. And now what we have is we're looking at new things which are currently in the relapse setting, which is CAR-T and bispecific monoclonal antibodies. And what we're going to be hearing is what will be probably the next transformation where those therapies will be moving forward into an earlier and even an upfront setting is the way things are going to change.

And that change will include ideas about whether or not patients should still be having an autologous stem cell transplant. And there've been two trials with that, which Dr. Abonour will talk about, where patients received that VRd with and without transplant, and they also had lenalidomide as a maintenance. And in that setting, the big thing that showed up actually is that transplant does make a difference in terms of the length of the remission. And what's shown here is that whether or not you stay on maintenance makes a difference. Patients who stayed on the lenalidomide as an ongoing maintenance actually stayed in remission significantly longer, with a median survival over five years in the Dana-Farber study, with a little bit less than that in the French part of the trial. But the main thing is that the patient receiving upfront transplant did have longer remission.

And Dr. Abonour will talk about, is that sufficient to say that patients should still be getting the transplant? And that'll be an important part of the discussion. Should patients be also getting Daratumumab along with their VRd? This is a GRIFFIN study where half of the patients did get Daratumumab along with their VRd. Daratumumab is a monoclonal antibody against CD38 and is a very, very effective treatment. And you're going to be hearing a lot more about that as we go forward. This GRIFFIN study shows that if you take the Daratumumab then you're more likely to have a deep response, which is those dark blue curves on the left, versus the green ones on the right, with almost a 20% difference there in the deep responses over time. And so taking Daratumumab, four drugs versus three drugs, may be the way to go, and we'll talk more about that.

But what is perhaps the most exciting, and Dr. Usmani will talk a lot about all of the different exciting immune therapies, but I think what caught people's eyes at ASH maybe two, three years ago now was the CAR-T cells, the engineered CAR-T cells, immune therapy where T-cells are taken from patients, engineered to attack the myeloma, in this case the B-cell maturation antigen on the surface of the myeloma, BCMA. And with a staggering 97.9% overall response rate in patients with relapse refractory myeloma. And so this really drew to attention the fact that CAR-T cell therapy and now many of the other very, very active bispecific and other immune therapies can have a huge impact. And we just are waiting to see who will be the ideal candidates and what will be the impact as we move these earlier into the disease course.

And so during the rest of the session today, we're going to be talking about all of the different active drugs that we have for myeloma. And this particular slide I suggest can be a cheat sheet for everyone. It's got a listing of all the drugs. It's got the ones in black which have been approved by the FDA. And so on this particular slide over on the left you have the old chemotherapy type drugs, Melphalan and Cytoxan, that we don't use that much anymore. Steroids, dexamethasone and prednisone, which we do use. And then the Adriamycin, which is a drug that many of you probably have never even heard of that we used to use in the past.

IMiDs we still use frequently, the lenalidomide or Revlimid being the main one that we use early on with Pomalidomide being used later. And then what we call the proteasome inhibitors, Bortezomib or Velcade as the main one that we use upfront. But also you'll hear about Carfilzomib, which is a very, very important proteasome inhibitor, and Ixazomib as well, which is an oral formulation which can be helpful in maintenance or other settings. Then I think that one of the main boxes is the one in the middle, the anti-CD38 monoclonal antibodies where we'll have a lot of discussion about Daratumumab, which is the main anti-CD38 monoclonal antibody, which is so active. And a very similar drug, Isatuximab.

And then Belantamab in the bottom box in the middle is actually currently been withdrawn on the US market, but we still will have some discussion about that. Selinexor is approved. Obviously the CAR T-cells too, Cilta-cel and Ide-cel are approved. And then Teclistamab, a bispecific monoclonal antibody, was approved. And actually, we're privileged to have Saad Usmani with us, who was the principal investigator that led to the approval of this particular monoclonal antibody. But what you see is about half of the drugs on this slide are in red and we'll be moving forward I think with many of them getting FDA approval in the coming years. And we just are waiting to see what will be the place for these and how big of an impact that they will have. But this is really exciting knowledge for all patients with myeloma.

And you can divide those basically up into the immune approaches and we're going to be hearing a lot about that. But also the targeted agents, the Selinexor, the Venetoclax, and I think maybe you'll hear a little bit about the cell mods, another group of agents. But as we start out the discussion today, I want to emphasize, how do we track if those various therapies are doing a good job for you as a patient? And so we're interested in two types of things. Number one, is the myeloma coming under control and how do we assess that? And what are the side effects or negative impacts of the therapy that you're taking? And this will be a big topic for Ann in her discussion coming up next. And these toxicities can be side effects that we can manage, but they can also be things like the cost of one therapy versus another. Can this be managed? And the logistics of IV treatments, infusions, having to be in the hospital for one therapy versus another.

And so those are very, very important things that will be discussed in some detail coming up. But taking these one at a time, keeping track of your myeloma, the key things are to track your blood counts to make sure that they're not dropping down because of the impact of the therapy. That means your white blood cell count as well as your hemoglobin and your platelet count. And that is done every time that you go in to see the doctor for a next treatment. But the key testings are SPEP and UPEP. This is the serum protein electrophoresis and the urine protein electrophoresis. If your myeloma protein happens to be in the urine, sometimes it is only in the urine, but sometimes it's both in the serum and the urine. But these tests tell us the amount of the myeloma protein in the blood and in the urine, and that's how we can tell if the myeloma is still active and the percentage that it has improved as you go through your treatment cycle.

One of the amazing things about these new therapies that we have with Velcade, Revlimid and Dex, or especially with for example, Daratumumab, Velcade, Revlimid and Dex, there is a dramatic response where in the first one, two, three months, these tests will show that your myeloma protein has dropped not just by 50%, which would be enough to call it a partial response, but maybe a very good partial response or even into a complete response. And Dr. Abonour will talk about looking for evidence of minimal residual disease when the treatment has been dramatically effective. We also look at free light levels in the blood, which indicate the level of the myeloma. And of course we do scans. We do MRI, X-rays, whole body CT, PET scanning to see where is the myeloma, what is the extent of the myeloma, and is it responding to treatment? And fortunately we do need that bone marrow for the initial diagnosis, but we don't routinely need to check the bone marrow unless there's some doubt about the status of the myeloma.

We can rely upon the levels of the proteins in the blood and the urine mostly to guide us in terms of how are you tracking with your myeloma. When you get that initial bone marrow done we are interested in chromosome testing, which is called FiSH testing, fluorescent in situ hybridisation, and we're looking for particular things. This t(11:14) is one in particular where we have a medicine, Venetoclax, which you'll hear a little bit about, which can work specifically in that situation. We're also interested in high-risk myeloma where there is a tendency to having shorter remissions, and that is indicated by some other chromosome changes, particularly chromosome 17 and chromosome number one. As a patient, what you'll hear about from Ann is that you do need to be in close touch with your myeloma team. I'm sorry, Ann, I should have put nurses as well as doctors on this particular slide here. I'm so sorry about that.

But you need to alert your team to what's going on. Are you having any side effects, any problems? So, the adjustments can be aware. And I think that having ongoing discussions is very, very important. If things are going well, that's great, but if the things are not going well, you need to be aware and have some ongoing discussions about what would be some future options. At what point do you maybe need to get an expert opinion, to get some new advice? So, be proactive about that. Be aware, does your center have possible clinical trials, some new therapies available in a trial that you could have access to, or where would be the closest place that you might need to go? And just to be thinking about that and set expectations with your current therapy as well as thinking about what would be happening for the future.

And the good news is, as I've been saying from the beginning, is that the key thing for myeloma patients to be aware of is that there is a future. That first remission quite likely will be a long one, four or five years, even longer. And with all of these backup therapies, there's likely to be several future maybe long remissions as well. And so understand these expectations with your primary doctors and nurses. And so I'll stop there for questions and comments. So, thank you for your attention.

Okay. So, "Does your definition of a cure mean very long remission, albeit possible side effects and continuation of drugs or does it mean finding the cause of the myeloma and eliminating it?" Well, we can all talk about that one. So, the definition of a cure is actually rather tricky. I would say that there's two definitions. One is where we don't find any evidence of myeloma, and this is MRD negative, but even if we don't find any evidence of myeloma with a particular test, we don't know necessarily how long that might last. But there's also another category of patient where there may be a small amount of myeloma remaining, but that myeloma is not active and this is almost like an MGUS.

And there was another question that came in which was asking, "What is this MGUS-like app?" And this was a new thing published by the Spanish group where they indicated how we can diagnose patients who are likely to be MGUS-like. So, they maybe have a small amount of myeloma left, but they can be stable and maybe something that we could describe as a functional cure where they're not having any problems even although we can find a little bit of myeloma left. Maybe I can ask my colleagues, what did you think about this MGUS-like paper that just came out, and also there's an app that goes with it. Did you guys see that? Maybe not.

Dr. Rafat Abonour:
Yeah. This is obviously a very interesting, exciting tool. I think for a long time, I think the question with MGUS is that, what is the risk of progression? And obviously we know that the risk is quite small to progress to multiple myeloma. So, biologically there is a clone of plasma cells that they just stayed dormant for a long time. And I think the Spanish group tried to say, "Okay, do we have that kind of phenotypes?" And I guess based on a large number of patients they came up with a way to calculate the risk. And I think it's very useful because it may give some comfort to the patient that based on this calculator that your risk is not going to be that high.

And I think one of the most alarming thing about when you get diagnosed with MGUS, and I was in the clinic today and I had several patients that I tried to say, "Okay, this is MGUS. This is what we know about it. Usually it's a benign condition. We cannot say it's a benign monoclonal gammopathy because there is a small risk of continuing to progress. So, we need to keep eye on you." But I think we can use certain criteria to say, "Okay, are you going to progress quickly? Are you just going to smolder for a long time?" So, I think it's kind of useful that way.

Dr. Brian Durie:
Right. So, will you be able to do that at MSK, Saad?

Dr. Saad Usmani:
Yes, I think so. And I would echo Rafat's enthusiasm about this model. And we are entering a very interesting era in cancer medicine, in medicine in general actually, where we'll be able to utilize AI-based platforms to actually dynamically assess the risk. So, I think that's where we are headed and this is our first step, and it's good to have these kind of models available to both physicians and patients and have an open two-way conversation about it as well. No, I agree. I think it's an excellent first step in that direction.

Dr. Brian Durie:
Right, right, right. Yeah. We have a similar effort that will be moving forward in the smoldering myeloma space where we will actually will have a newer one there, an app, which are more of a dynamic model, as you say, where it can be changing over time and the risk will change as patients come in for follow up. Let's see. "When I was initially diagnosed, I diagnosed..." Well, Saad, you may wish to comment on this. Aggressive high-risk. "How is the aggressive high-risk determined and what does it mean with regards to relapse or other health issues?" So, you want to make just a brief comment? You'll talk a little bit about it maybe related to relapse. You want to comment a little bit about high-risk?

Dr. Saad Usmani:
Certainly. So, what high-risk active myeloma means is that patients are at a higher chance of the myeloma coming back sooner than expected. And we have certain chromosome abnormalities as well as clinical features that can be prognostic for that. And what we have started to do now from a treatment standpoint is develop different strategies for our identified high-risk patients in terms of the kind of induction treatment we may give them or maintenance treatment that we may give them. So, that's the key issue. However, I think even the outcome of our high-risk patients has improved quite a bit over the past decade with the introduction of novel treatments. And so I would welcome comments from Dr. Abonour as well because we are really fortunate to now have several clinical trials just focused on high-risk patients and trying to find the best strategy for them.

Dr. Brian Durie:
Absolutely, absolutely. Yeah. Also, two ways to manage them. One of them, again, is what's called a functional high-risk. This is patients where they have actually relapsed within that first year and then you know that there is a problem with a tendency to early relapse. And managing those patients is an important strategy. And as you say, Saad, many of the newer therapies are actually doing a pretty good job for this subgroup of patients.

Dr. Brian Durie:
Why don't you ride off into your talk, Ann, Taking the Reins for Your Care?

Ann McNeill:
Sure. Thank you, Dr. Durie. So in the interest of time, I'm going to get started. As Dr. Durie said, this is an analogy of the horse and the stable and how it applies to myeloma. So we'll talk about the stable of treatment, finding your gait, and going the distance. So the stable of treatment is the treatment options, side effects, symptom management, and supportive care. So treatment goals, our goals for myeloma therapies are rapid and effective disease control, durable disease control, improved overall survival. We want to minimize side effects, allow you to have a good quality of life, and of course with our supportive treatment options, we want to prevent disease and treatment related side effects while optimizing symptom management and still allowing a good quality of life. That's one of our major goals and we always encourage you to discuss your goals and priorities with your team.

So very busy slides. The stable of treatment options, thought the jury hit on some of these. Just showing you the columns. From the left, the proteasome inhibitors, we went to the monoclonal antibodies, then the imides, steroids, alkylating agents, immunotherapy, some others that don't fit a definite category, and then the cellular therapy is all the way on the right. So just showing you the drugs used in frontline maintenance and relapse setting in these categories. Some of them are FDA approved, some of them are not. Actually Belantamab is still on the list for immunotherapy, that was pulled from the FDA. And then some of the notable side effects are listed on the bottom. So we are going to go into a little bit more detail with some of these categories, but this is just an overall of the treatment options that are available for all of our myeloma patients.

Teclistamab and CAR T, we are going to have a special slide on bispecifics and CAR T therapy so I'll talk about that again. So CAR T here, the New Treatment Approach and I'm sure Dr. Usmani is going to talk about this a little bit. Basically it's a specialized procedure. We select the appropriate patient. Patients are screened, they undergo apheresis. We collect their cells, we do some bridging and lymphodepletion chemotherapy. Those cells are sent to an outside lab for alteration to actually attack the specific myeloma cells. In that interim, because they're gone for a couple of weeks, we do some bridging therapy if necessary and then once the cells come back, we do lymphodepletion chemotherapy before you get your cells back. The treatment is the cell reinfusion. And then we do a lot of post-treatment monitoring. We manage you for quite a while for side effects and for response to treatment.

So some of the tips for CAR T, I mean this is the big buzzword, right? Actually on the right-hand side is showing you the patient's own T-cells. So these are the T-cells that we apheres or collect from you. They are sent to a lab for alteration, for personalization you might want to say, to really target that BCMA on the myeloma cell. That cell there is the myeloma cell and once we give you your cells back, hopefully we have more myeloma cell death. But asking for a referral to a CAR T-cell specific center before relapse is a good idea. The insurance authorization is required, which can take a little bit longer. You must have sufficient blood counts and organ function to be eligible. Sometimes there's a wait and you might need bridging therapy kind of to give you some therapy to control the myeloma before these CAR T-cells are ready for infusion.

This unfortunately has a wait list so there's only specific slots that we get per month. Once you are eligible and you have your pheresis and your cells are prepared, you're in the hospital for a short time. You need a caregiver and must stay within proximity of the CAR T-cell therapy center for about a month. There's some requirements, no driving for eight weeks and some other requirements. It's a one and done procedure. So this is not a cyclic procedure as some of our other therapies are, but patients need ongoing monitoring. So some patients may need transfusion support and other supportive care after the procedure. CRS and neurotoxicity or infection are some of the possible side effects. Bispecifics are another treatment that target BCMA. BCMA is a very specific target on that myeloma cell. As Dr. Durie said, it stands for B-cell maturation antigen.

So different bispecific antibodies have differences in efficacy and side effects. About very good response rates, about seven in 10 patients responded. CRS is common just as in the CAR T therapy. Some people have had skin and nail disorders. The only FDA approved bispecific right now in May of 2023 is called Tecvayli or teclistamab is the first, but actually more are expected in the next year or two. This is an off the shelf treatment, which means that it's not personalized for you. The doctor can order it and we don't have to wait to give you this treatment. The route of administration and dosing schedule will vary depending on the specific product. Teclistamab is a subcutaneous injection. Some of them are IV. CRS, again, neurotoxicity or infection are possible side effects and if you look at the picture on the right, it's just showing you that the bispecific antibody in the middle there, it's just bringing your myeloma cell on the right in very close proximity to a T-cell, which is a very important cell in your immune system, and that leads to cell death.

So that's kind of an easy way to describe how bispecific antibodies work. Too little sort of edges to the molecule that bring two cells together. So again, CRS is a common but usually mild side effect for CAR T therapy and the bispecific antibody therapy. CRS can show up as fever, fatigue, headaches, some nausea, vomiting, shortness of breath, diarrhea, weakness, confusion, some low blood pressure and CRS stands for Cytokine Release Syndrome. Basically it's sort of your immune system going into a little bit of an overdrive and you can have some symptoms related to your immune system, sort of like getting hyper-stimulated.

Neurotoxicity is another side effect of CAR T and bispecifics. It's not common but it can be very serious. Some of the side effects in this category are headaches, confusion, hallucinations. You can have weakness, nerve palsy, tremors, seizures, encephalopathy which is altered brain function. So we really monitor you from a neuro perspective while you're getting these drugs just to make sure that this side effect isn't going to show up. Infection awareness and prevention is very important. So again, infection prevention tips, you want to maintain good personal hygiene, always wash your hands, avoid crowds, and avoid sick people. I always tell my patients on active therapy, "Pretend it's March, 2020," and we all remember what happened in March, 2020, right? Covid really reared its ugly head. I mean we always wanted our patients to have good infection control awareness, but I think we have to really stress these infection prevention tips.

Sometimes we have to institute growth factor support with injections to raise your white count. Sometimes immunizations but no live vaccines and sometimes we give medications to help reduce the incidence of infections. Covid, the best way to prevent illness is to avoid being exposed to the virus. Again, staying away from sick people, using a mask when you're in crowded areas, get the Covid vaccine and booster. We still recommend these vaccines for our patient population. Even though they may be a little bit less effective in patients with compromised immune systems, we still are recommending them. Again, remember, make believe it's March, 2020. Wear that mask when you're in an area where there's a lot of people and there's a risk of spreading respiratory diseases. Avoid crowds and sick people. When you're indoors, especially I'm on the East Coast, in the winter, everybody's indoors and it's a lot of crowds and sick people are just in close contact with each other. You want to avoid kind of that.

And of course washing your hands. Washing your hands often and then reporting fever to your healthcare team. Anything above 100.4. Shaking chills even without a fever, dizziness, shortness of breath, difficulty breathing, low blood pressure, these can all be signs of infection. The compromised immune system that the patients can experience comes from the disease and from treatments and infection is a very serious consequence for myeloma patients. We do have to be mindful of this and patients need to know what to report, when, and why. Some infection guidelines. So the type of prophylaxis, so HSV and VZV, this is the shingles kind of prevention. We give the standard prophylaxis recommended for all patients with myeloma. You might be on Acyclovir or Valtrex. PJP is another bacterial infection, very noted with bispecific agents in CAR T therapy.

We can give you some prophylaxis, some medication to reduce the incidence of this infection. Other bacterial and fungal infections can occur. We might also give you more medication, especially if your absolute neutrophil count, a special white cell count, is low. COVID-19, we can consider monoclonal antibody therapy for patients receiving a bispecific so CAR T therapy based on your institution specific protocols. If you have low gammaglobulin levels, which is common in myeloma patients, we might recommend IVIg infusions. GCSF is the shots, the Neupogen, Neulasta, Granix, Zarxio. These can be given to help maintain a sufficient white count to help you fight infection. So supportive care to address side effects. Don't change the horse midstream, right? It's important to stay on myeloma treatments to control myeloma cells and get the most from each treatment. Responses tend to deepen over time. Talk to your team if the side effects are becoming bothersome.

Your team can help you, but only if they know. We're not mind readers, right? You have to communicate with us. So some of the side effects or issues are listed here in the columns and there on the row is some of the medications and stuff that we can do to offset this. So DVT and PE prevention, these are the clots that some of our treatments can increase the incidence of. We might recommend blood thinners, compression stockings, and some lifestyle options like stopping smoking, lose some weight, maintain activity. Bone health, we might recommend bone strengthening agents like Xgeva, Zometa, pamidronate, calcium and vitamin D. Sometimes we also do physical therapy, increasing activity, keeping your kidneys healthy, staying well hydrated. Sometimes our patients are on dialysis for a short term. We recommend avoiding harmful medications and using dose reductions of other medications that are harmful to the kidneys.

Again, I don't want to belabor this, but infection prevention, using antimicrobial prophylaxis, IVIg infusions, injections, masking up, hand washing, avoiding crowds, avoiding sick people, monitor for fever, and taking the appropriate Covid precautions. If you're a patient that has neuropathy, again, very tough to manage. Getting diabetes under control can help. Sometimes we have certain anti-depression medications or anti-neuroleptic medications that can help. Vitamins can sometimes help, massage, acupuncture. There's a lot of anecdotal supportive care, things that can help. GI symptoms can also occur. We can see nausea, vomiting, diarrhea, constipation. I think we can meet with our nutritional support people in the clinic and the nurses and doctors can also help you with prescribing anti-nausea meds, medications to help your bowels. Making good dietary choices and avoiding certain foods can help. Maintaining an active lifestyle and staying well hydrated, also very important for GI.

So the symptoms of myeloma, they're physical, fatigue, constipation, pain, neuropathy, sexual dysfunction. These are all physical, but we can also see psychological symptoms of myeloma, right? Some of our patients are depressed, some of them are anxious, some of them have insomnia or a lot of sleep disturbances. Decreased cognitive function, that so-called chemo brain, right? Decreased role in social function. And of course we can't not forget the financial burden. I always think that one of the side effects or toxicities of myeloma is the wallet, right? The financial burden or the financial toxicity is definitely something we need to address. Steroids, I'm sure, as patients and caregivers, you're all familiar with steroids, the good, the bad, and the ugly, right? Steroids are a backbone and work in combination to enhance myeloma therapy. So they work synergistically to increase the efficacy of a lot of our agents.

I think managing steroid side effects is important. Have a consistent schedule. Some people, it's best to take it in the morning, some people, it's best to take them at night depending on when they get that sort of hyperactivity related to the steroids. Always take them with food. They can cause a lot of stomach upset. You can use over-the-counter or prescription medications to help with the abdominal discomfort. Medications that prevent shingles and other infections is important because steroids are also immunosuppressive and the steroid side effects are on the right hand side here. Basically steroids affect every single part of your body. They can affect your mood, your sleep schedule, your vision. They can increase the risk of cataracts. They can make you sweaty and cause flushing. They can make you have an increased risk of infection. They can cause palpitations, increase your blood pressure.

They can cause stomach bloating, hiccups, heartburn, ulcers, gas. They can make your muscles weak, they can make your muscles cramp. They can make you retain fluid and gain weight. They can make your hair thin and can cause some skin rashes, right? Again, fluid retention and increased blood pressure. If you're a diabetic, it's important to realize that steroids can increase your blood sugar levels. So very important to note this. I mean these drugs sound pretty interesting, right? These are not benign drugs. So even though they are not technically chemotherapy, we need to be aware of all the side effects of steroids. GI symptoms, diarrhea can be caused by medications, constipation can be caused by medications. Again, avoiding caffeinated, carbonated, or heavily sugared beverages. Taking anti-diarrhea medication if recommended. The BRATT diet, bananas, rice, applesauce, tea, and toast is sometimes recommended for the diarrhea.

Constipation, increase fiber, fruits, vegetables, high fiber whole grain foods. And sometimes using Metamucil, Benafiber, those kinds of things can help. Always increase your fluid intake with both diarrhea and constipation. That can help with the GI function and helps kidney function. And also just tell us what's going on so we can make adjustments to your medications and help you control these side effects. Pain can significantly compromise your quality of life. Many sources of pain including bone disease, neuropathy, sometimes medical procedures, we like to manage pain, but we like to prevent it whenever possible. So bone strengthening agents to strengthen your skeleton, medications to prevent shingles, sedation before procedures, interventions depends on the source of the pain. We can give you analgesics for medications to control pain. Sometimes activity can control pain. Surgical intervention if it's back pain. Radiation therapy can help control pain.

Complimentary therapies, yoga, supplements, acupuncture. Again, let us know what you want to try. Usually these things can help. Scrambler therapy is using electrodes to manage pain. That can also help with neuropathy. It's very important, again, those lines of communication need to be open. Tell your healthcare team about any new bone pain or any chronic pain that is not adequately controlled. Peripheral neuropathy. What is peripheral neuropathy? It's damaged to your nerves. Tell us about numbness, tingling, any kind of pins and needle sensation, burning sensations, cold sensation, muscle weakness. Prevention and management, Velcade can be given subcutaneously. Now it's mostly given subcutaneously, which reduces the incidence of neuropathy. It can be given once a week, which further reduces the incidence of neuropathy. Massaging the area with cocoa butter can help, sometimes B complex vitamins. Sometimes amino acids can help. Safe environment, making sure that you have a safe environment if you have neuropathy in your feet with rugs, shoes and furnishings. If it worsens, your provider may change your dosing schedule, may change your treatment altogether. May prescribe oral or topical pain medication and may suggest physical therapy.

Fatigue, right? Look at the horse with the long face. Fatigue, right? 98.8% of you will complain about fatigue. Fatigue is the most commonly reported symptom and there's a variety of reasons for that. The sources may be anemia, pain, reduced activity, sleep schedule disturbances, treatment toxicity, bone marrow suppression. Anxiety can happen in over a third of our patients, depression in about a quarter. So I think that a lot of our patients do not share these symptoms with us but it's important to talk to us about these symptoms that are not well controlled or if you have any thoughts of self-harm because help is available. We need to have you live a good quality of life while undergoing treatment for your myeloma. Rest and relaxation contributes to good health. I think that's kind of a no-brainer, right? Adequate rest and sleep are essential to a healthy lifestyle.

If we don't get good sleep, that really increases our risk of anxiety, weakened immune system, heart related death, worsens pain, increased risk of falls. Things that can interfere with sleep are medications, psychological reasons, fear and anxiety, stress, and sometimes sleep apnea, heart issues, and again, pain can really interfere with our sleep schedule. Sleep hygiene is necessary for quality nighttime sleep and daytime alertness. Engage in exercise but not too near bedtime. Increase daytime natural light exposure. Avoid daytime napping. Establish a good bedtime routine. Maybe you want to have a certain routine before you go to bed, a cup of warm milk or tea. Associate your bed only with sleep. Everybody has their tablets out, their cell phones and the TV. All of that is probably not good environment for sleep. Sometimes a sleep aid may be needed. What you want to avoid before bedtime is caffeine, nicotine.

I hope you guys aren't smoking. Please stop the smoking. Alcohol and sugar is also good to avoid before bed. Large meals and especially heavy meals can interfere with your sleep. And again, computer screen time. And that includes your cell phones, your tablets. Kind of cut that off a couple of hours before bed. That will lead to better sleep. And again, the financial burden. I always talk about this. Financial burden comes from a lot of different sources. Medical costs, right? Premiums, copays, travel expenses to get to the clinic, supplies, copays, prescriptions, loss of income. Maybe your treatment, you need a lot of time off from work, the caregiver time off from work. So you and your caregiver are taking time off from work, which will lead to a financial burden. There is a lot of assistance that is available. There are funding programs. There are federal programs, there are pharmaceutical supports, nonprofit organizations. There's a list of websites here.

I think you really need to reach out to your team. There are lots of resources available that we can tap into to get you help with some of these specific financial issues, maybe copays or prescription drug costs. Please reach out to us. Don't be a hero. If it's a burden, let us know. We can utilize our knowledge of all of these programs that potentially you may be eligible for. Be an empowered patient. Engage in your care, right? That's important. So you are central to the care team, okay, right? Be empowered, ask questions, learn more, participate in decisions. I mean, just being a part of this webinar is a plus plus for you. You can see the whole team there. You are in the middle there, you and your care partner. Then you have your primary care provider, you have your pharmacist, your hem-onc, your myeloma specialist, your support network, family, friends, the allied health staff, the subspecialist. Everybody is a part of your team.

Understand the role of each team member, who to contact for what. Participate in support networks if you have a support group for myeloma. Even virtual, I highly recommend that. It can help you and the caregivers with some psychological support. Knowledge is power. Again, the IMF has a lot of resources out there. There's a website listed here. We have videos, we have e-newsletters. We have booklets that can be ordered so you get the actual hard copy. And there's also downloadable forms of these. You can see them on the left. Every single treatment option has a little patient pamphlet. There are also generalized pamphlets. I have a slew of them in my office about myeloma in general, treatment options, about stem cell transplants, about laboratory, how to read your labs, your myeloma specific labs. They have a lot of information for you.

Healthful living, infection prevention, renal and bone health is really the goal that you can help us help you. Again, we talked about maintaining good kidney health, okay? Managing the myeloma, keeping well hydrated, avoiding drugs that are harmful to your kidneys. Some of these drugs maybe had to be dose adjusted because of your kidney function. Diabetes management, remember, diabetes that is out of control can also hurt your kidneys so you want to keep your diabetes under control. You want to protect your bones. Nutrition, calcium, and vitamin D support, weightbearing activity. Walking is excellent. Bone strengthening agents from your primary care or from your myeloma specialist, preventive healthcare, health screenings, vaccinations, stop smoking, eat well, dental care. And just because you have myeloma doesn't mean you don't have to get your mammography, your colonoscopy, your PSA checks. We want you to continue to have all of these health screenings that are suitable for your gender and your age group.

Try to maintain a healthy weight with good nutrition and activity and exercise. Manage stress. It's tough. You have a lot on your plate. But rest, relaxation, good sleep schedule, mental health, social engagement. Again, try to join a support group. That can be helpful. Complimentary therapies do have a role and an ounce of prevention is worth a pound of cure. That is true, right? Keeping active, right? Movement therapies can reduce stress, promote sleep. Yoga, Pilates, they have both shown to improve sleep and sleep quality. They improve your mood. So definitely something that you might want to look into. Keep a log or journal of your activity. Notify us, your healthcare provider, about any sudden onset of pain, progressive weakness, headaches, blurred vision, numbness, tingling. We do want to know about these things.

Dehydration is really not a good thing. That can lead to low blood pressure and falls. Please stay well hydrated. Of course if you're undergoing dialysis or have some other issue like heart disease where you might be volume sensitive, you're going to need to listen to your other healthcare team members about your fluid restrictions. But in general, you want to stay well hydrated. Do not overdo it. Do not force exercise. If you're hurting, you want to stop. And also don't try things without discussing it with us. We will let you know if it's a good idea or a bad idea. But in general, we want you to have a good quality of life. Myeloma bone disease may affect your ability to do certain movement activities. Again, check it out, review your activity interest with us and we'll let you know if it's a good idea or not, okay?

The Nurse Leadership Board is something that I am proud to be a member of. We are a professional partnership that includes oncology nurses throughout the country and throughout the world. And there's a myeloma university. So this is a comprehensive online educational program on myeloma. And you can actually visit the website. There's the QR code here. I highly recommend. It's www.myeloma.org. So it's something you might want to be interested in checking out. And I think that concludes my presentation. I'll open it up for questions and answers, but I'll leave Dr. Durie to control the questions and answers. Thank you so much.

Dr. Brian Durie:
Thank you so much for that comprehensive review of what's really important for so many patients. So quite a few questions have been coming in. Well, I'll start with a fundamental or simple one. So somebody says, "Well, CRS, oh gosh. So what exactly is CRS?" So just cytokine release syndrome, right? So you talked about it, but-

Ann McNeill:
Right. It is sort of the immune system going into overdrive. The easiest way for me to say it is it's a simulation of your immune system. I know Dr. Usmani is going to be talking about some of these therapies. He might touch on that as well. But it's sort of like... It shows up, it could be a fever... I mean, I mentioned something about fever, hypotension, hypoxia. You might be a little short of breath, you might have low blood pressure, you might have a fever. It's just a sign that your immune system is responding to the treatment. So is it a good thing? It could be a good thing, but sometimes it gets out of control and we need to quiet it down a little bit.

Dr. Brian Durie:
Right. So we talk about that fairly casually but CRS is a really important collective name for side effects that we get with these immune therapies, particularly CAR T, but also with the bispecific therapies. So another one for you. "This word, a scrambler therapy. That sounds amazing."

Ann McNeill:
I don't know too much about it. It uses electrodes to block transmission of pain signals. So again, I'm not too familiar with it. I don't know a patient who's had it, but it's sort of like electrotherapy. If anybody knows a little bit more about it, I'm willing to hear about it. But I've heard of it, but I don't know anybody who actually has used it.

Dr. Brian Durie:
Okay. All right. Do you guys, Saad or Rafat, do you use this type of therapy? No. Okay.

Dr. Rafat Abonour:
Yeah.

Dr. Brian Durie:
Doesn't seem to be much scrambling going on, okay. All right. Then the slides will be available. "A second dose of Evusheld, should you take that?" I think maybe we could talk a little bit... There was a broad question that came in about a about Covid and you did talk a little bit about Covid, but maybe... By the way, the scrambler, I think it is a little bit like a TENS unit.

Ann McNeill:
Yes, yes. I was going to mention that.

Dr. Brian Durie:
Think of it as a TENS unit.

Ann McNeill:
Yep, yes. Very, very simple.

Dr. Brian Durie:
Maybe Saad and Rafat, maybe you could comment on how are you managing Covid day to day now? We were so obsessed with keeping up with our vaccinations and masks and all kinds of different things, but how would you describe your day to day care related to Covid right now?

Dr. Rafat Abonour:
I mean, the good news is that I think a lot of people are immunized and the strain that we have right now is not very virulent. So I think we are not seeing really the severe cases we saw in the early days of COVID-19. Patients that are getting it are getting over it. Obviously we do recommend the immunization. I am in the habit of monitoring the antibody against COVID-19 so I can tell my patient if they have antibodies or not. I think it'll give me some level of comfort that if they have antibodies against the COVID-19. So I monitor that. If I start seeing that they are losing it, the equivocal results are negative, I encourage them to get vaccinated. We have a lot of patients now who are being treated with anti-plasma cells directed therapy, BCMA targeted therapy, CD38 targeted therapy, the daratumumab, the bispecific, the CAR T-cells.

All of these patients become, as you heard from Ann, hypogammaglobulinemic. Their normal IgG... And I always calculate the normal IgG because some of the IgG can be monoclonal protein so you have to know what is your normal IgG. And if they are low, we're giving intravenous immunoglobulin, we supplement their immunity with normal immunoglobulin. And because the immunoglobulin is coming from normal healthy donors that have been around COVID-19 for the last couple of years, they do have antibodies against COVID-19. So I am totally impressed by the level of protection that our patients have today, our ability to provide extra protections. I encourage vaccination. And again, the most important thing is that we always have to be careful. I mean, when I get on an airplane, when everybody's coming on an airplane, I have my mask on and I probably don't take it-

Dr. Brian Durie:
Be careful.

Dr. Rafat Abonour:
Off until I'm sitting to people around me who are not coughing, sneezing ,and doing all that stuff. So it's very important that we are careful, but we are not going to live in a bubble. It's time to live your life.

Dr. Brian Durie:
Let's loosen up a little bit. Yeah.

Dr. Rafat Abonour:
Yes.

Dr. Brian Durie:
There's some questions about vaccination and boosters and maybe Ann or Saad... And I get this question all the time. Most of our patients, and I suspect most on this webinar, have had their vaccinations and probably at least one of what we call the bivalent boosters. But now patients are coming up to four to six months and they are wanting to know, well, should they be getting another booster perhaps? I don't know if either one of you would want to comment on that.

Dr. Saad Usmani:
No, I can begin. So again, every institution has different policies, but we are proposing our patients to proceed with getting that booster. Just as Rafat very eloquently made the case of how safe it's become where we've gone from pandemic to maybe endemic Covid infection in certain areas, I do feel we cannot let our guard down from a vaccination standpoint.

Dr. Brian Durie:
Right.

Dr. Saad Usmani:
So we are recommending our patients to get it.

Dr. Brian Durie:
Right. What's your policy in Hacensack?

Ann McNeill:
We are also recommending that they get it. Absolutely.

Dr. Brian Durie:
In that four to six month timeframe?

Ann McNeill:
Yep.

Dr. Brian Durie:
Right, right. All right. And so are patients wearing a mask when they come into the center? Do they have to for your centers or no?

Dr. Rafat Abonour:
Yeah, I mean in our transplant unit, in our cancer... The hospitals is not mandating masks. But in oncology areas, we're still doing masks.

Ann McNeill:
Same here. So actually the guidelines are a little bit less restrictive for the solid malignancies. But for the blood cancers, it's still highly required in the transplant units and the leukemia, lymphoma, myeloma world.

Dr. Saad Usmani:
Yeah, I agree with Ann. That's exactly what we're doing. I think the policy is more lax for solid oncology patients and then even on the physician side, in the ambulatory staff setting, we are not letting our guard down.

Dr. Brian Durie:
Right. So I certainly agree with that. And there's some questions along that line here.

Dr. Rafat Abonour:
Brian, somebody asked a question, he had a stem cell transplant and he said does he not have any immunity? I mean, I think the way I describe it to my patient is that after a stem cell transplant, you have some immunity.

Dr. Brian Durie:
Answer that one.

Dr. Rafat Abonour:
But you need to get reimmunized just to boost your immunity against things. And we start that six months out.

Dr. Brian Durie:
Right, exactly. Exactly. This question about Dex. For Dex, that one day a week on the dex is most important. It's good to have time off of the Dex. Seeing if there's anything else that we could easily cover here. The slides will be available and we're obviously just halfway through the webinar, so both Rafat and Saad will be talking after we take a short break here. And Denise is letting you know that the copay with LLS is open again, which is good to go, right?

Ann McNeill:
Yes. I just saw that email. I just got an email today. So the LLS is now the copay... Because sometimes I guess the funds run out or whatever, but now it's open for myeloma. I just got the email today, this afternoon. So that's good news. Again, patients should always look for help with the healthcare team about tapping into these resources.

Dr. Brian Durie:
Right, right. So I think that we've covered... Because some of these we're going to touch on later. The bispecific and the CAR T, we're going to be going over quite a bit in a little bit here. All right, well, there was one question here about the MGUS-like phenotype. Yeah. So this is a little bit confusing in the sense that this MGUS, the monoclonal gammopathy of undetermined significance, which is a very, very early precursor of myeloma is MGUS, but this whole thing is about patients with myeloma who've virtually gone through therapy. So patients have gone through treatment for myeloma and then they're stable and then it kind of looks like an MGUS again.

So it's kind of like a secondary MGUS where after going through all the treatment, maybe a transplant, all kinds of things, levels are low and stable. And this is what we call MGUS-like. And so what the Spanish group were able to show is that it's possible to identify patients who are MGUS-like, which is very helpful because they're stable and they don't need to have any treatment and one can safely monitor them possibly for quite a number of years. So this is a category of patients who have actually had myeloma but are now being followed after treatment.

Dr. Brian Durie:
I would very much like to welcome Dr. Abonour, who will talk about frontline therapy, the initial therapy for myeloma patients. Very, very important first step for myeloma patients, so very pleased that Dr. Abonour can be with us today to present this topic. Welcome Rafat.

Dr. Rafat Abonour:
Thank you, Brian. Good afternoon and good evening wherever you are. Thank you so much, Brian. This is an exciting time in multiple myeloma. We've been doing this for a while. And we haven't seen such amazing drugs and amazing results in a long time, so it's a good time I guess. And hopefully I'll show you some of the progress that we've made in upfront therapy. Okay, so we are going to try to move the slide flicking.

Dr. Brian Durie:
There you go.

Dr. Rafat Abonour:
Here we go. I guess when you diagnosed with multiple myeloma, what are the goals of therapy? I mean, I think two things. Obviously you are diagnosed because you have symptoms related to the myeloma. You have bone pain, you have anemia, you have kidney failure. We're so excited about the slide here. Let's see what's going on. Let's go back to the previous slide. My clicker does not want to cooperate. Okay, previous slide please. Previous, previous, yeah, let's go here. All right. Symptoms control. That's really important, so we need to get you under control quickly. And probably part of the important thing is that if you have kidney failure, high calcium, we're going to hydrate you, we're going to give you steroid. Believe me, steroids are very important in the first month or two of therapy. After that, we can ditch them. And obviously you want to control the disease, you want to make sure that you get rid of as much myeloma as you can and you want to minimize the toxicity.

And the goal is to live as long as possible and we need to achieve that. So I think what's evolving is that the depth of response matters, how much myeloma you get rid of is very important. In the old days, the best we could do is partial response, get rid of 50% of your myeloma. And when that happens, the patient didn't live that long. The median survival 20 years ago used to be two to three years and then 10 years ago, five to seven years, and now it's getting better. Why? I believe because of the depth of response. Because look at it. If you leave PR here, that's partial response on the left. What you're seeing is that it's taking not much that long to go back to where you started. But if you get rid of it, complete remission is going to take longer.

But if you start getting rid of a lot of myeloma, stringent complete remission, your myeloma protein is gone, your free light chain is normal, no myeloma cells in the bone marrow, it's going to take much longer to relapse. But then what happened we start looking at something you heard from Dr. Brian Durie, minimal residual disease detections, we start improving on that. And when we improve on that and we get rid of the majority of minimal residual disease, you can see the curve. It takes much longer to relapse And hopefully when you reach these amazing minimal residual disease undetectable, your relapse may not happen for 30 years and that means hopefully you are cured, so getting to that level of response I think is really very important. Okay. So for some reason it is...

Dr. Brian Durie:
It's working, it's working, yeah.

Dr. Rafat Abonour:
It's working?

Dr. Brian Durie:
Yeah, there's a slight delay I think.

Dr. Rafat Abonour:
Yeah, there is delay. I don't know why. Anyway, so basically what we're trying to do here is to how we detect minimal residual disease. And there are two ways to do it, but why is it important to get minimal residual disease? I think it's emerging as an important marker of lasting clinical benefit, so when we look at clinical trials that have looked at minimal residual disease, patients who achieve minimal residual disease tend to have longer remission and longer survival. And we use two ways. One is a flow cytometry that the IMF really sort of brought to America from Europe. The flowcytometry using eight colors and 10 colors flowcytometry has a decent sensitivity of one in a hundred thousand. And in good hands it can be even one in a million. And it's really nice because what the pathologists, when they're doing the flow, they're looking at actually abnormal plasma cells and they can tell you if they have one cells in a million or 10 cells in a million. And that's usually informative and it's easy because you don't have to have your initial bone marrow to know that you have abnormal plasma cells.

Abnormal plasma cells are there when you are diagnosed, when you relapse, and when you still have disease. The other more sensitive assays is the next-generation sequencing. You have to have the original myeloma samples When you are diagnosed, we generate a sequence specific for your disease and then we follow you. And that's after transplant, we can use these sequences to look at these cells and find them. And the sensitivity is usually one in a million, so one log more sensitive, so why is MRD useful? Because it predicts the outcome. Here there are two data's showing if the patients achieve, this is a large set of patients, if you achieve minimal residual disease negative, you are going to enjoy a better time without relapse and you're going to enjoy a longer survival. That one on the right is looking at overall survival. And on the one on the left, that graph is looking at progression-free survival, those times without relapse. And the more sensitive the assay, the results are more actually important and reliable.

Okay, so now the thing about it is that if you get minimal residual disease, it may lead you to enjoy a very long progression-free survival, living without the disease. And what you can see on top is that even patients with high risk disease who achieve minimal residual disease are behaving like patients, what we call standard risk myeloma, so when we say you are high risk versus standard risk, risk of what? The risk is for a short remission and short survival and you can overcome that by getting rid of the myeloma to a level undetectable by these sensitive assay. Because if you don't have the myeloma cells around you get rid of the high risk clone, that's a good thing because they're not going to become more aggressive and cause relapse quickly, so that's very important things. Obviously when you don't achieve that you're going to have a sort of shorter time to relapse, so we need to work on that group of patient to try to improve their outcome. And the next slide, basically these are data showing effect of sort of maintenance.

And this is a study that was done in France looking at patients who had received induction treatment, high-dose chemotherapy, and autologous stem cell transplant. And if they achieve MRD negativity, they enjoy and they had a longer time with good survival. And what it means that achieving MRD negativity can save the patient taking medication, side effect related to the medications, and also cost, so this is great things. So most patients with just a year of maintenance enjoy that. Again, the thing about it is that there is a great benefit of maintenance but can be a downside for it. And that's why for example some of the work that is being done, and I'll show you example of clinical trials that focus on achieving minimal residual disease that is sustained and showed that actually that's maybe a different way of managing patients. All right? And this is just, I'm trying to make the case that minimal residual disease negativity is very important. And again, when you achieve a sustained minimal residual disease, the survival is.. Look, it's flat.

I mean there's nothing better than seeing a curve that is flat, when you start seeing a drop-off when people are not doing well either relapsing or not surviving, that's a not good thing, so MRD negativity is so important for improving overall survival. All right, so you saw a similar slide earlier. The evolution of myeloma therapy is incredible and you can see when few years ago we used to say RVd is a good thing, Revlimid/ Velcade, Kyprolis/Revlimid, things like that. Now we start using instead of three drug regimen, we're using four drug regimens. We're seeing amazing result. A lot of patients still getting consolidation with stem cell transplant and then they post-transplant setting, you're getting maintenance. It used to be Revlimid alone. Now Revlimid/Daratumumab and you can see the number of immunotherapies. So we've been around for a long time and we used to say okay, if we look at Revlimid, it used to be in the relapse setting now is upfront. Revlimid and Velcade used to be in the relapse setting. Now upfront DARA used to be just in the relapse setting is now upfront.

I really think some of these drugs in the relapse setting, in the rescue setting, because we understand how well they work and because we understand their side effect profiles, we probably going to move a lot of these drugs that Dr. Usmani is going to talk about, earlier on in the course of the disease. And I think that will generate better responses, more patient getting minimal residual disease undetected, and hopefully we can cure a large number of patient. What's really important is that in the old days we used to think about, okay, let's sequence drugs, okay we're going to use Revlimid Dex first and then maybe use Velcade Dex. But the most important thing is that using combination therapy. Combination therapy, that's what made the difference in the survival of patients. Just using one or two drugs is not enough, three drugs is a great and using four drugs is maybe even better like adding Daratumumab to RVd, Revlimid/Velcade, it's a great thing, so I think more to come and it's going to change quickly here, okay.

All right, so you heard about the trial that Dr. Brian Durie actually led and presented several times now, it's basically we used to say Revlimid Dex is a good induction treatment for patient not going to transplant. Can we use Velcade/Revlimid Dex? Is it three drugs better than two drugs? And yeah, I mean you know you saw earlier results that he Dr. Brian and 101 showed you and basically what you can see is that time to relapse and overall survival was in favor of using a three-drug regimen, so that makes the case, yes, we need a three drug regimen because we need to try to get rid of all the different clones that the patient has because not all myeloma patients have the same sort of correct, the baby, the myeloma cells coming from the original cells, they don't all behave the same way, so some will benefit from drug A but not drug B and vice versa, so the combination therapy makes a difference.

The next thing was, okay, can we add something called Daratumumab, the monoclonal antibody that bind to CD38 cells to Revlimid Dex, would it be better than Revlimid Dex? And so this is called the MAIA trial and was done mostly in Europe and also in North America. But these patients were not transplant eligible, they thought they are now going to be able to get a transplant, so can we improve their survival? And basically what it showed here is that there is significant improvement in the duration of response and the overall response, and a lot of patients who were able to stay on therapy without having to stop treatment. If you look at the overall response that mean how many patient responded well to the combination of Dara/Revlimid Dex, you can see it's 93% versus 81%. But if you look at the quality of the response was much better when Daratumumab was added that mean you're getting more patient into complete remission, stringent complete remission.

And so the initial data looks great and the follow up data looks even good and better. For example, if you look at complete remission and stringent complete remission was 51% versus 30% in the Revlimid arm, so clearly combination therapy does make a difference, does lead to a better response, deeper response. And again translates to better time without having to worry about relapse of your disease. You can see that the difference was at 60 months of follow up, yes five years of follow up was 52% versus 28%, so a lot of patients in the Revlimid arm have relapsed and a lot of patients in the Daratumumab-Revlimid arm, the combination of three drugs led to a better duration of response and it does look like it translated to improvement in overall survival. More patients are alive when they get the three drug regimen versus two drug regimen. And they follow them for some times and the median time to next treatment, that mean because you can judge the regimen is that how long it took you to get to a different line of therapy?

You know progress because you're not responding was the DARA arm was only 42 months before you needed something. I mean not reach for the DARA arm and for the Revlimid was 42 months, so clearly you can stay without needing a new therapy much longer when you use a three drug regimen versus two drug regimen. All right? That's I think an important observation, and the subsequent therapy is just based on what's available in these countries. All right, so I think the conclusion is that I think Daratumumab added to Revlimid Dex does improve overall survival and does improve time without disease and it takes much longer to needing a new therapy, all right? Now we are going to go to see the patient who will probably need a transplant and we already established that RVd, the regimen that Dr. Brian Durie studied is a really good treatment compared to Revlimid Dex.

Can we make it even better? Can we add Daratumumab to it, the monoclonal antibody to it? Can we make the results better? And this is a sort of phase two randomized study called the GRIFFIN, Dr. Usmani and his colleagues or were the leader when he was in North Carolina on this. And basically what they did is that they added Daratumumab to RVd and compare it to a group of patient who get just RVd and they give him induction, four cycles, consolidation with two cycles with transplant in the middle between the induction and consolidation and the patient get maintenance Revilmid Dex versus Revlimid. And this study's been going on for a while so we have some mature results, so what does this mature result show? So first of all, let me show you the DARA arm is on the left here. The kind of purplish color and the orange-ish color is on the right is the just Revlimid/Velcade/Dexamethasone.

And what you can see is that with each step the number of patients getting stringent complete remissions increasing and after one year it reached 63% and at two years 66%. In the RVd arm that stringent complete remission is lower, so this regimen adding now Daratumumab to RVd for drug regimen is inducing more responses that are deep quality responses. And this is the result of minimal residual disease testing we talked about earlier that MRD negativity is very important and what you can see here is that getting MRD negativity increased with each step in DARA arm from 22% to 64% in the Revilmid arm went from 80% to 30%. So twice as many patients after two years of therapy are achieving minimal residual disease. That's unheard of, I mean so I think it makes sense that the four drug regimen are producing deeper response to a level that is undetectable in the bone marrow. All right.

Dr. Brian Durie:
Okay.

Dr. Rafat Abonour:
I have to figure out my clicker here and you can see the time to MRD and activity is faster in DARA/Revlimid arm and you can see larger and more patients achieved that while the people who just get Revlimid Dex, they get there but not as high the percentage and not as fast. So basically the beta duration to MRD negatively was 8.5 months in DARA RVd and took 34 months for the Revilmid/Valcade Dex to get there, so you get there, you get MRD negativity faster, and more patient gets that, okay?

Dr. Brian Durie:
All right.

Dr. Rafat Abonour:
I may have done something to my, and obviously the progression-free survival based on intention to treat was also in favor of the patient who get DARA RVd, you can see almost a flat line. The majority of the patients have sustained a sort of lasting remission, so that's what we want. We want to get more patients getting MRD negative and more patients have a sustained control of their disease. We don't want a patient start relapsing in a year or two, the longer the better, all right? The second thing I think that is really exciting is this approach by Dr.

Luciano Costa from Alabama a very, he recruited other academic centers and came up with this trial called the MASTER trial and I start calling him Master Luciano because I think it's really a beautiful way of looking at how we should be treating multiple myeloma. And basically what he did is that, all right we know that four drug regimen is good and we believe that Carfilzomib is a very good PI, so can we use Daratumumab, Carfilzomib, Lanalidomide, and Dexamethasone, a combination in a way that will use it for induction followed by transplant and then get guided by MRD negativity to decide what we are going to do next, okay, so what did he do?

What did he do? Basically what he did is four cycles of induction with this four drug regimen DARA, Carfilzomib, Lanalidomide, and Dexamethasone followed by autologous stem cell transplant. He did check MRD after each sort step but didn't make a decision what to do until after transplant. And if you got MRD assure or MRD-SURE that means you know get tested twice you're MRD negative, we are going to just watch you. But if you still have MRD positive cells, minimal residual disease still detected in the bone marrow, he gives another consolidation four cycles and then decided he's going to do four more cycle of induction. And if they are MRD negative, we're going to call it a day. But if you still have disease, you're going to get Lanalidomide maintenance, so what happened? Let's see what happened.

First of all, if you look at all patients by sensitive next-generation sequencing assay, he's getting a lot of patients who achieve MRD negativity and when he looked at patients who use several, the top is the flow, the red and the blue is the next-generation sequencing. And what he showed is that you're getting really large numbers of patients getting MRD negativity. And if you look at patients who have no high risk cytogenetic or one high risk cytogenetic like 17p Deletion, the response is still really good. The patients who do not achieve such good results are the patient who have what we call double head myeloma that mean they are two different kind of high risk features present.

And so if you look at the patients who in term of progression-free survival, the patients who have one high risk cytogenetic or none actually looks like majority of them stayed without progression with the now follow up of a couple years or more, but the people who have high risk still not enjoying the same duration of disease free survival. And the overall survival looks better for the patients who have standard risk myeloma or one high risk cytogenetic, so the majority of the patients are benefiting from such approach that is MRD directed go or no go based on where you are after you get your induction in transplant, so this is an opportunity for us to say does everybody need maintenance? Does everybody need consolidation? I think it's generating a lot of questions that ought to be tested in a bigger trial and I think there's a lot of interest in those kind of trials and a lot of cooperative group are testing that.

I think the conclusion from the MASTER trial is that next-generation sequence response adaptive therapy is feasible in the majority of the patients and in the multicenter and 72%, 72% of the patient enrolled on this trial achieve what we call MRD-SURE. And patient with standard high-risk cytogenetic have similar depth of response and low risk MRD, so I think this is a good group. If you have one high-risk cytogenetic, you're going to do good and that's an improvement because we use this thing that these patients are going to relapse in a year or two, so I think quadruple therapy achieving MRD negative will able to explore this concept. Where are we still struggling I think, is the ultra high risk when you have for example, gain a point Q and 17B deletion or a P deletion or some of the translocation 4;14 and things like I mean the 6;14 and like that.

I think it's a really amazing trial, so we don't have really time to talk about all the trials that have been going on, but I'm trying to give you a flavor of some of the other things that are going on. For example, this is going on in Germany where they added isatuximab is the other anti‐CD38 antibody to the RVd regimen in newly diagnosed patients, so what did the German show? So basically randomized them a large number of patients to induction, stem-cell transplant, and then maintenance either with Revlimid alone or with Revlimid and the antibody Cetuximab. And the goal is to see how many patients will achieve minimal residual disease. And you can see that by next-generation sequence flow, which is detecting one cells in a hundred thousand cells. What you can see is that when you use the four drug regimen, a monoclonal antibody with RVd, you're getting more patients enjoying a better overall response rate. And with each step the number of patient achieving complete remission is increasing.

And you see in when you add an antibody, there are more patients achieving very good partial response, more patients achieve stringent complete remission, so it is again another trial showing that four drug regimen improve overall response rate and improve the depth of response. And this is just a sort of a breakdown of some of the side effect that we're seeing. And obviously when you add more drugs, you're going to see more side effect. Some of it is related to drop in a blood count, some of the related to infection. For example, in the four drug regimen you're going to see more, for example infection 43% versus 34%. But I think we are aware that this is happening and we can manage those things safely. Okay, where are we next? I really think, I mean the upfront therapy is evolving and I didn't say, I mentioned to you trials that was testing three drugs in transplant ineligible patients.

I show you trials that testing for drugs in transplant eligible patients where the induction is for drug regimen and followed by transplant. And basically what I'm showing you here is that right now I think commonly used in the US for patients who are going through transplant, at least a four drug regimen, you add a monoclonal antibody against CD38 to VRD or KRD and we have the thing is feasible with limited toxicity, you're getting deeper response and you're getting more patients achieving minimal residual disease, negative disease. And I think MRD is becoming an important measures that we probably start to include it in our assessment of how well our patient is doing and use it maybe to escalate, deescalate the therapy and guide us where to go with high risk disease that's still a challenge, but it seems like maybe not your typical high risk, the ultra high risk continue to be a group of patients that need more attentions, more clinical trials to try to answer the question.

And I didn't spend a lot of time about transplant. Is it important? I think if you look at all of the study that's showing much deeper response, more MRD negativity, better overall survival has really included transplant high-dose melphalan still play a role until we have better trials in the era of better induction treatments and better monitoring, it still has a room for it, so we still recommend it to our patients who are eligible. The question is that will we replace it one day with something else? We don't know. We don't have the data yet, so we still include it. I think that may be my last slide. Let me see. Okay, so let me just go to one more sort of futuristic trial that is called the MASTER-2 and it just addresses what I was saying earlier here in the last slide is that can we now say okay, what he did is that he used consolidation when he doesn't get MRD negative after the induction and transplant.

Well you're going to hear from Dr. Usmani about the bispecific and the CAR T-cells and he's going to tell you how we are able now to manage a side effect. How can we control cytokine release and neurotoxicity? They would becoming familiar with these side effect. We can manage them and we can probably bring those therapy early on. Why should we wait until the patient has a horrible myeloma that we cannot control? If we have a high risk patient's double head myeloma, we are not getting m MRD negativity, we can consider some of these new therapy because you're going to hear about the mechanisms of action. They're totally different than the drug we use upfront. If you're going to keep using the same image, the same monoclonal antibody, you're just not changing anything, you're not changing the biology. But when you use the T-cell specific by specific engagement, for example, what you're doing here is that you are making the immune cells work in your favor.

You're trying to get your myeloma cells to be recognized by the T-cells. You're making the T-cells angry, get rid of the myeloma cells and hopefully get rid of all the ugly cells that are left behind and the patient then will achieve a sustained MRD negativity and perhaps cured, why not? All right, I think I am here toward the end, I have to figure out why. Okay, so you better watch it myeloma, so we are going to take care of you. And so there are three myeloma patients here and one guy trying to pretend that he's a cyclist, but we're going to take care of myeloma. I think this is a really exciting time. Some of the drug you hear from Dr. Usmani, I really think they should be used early on and we start thinking about myeloma as history, not as a continuum that we have to deal with all the time. With that, I'm done.

Dr. Brian Durie:
All right, so thank you so much Rafat, and a number of questions have been coming in and most of them you've touched on and made it clear that they are actually still questions. One question is about high risk. Were high risk patients included in the GRIFFIN study? And then obviously the MASTER trial really evaluated high risk with the finding that the ultra-high risk really still need extra attention, so maybe you and Asad might want to comment on the current status of high risk. I think earlier you mentioned Asad that there were seven trials for high risk going on. Somebody wanted to know, well, where are those seven trials?

Dr. Saad Usmani:
I'd mentioned that there have been seven trials that have been reported and there are others that are actively being planned. And we will have three frontline high-risk studies open in the United States by early part of next year. One is going to be a cellular therapy based concept or clinical trial where we are going to use CAR-Ts in early alliance. There's another one which will incorporate bispecific antibodies. And then there's a third a consortium platform study which will be exploring different questions, whether we need to change something in induction, whether we need to change something in consolidation, so I think those are coming, so there's a lot of hope for high risk patients, but yeah, I mean some of the newer therapies that I'll talk about for relapse patients, we are going to be moving them up for high risk patients soon.

Dr. Brian Durie:
Yeah, maybe you can just touch on that as you go through a variety of those new therapies in a moment. Yeah. Rafat, any other comments? I mean the two comments really are the role for autologous stem cell transplant and basically you've said that we're still doing that for the time being because it prolongs remission. There was a question actually which was indicating that maybe the high-dose melphalan increases genomic damage, which is something that one of our colleagues, Dr. Richardson frequently talks about. I don't know if there are real pros and cons to doing the stem cell transplant, but you are still recommending it, right?

Dr. Rafat Abonour:
Yeah, I mean I was still recommended it. I mean obviously some of the data on the genomic instability is probably related to having cells to become genomically unstable. I mean, getting rid of it to a minimal residual disease undetected, you're not going to worry about genomic instability, so if you look at all the trials that really had a high level of MRD negativity, included induction with four drug regimen followed by transplant and maybe some consolidation or maintenance, and that's when you're not going to see that, so I really think it's not totally wrong to say that there's genomic instability.

What I really think is wrong is to think about myeloma is a disease, that we are going to be able to deal with continuous therapy that also will generate genomic instability. Having myeloma cells around, they're not going to be behaving. I mean, I always say that when you live in a bad neighborhood, you're going to become bad, so you know want to get rid of these cells, so that's why I sort of like the idea that if it's feasible with a limited duration of treatment to get MRD negatively, why not? What do you think, Asad?

Dr. Saad Usmani:
Yeah, no, I agree with you. I think there are two important things and when we listen to other experts, it's very important. People say things in passing, so I want to be very specific about the data. What we comment on is this observation that actually came from the Memorial Sloan Kettering data set, actually. It was a paper that was published by us in collaboration with the Arkansas group, some European colleagues and with Ola and Francesca Mora in Miami now. And the observation is that high-dose melphalan increases the gene mutations in myeloma cells, but there is no data to suggest that that's a bad thing.

Why? Because the PFS is always better on the transplant arms. And the issue is that transplant has set such a high bar of progressions free survival. It's going to be very, it's a high bar and we'll have to beat it with frontline studies, which we do not have now, so until then we have to follow the data because if anything, one can actually argue the other case that if you have more genomic instability, you actually create more new antigens that the immune system can take those cancer cells out better, so I think that there are a few different ways in which we can look at that data, but I support what Dr. Abonour was saying.

Dr. Brian Durie:
All right. Great. Great. I'm going to cut you on, there's a couple of questions. Why is MRD status not standardized? Well, I think that the definition of MRD negative is standardized in that we have 10 to the minus five as the cutoff. You're not supposed to be MRD negative unless you're at least 10 to the minus five. But what I would say is the reporting of it is all across the board, 10 to the minus four, 10 to the minus five, 10th of the minus six. And so 10 to the minus six is obviously better in terms of outcome versus 10 to the minus five. But really we should not be reporting MRD negative unless one has achieved at least 10 to the minus five, either by NGF or by NGS. Then a question about the timing.

I think that the best timing for doing MRD testing is still a little bit up in the air. However, one question and some of the data you saw is that with ongoing therapy response deepens and so about 10 to 15% of patients will achieve their best level of MRD negative after or during the maintenance period. And so actually overall, one of the best times to do an MRD test is after about 12 months of treatment where the maximum number of patients will have had an opportunity to achieve MRD negative, if they're going to do that. In a relapse setting, it is probably a good idea to test the MRD a little bit sooner more in the six to nine month timeframe, so that maybe covers some of the things.

What is PFS? Yeah, some of these basic questions. What is PFS? Progression-free survival. This is basically the time that a patient stays in remission without the myeloma progressing, progression-free survival. How do we know for high risk? That is based on either the fish testing, which shows those problems with chromosome 17, chromosome number 1, 414, things like that. Or if relapse has occurred in that one year timeframe or if some other things have happened like plasma cell leukemia with myeloma in the blood or myeloma in soft tissue areas, what we call extramedullary myeloma.

Dr. Brian Durie:
Okay, Saad. I think we've covered some of the questions that were listed there. I think it's time to take a look at all of these exciting new immune therapies and how do we handle relapse in the first instance, and then how do we integrate into that some of the therapies that we've used for relapse versus these new exciting cellular and antibody therapies. Please welcome Dr. Saad Usmani, who is now the chief, I was going to say the head, but you're the chief of the myeloma service at Memorial Sloan Kettering in New York, having moved from Charlotte from the Levine Cancer Center there. Welcome.

Dr. Saad Usmani:
Thank you so much, Brian, and it's a pleasure to be on this panel with you and with Rafat. I look forward to meeting in person probably next month for the summit. I'm going to try to cover the relapsed myeloma landscape and try to build on what both of you have talked about, and then we would love to have a question and answer session and address other questions and concerns that patients may have. These are my disclosures. I'll try to start off by sharing that journey to that first relapse.

I think for the most part, regardless of whether patients are transplant eligible or ineligible, if we look at the landscape of myeloma treatment internationally, patients are receiving more three-drug and four-drug combinations today based on all the data that has been shared. And very rarely now do we use two-drug combinations, but I wanted to share the data there just to give an idea of all the different treatments that patients receive. And then as patients get into maintenance, typically it's with one or two drugs at the moment as a standard of care.

The expected median PFS or progression free survival, the period in which the patients remain in a good response after initial treatment until the myeloma starts acting up, those average months of median PFS that I've shared on the slide reflect the disease biology, whether patients have high risk or standard risk disease. As you can see, we have patients who have different treatments and different disease biologies. When they're relapsing, there are many different considerations that we have for them in deciding treatment. The way that we think about this is there are patient specific factors, which include their age, other comorbidities, performance status.

Then we also pay attention to how the disease is relapsing. Are there any high risk features to the disease? Are there myeloma cells circulating in the bloodstream, which is a little atypical and perhaps tells us about the myeloma getting aggressive? Or is the myeloma now spreading to lymph nodes or soft tissue or other organs outside of the bone marrow? That's called extramedullary disease. And then we also pay attention to what were the previous treatments received, what kind of side effects patients had.

I think one of the patients in the question mentioned the risk of second primary malignancy, which happens in a very small proportion of patients, but it's something that we do pay attention to as we're thinking about the next treatments in myeloma patients. All of these things are taking into consideration. The good news is that for our early relapse patients, we have many options. We have many three-drug and two-drug options with lenalidomide-based combinations, carfilzomib-based combinations, pomalidomide-based combinations. And then there are other treatments like selinexor being approved with one of the proteasome inhibitors, bortezomib, dexamethasone.

And then for translocation, 11;14 patients, there's a drug venetoclax that is quite active. For certain patients, we can actually get it approved through their insurances and use it to good effect. I wanted to mention all of these options to give an idea of measured hope to our patients that we have so many options. I still remember a time, and I'm sure Dr. Durie has actually been such an integral part of this therapeutic landscape journey, that we did not have many options. We only talked about one or two drugs even when I was in my training trying to become a myeloma physician and researcher. We have come a long way, and there are so many other options that we have for our patients.

As we think about all of those factors when patients are relapsing for the first time, we want to see if they have been on lenalidomide and are progressing on it, because the treatment options for those patients are going to be different than patients who are not refractory to lenalidomide. And then for patients who relapse after that second line of treatment, we try to use options that have been not used before or try patients on clinical trials, and then autologous stem cell transplant for young patients who either did not receive a transplant as part of their initial therapy, or they actually had a very good response to that initial transplant.

That's something that we do consider for for patients. But what about later? This is where there is so much excitement about the promise of T-cell redirection. What does T-cell redirection mean? T-cells are a very important part of our immune system. There is a strategy called CAR T-cell therapy where we can take a patient's T-cell, teach that T-cell through introducing an engineered protein moiety to help recognize the cancer cells. In this case, there is a protein called BCMA on the surface of myeloma cells that these T-cells are taught to recognize, and then they're grown ex vivo or outside the patient after the collection.

And then once they've expanded, when we have enough quantity, we give patients a lymphodepleting chemotherapy and then infuse those T-cells. These T-cells then go identify myeloma cells and take them out, and they also expand. That's one way of using patients' T-cells. We now have two CAR T-cell therapies that are actually approved for advanced myeloma patients. Then the other technology is what we call bispecific antibodies or bispecific T-cell engager. The difference between those two is the peptide structure essentially, but they're doing the same thing.

One part of that structure can recognize a specific surface protein on the myeloma cell, and the other part recognizes CD3 on T-cells. It brings patients' T-cells to the cancer cell and helps skill the cancer cell. If we look at our T-cells, and I promise I'm not going to be taking a quiz from you guys on this, you don't have to remember all this data, but the only part I've highlighted is how impressive the responses we've seen with CAR T-cell therapies. If we look at the previous drug approvals we've had in myeloma with pomalidomide, daratumumab, carfilzomib, all those drugs, the overall response rate was between 25-30% of overall response rate.

Here, for very advanced patients who've seen five or six or more prior lines of treatment, we are seeing responses well over 65-70%. In case of Cilta-Cel, which is an FDA approved BCMA CAR T-cell therapy, in that single arm trial, the overall response rate rate was 98%. Almost every patient responded. Very remarkable results with CAR T-cell therapies have been seen, and we have two approved products that we utilize for our patients. We are starting to now move those treatments into earlier lines. Here is an example of Ide-Cel, which is a BCMA directed CAR T-cell therapy. In fact, it was the first one that was approved by the FDA.

This is data that was presented at ASH where we looked at patients who have early relapse after autologous stem cell transplant and what happens to these patients if we give them treatment. This was a group of patients who did not have a good response to their initial treatment. In fact, only 24% of these patients had a complete response. When they got this CAR T-cell therapy, the overall response rate is 84%. But look at that complete response rate, 46%, even better than the first line treatment is what they got. Similar results have been seen with the Cilta-Cel as well.

But the bottom line is for our difficult to treat functional high-risk patients who are relapsing early, these CAR T-cell therapies are showing very good promise. We're looking forward to having these therapies available for our patients in the future in earlier lines of treatment. It's not that BCMA is the only target. We have another new target called GPRC5D. Again, my previous colleague, Eric Smith, who is now in Boston, he actually as a fellow identify GPRC5D as a target in myeloma and started to develop a homegrown CAR T-cell therapy. And that GPRC5D directed CAR T was then licensed to BMS for further development.

This is the early data that was shared at ASH with some of that experience, heavily pretreated patients with high proportion of patients with high risk cytogenetics, as well as extramedullary disease. And then 40% of these patients actually had a prior BCMA directed CAR T-cell therapy and additional 15% had BCMA directed other treatments. With this patient population, you can see that very high response rates were seen with this particular CAR T-cell therapy. If patients did not receive a BCMA directed treatment, 100% response rate. Even in those who had prior BCMA, 78% response rates were seen and very high rates of complete responses.

Even though the numbers are small, this is a very important slide demonstrating to you the wonders that these immunotherapies can do for our patients. We are really looking forward to further developing this specific GPRC directed CAR T-cell therapy for our patients. If we look at the safety profile... It's not just important to take a note of the activity, but we also want to see if we can manage the side effects of these therapies. What was important to see that unlike some of the CAR T-cell therapies that our lymphoma colleagues use, the neurologic side effects appear to be lower than that patient population for our myeloma CAR T, whether it's BCMA directed treatments or GPRC5D directed treatments.

I think one thing that we all are concerned about and have to keep an eye on is the infection risk for patients as these therapies are utilized more in clinical trials. The other important group that I talked about is bispecific antibodies. This slide actually shows you the why there are so many different ones. Depending on the structure, these are bispecific antibodies or T-cell engagers, can take different parts of the immunoglobulin structure, put them together, and that creates different kind of half lives for these antibodies and different kind of targets that they can bind to. They can bind to the same target, but different parts of that same target.

That's why you're going to see a lot of these different bispecific antibodies. They're going to vary in the kind of characteristics they have. Teclistamab, I appreciate Dr. Durie actually giving me a shout-out for helping with this first FDA approval and a lot of hard work and contributions from our patients, caregivers, as well as the study team. But there are many other bispecific antibodies that are coming down the pike. Teclistamab was our first one, first BCMA directed bispecific, but we also have elranatamab, which is knocking at the door for an FDA approval. We have the ABBV-383, which used to be called the Teneobio 383B.

We have Alnuctamab. We have the Regeneron, bispecific which is now called Linvoseltamab. We are going to have many different bispecifics. The good news is each of them are very active, but they're probably going to have different schedules because of half lives. We'll have to figure out how best to use them in the clinic. And then for academic centers, the use may be a little different because we have access to a more dedicated inpatient service that can care for these patients. Whereas for our community colleagues, the challenges might be a little different. We have a lot of work to do on working out the logistics.

Elranatamab, very similar to teclistamab, the overall response rate for a relapse refractory myeloma patient population, patients who've seen five different lines of treatment, again, response rate is very impressive at 61%, very similar to what we saw with teclistamab at 63%. The good news about if you look at this progression-free survival curve, there are patients who have stability of response. There is durability of response with these bispecific antibodies. However, the important risk that we need to consider is the infection risk, and that's what you see in this right table here.

The way that the original bispecifics have been studied in clinical trials is to continue giving them on a weekly or every other week basis depending on their structure and their PKP, pharmacokinetics and pharmacodynamics, their half lives. But we are now learning that we can give it less frequently to patients or give it for fixed duration of treatment. That infection piece is something that we as researchers are looking at right now to help make it a better option for our patients long-term. All of us have those anecdotal patients who've been on these therapies now for many years on clinical trials.

Alnuctamab is another bispecific antibody. It's showing, again, very similar kind of response rates and the same signal that we see with infections is being seen with this particular antibody as well. I think it has to do with the BCMA bispecific portion of it. Again, overall response rate, very similar, in the 60s percent. Overall response rate of 65% being seen with this particular bispecific antibody as well. Instead of just going on and on about the BCMA ones, I wanted to talk about Talquetamab, and I'm sorry, my slide because of the I guess MacBook versus other, the formatting changed a little bit.

Talquetamab isn't showing up the way it should, but the development of this particular specific was led by my colleague Dr. Ajai Chari, who's actually moving to the West Coast, Dr. Durie, to be closer to you in San Francisco.

Dr. Brian Durie:
That's right. San Francisco.

Dr. Saad Usmani:
Yes. This bispecific showed very high response rate in the 70% range and two different doses were studied, the 0.4 milligram per kilogram being given weekly and the 0.8 milligram per kilogram being given every other week. It looks like the durability of response may be better for the Q2 dosing. The data looks promising. I think this is being examined by the FDA right now, so we'll get a better idea of the approval timelines I guess later in the summer. Even in patients who have had prior CAR Ts or prior bispecific therapy, we are seeing response rates of 62.7%.

It's important to see that this is an important question that I think many doctors and researchers are asking how best to pick one treatment versus the other. Can we sequence treatment? What we're finding with these different treatments is that patients do respond to other therapies in terms of sequencing. The response may not be as robust or good, but patients do respond to treatment. I think that's another message that you can go from one treatment to the other immunotherapy treatment. And then with GPRC5D, we just learned about this new bispecific called forimtamig. Forimtamig actually has two different epitopes or parts of the GPRC5D structure that it binds to.

Initially, it was looked at as an IV formulation and now there's a subcutaneous formulation. The interesting thing about this one is the dosing is every three weeks. It's not on a weekly basis like talquetamab. You can give it less frequently. The data were early, but response rate is, again, in a very similar kind of range. You can take one structure and show the same kind of responses in highly relapsed refractory myeloma patients. The safety profile, any cytokine release syndrome side effect that patients get, it's quite manageable, grade one or two for the most part. Very few patients get high grade symptoms.

Just to give you an idea, I think we had Anne wonderfully talk about what cytokine release syndrome is, but grade one cytokine release syndrome is just having a fever and taking Tylenol. I think understanding these grading is important for patients as well, but it's very, very manageable. There are also efforts to improve cytokine release syndrome. There is a medicine called tocilizumab that we typically give to patients when cytokine release syndrome happens.

But in this study, Dr. Trudel, a wonderful colleague from Princess Margaret Hospital in Toronto, Canada, she did a study where she compared giving cevostamab, which is a bispecific that targets a different surface protein called FCHR5. They did a study where a group of patients did not get any preemptive tocilizumab, another group got tocilizumab to prevent CRS, and they saw quite a bit of reduction in the overall percentage of CRS between one arm versus the other. Just telling us that there are going to be strategies that we can use to reduce the cytokine release syndrome for our patients. And then now I want to talk a little bit beyond the CAR Ts and bispecifics.

What we used to call immunomodulatory drugs, there is a newer class of drugs that belongs to that same family, but they're called CELMoDs, because they modulate the immune system. There are two different agents, iberdomide and mezigdomide, that have different ways in which they can affect the proteosome machinery in trying to kill myeloma cells. One of them is more active or hypothetically more active and more proliferative kind of myelomas, and the other drug is more immunomodulatory or cellular modulatory in nature. These agents bind to a protein called cereblon, and that reduces the likelihood of degradation of certain proteins within the cell that can lead to this modulation.

With iberdomide, this particular CELMoD was studied in an open label dose escalation and expansion study on its own and then in combination with other therapies. My colleague Dr. Sagar Lonial from Emory is leading this study. What Dr. Lonial has shown is that iberdomide was active on its own in about 30% of the patients. But in combination with daratumumab and with bortezomib, along with dexamethasone, it appears to have a very similar safety profile to what we have seen with lenalidomide or pomalidomide. Very similar safety has been observed. And then the overall response rates even in patients who have had these therapies before appears to be quite high.

Very promising results even in patients who have seen therapy drugs in that same class, even in patients who were daratumumab or bortezomib refractory getting this combination, they appear to respond. That gives us that there is this new class of these oral therapies coming that will actually be more effective for our myeloma patients. And then same is true for Mezigdomide. This is a little bit different than iberdomide in terms of how quickly it can act on proliferating myeloma cells. This may be an important CELMoD for our high-risk patients and patients with extramedullary disease.

Dr. Paul Richardson had presented these early data showing an overall response rate of about 50%, or rather, sorry, 40% in all the patients, but 50% in patients with prior anti-BCMA treatments. Now Mezigdomide is being combined with bispecifics and other proteosome inhibitors. We are going to hopefully see more data with this particular CELMoD later this year at ASH. And lastly here, I do want to mention this, another very interesting mechanism of faction being called immuno cytokine. This is Modakafusp alfa, which is a CD38 targeted treatment, but it delivers interferon alpha 2B to CD38 positive cells.

CD38 is the same target that daratumumab and isatuximab utilize to help kill myeloma cells for our patients. Very interesting data in this particular study. You can see that this study had one part where there was a dose escalation to figure out what's the right dose for patients, and then there was an expansion of two different doses, and this therapy is given either every three weeks or every four weeks. But if you look at the patient population enrolled on each of these on the study, vast majority of patients, 85%, 85 out of 100 patients, had prior anti-C38 antibody and they had become refractory to it.

Despite that fact, what we see in patients here is a response rate of 43%. If we look at patients who were either daratumumab or isatuximab refractory, we are seeing a response rate of 39%. Despite the fact that the patients had seen CD38 treatments, the response rates were quite high. In prior patients who had BCMA exposure, overall response rate was 27%. In those who did not have BCMA exposure, it was 60%. The important thing about the response is it's durable. The median duration of response was over a year, 12.5 months. All of these therapies are very exciting and there are a lot of possibilities for us to use each of these therapies in earlier lines of treatment.

This is what we are doing for the CAR T-cell therapies and the bispecifics, but the CELMoDs and Modakafusp won't be far behind as well. We just have to come up with a good rational way and figure out which patients would benefit from which therapies. The key message is of measured hope that there is a better future ahead for all our patients, and we are all in this together marching towards that goal. In the end, I would like to acknowledge the myeloma service team at MSK, as well as our transplant cell therapy team. Thank you so much for this opportunity, Dr. Durie.

Dr. Brian Durie:
Well, thank you. Thank you so much, Saad, for that comprehensive overview of these exciting therapies, the immune therapies and then also these more targeted therapies that you just discussed at the end. While you've been talking, a lot of interest, a lot questions coming in. I don't know how many we can handle, but I think that one key question is related to the sequencing.

There's so many exciting things. I think that one important question comes in from Jack Aiello, for example. If a patient has relapsed on a BCMA CAR T, would you consider a BCMA bispecific, or would you move over to a different target? We already have some data that relate to that. Maybe you could comment on that first, relapse for BCMA CAR T.

Dr. Saad Usmani:
Yes, we have some real world data, Jack. By the way Jack, it's good to know that you are here on this platform. We have data from the CAR T Consortium that was actually presented at ASH looking at the real world experience of patients receiving Ide-Cel and then what happened to their outcomes and what subsequent treatments they received. What we find is yes, you can use other bispecific therapies, but the duration of previous exposure has to be more than six months.

That's not just from the CAR T Consortium data, but also from the Mount Sinai experience. There are a few other examples of experiences. If someone had a BCMA CAR and they got more than six months of response and the CAR T-cells are gone, if the myeloma starts coming back, the BCMA on those myeloma cells doesn't go away and one can utilize a BCMA directed specific. However, if they did not respond and they're progressing, then it's better to use a different target.

Use a GPRC5D in that case. That's how we're thinking about it right now, but I think we'll have more data later this year because one of my fellows is actually looking at this and also looking at immune profiling to figure out if we can tease out who would benefit from one strategy versus the other.

Dr. Brian Durie:
Right, right. As I think actually Jack knows, we do have this immune therapy registry or database starting. I think, Saad, you're participating in that where we're trying to have real world data so we can try to answer all these questions. Can you go from CAR T to a bispecific, from a bispecific to a CAR T? And then what happens if you switch from one target to another?

But I think that what was exciting to me was to see the very strong data with the GPRC5D, both the bispecific, the talquetamab, as well as the early data with the CAR T with this target. Very exciting actually. Let's see. Let's go through some of these other ones here, sorry. Can you try several bispecifics? I think that's certainly true.

Dr. Saad Usmani:
Yes, we can. In fact, we have anecdotal experience with someone who did not respond to one bispecific antibody because the target was different responding to another bispecific antibody. I think just as Dr. Durie said, all of us are trying to put our cumulative experience into this big International Myeloma Working Group database database, and it's led by our colleagues, doctors Tom Martin and Elen. We'll get to understand this better, how do we sequence these treatments?

Dr. Brian Durie:
Right, exactly. There's a sensitive point here. A patient with kidney failure, are they eligible for bispecific antibody trials or treatment? Is there an exclusion by renal status? I'd imagine if you have renal failure, that's a problem, right?

Dr. Saad Usmani:
Yeah. For clinical trial purposes, because these were early phase clinical trials, I think there was a cutoff for estimated GFR of 30 or more. But in the real world experience, we are treating patients who have lower EGFRs because we need to provide these treatments for our patients.

Dr. Brian Durie:
Absolutely.

Dr. Saad Usmani:
That will be another benefit of the cumulative wisdom that we collect under the International Myeloma Working Group umbrella in our immune database.

Dr. Brian Durie:
Right, right. We'll see how that all works out. Yes, yes, yes. Out of nowhere, STAR-LLD lenalidomide patch, do we have experience with that? I don't. I don't know that anyone's used that particular patch. Anne, did you know about the STAR-LLD lenalidomide patch?

Ann McNeill RN:
No, I have not heard of it.

Dr. Brian Durie:
I've actually heard of it, but I haven't seen use of it. Yes, yes. Well, I think that we've given a lot of insight to patients that these are so striking new therapies, so many of them with promising, promising results. 62% response seems to be a magic number. Many of these bispecifics have a 62% response rate. I don't know what that means, but maybe in closing we could have some comments from each of you. Maybe Rafat, of all of these exciting therapies, what are your top one, two, three that you think are really going to have an impact moving forward? You're muted. You're muted. You need to unmute.

Dr. Rafat Abonour:
You heard how complicated the field is. It's really not an easy answer. I've been doing myeloma for a long time, and I remember the early days of testing lenalidomide and bortezomib and the responses we got. And then we get the carfilzomib, and then we get the anti-CD38 antibodies. We studied those in relapse patients and very difficult patients. What I have not seen is the responses we've seen using bispecific T-cell engager in patient with advanced myeloma.

I mean, when you look at patients who have no count, have a plasmacytomas growing everywhere and basically you almost were able to get them on clinical trials, almost met the criteria for clinical trials and you put them on this bispecific T-cell engager, and then in six weeks, they're back on the motorcycle. It's just unbelievable.

Dr. Brian Durie:
Right, right. It is remarkable.

Dr. Rafat Abonour:
I think the bispecific T-cell engager is just opening the door for understanding something really important, because we have the myeloma cells in the body and we have the T-cells in the body. Why you just need to bring them close to each other and that's what you get the benefit. Is it really that simple? I don't think so. Basically what I tell the patient is that when we give you the bispecific T-cell engager, it's like when you're having a bad infection, the T-cells get activated. They get angry. They produce cytokines. Some of these cytokines are good, they're destroying the myeloma cells, but there's some of the cytokine causing the fever, the tachycardia, hypoxemia.

I think the science is going to be amazing when we discover how these T-cells are now recognizing the myeloma. What is the antigen? Is it really the BCMA antigen or some of these other antigens that we don't know? I'm really excited about bispecific. I think the way that we use them now, even in advanced disease, the ability to manage the side effect is incredible and I think that's really where we're going to build the future of myeloma therapy around that.

Dr. Brian Durie:
Fantastic. Anne, I'd be interested in your comments in terms of patients that you've seen. We haven't really talked about this. For the BCMA bispecific like the teclistamab, there are concerns as patients stay on the therapy about the infections. However, with the talquetamab, this seems to be less of a problem. Do you have any comments about that?

Ann McNeill RN:
I do a lot of inpatient myeloma work and I agree that the bispecific teclistamab, we've had quite a few admissions since the beginning of the year, and we've seen some nice responses from a myeloma perspective. But unfortunately, some patients have had to discontinue therapy. We've had some very challenging infections. As Dr. Usmani mentioned during his presentation, the infections are quite problematic at times.

We've had some fungal infections and some issues where patients had to discontinue therapy. Great drugs for myeloma, but again, they come with some issues that are quite challenging. Again, from a myeloma perspective, some very good outcomes.

Dr. Brian Durie:
I think just my 10 cents before I go back to you, Saad, for some final comments, but I mean, with that in mind, for me, the CAR T approach, the one and done, you have a decisive therapy with the CAR T that is working, that is more attractive in my mind. If we can come up with a second generation or a third generation CAR T, maybe incorporating both BCMA and GPRC5D, whatever, maybe for me, if those could be made accessible, the problem is access, that would be a way to go. What do you think, Saad, in the balance between the bispecifics and the CAR T?

Dr. Saad Usmani:
I think there is clearly merit in the CAR T technology potentially having... If we can overcome the cost accessibility globally and reliability of how quickly we can produce it and get it to our patients, I think that approach of giving it and patients recovering from it and then not being on anything is very attractive. But we have our work cut out. The other piece of this is I think we are probably going to have patients who are not going to be eligible for CARs because of age or comorbidities and other issues where I think the bispecifics may come into play.

But these are good problems to have with those responses and figuring things out. I do feel that CARs will win for majority of patients, but then we will always have room with bispecifics. I think to Anne's point, we are learning to limit the duration of treatment with bispecifics. I want to share one anecdote, because it's one of my patients who was on the MajesTEC-1 trial who came off of treatment because of recurrent URIs with funky infections like NSAID after eight cycles of treatment, and then stayed in an MRD negative state without any treatment for almost three years, just like they would with CAR T-cell therapy.

They had never been off of any treatment. This was their 16th line of treatment and they had been always on something continuously. I'm just sharing that for some patients, even the bispecific use for a short duration would be able to give you the same outcome as CARs.

Dr. Brian Durie:
Right, right. I think that this is a key point. As I know you're aware, Saad, I think that some studies with that, limiting the duration will be quite key moving forward to get the efficacy and try to limit what can be pretty challenging toxicities with those infections. I think that we've had a lot of really excellent presentations and discussions. I'd like to thank all of you for participating, take time out of your really, really busy schedules. Anne, Rafat, and Saad, really, really appreciate it. You can have some late dinner now. I'm not sure how you're going to handle that, but...