The Best Way to Manage Multiple Myeloma During COVID-19

- Everyone to today's webinar, Best Myeloma Management in this Era of COVID-19. Very pleased that so many patients, and caregivers, and supporters are able to join today. Very happy that three experts have set aside time on this Saturday to join us and give us the benefit of their knowledge.

Dr. Rafat Abonour, from Indiana University, so welcome, Rafat. Kevin Brigle, from Massey Cancer Center in Richmond, Virginia. And Dr. Noopur Raje, from Mass General in Boston, Massachusetts. So thanks to them for joining us today. We are very pleased to have the support of our sponsors, Amgen, Binding Site, Bluebird, Bristol Myers Squibb, GSK, Genentech, Janssen, Oncopeptides, Takeda, and Sanofi Genzyme.

Welcome to the program here. This is the summary of the agenda. I'll show you the agenda, which is broken into two parts. First of all, there is this welcome, which I'm doing right now followed by a 101, and then Life is A Canvas, looking at the different side effects and symptom management with Kevin Brigle. And then what has become a very important topic is COVID-19. And so I just wanna let everyone know that we will move forward, so that we have plenty of time for the panel discussion about COVID-19. Particularly the new information about the third booster shot, which was just approved by both the FDA and the CDC. And so we will be able to discuss the details of those recommendations and try to answer questions that you might have. And then we'll take a short break, and then after that, we'll come back. And very excited to hear an update from Dr. Raje about the immune therapies, and from Dr. Abonuor about what are the currently approved approaches to relapse management. And again, we will have plenty of time for discussion.

This first 101 session is intended just to give a broad background with some updates for everyone. Looking at everything from initial diagnosis, testing, initial therapy, and general expectations, for the myeloma management in 2021. Some key points just for everyone to be aware of is it when a patient is first diagnosed, or aware of myeloma, it is a treatable condition, and over 90% of patients will respond to initial current therapies. And so this is really the very good news.

And with the new therapies, the average first remission for most patients will be four years or even longer, as you'll see in data that we're going to talk about. And in 2021, the average survival has extended out beyond seven years, out to 10 years. And some patients can even be living out into the 15 and 20-plus year category. And so, although we will talk about it, we're not able to recommend a therapy that will cure myeloma. Certainly we are expecting these kinds of initial results. And new therapies are constantly improving the outlook. So to get those best results, expert consultation really does help. And I think that we all recommend to get, if you can, at some type of expert consultation initially, to make sure that you're on a good path forward.

And so that expert can be available these days through a virtual consult, which have become much more available and accessible. And so I would encourage all patients to seek that out. It doesn't mean that you need to give up your doctor, but you can get some expert input, and make sure it, particularly initially, that your initial choices in therapy, and other supportive elements are good. This can really have a joint plan with you, and your local doctor, or doctors, your myeloma expert, and maybe even your GP, along with an outside expert. And you see that we provide a link here of questions that you can be ready to ask your doctor. The sort of things, where you really do need to have some answers to help understand the disease, which is a complicated disease. and some of the details of expectations about the treatment.

How quickly will you respond to treatment? How will we know if you're responding to treatment? Some of these key initial questions that so many patients have. And so, increasingly, we get questions from patients who have smoldering myeloma because indicators of an abnormal myeloma protein are often picked up much sooner than they often were in the past. And we have been looking at indicators that will indicate whether or not a patient with early disease, either just a monoclonal protein discovered in the blood, or with some other features, actually have some kind of what we call a smoldering myeloma, which could progress into myeloma at some point.

And so the question is, what are the tests that can help determine, is a patient likely to be on that path for some progression? And in general, we've been looking at that risk of progression within 18 months to two years. And so we have been working on a new SMM, Smoldering Myeloma Risk Scoring Tool. And the three tests which turn out, right now at least, to be the most helpful are the 2/20/20 model. Which is two, is the level of the serum myeloma protein in the blood, so two grams per deciliter. 20 is the free light ratio. And then 20 is also the percentage of plasma cells in the bone marrow. Patients who reach a combination of those levels are the ones who are at the highest risk of progressing within 18 months to two years.

In the scoring tool, we've broken it down into different levels. You can see, there's not just a single break-off point. We've broken it down into three or four different categories for each of those factors, the free light, the serum protein, and the bone marrows. And then you can come up with a score. And I'd like to emphasize three things about the scoring. First of all, we have that low risk group. And so if the numbers are low, the risk of progression is really very, very low, even out to five years, or beyond. And so this is very, very reassuring if the numbers are in those lower categories. And then in the higher risk group, you can see if you look at the bottom, some of the higher numbers for scoring fall into the bone marrow plasma cell percentage. And so one of the biggest factors, which indicates a possibility of spreading. And active disease is if the bone marrow plasma cells are increasing from 20%, to 30%, to 40%, or higher, and this confers a higher risk.

And so when should treatment be started? And so obviously for myeloma patients, if you have the CRAB features, which I'll show in just a moment, then there is active myeloma. If there are none of these features, then this is where it falls into these smoldering categories, where we need to think about, do we want to observe, or treat in some fashion? And so for the low risk group, observation monitoring definitely recommended. In the intermediate group one certainly can consider therapy, and there are options of trials. And then simple things that could be either two drugs like Revlimid and Dexamethasone, or Velcade, Revlimid, or Dex, or even something in a trial setting that could include even four drugs, next slide.

But really one of the main things that we're looking at right now is what we call the ultra high risk, where the score is 12, or higher. And in this group, there's a definite risk of progression. And so we are thinking that this kind of a patient should at least receive something simple like Revlimid, or maybe even something like a three drug combination. To be looking at the diagnosis in this way, you need to have these baseline tests.

So obviously in myeloma, the bone marrow indicates the percent of the myeloma. And as you just saw, the percentage of the plasma cells has a big impact in assessing the amount of the disease, and whether it's likely to progress in the coming months. But we also need to have an indication of, in your case, what is the tendency for the myeloma to cause damage to the bones? And this varies a lot from patient to patient, where those plasma cells, in some cases have a strong tendency to damage the bone. In this X-ray here, you can see the tiny black areas in the arm of a patient, and the bones, the radius and ulna bones there. And those are areas where the myeloma has triggered some areas of damage that we call focal lesions. Lesions of the bone areas of damage. The myeloma is in the middle part of the bone, which is kind of like a tube. And then as it's growing outwards, it damages the area around the outside of the tube, so to speak, next slide.

And so if we're looking at the diagnosis of myeloma, the criteria that we use, or the CRAB Criteria, which include if the blood calcium is elevated, if there's kidney problems, the creatinine, if there's anemia. And if there are any of those bone lesions that I was just showing you. And then for the new criteria where you may or may not have symptoms, we look at the percentage of plasma cells by itself. And 60% is highly linked to early active disease, as does a free light ratio of a 100 or better. And if you do have more than one lesion on some type of imaging, next slide.

The two additional types of tests that are the most helpful, and many patients will have seen or been given results of these tests, one of them is the chromosome tests, which is evaluated using FiSH testing. This is a testing which has to be done on the bone marrow sample. So at the time when the bone marrow sample is taken, it needs to be sent off to the lab, and tested with a fluorescent in situ hybridization, a fluorescent color test. Where the pathologist can look and see if the colors are mixed up, which tells if there have been changes in the chromosomes, where pieces have been added, or parts have been lost or moved around.

And this can indicate whether the myeloma is a standard risk, or maybe at a higher risk of early relapse. We then look more closely at the bones beyond X-rays using MRI or PET scanning. Clearly these are much more sensitive, and they will show lesions, which have not shown up on X-ray. Although the standard testing for myeloma these days is not just the regular X-rays, but whole body, low dose CT. And if this can be done up front, this is particularly helpful to document or assess the amount of bone damage, next slide.

And so just broadly, the major components of the treatment are linked to the age of the patient, and the general health of the patient, and any other complications the patient might have. The initial therapy is often the same, or very similar for older patients, or patients who are not able to undergo autologous stem cell transplant. After initial therapy, there is consolidation in maintenance. And if a transplant, an autologous stem cell transplant is discussed and planned, this can be done after four to six cycles of therapy, and then maintenance therapy after that. A very, very nice source of an update is an annual update that is provided by Dr. Vincent Rajkumar. We provide a link here to Vincent's most recent overall update for diagnosis and initial management, which is I think quite helpful, next slide. I think the fantastically good news for myeloma patients is that in the little bit at the bottom of the slide you'll see the old therapies that we used to have.

But then starting in 1999, 2001, 2002, we started to have the availability of the new therapies, the IMiDs, Thalidomide, Revlimid, and Pomalidomide, the proteasome inhibitors, Velcade followed by Carfilzomide, and then Ixazomib. And then all of the new immune therapies and other novel therapies over in the relapsed or rescue section. And we have so many of those now. The most recently approved being the Melflufen, the Belantamab, the Selinexor. And so many, many options, which is very helpful, if the disease has relapsed, or is not coming under control. The standard of care, at least using three drugs continues to be the VRd, which is based largely on the SWOG trial, which compared the three drugs Velcade, Revlimid, and Dex, Bortezomin, Lenalidomide, and Dex versus Revlimid and Dex, Lenalidomide and Dex, next slide.

And so the main thing here is that there is a basic level of response and survival that we can now expect, using just this type of a three drug regimen. And so the first remission is between three and four years. And the overall survival has improved, so that over half of the patients are continuing to do well at seven years. And the other thing that you can see here is that the red curve is the VRd, but you can see that the doublet, the Revlimid index, those patients are also doing really quite well. And so an elderly patient, or a more fragile patient can also do quite well if they are taking a doublet, if that happens to be what is feasible, next slide.

And so what does that mean that patients can expect these days in 2021? Well, using a triplet or adding in, and maybe even a quadruplet, if we add in anti CD38 monoclonal antibody, such as Daratumumab, or as Rituximab, we can have a deep response in the vast majority of patients. And then that first response can be in the four year range. And as I'll show you in a moment, even in out to five year range. And then we have the option to come in early, and that second response, if you come in early can also be a significant and substantial response. And before you know it, a patient can be out in that five to 10 year level and beyond. It really is amazing that we can have these expectations for treatment in 2021, which are so different than they were 20 years ago. Next slide.

And so right now, when we start out, we're looking at that VRd triple therapy, which can be enhanced to make it a quadruplet by adding Daratumumab, for example. And then the big option is whether we should conduct an autologous stem cell transplant. And this has become much more of a discussion point, because early autologous stem cell transplant clearly improves the length of a first remission. However, the data are not there yet to show that that really impacts the ultimate overall survival. We still recommend using bone therapy for all patients, either Zometa or Aredia, or the newer agent denosumab, which is obviously much more convenient and equally active. Next slide.

I just want to draw attention to something that happened this year at the European Hematology Association meeting virtual, where Theirry Facon from France presented the results with the three drug combination. Rather than using Velcade, Lenalidomide and Dexamethasone in the frontline setting for transplant ineligible patients, he had a study using Daratumumab, the anti CD38 monoclonal antibody combined with lenalidomide and Dex. And these results in this Maia trial have been really amazingly good, next slide, yeah

. And so this shows you what we call the progression-free survival, or the length of remission with the three drug combination, Dara, Rev, Dex versus just the Rev, Dex. And you can see that at 60 months, five years where that dotted line comes down, 52.5% of the patients are still in remission. And so really a substantial impact in that first remission out to five years.

And if you go to the next slide, overall survival, doing very, very well out at five years as well. And you can see that even the doublet is doing quite well, but clearly the three drug combo is 10, 15% better. So obviously in that trial, you can continue with the combination therapy Daratumumab. One advantage of the Daratumumab is that you can continue to take that. Other typical maintenance therapies are to use Revlimid as a maintenance plus, or minus Velcade or Ninlaro, which is oral and has a lesser impact in terms of neuropathy. And you'll see that we give you a number of articles. There are references that discuss the role of maintenance in different settings. We would tend to use Velcade or Ninlaro in patients who have more of those high risk chromosomes on the FiSH testing. Next slide.

So what are the overall strategies? Well, for now, the strategies are to use three drugs, or add in a fourth drug such as Daratumumab, or Isatuximab with VRd or KRd if Kyprolis is used as the proteasome inhibitor, instead of Velcade. We adjust the maintenance in terms of the risk factors. I think increasingly we want to come in early, if there's any indication of relapse, and come in with a triplet again, to have a very significant next remission. And now, and we'll hear about this more from Dr. Raje later, what is the impact of these new immune therapies, which we're also looking to bring in earlier in patients who might benefit?

And obviously, we're not forgetting about the caregivers, and the International Myeloma Foundation. We're very much focused on trying to enhance our programs specifically for caregivers. In this next few months and years, we will be talking more about programs and activities that are more specifically targeted to help caregivers who are such a key part of the caregiving team. And so a lot of this is available on our website. And so thank you for your attention. I hope that this has been a helpful introduction, just an overview of where we are. Really a very positive situation right now, in terms of initial options that can be offered. And then as you'll hear later in the program, the many backup options, if other therapies are needed moving forward.

So I'll stop there for now. And so as part of the program what we'll do is move forward. I see that we have there's questions coming into the chat box already. We'll be starting to be ready to answer some of these questions.

But in the meantime, I'd like to invite Kevin Brigle to go ahead and tell us about Life Is A Canvas. The artist in Kevin is going to reveal his perspective on side effects and symptom management, Kevin?

- Thanks, Dr. Durie. I am no artist. This is a slide deck that's put together by the Nurse Leadership Board of the International Myeloma Foundation of which I'm a member. It actually consists of 18 nurses and advanced practice nurses. And this slide deck is updated yearly. And the goal of the Nurse Leadership Board is really patient education and nursing education in terms of a multiple myeloma. And this particular slide deck is Life Is A Canvas. And so yeah, this is the artist part of this.

This is really thinking about, again, you are painting the picture of your treatment from basically from diagnosis through the whole course of treatment, and some of the things to think about as well. This artistic theme, this is actually a short version of this particular slide deck developed for this webinar. And you guys are the first to see it, so it changes from year to year. All right, so again, you are the canvas. And I'm sitting in Richmond, Virginia now, beautiful day, a little sunny and a little hot.

All right, so when we think about painting a picture, of course, we first have to start off with what are your goals? And I think the important part of this down here is listed in terms of discuss your goals with the priorities with your healthcare team. Now they should align. So what you think is important in life should align with what your providers and the patient, and the individuals, the individual care team who's treating you are thinking about. So in terms of the care team, they're thinking about, of course, myeloma treatment and supportive therapies. In terms of myeloma treatment, it's that getting that disease under control quickly.

So rapid effective disease control. We want it to be durable as well, as Dr. Durie said. Now we're getting, at least with initial therapies, we could see maybe four to five year duration of therapy, which is pretty impressive. And that then translates into improved overall survival, which is really what we're looking for is increased overall survival. But along the way, minimizing side effects is always important. And again, the whole point here is allowing for that good quality of life.

And that's where the supportive therapies come in. And that's preventing both disease related side effects, and treatment related side effects, and managing those things. And again, that's what the Nurse Leadership Board really focuses on in terms of nursing education as well. So optimizing symptom management, and you can see again, allowing for a good quality of life. So not just having a longer time, but improving that quality of life as well. So in of medications, and I think Dr. Durie's touched on this as well.

The color wheel, our treatment options has never quite been quite this robust. It's really pretty impressive. And across the top, this particular slide looks across the top, the various classes of drugs, or agents that are available. With Mibs, which are the proteasome inhibitors, the Mabs, with monoclonal antibodies, the Mides, or the immunomodulatory agents. We have steroids, alkylators, immunotherapy, and cellular therapies.

As we move down those you can actually see some of the agents that are in those, such as Velcade Kyprolis. And you might be familiar with all these from things which maybe you or if you're caregiver that the person you're caring for has received. And so we're looking at really about eight different categories, 14 different drugs. We've had two approved this year. And so we're not talking about just one of these drugs, you know, used by itself. But again, it's a tapestry.

Now we're able to mix medications and find something that's really the perfect color for you, if you wanna continue in that type of metaphor as well. And so if we look at the most recent NCCN guidelines for relapsed refractory disease, there are 47 regimens that are listed in there. So again, these are combinations of different regimens things as well. Now, you can see again, those medications are listed there. Of course, across the bottom, you can see the noted side effects. And that becomes the part where we really have to manage, not just the disease, but manage the side effects, potential things that are related to the therapies, which we give you.

Now, unfortunately, some of those side effects might guide, and/or actually suggest what treatment we might use. So if you look at that first category, we see neuropathy, we think about the drugs, which cause neuropathy. Well, if a patient is an older patient, and has really severe diabetic neuropathy, it may negate using a specific drug, because of the risk of neuropathy worsening. That neuropathy is going to be worse. So when we think about mixing and matching, we look at those side effects along the bottom, and think about that might be part of what we choose to treat a person with as well. Again, that's just choosing the right color mixing and matching for patients. Now, along those side effects, if we would think about that middle one, the steroids, that's really the big one. When we think about basically public enemy number one for both patients is really the steroids. They're pretty much in every regimen. And the bright side is they work, and that's why we put steroids in them. Unfortunately, we have to put in at pretty high doses. But they're really a backbone drug, and they help the other drugs act better. So it's that idea of one plus one equals three, or one plus one equals four. That's why they're present.

And unfortunately, they are present in high doses, because that's what it takes to really effectively combat the multiple myeloma cells. The dark side, of course, shown over on the right are the steroid side effects. And I probably don't have to list, read out all of those, but probably the biggest ones are the irritability, the mood swings, the depression, the difficulty sleeping is a really big one. From a more physical standpoint, the increased blood sugar levels for patients who have diabetes can be a challenge. And sometimes we'll have to get in contact with primary care providers to help manage that as well.

But how do we manage that? How do we help you manage some of those side effects? Over on the left we talked about a consistent schedule. So with some patients who work five days a week, they may have the weekend off, and so better time to give them their drugs might be on that weekend or on that Friday when they can have a little bit time to recover. Patients may work during the day, they may work at night, for patients who work during the day and want a good night's sleep. Very often we'll have our patients take their steroids that evening. So they get a good night's sleep by the time those more psychological side effects, the irritability and things like that take effect. It'll be in the morning, so they have a little bit of time to recover.

Steroids are generally better taken with food. It's a little bit easier on the stomach. And sometimes they basically put a lot of acid in the stomach. So we think over the counter medications can be good. Sometimes it requires prescription medications, as well. So we fully understand the steroid side effects, and we do work to reduce the dose of those steroids as soon as possible as well. So we don't have to continue that all the way out. Fortunately, very few maintenance regimens involve those high dose steroids. So if we were to look at other side effects that we think about them as well. So again, what are other tools we use to complete the picture?

These are some other side effects that we think about when managing patients with multiple myeloma. Those are listed across the top. DVTs or the deep vein thrombosis, pulmonary emboli, again, preventing those. We're always concerned about bone health, because patients, about 70, 80% of patients are gonna have some sort of bone issue related with their multiple myeloma. Renal health is very important. The pathology of multiple myeloma unfortunately causes kidney dysfunction. And we talk about infection prevention as well, which is really a big thing. Again, this whole COVID that's going on now, and a big component of this webinar today. Then peripheral neuropathy and GI symptoms, and we'll focus on those a little bit more later. But along the left there, you can see there are non-medication therapies for these and lifestyle options, so we think of. Of course, we do have pharmacologic options as well, but these are some things you can think about doing that are not pharmacologic.

So DVT/PE prevention, compression stockings are important. Activities, so if you're going on a long drive or on a plane trip, get up and walk, those types of things. Smoking is associated with pulmonary embolism, as well, and so is obesity. In terms of the bone health really activity is a very, very big one. We do have agents, it was pointed out early the bisphosphonates or the Denosumab, which can really help with bone health. But sometimes we require radiation, or surgery, or physical therapy activity, really important to help strengthen the bones as well. The renal health, unfortunately, patients will sometimes need dialysis. We hope to get them off dialysis, but a huge focus for the patients with multiple myeloma is hydration, so plenty of fluids. Keep those kidneys flushed and functioning well. Avoid agents that can cause some kidney dysfunction, such as NSAIDs, think of aspirin, ibuprofen, CT contrasts, and things like that. Infection prevention, masking activity.

I know masking gets kind of a plus minus among the general population, but I'm sure everybody else on the talk today can assure you that for the at least 25 years, I've been in oncology, oncology patients have masked all the time. And so masking is something now that the rest of the, obviously the rest of the world, our patients were really kind of trendsetters that they were always masking. And doing all the good things, hand washing, avoiding crowds and things like that. So those things are always really good. We think about being at home, basically cleaning those things that are commonly used, refrigerator handles, iPads, keyboards, things like that as well. So infection prevention is a huge component of teaching. And it's listed here peripheral neuropathy and GI symptoms, and I'll talk about those a little bit later here then as well.

Now, if we go ahead and say, we ask patients, we say, "What bothers you and what most impacts your quality of life?" And that's a really important question. You know, we think we know, but there was a large study of meta analysis, which really looked a whole large number of studies, and compiled the information and said, okay, what is a huge symptom that impacts your quality of life? And they're going from diagnosis all the way through end of life. And you could put these into three broad categories, the physical, the psychological and the financials.

We look down the physical, see fatigue, constipation, pain, those types of things. Psychological, depression, anxiety, sleep disturbance, insomnia. Of course, financial that kind of is its own obvious, but problem there, the financial burden and financial toxicity. Now, not all of these are specific to physical or psychological. And we'll talk about how fatigue, what we think it as physical also has a component in the psychological realm as well. But if we wanna focus on just a few of the physical ones, which we have here, GI symptoms. And so we think about constipation and diarrhea. Fortunately, the vast majority, the majority of the agents which we use to treat multiple myeloma do not cause nausea and vomiting. There are a couple that do, but the majority of them do not.

However, the constipation and diarrhea can really be quite significant. So we think about those agents that cause those. And of course we can work on that, but also think about the non-treatment related drugs that you might be taking that are contributing to that. Showing on the left for diarrhea. If you're taking laxatives, antacids with magnesium, some antibiotics, antidepressants, and some of those things you might think like herbs and things like that, which might be helpful can lead to diarrhea as well.

So think about those things. Look at your med list. I always have patients bring in their meds, including the over the counter and herbal supplements as well, so we can look at those things. In terms of how do we manage it, avoid caffeinated, carbonated, heavily sugared beverages, take your antidiarrheal medication. Imodium is over the counter. Some of these other ones here, Lamotil, Colestia, Welchol, those require prescriptions if necessary. And then fiber binding agents, Metamucil, Citrucel. Again, those agents bind fluid. And when they bind fluid, they bulk up the stool and make that a little bit less loose, and that's the important thing. In terms of constipation, again, some of our medications can our treatment medications, but also think about what you might be taking. Some opioid pain relievers, which are really significant in terms of constipation.

Think of some antidepressants, some supplements patients can certainly get constipated with calcium and iron, which are probably the two most significant ones. And again, you'll see here, what do we do for this? Well, you can do something at home, which is, again, increase your fiber. So fruits, fibers, vegetables, whole fiber grains. And again, think of those fiber binding agents. What do they do? They hold onto water. So they help prevent diarrhea by bulking up the stool. Here, they can help prevent the hard stools that you get by holding onto the water and helping with constipation. In the blue box down there, in that little pallette, we can see that fluid intake can help with both diarrhea. We don't want you getting dehydrated. It can help with constipation as well to help get put fluid into that.

And then most importantly, again, kidney function. We're always patients plenty of fluids, and so we can help GI and renal issues by drinking plenty of fluids. Probably the other one, which is pretty significant all the way down the line is pain prevention and management. And pain very often is the number one presenting symptom when it comes to patients with a multiple myeloma. And it can continue throughout that, the whole disease trajectory, but sources include the bone disease itself. Neuropathy can be a significant, of course, significant cause and medical procedures as well that we perform ourselves. How about management? Well, prevent it with all possible. That's probably the big thing. Dr. Durie discussed again, those bones strengthening agents, the Zometa, the Denosumab, things like that, which helps strengthen the bones. We always think of antivirals to prevent outbreaks of shingles, which can be extremely painful also. But what about interventions?

What if we can't? What if we can't do something about the pain preventative? Well, it really depends upon the type of pain as well. So neuropathic pain is treated different than bone pain. And so some interventions could be we have medications again, opioids or something lesser, activity, surgical intervention. Radiation is very often used to take care of bone pain as well. And then some complimentary therapies as well, just some meditation, yoga supplements, acupuncture can be very effective.

Unfortunately, it's not paid for by most insurances, but I've had patients who have great success with acupuncture. Now, when we think probably more specific type of pain, it's that peripheral neuropathy. That's a pain, which is really difficult to manage. And instead of managing it, probably the most important part here is listed again, in that little blue palette down at the bottom. And it says report symptoms of peripheral neuropathy early to your healthcare provider. Nerve damage can be permanent. And so what we like to do is prevent the neuropathy rather than treat the neuropathy. And we have a number of agents that certainly can cause that neuropathy as well.

One of the problems is if the neuropathy gets so bad, we may have to discontinue a drug. And we don't wanna discontinue a drug that's working, and effectively treating your myeloma just because the neuropathy has gotten so worse. So when we think of peripheral neuropathy up here on the left, it says numbness, tingling, prickling, and even muscle weakness, cramps, things like that as well. Those are things to report to your provider, which would suggest the neuropathy. When we think of management up here, on the right prevention management, through the patients, getting the Bortezomib twice weekly. We can go to once weekly dosing, the subcutaneous administration causes a lot less neuropathy as well. Massage an area, dry skin tends to have issues more with neuropathy than moist skin. So keep it well lubricated.

We can have some supplements as well, which seem to help with some people. B vitamins, some amino acids as well. There's some, again, herbs that are suggested to help, but what we don't know is how some of these might interact with the medications that you're taking. So let's say you're getting a Bortezomib infusion is listed on here. Don't take those herbs on the same day, just because we don't know how they interact. If the neuropathy worsens, what might we do? Well again, we might have to change your treatment if we can't do anything about it, but we can also do dose reductions. Very often the patients report neuropathy, we do dose reductions, and the medication still is very effective. We think about how these medications are approved, or really looking at the medication that we can give you has a great effect, but it's really the maximum tolerated dose. And lesser doses, partial doses work really, really well.

So don't think that reporting the symptoms means that your therapy's gonna be any less effective. If it gets really bad we can also prescribe, medications as well, sometimes opioids. And again, physiotherapy, sometimes acupuncture is going to be available then as well, Fatigue, if you recall, fatigue was listed under the physical category when we looked at those quality of life measures. And it's listed here under physical and psychological. And over on the left, you see that fatigue is the most commonly reported symptom. Almost 100% of patients with multiple myeloma at some point are gonna complain of fatigue. Now it's listed on this slide again, as both, fatigue, anxiety, depression, and that's a triad. It's very often because they go hand in hand. The fatigue can cause anxiety and depression, and the depression and anxiety can cause fatigue. So it's working on all of those together, not just one or the other.

So nausea the most, we think about the most commonly reported one, but the sources over there on the left are shown to be anemia, pain, reduced activity, insomnia, which we'll talk about in a little bit as well, toxicity, bone marrow suppression. So some of those physical things are things related to the therapy that we can help take care of. But over on the right, again, these are more the psychological things. Anxiety reported more than 35% of patients with myeloma, depression in nearly 25% of patients. You can see the reasons for it. Financial concerns, disease progression, end of life issues, changes in social and sexual function. So all of these things, we have to work on those.

Unfortunately, anxiety and depression aren't always that well reported to providers. And so when we think about this triad, fatigue, anxiety, depression, we wanna work on all of those. And I would suggest to you that if these things are bothering the anxiety, depression sometimes there's a stigma, which says we shouldn't bring up, talk about those things or bring them up. But really we should because there's help available.

We can certainly have pharmacologic help for the anxiety and depression, but also point you in directions of social workers, and counseling, and things like that, that we have available that can help. So hearing one, or helping one, certainly helped all three of these things, as well. Sticking then into the rest and relaxation, and keeping into the psychological theme here. Again, one of the things that we saw with the quality of life measures, one really important one was that sleep disturbance. And so sleep disturbances isn't just important if you're being treated for multiple myeloma, but it has a number of problems in terms of your overall health. Those are listed up here on the left.

Again, adequate sleep and rest are essential to a healthful lifestyle. So if you have disturbed sleep, interrupted sleep, you can have increased heart disease, anxiety, weakened immune, worsened pain. And of course, you can have stumbles, and falls and personal injury as well. What interferes with sleep? Well, sometimes it's what we do. And of course, I brought up the point steroids. Those can be probably the biggest problem when we think about, with your therapy, that can interfere with sleep. But there are other things as well that you might be taking stimulants.

And again, think about those other supplements you might take and the herbal supplements and things like that. Let us look at them, 'cause some of those, instead of actually helping you can also lead to some issues in terms of sleep disturbances. We have the physiologic things as well, patients with sleep apnea, if you've been prescribed CPAP, you should be wearing that. Heart issues, pain can be associated with difficulty, as well. And of course, those things, again, we just mentioned fear, anxiety, stress, depression, all of those can lead to poor sleep, a poor restful sleep. On this right side is probably stuff that you've all heard before, but sleep hygiene's really necessary for that good quality restful nighttime sleep. Exercise is great during the day, just don't do it real close to sleep.

Avoid daytime napping. I would say excessive daytime napping. And that's simply because if you sleep during the day, it's gonna be very difficult to sleep during the night. 'Cause you'll get your restful sleep during the day. And even with some sort of pharmacologic thing, if you need that, it's gonna be very difficult to get a full, good night's sleep. But I was talking about establishing a bedtime routine here. It's a warm bath, cup of milk or tea. Some people will read for a little while. Some people will knit, or something like that. But get that pattern when you're ready to go to bed, get the pattern that you want to go to sleep. But the important part about this too, is that next line, it says associate your bed only with sleep. So don't go in there and watch TV. If you're having those bedtime things, typically don't do those things. Do your little bit of knitting in whatever room you're in, things like that.

But when you go to your bedroom, then you are ready for sleep, and associate that bed with sleep. And I do tell patients that they do take their cat naps during the day that they should not go to their bed and do those. And again, associate that bed with only restorative nighttime sleep. If you're gonna nap during the day, do it in a chair. Sometimes regardless, a sleep aid may be needed. That's absolutely true. And we can help you with that then. There's some over the counters as well. Before bedtime, these things are I think are obvious, avoid caffeine, nicotine, large meals, and lot of computer screen time, that's really gonna kinda keep you a little bit wired. Okay. And then this slide kind of says it all.

This was a third category in terms of quality of life and financial burden. Our drugs are really expensive. When we think about some of the immunomodulatory agents, which are running 20,000 a month, we can really see why people have a lot of angst about finances and treating their myeloma. Over in the left talk about a financial burden, coming from premiums, co-payments, travel expenses, medical supplies, and those prescription costs. And loss of income's a big one too, and not just for the patient. So the patient can have loss of income. But what about a caregiver who has to bring that patient to work? They can have loss of income then as well.

There is some help available. And certainly contact social services, contact a social worker where you get treated. They should have some resources available. You can see some of the funding assistance that can be available here, the federal programs. Some pharmaceutical companies have really nice support systems. There's some great nonprofits out there as well. And again, any social worker should be able to direct you to these. There's a lot of information on the web as well. And if you're not capable there are probably some family member that you know, that can really help direct you to those things as well. So those are the broad categories, and some of the things that we look out for.

And so the last thing I'd like to do is just shout out to everybody who's on this, on this program today. Is the fact that, you know, knowledge is power, and use reputable sources. You're doing it today, you're here at this International Myeloma Foundation seminar, listening to some experts talk about myeloma. Great, if you're not doing this live, again, I think this is recorded, so you can actually listen to this at some other point. But the International Myeloma Foundation has a lot of stuff available online, and you can see the website there as well.

So anyway with that I'm gonna turn this back over to Dr. Durie, I believe, it's yours now.

- Well, thank you so much, Kevin, for that wonderful, comprehensive overview. In the chat box, you can see already some comments from patients who really, really appreciate the details that you've provided. We'll be trying to answer a number of the questions that are coming in. And thanks to Rafat who has already been jumping in to try to answer some of the important questions. And we'll try to do that. If we can answer them just directly in the chat box, we'll do that. And those that we don't we'll try to cover before this first break. So without further ado, I'll give a short presentation about COVID-19, and leave enough time so that we can handle a lot of your different questions that I know that you have and have already been coming in.

Next slide, so just some background information for those who want to keep up, you can go to the CDC and WHO websites, and you can see where is COVID active right now. Unfortunately, you can see the dark, dark blue includes the United States as we're all unfortunately, very well aware in most of our communities. You can see that Latin America is badly affected as is Western Europe. So a lot of COVID infections right now in the unvaccinated due to this new Delta variant. And if you want to track the amount of vaccination, which is helpful to know, you know, what is the percentage chance that when you go out that people are vaccinated?

One interesting thing is if you look at the very bottom here, people over the age of 65, the number vaccinated is up in the 90% range, 80, 90%. So if you stick in that older age range, likely the people are vaccinated. What you need to be wary of is younger people who are not vaccinated, and younger people and even children who have not had the opportunity to be vaccinated, next slide.

So I think that the Delta variant is really an important development for all of us. And the last couple of weeks I've written blogs about it this last week. It included commentary about the role of the booster. So those of you interested in that you can see I've got references and links about the booster already in the blog, which came out on Thursday. But the Delta variant is just so much more infectious. And you can see, instead of passing the infection on to just a couple of people, it could be 5, 8, 9 people that get infected. And this is because the load of the virus in the nose and upper throat area with this Delta variant is 1,000 times higher.

And so the risk of spread, even from a vaccinated person who might have somewhat lower antibody levels can happen. And so this is why it is of significant concern. So vaccination for myeloma patients thumbs up, absolutely. Particularly the Pfizer and Moderna vaccines, which are proven to be very, very safe and reliable. I think that there are definitely issues for myeloma patients related to the impact of ongoing treatment. And we can bring that up in the discussion, but just use some common sense. If there's a break in your treatment, or if you could perhaps limit maintenance for a little bit of time, then this could be a good time to get vaccinated. Next slide.

Yeah, and so it is possible to check the key antibodies, the neutralizing antibody levels. There are some labs which are more reliable than others. A national lab, which is really quite reputable, a company called Labcorp. They do have this as a reliable testing service across the country. Within each state there are a number of quite reliable places where samples can be sent. But for myeloma patients, the key thing, which I emphasized in my most recent blog is that about half of the time myeloma patients do not get adequate neutralizing antibody levels, even after two doses of the Pfizer or Moderna, tested two to three weeks after that second dose. And so it was fantastic this week that on Thursday, the FDA approved a third booster dose. And this was approved by the CDC yesterday. And this approval is for individuals who are immunocompromised, which absolutely includes every patient with myeloma, and possibly even a smoldering myeloma and MGAs.

A key point is that you do not need to have a letter or a note from your doctor to get this third shot. The patient just needs to, in the words of the CDC, attest or declare that they're in this immunocompromised group, and then you can go ahead and get the shot. It's approved just for the Pfizer and the Moderna.

The booster should be given sometime after four weeks after the second dose. For those of you who were vaccinated some time ago, that means that you could go in any time and get that booster dose. Now, even with the booster dose, it may be that your neutralizing antibodies are still not spectacularly high. And especially with this Delta variant, which is so infectious, it's strongly, strongly encouraged.

And the CDC have now become quite clear on this, that they do continue to recommend masks. And I certainly recommend the KN95 masks, the best that you can get. Or you can even use double masking to get the best protection. And be very, very cautious in indoor spaces, particularly if you're mixing with people that you don't know, people who might in fact be not vaccinated.

So Pfizer or Moderna are best. If you've had the J&J in some places, for example, in San Francisco, San Francisco General Hospital, you can go in and get Pfizer or Moderna if you happen to have received the J&J in the past. And now there is a feeling that you could possibly mix and match Pfizer and Moderna. For example, if you had Moderna before, your booster, preferably would be the Moderna, but I mean, if you can get the Pfizer, it's probably okay. And that's allowed within these new guidelines.

But the key thing is for those who are vaccinated, and I do believe with this third booster, there will be hopefully a 100% reduction of hospitalizations and death. So it really is such an important thing. Masks still required. It's a airborne spread. The variants are a challenge and be wary. I mean, many people who may be transmitting the infection are without symptoms. They may not know that they have the infection. They may be vaccinated and feeling quite safe, and actually feeling quite well, but still they could have some infection in the nose, and especially younger people. And still be very cautious about travel, and planes, trains, and just be very cautious about any crowded indoor spaces. I think the KN95 or double masking. And if you're very worried you can wear glasses or goggles. Next slide.

What can you do once you're vaccinated? And this has kind of evolved. There's a lot of advice out there right now, what you can do once you're vaccinated. This Delta variant has kind of changed the perspective on that, next slide.

And I think that you just need to be just so much more cautious. There are things that you can do, but, wear a mask and just be very careful, even in social settings, outdoors like a barbecue, particularly if you're around people that you don't know, or who might not be vaccinated, next slide.

Go for a walk, very important for myeloma patients to get out and about, go for a walk, wear your mask. And if you're out in the open, obviously, you can take your mask off, if you're taking a walk in the park, or through the woods or something like that. Some places that you might need to go, there are very, very good protections. Like in the dentist office, if you gotta go to the dentist, they are particularly taking very good precautions with masking and the like, so it's probably good with care. As you were just hearing about it's common for myeloma patients to have fatigue, but really the COVID-19 pandemic has been stressful for everyone. When you get up in the morning, you may not be feeling so resilient, and it takes teamwork and help, you know, to get ready for that next Zoom appointment, to talk to your doctor, or to do this and that. And so just be aware to give yourself time, and really be aware that this is something that might need counseling or help. Because it's not so easy to get through all of this. Next slide.

Yes, it's real for everyone, and there are some crazy things that you can do. This is a fun video that I liked that was pretty popular two or three months back. The Shedd Aquarium took the penguins out for a walk, and it turned out that the penguins are quite inquisitive. And so it's wonderful to watch what the penguins do when they, when you take them out for a walk around the aquarium, where they check out the dolphins, and the other otters and the like. But then they started taking them outside of the aquarium to the museums and around and about. This is really a fun thing to do to de-stress. And maybe you yourself could go to the museum with good masking and with good spacing, to try to recover, and work on your resilience. And we have a lot of information available to try to help build your resilience, and help during these challenging times.

What does the future hold? Well, as I've said, vaccination I consider to be essential, and I would recommend every patient to get a booster shot. And we can talk about questions you might have about that. I think masks are still strongly recommended any situation of risk, particularly indoors. And beyond that, I think that we are looking at a situation like this for some time to come, where there probably will be new boosters next year, that will do a better job against new variants as they come along. I do think that we will be having to keep our masks in our pockets for quite some time to use them if we're traveling or meeting people. Unfortunately, around the world, many, many countries have even less vaccination than we have. And so we have to remember that we're living in a global community and travel does need to happen for business and other things and travel. So we're gonna have to be cautious in our lives, both locally, and especially if we're traveling, for quite some time to come.

So we have many resources as Kevin was emphasizing. These resources include materials from the experts that you have with us here today, as well as many others who have been kind enough to tape their presentations on many different topics. And we're very happy to be able to make these available to patients. Our support groups are virtual, but as you can see here with the many happy faces, our virtual support group meetings have been, I think, usually, popular if that's a correct word. I think that people have really appreciated the ability to get together, and see how other people are doing, get advice and the like. In fact, there has been a high level of participation in these Zoom kind of meetings from all across the country.

And great thanks to Robin Tooey, and her team, also our regional community workshop team, including Kelly Cox. Who have really helped enormously to expand these activities and to, Rafat and Noopur who have also participated in some of our programs. Even when it's very, very bad things continue, myeloma has no boundaries. Nature continues to grow. When you look out the window, even although we are having a lot of problems, the seasons continue. Even although we have these deep concerns about the climate right at the minute, but mostly we are hanging in there, and doing the best that we can.

Okay. So I'll stop there. And with that, we really do have a lot of questions that have come in. But perhaps we can start by maybe inviting our guest speakers here to maybe comment, particularly major points that they would like to make about the COVID-19 and particularly related to the booster shots, perhaps. So maybe start with you, Noopur. What comments would you have about the current situation with the COVID-19?

- I think you, can you hear me, Brian?

- [Brian] Yes, yes.

- Okay, perfect. I think you summed it up beautifully. I think the Delta variant is really important for all of us to think about, and I agree 110%. I think anybody and everybody who can get a booster should get a booster. I think all multiple myeloma patients can be categorized as immunocompromised. I don't think you need to show any kind of proof. And if you can get the vaccine, it's just gonna augment your immune response. So I would urge all our patients as and when the vaccine becomes available to get whichever one they can have access to.

- Right. Do you have any thinking about the therapy? There's a lot of questions about adjustments in therapy around vaccination. Which is very tricky because we don't want to interrupt therapy, which is really working well. Any particular thoughts about that?

- I think it's really important. And I think what we've done as a myeloma community is looked at outcomes in patients who have myeloma, and have developed COVID. And what we have been able to sort of gather from that is it's really important to control your multiple myeloma as well as you can. That's important for control of COVID, as well as response to vaccination. So I don't think you should interrupt treatment. I think it's really important to continue with treatment.

As far as vaccination and treatment is concerned, Brian, you bring up a really important point. We do know that there are certain types of treatments which can interfere with your immune system. Specifically monoclonal antibodies, for example, can dampen your immune system a little bit. So if you are getting something like Isatuximab or Daratumumab, stay away from it for a few weeks before you get your vaccine. Be away from things like steroids would be helpful as well, and some of the proteasome inhibitors. Immunomodulatory drugs though, we've shown over and over again, if you're on Pomalidomide, if you're on Lenalidomide, for example, they in fact will augment your immune response to vaccine as well.

- Yeah. So you don't need to worry about that. So Rafat, other thoughts you'd like to add in here in your practice? What are you seeing that is of importance or concern?

- No, I think both of you really outline everything thoroughly. I just want to emphasize the treatment that directly affect plasma cells, such as NTCD38, Daratumumab, Isatuximab. Or BCMA antibody therapy or CAR T-cells, definitely deplete your antibodies. And antibody, neutralizing antibody is an important part of the immune system. Obviously is not the only part that will help you get rid of COVID infection. You need antibodies and you need cellular immunity.

So, but in term of the antibody, if you are going to get a vaccine, as you heard from Dr. Raje, you have to, you know, probably I think the most important thing is really after you get the vaccine is that you wait at least four weeks to get one of these drugs that can affect the plasma cells, Daratumumab, Isatuximab. So there's data came out of France published recently, and we actually have data on 398 patients. We're doing the analysis. And if you're giving an NTCD38 more than once a month, you're not gonna develop an immune response. Once a month maintain a kind of schedule, or every other month, and you time the vaccine correctly, you can develop antibodies and you can maintain it. So that's, I think the most point. It's something you need to pay attention to.

- Very, very helpful. Thank you. So Kevin, thoughts from your perspective about the COVID-19?

- Well, I think you guys covered a lot of it. But one of the things, what we will tell patients is that, such as those patients who are on RVd, a weekly regimen is probably not to get the vaccine on the same day that they take their steroid. If we can separate those, or if they're on a three one schedule and they get an off week to take it, get it on a week when they're not getting the high dose Dex.

- Right, very, very good. So I'm looking at the chat box here, and we can maybe go through together. Oh, start at the top, just leave it at the top there. Yeah. Oh, where was it? So one question is, is the booster vaccine different than the current vaccine? And so that is confusing. So right now the booster is just the same as the one from before, it's just a third dose. So a better terminology is actually a third dose, because we are anticipating that there will be boosters coming either later this year, probably early next year, which will be different. Which will be fine tuned against the Delta and potentially other variants. But this one is just a third dose of either the Pfizer or the Moderna. And it is good to take whatever it was that you got before, although between the Pfizer and Moderna, they're both this mRNA type of a vaccine. And so it's probably okay to mix and match those, although we don't really have a lot of data on that yet.

And then there's questions coming in about the maintenance. And then you got some good advice there about maintenance. Really, if you can have a little bit of a gap, it will definitely help your antibody response. And then someone is asking, get a Velcade shot. Yeah, obviously it would be good to potentially skip one week. As Noopur was emphasizing, we do not want to compromise your ongoing therapy, but minor modifications could really help perhaps your antibody response to the vaccine. I'm just seeing if there are any other questions that relate to the COVID that we can cover right now. Several questions about the timing. What's the best time to get it? Now would be the answer to that. Yes. I'll scroll down and see if there are any others. Yeah. So I think that there are several sites.

There's a question about the KN95 masks. There are several sites that do online. I don't want to give brand identification, but you can definitely get the legitimate KN95 mask, which were in scarce supply earlier. Or just a double masking is very effective. There's several studies on that just to wear a double mask. If you're out and about, and you feel like you might be in contact with someone who's not vaccinated or at risk, especially indoors. I'm just seeing if there are any other immediate questions on the COVID. There are different types of antibody testing. The neutralizing antibody, and then there's also the other antibody tests. Which against the spike protein, which basically were used quite a bit, many of them widely just to see if you'd been exposed to the virus, but was not really quantitating.

Some groups have been emphasizing now that with this neutralizing antibody test, you can do it in a quantitative way. It's what's called a PCR test. So you can tell not if you just if you have an antibody, is do you have a lot of antibody, or a moderate amount of antibody. And so some people are saying that actually, especially the group out of San Francisco are saying that looking at the PCR results might be helpful in assessing the status. Yeah, I'm just looking to see a number of other questions here. Any of our guests have any other final comments on the COVID before we'll move ahead? There are a number of other types of questions that we can just cover briefly before we go to the break here.

- Brian, I'll just add one thing for patients, because I know they get worried if they see a low antibody response. Remember that your antibody response is just one part of your immune system. There is something known as T cell immune response as well. And as of right now, we're not regularly measuring that. We're doing that in some research studies. So even if you don't have a very robust antibody response, the fact that you've had your vaccine is probably a good thing because it's woken up some of your T cells, for sure.

- Right. I think that this is really, really an important point. Which accounts for the fact that in general patients who've been vaccinated really do much better, even if the antibody responses aren't maybe not quite as good. Because there is what the cellular immune response, there are other responses that are protecting you, and these are quite important. There's a very strong correlation between having the vaccination. And I think that the third dose will really move even the majority of myeloma patients up into the range where they'll have this protection against severe illness, or the need to be hospitalized.

- Brian, there was a question about the timing of the vaccine after autologous stem cell transplant.

- Right, yeah.

- That's a question on that.

- Yeah, so traditionally we have started vaccinating people about six months after autologous stem cell transplant for hepatitis, and for influenza, diptheria, things like that. There's really no clear data when to do it, but because of the pandemics, we've been starting to do it early, two to three months after autologous stem cell transplant. And our patients are developing neutralizing antibody. So I think, you know, I think discuss it with your, you know, transplant physician, your myeloma doctors, but consider doing it earlier.

- Right, I agree with that. One other point and I'd be interested in input from our guests here, is that right at the minute, I'm suggesting to patients who are kind of scheduled to come in from autologous stem cell transplant right now, is perhaps maybe delay that transplant for two or three months right now, just because of this Delta variant surge. It's probably not the best time to be coming into a hospital certainly in different parts of the country. And so I know that we went from not doing transplants through the spring, into the early summer. We got back where we're doing transplants again. But then right now I think it might be reasonable to perhaps delay transplant for two or three months. I don't know.

- Yeah. I mean, if you're living in Mississippi or yeah. I agree with you. I think it's, you know, probably you can delay it. The therapy is great right now, and keeping the disease under control, you can collect the stem cells for them, and do the transplant later.

- [Brian] Right.

- Probably not a bad idea during, you know, this peak that we're seeing.

- Right, right, right. Okay, so let's just touch on some of the other kinds of questions which have been answered. Let's see. Imaging, question about imaging. There was a study presented at the meetings. I think it was ASCO that MRI can be more sensitive than, than PET CT, for example. It's important just to think about the types of imaging. CT shows bone damage, and so whole body low dose CT is the most sensitive in picking up any indications of even tiny lesions that are damaging the bone. MRI can pick up disease in the marrow, even if there's not bone damage, and it's actually very sensitive. And this study that was presented earlier in the year showed that it picks up more areas where the myeloma is existing. Because there are some of those where there's not actually bone damage.

And then the big thing about the PET CT is that it's telling us something different. The PET, positive emission tomography, this is where you inject a tiny amount of sugar, which is F18 radio labeled. And so it tells you if the spot of myeloma is active and growing. And so it gives you a little bit of more precise information about whether something that you might see on an MRI, is it growing or not? And so it depends on the question. If you want to know if you have a spot of myeloma which is active, PET CT might be the way to go. Looking at some of these other questions here. In the risk scoring for smoldering myeloma, we actually do use high risk cytogenetic. So in the scoring system, if you have smoldering myeloma and you have high risk features, you do get a couple of extra points in the scoring system for that, yes. Let's see. I think Rafat, you answered some questions related to bisphosphonates.

- [Rafat] Dr. Raje knows all about it.

- Yeah. That's right. Someone was saying that they were getting Denosumab, rather than Aredia or Zometa. Do you have any overall thoughts about bone therapy right now, Noopur? What's the status in terms of broad use of Zometa versus Daratumumab, I guess Aredia?

- Yeah. So, you know, I think it's important that anybody who's getting active therapy for myeloma get a bone targeted agent. And you can choose between Denosumab or Zoledronic acid. Either one or the other is perfectly reasonable to use. I do think, you know, we've done a large randomized trial comparing the two, and both were equally efficacious in terms of controlling bone disease. I think it's important to remember that some of them, Denosumab for example, is given subcutaneously. So if you're on completely oral treatment, don't need an IV, it's an easier drug for folks' sake. But as far as scale related events are concerned, both were equally effective. We did see somewhat of a disease, a specific benefit with Denosumab when we studied it in the large randomized trial. But really one or the other is perfectly reasonable.

- Right, right, so there's one question that comes up, particularly if you're taking the Denosumab. In general, we're recommending a limited therapy, like two years, let's say of therapy, then you can stop. But if you stop the Denosumab you might have to have some degree of caution, and maybe use a bisphosphate after that. What's your feeling about that? When you have to stop, what do you think?

- So you shouldn't stop a drug like Denosumab completely. The reason is it's a reversible monoclonal antibody. You're gonna have activation of the rank ligan system, and you do not want that. So for whatever reason, if you stop the Denosumab at the back end using one dose of a bisphosphonate, like Zoledronic acid is important. Otherwise it will increase risk of increased fractures, just stopping Denosumab. We do use it less frequently. We have some data to support that, in certainly with Zoledronic acid where we've gone to every three months, there's randomized data with that. We have single arm data and Denosumab is being studied in that context as well right now.

- Okay. Thank you for that. Okay. Well, I think that we've used up our time, and we've tried to cover most of the questions. And those that we've not covered we will try to get back to people. So thanks to our guests. And we'll take a 10 minute break or so, and we'll be back at 11:00, well, actually 45 minutes after the hour, I would say. All right, so welcome back to everyone. I think we all enjoyed to have a short break here, but we are ready to reconvene. So hope all of our guests are ready to take notes. We are very pleased to be able to welcome Dr. Noopur Raje, from Mass General in Boston, who will be talking about the immune therapies. These very exciting new therapies, which are working so well, and where we stand with those therapies. So please welcome Dr. Raje.

- Thank you, Brian. What I will do over the next few minutes is obviously talk about immunotherapies, as Dr. Durie has alluded to. And really talk about how your own immune system is sort of used to help with some of the treatments that we have available for us today.

Here are my disclosures. You know, harnessing the immune system is not something which is new to multiple myeloma. We all know that myeloma is an immune-based disease. And over the last 20 and 30 years, we've actually been working with the immune system to try and augment the immune system with some of the drugs that you are so familiar with. Such as the monoclonal antibodies, and some of the new, the old immunomodulatory drugs as well.

What I will focus on in the next 20 minutes or so is talk to you about some of the new monoclonal antibodies. We're not gonna spend a lot of time on Isatuximab. This is the other CD38 monoclonal antibody, very similar to Daratumumab. And if you've used Daratumumab, Isatuximab is just another CD38 monoclonal antibody, which can be used. I will highlight some of the new immunomodulatory drugs. These are also referred to as cell mods. And we'll talk a little bit about Iberdomide, or CC220, and the new normal cell mod, which is CC-92480, which are also very effective. We'll spend a little bit of time talking about conjugated antibodies, and obviously a lot of excitement around the bispecific T-cell engagers, as well as the cellular immunotherapies.

So I want to get started by talking a little bit about precursor disease states in smoldering multiple myeloma. Dr. Durie has already highlighted this earlier on. And the biggest question here is does the immune system see precursor lesions? And does this recognition correlate with outcomes? Well, we all know that Lenalidomide has been used in the context of smoldering multiple myeloma. We also know that the use of Lenalidomide decreases the risk of progression in specifically high risk smoldering myeloma, which Dr. Durie has already alluded to. The problem with that approach though, is that there are side effects to drugs like lenalidomide in patients who are otherwise completely asymptomatic in the smoldering multiple myeloma state. And because of those side effects, we do see discontinuation of Lenalidomide. And as of right now, at least we haven't seen an overall survival benefit. We've used a slightly different approach.

We've talked a lot about vaccinations where we've used vaccination approaches in smoldering multiple myeloma as well. And what we've done here is try to identify the few peptides against which your body can, in fact, mount an immune response. And by doing so, we've come up with this tripeptide immune approach called PVX-410, which is a vaccine, and we've used it with and without Lenalidomide. As I was alluding to earlier on Lenalidomide is able to augment your immune responses to vaccination strategies. What we were able to show, this is a vaccine against three different proteins, XBP1, the spliced form, as well as the unsliced form, CS1 and CD138. And over time as you get this vaccine we're able to see vaccine specific immune responses in patients. This is an ongoing trial in patients with multiple myeloma. The only limitation here is you have to be HLA-A2 restricted for this vaccine to be effective.

What about some of the new cell modulatory drugs, also called cell mods? Well, I told you we have two different ones, Iberdomide, and the more recent 480. This is even more potent than Lenalidomide and Pomalidomide and it can in fact, augment your immune response, as has been shown by upregulation of IL2. This has been used in combination with dexamethasone, and then our ongoing trials in combination with some of the proteasome inhibitors, as well as the CD38 monoclonal antibodies. Sufficely to say that when you look at CC480, now you see an overall response rate of close to 55% at the recommended phase two dose.

And this is in patients who have failed both Lenalidomide and Pomalidomide. So really an important advance in the future of taking care of people with multiple myeloma who have failed some of the new currently available immunomodulatory drugs. Obviously, the excitement though has been around BCMA. And just to get everybody on the same page here, BCMA stands for B cell maturation antigen. It is a protein which is present on multiple myeloma cells. It belongs to the TNF family of receptor proteins. And we know that BCMA is important in the survival of myeloma cells.

There's a lot of different approaches of targeting BCMA. We're gonna talk about some of these. We're gonna talk about the BCMA-ADC approach. We'll then talk about the BCMA CARs, and BCMA BITEs as well. So we'll start off with the antibody drug conjugate. This is known as Belantamab Mafodotin. All of you are familiar with this known as BLENREP. This is humanized antibody against this BCMA protein, and it also has a toxin attached to it, which is called the MMAF. And this is the toxin which causes multiple myeloma cells to actually die. Now, this has been approved by the FDA based on this DREAMM-2 study design.

This was a randomized study looking at two different doses of BLENREP. And when you look at these two different doses of BLENREP, it translated into an overall response rate of about 30%, which translated into a progression-free survival of about three and a half months. But the duration of response was much longer than that. This is something which we are using. One of the things to highlight here though, is the ocular toxicity. Those of you who have seen BLENREP you can end up with some eye toxicity, which is generally irritation in the eyes or blurry vision.

So it's important when you get BLENREP that you get the ocular testing every so often. And we're doing studies to look at mitigation strategies of reducing this ocular toxicity in patients with multiple myeloma. What about the other interesting drug products, which we are studying now in the context of myeloma? And these are known as bispecific antibodies. And what they do is this is a monoclonal antibody, which targets this protein of interest, in our case BCMA. And at the same time in vivo, it can activate your T-cells and bring those T-cells close to the multiple myeloma cell, and cause killing of the myeloma cell.

One such example is CC-93269. And as you can see in this figure, it is a bivalent antibody which binds to BCMA. Then you have that red piece in the middle there, this goes and activates your T cells. These are all joined together. So this is something which is really a huge advance in the context of myeloma, which is an off the shelf approach. And you can do what CAR T-cell does, that is bind your myeloma cells against BCMA, and activate your T-cells, bring them close to your myeloma cell, and cause killing off your myeloma cells. With this, what we are seeing is absolutely remarkable response rates. Close to 80 and 90% in terms of response rates. Once you get to the maximum tolerated dose, or the recommended phase two dose of this drug.

And really importantly, what we are seeing is stringent complete responses as well as very good partial responses, which are lasting as much as nine and 12 months in certain situations. There's another bispecific. There's a lot of bispecific antibodies, which are in clinical trial development as we speak. Here's another example. This is PF-06863135, it's got a new name called Elranatamab now. And this has also been tested in a phase one slash two study in this context, again, targeting BCMA. What you see here also is very high response rates in excess of 80% where we are seeing minimal residual disease. And again, as with the previous bispecific T cell engager, you are seeing responses which are long lasting going as much as a year as well. Now, obviously there's a lot of enthusiasm with these bispecific T cell engagers, because they're off the shelf.

As you can see on this slide here, I've just highlighted the number of different clinical trials, which are ongoing. And we hope that by the end of 2022, we'll have at least one or two of these bispecific T-cell engagers approved in the context of multiple myeloma. As highlighted before, high response rates, no matter which bispecific T cell engager you look at, anywhere between 60 to 80%. I think a little bit to think about here is the toxicity very similar to what we see with CAR T-cells. You see cytokine release syndrome. You do see neurotoxicity as well, specifically with dose one and dose two of these bispecific T cell engagers.

So it is important that they be given in the context of right now, certainly in the context of a clinical trial. But also at an academic institution, which is familiar with managing neurotoxicity at CRS. I will say though, that the CRS neurotoxicity with bispecific T cell engagers is a lot lower than with CAR T cells. The difference with this though, is these are weekly treatments or every other week treatment. So this is something which is continuous treatment in the context of multiple myeloma. Again, as you all are very familiar, we are all very excited with the Chimeric antigen receptor technology.

We have our first CAR T cell product, which is approved in the context of multiple myeloma. And we hope that we will have the second one approved later on this year as well. What CARs essentially are is we take your T cells out and we genetically engineer these T cells. One is by inserting the CAR receptor, and that's where the name comes from. And this CAR receptor is able to recognize different proteins. The ones which we have in clinical trials right now are mostly against BCMA, although newer versions are looking at other CAR constructs as well. And then within the CAR construct we then activate the T cells the way we do it with the bispecifics.

And by doing so these T cells then expand, go and find your myeloma cells and actually cause killing of your myeloma cells. Here's how CAR T cells are manufactured. You have to go through the process of Leukapheresis, so you get onto a machine, very similar to how stem cells are collected. But in this case, instead of stem cells, we're just collecting lymphocytes. So you do not have to get growth factor before that, nor do you have to get any stem cell growth factor for stem cells, but it's just lymphocytes.

Once these lymphocytes are collected, we then have to do this engineering of these T cells, which takes anywhere between three and four weeks. And by the time we give these back to you, it's about a month or so. Before giving you back these T cells, we do give you a little bit of chemotherapy, which is referred to as lymph depleting chemotherapy. And that is in general Cytoxan and Fludarabine. The one which is approved right now is Idecabtagene vicleucel, also known as a BCMA, for those of you are familiar with this. This is the CAR T-cell construct, which is against BCMA using 4-1BB and CB3 zeta as activation domains within.

The way this drug product got approved in the context of myeloma, whether it was with this pivotal phase two trial called the KarMMA trial, which was really quite remarkable because 128 patients globally were treated. So not just in the United States, but in Europe as well. And what we saw with this is once you get to the recommended dose, which is 450 million cells, you get an overall response rate of 80% with this CAR T-cell product. And this translates into a progression-free survival of close to a year. Patients who actually achieve a complete response with this CAR T-cell product had a median progression-free survival of close to two years. There's another drug product, CAR T-cell product, which is in clinical trial development. And our hope is that this is gonna get approved very soon. This is referred to as Cilta-cell. The difference between ITA-cell and Cilta-cell is they're very similar. In fact, Cilta-cell is able to bind two different epitopes of BCMA as shown in this cartoon on your slide.

What this does is translates into a really nice, robust progression-free survival. The overall response rate with this is close to 97%. And on an average, and we haven't quite reached the median yet, at 22 months, you have, that's where our progression-free survival is with this CAR T-cell product. Again, both ITA-cell, and Cilta-cell are very active CAR T-cell products. They're very similar in terms of toxicity of neurotoxicity and CRS, but along the last three and four years I think we've become very familiar with this technology now. And we are pretty good at managing both CRS and neurotoxicity without any problems at all.

Again, because of the excitement with CAR T-cells here are all the different CAR T cell products, which are being tested in clinical trials as we speak. And we are very excited about the possibility of using this earlier on in the course of multiple myeloma care for our patients. Now targeting BCMA is no longer a, maybe a potential. You have two drug products, as I've already mentioned to you. We have Belantamab mafodotin, or BLENREP, and we also have the CAR T-cell product, ITA-cell, which is approved. Our hope is that the bispecific T-cell engagers will get approved shortly, hopefully by the end of next year.

Obviously there's subtle differences between the three. And I think one has to talk to your clinician and see which ones are the best suited for you during your course in the disease. Obviously, you know, we are not satisfied with what we've done with CAR T-cells as yet. And we are wanting to try and do better, so we are, as we speak, studying in the laboratory of the different mechanisms of resistance, or what happens to you once you relapse post CAR T cells, or post one of these BCMA direct strategies.

How can we begin to start thinking about you? And we have different ways and approaches by studying the mechanisms of resistance of these treatment modalities. One example of such a modality is bb21217. This is a CAR T-cell product, which is being produced in the context of a PI3 kinase inhibitor. And by doing so, we are creating a more of a memory T cell phenotype. And by doing so we are ending up with a more potent and more sustained response with some of these CAR T cell products.

So in general, I think our current understanding is certainly BCMA is a really promising target. I've shown you data with antibody drug conjugates, with the T cell engagers as well as cellular products. All of them are showing very, very high efficacy and pretty high durability as well. We do know we need to do better. And I think in the future we are going to begin to understand how we can begin to combine some of these and sequence some of these. And we are already looking at the next generation of approaches. And I've shown you one example of this, which was BB21217.

With that, I thank you for your attention, and I look forward to the panel discussion, thank you.
 

- Thank you so much, Noopur for that excellent presentation, summarizing these, as you emphasized several times, really exciting new data. And just to say that the results in the patients treated so far in the relapse setting are really triggering the idea that we will increasingly be using those exciting approaches earlier and earlier in the disease. Especially for patients with high risk or earlier relapse, these types of situations.

But talking about relapse, I'm very, very pleased to welcome back to our series here, Dr. Rafat Abonour from Indiana, and he will talk about relapse, and some of the other types of relapse therapies that are available in 2021. So please welcome Dr. Abonour.

- So again, thank you for inviting me. Yes, thank you for inviting me to come and talk to you about relapse multiple myeloma. I look forward to the day that we can meet in person again.

So hopefully more people get vaccinated, so we can end up in the mutations of this virus, and hopefully we can get together again. So when should we treat a relapse disease? Do we treat the patient when they have biochemical relapse? That mean the myeloma protein start rising, or the free light chain start going up? Or do we treat at clinical relapse, when they start having symptoms related to the disease, anemia, kidney damage, high calcium or newborn lesions? Or do we treat when they have extramedullary disease? We call that plasmacytomas.

And you know, we don't know, but we can speculate when to treat. Because most of the approved treatment today, excuse me, for relapse multiple myeloma is really done at biochemical relapse. And some observation does support better outcome when treating biochemical relapse. So if you look at one study for Mayo Clinic looking at overall survival, the median was 125 months versus 81 months, if you treat at biochemical relapse versus symptomatic relapse. So early intervention may be useful.

So, but there are cons and pros for each approach. And treating at biochemical relapse about 25% of the patient will have a smoldering course, and they don't progress for at least two years. So you may be treating, you know, a lot of patients and a quarter of them may just behave like any other smoldering myeloma. And probably prior presentation if somebody smolder in the past for a while and you treated them, and now they're relapsing. You can probably be patient for a couple months to see what is the tempo of the relapse.

But the pros against this approach is that most of the studies suggest that the time between biochemical relapse and clinical symptoms related to myeloma is about five to six months. And data, you know, suggests that if you don't get it right at the first relapse, you may not get it right at subsequent relapse. And this may be changing, but you can see with each line of therapy, the sort of duration of response is shorter. So you get, you know, duration of response was now in good induction treatment, maybe four years as you heard. And the second is maybe three years. And with each third in line of therapy, that number keeps going down. So I think getting it right early on is very important. The other concept in approaching relapse patient is that when you relapse, you are relapsing with a disease that is not uniform. and we call that clonal heterogeneity. And especially with each relapse, you will get a different sort of subpopulation of your myeloma, your cancer sort of taking over.

So if you really want to get rid of myeloma, and get rid of myeloma for good, you want a therapy that sort of attack all different clones. So say that in English, I mean, I think it's myeloma cells and each patient of is like a family of odds and aggressive members. So the longer they stick around the odder, and the more aggressive they become. And families therapy is not gonna work. You have to really make the case for treating them early, and with combination therapy. So what are the factors that influence the choice of therapy at relapse?

Well, there are three areas. One is disease related. One is prior regimen related and one patient related. So if you look at disease related factor, you know, what is the feature of relapse? Are they just having symptoms, you know, such high calcium, renal failure, anemia? You don't have to address that quickly and fast. If you, you have extra majorly disease, that's an aggressive disease. You have to come up with a combination that known to work in that population. Patients who have high risk cytogenetics tend to be aggressive.

Again, you need to address sort of the disease nature initially, and at relapse. So regimen related, so always the question is that, do you repeat the same regimen you had before? And I think it can be, but you have to look at what was the previous treatment, the dose, the duration of the treatment? What were the side effect? How did the patient tolerate the prior treatment? Any residual side effect that may influence the choice of new therapy? If you have significant neuropathy, you don't want to use a drug that affect that. If you have renal impairment, you have to be careful choosing the right drug. And depth and duration of previous treatment is also important. If you just get a partial response from the first treatment, why would repeat that? I mean, you want to use more combination that are quite known to produce a deeper response.

And I think patient related factor also very important, you know, performance status and how frail is the patient is important. Other comorbidity, we talked about diabetes, and neuropathy, renal failure, heart failure. Those can influence what we do. Is the patient transplant eligible or not? Because sometimes we use a second transplant. And, you know, we have to listen to the patient, and some patients have difficulty coming to the clinic every week or three times a month, whatever. So we need to listen to the patient, obviously sometimes costs, and socioeconomics influence also the choice of the salvage treatment. So you heard about a lot of things today. What's currently available for anti myeloma therapy? And obviously we have the steroids, the conventional sort of chemotherapy, and then you have the ImIDs, the proteasome inhibitor, the new immunologic approach, and then the XPO inhibitor

. And so obviously we don't have all day to talk about all of these, but I'm gonna highlight some examples of these drugs and how they work. And maybe talk about some of pros and cons of some of these approaches. Obviously, if I have my choice, I will take some of these medication off this list, but I'm trying to be inclusive. So how does your doctor decide what to do? Like going to a Greek restaurant and trying to figure out what dish to order, it's a very complicated menu. And believe it or not, the doctors go by this called NCCN guideline, the National Cancer Center Network. And if you look at this guideline for relapse patient, and this probably been updated since I took that slide from the website, and you can see how complicated it is.

The good news is that we have options. The bad news, your doctor may get confused, because obviously what do I do when my patients for relapse? But I think the principle is really knowing what the patient's condition is, prior therapy and choose one of these options here. So the similar approach is really the Mayo Clinic approach, where they say, okay, this is what you do at first relapse. And you can see, for example, if somebody was on maintenance Lenalidomide and they have a relapse and they fit you can consider a Carfilzomib, Pomalidomide-based regimen, or Daratumumab for a plasma based regimen.

If they have indolent relapse, you know, you may not need to be that aggressive, and you can consider Isatuximab, Thalidomide, Dexamethasone. If a patient was not on maintenance, again, you can consider Carfilzomib, Kyprolis, Lenalidomide, Dexamethosone, or Dara, Revlimid, Dexamethosone. But if the patient indolent and frail, you can do an oral regimen, like, Isatuximab, Lenalidomide, Dexamethasone. And this is for second relapse.

And, you know, my idea is that I think what, you know, you use what is really known to be very effective. And there are a lot of options here. So the image change from Lenalidomide to Pomalidomide, and you get then options of monoclonal antibody, or Carfilzomib in the relapse setting, so a lot of good option there. So I'm just gonna highlight some trials that showed really combination is better. So this trial is called the POLX trial, and it was looking at, in the relapse setting in the old day, we did two drugs like Lenalidomide, Dexamethasone. So that was the control arm. The treatment, I mean, the study arm was the Daratumumab plus Lenalidomide, Dexamethasone, so DRd versus Rd, and it was a randomized study.

So what happened there? Well, I think what happened is that the patient who received the combination therapy actually did better than the people who were just received two drugs in term of, you know, staying free of relapse, or symptoms related to the disease. At three months, follow up was 58% versus 35%. So there was significant improvement in the, what we call PFS. Sometimes you say, if you have an early relapse, less than 12 months of last treatment, you may actually not do as well. So they did this analysis based on patient who had an early relapse versus late relapse. And as you can see, both group benefited from the combination therapy.

So again, that makes the case, that combination therapy either for earlier relapse, or late relapse is benefiting the patient, providing them a better control of their disease for the longest time possible. Again, there's another monoclonal antibody that has been studied Isatuximab, and approved by the FDA in combination with either Pomalidomide, Dexamethasone, or Carfilzomib, Kyprolis. And both trials showed that the triplet regimen is better than a doublet. So combination of three drugs is better than two drugs.

So you heard from my colleague, Dr. Raje about monoclonal antibody, and I'm not gonna repeat. But you know, that antibody therapy can be, you know, different. One of them, you just, we talked about the naked antibody, both Daratumumab and Isatuximab, but these are more sophisticated antibody. One will have a conjugate that it's like a bomb hooked to an antibody that when it gets inside the cells destroy the cells. And then you can bring the immune cells next to the myeloma cells, so these are the bispecific antibody, and then that can destroy the disease. I think right now, what we have approved is column, in the left and the right, the middle one is not yet approved the bispecific antibodies. But I doubt that, you know, maybe next year we'll see one of them approved. And so what are the pros and cons of these sort of approach? CAR T cells is, you know, you have to produce these cells. So you have to be able to get enough T cells from the patient, you have to send them for manufacturing. And so obviously that times, it takes time, four to six weeks.

And now, because there's a lot of demand, we're not getting enough slots to get CAR T cells produced. So the patient has to have their disease under control. And, you know, when you have really seen a lot of lines of therapy, it is very hard to wait four to six weeks. But the bispecific antibody and the antibody conjugates are off the shelf, you know, they're available, it's like any other drugs. But each has different side effects. And I'll highlight some of them here shortly. So why BCMA? That's actually the target that everybody is liking. So whether it's a conjugated antibody, bispecific antibody, CAR T cells, all trying to attack that BCMA.

So BCMA, as you can see is sort of present on the plasma cells, that's these cells that become myeloma cells. And actually also the kind of couple cells prior to these plasma cells that they are about to become plasma cells. So it's a great target because it's present on plasma cells and specifically on myeloma cells. And it's not present for example, on early B cells. So when somebody gets treatment that kills B cells, which doesn't happen in myeloma, it happens in lymphoma, their immune system is suppressed for eight to nine months. But if you kill these plasma cells and you stop the treatment, this immune response recovered quickly. So that's one thing about BCMA antibodies.

The other thing is BCMA is sort of control the proliferation of the cells. So if you block it the cells undergo death. So it's a great target. And that's why you're seeing great results with all these different studies. And you heard from my colleague Dr. Raje, about the drug that it's approved, the conjugated antibody that works in different ways. You know, it just bind to the myeloma cells and bring the immune cells to kill it, deliver this Mafodotin, which goes inside the cells and kills the cells. And, you know, it's a great drug, but I just wanna remind you that all drugs that are approved in the relapse setting right now approved as a single agent. So it's not a combination therapy. And when they approve it as a single agent, if you look at most of the study, except for the CAR T cells, the overall response rate is about 30 to 40%.

So it makes sense that we really need to move these clinical trials that use combination of such a drug with other drugs, like ImIDs, Pomalidomide, or Carfilzomib, Kyprolis quickly. Because I think that's where we will improve the outcome of patients who are now in their third or fourth relapse. So I'm excited about these drugs, but obviously we cannot depend on them as a single agent drug. They need to be used in combination and the trials need to be completed quickly. And that's, you know, so you heard about the overall response rate in this trial.

And you heard about the ocular toxicity. We don't know what really cause it, but basically the cornea, the lining of the outside of your eyes get damaged. And that's why you need to have an eye exam before you start and before each dosing, so you can make sure that you are safe enough to get this next dose. And then this drug, Melflufen was approved also in the management of patients with multiple myeloma. And these were refractory patients. And it looks like as a single agent, first of all, why is it exciting drugs?

I guess, because it really needs to go inside the myeloma cells and a specific enzyme will break this drug into its active form, and sort of maybe cause more damage to the myeloma cells than other cells. And I think, again, the response rate is about 30%, and if you break it to different group, we maybe go up to 50%. So it's an available options for patient with multiple myeloma. Right now, because of certain finding on combination studies, the drug is approved for patients. However, the combination trials are on hold until make sure that they understand some of the side effect that have been reported.

So I think this is my summary slide is that not all relapses are the same. So some relapses are mild, you know, indolent, and you can watch the patient. You don't make a decision based on first numbers you see. At least repeat it, if it's not in two weeks, four weeks and see what's going on with the patient. Do station well, check the bone marrow, check the PET scan maybe, and make a decision based on that. And again, the combination therapy is very important. I don't think we can hit a home run with one or two drugs. I mean, the combination therapy for a relapse patient makes sense. And then I think, you know, the good news is that, some of us on this talk have been doing myeloma for a long time, some much longer than others. And now we have great options.

We used to say at the relapse setting, we have one or two drugs. Now we have 13 drugs or more, and more are coming. So I think this is really great. And I think the optimal therapy for relapse patient is based on the patient needs, their disease needs, their socioeconomic needs, their social needs. We can't just say one size fit all. I mean, I think the good news is that, we can honor the patient wishes. And you know, the goal is not to live for myeloma, but to try to live with myeloma. So patient wants to travel. Patient wants to work. You know, we need to find a way to make that possible. And I think it's really good idea to try to get the response right at first relapse, because with each relapse, your chances of getting it right is reduced. So with that, I'll be happy to join the panel discussion.

- Thank you so much, Rafat. A really excellent overview of the approach to relapse biochemical relapse, clinical relapse, and the options to consider. Perhaps I can start as we often do we have questions from Jack Ielo, and he actually, he has three questions for you starting straight out of the gate here. So maybe I'll go through Jack's questions. So the first question that he asked, question 204 is, in the relapse setting, you highlighted all the different options. When you are looking at all the different options are there any that you prefer perhaps not to have at the top of your list when you're prioritizing your choices? Do you care to answer that one?

- So he want me to get into trouble.

- Right.

- I'm gonna avoid the, you know, straight answer, but I really think it's very important to look at, the prior history, the type of relapse, what the patient wants. And what is the side effect profile of the drugs available to the patient? Because the good news is that you have options for the patient, so you can afford to avoid certain unpleasant side effect, and things like that. But sometimes you really have no choice, and you use whatever available. I think I will have a good discussion with the patients. I will tell them about the combination therapy.

And I will say this combinations works really well. You know, sometimes we use drugs that are not FDA approved yet. For example, I mean I have patients who had multiple relapses was on a clinical trial with ABECMA. You know, the CAR T-cells relapse was in six months, and he's a translocation 1114. So we offered him Carfilzomib and the Venetoclax, and this guy is now seven months out in remission. We try to do the right things for the patient based on the science and understanding of the disease characteristic and the side effect.

- Sounds good, sounds good. So the second question I think is very reasonable. So right now we talk about in the frontline setting, a top regimen would be Dara, Revlimid, and Dex. So in the relapse setting, probably an excellent combination to consider would be to substitute Pomalidomide for Rev, and Kyprolis for Velcade, or maybe even think about Isa for Dara. So is that a helpful way to look at having a strong combination in the relapse setting?

- I think that's a very reasonable, good option.

- Okay. Jack, you, you get a thumbs up on that one, apparently. And then what about transplants? We've been talking about how, since the frontline therapies are getting better and better, especially with quadruplets, if you take Dara, Rev, Dex, or Dara, KRd, whatever, you might defer transplants. So what about the use of transplants in the relapse or what we call salvage setting?

- There's a lot of data on that, and suggests that it can be an effective way to reestablish control of the disease, improve the blood counts. Clearly, you know, those kind of transplant, they can be short lived unless you come up with a creative maintenance therapy based on the patient condition. But I think that option continue to be valuable, maybe benefit, 30, 40% of the patients. But the most important thing is that do it at the right time and also do the right maintenance setting. I don't know what you do, Dr. Raje.

- [Brian] Oh, I think they're very reasonable. Yeah, yeah.

- No, I agree completely. I mean, the good news is we have lots of different options. And as has been highlighted, I don't think it's one size fits all. I think considering a transplant at the time of relapse is important. And I think one of the most important things to sort of keep in the back of our minds when we have all of these options, is don't burn bridges, have all available options to you. And that's sort of

- No burning bridges, right.

- the discussion I have with all my patients.

- Right, there is a question here, Noopur, which I think might be personally important for you. It's a question about whether if someone has actually developed COVID should they later go ahead and get the vaccination?

- Yeah, good question. So I had COVID as all of you know, but I did get the vaccine. I think you have to consider your vaccine as the booster to the booster. So I would get the vaccine.

- Right, right. And I don't know if you had any side effects, but are you probably aware of these data where the long haul symptoms, some of these really troublesome things, neurologic and fatigue and different things. About half the patients who had those types of long haul features actually got better with the vaccination. You wanna comment on that?

- Yeah, no, we've seen this with patients. So, you know, personally, I did not have any symptoms to begin with with COVID, I did have symptoms with the second, the booster dose of the vaccine.

- Oh, I see.

- As with most people. But again, long haul symptoms, I don't think so, at least I don't think so, but yeah, no, we've heard of those. And there is some data to show that the vaccination actually helps with some of those long haul symptoms.

- Right. Right, right, right. Another kind of related question, which I think is quite important, and I've had some experience with this. If a myeloma patient does develop a COVID positive, and develops early symptoms, how should they be managed? And my strategy on that has been with the data that we have is actually to bring them into the hospital and give them the antibody therapy with, for example, the Regeneron product. I think my feeling is that's probably a good idea to intervene in kind of an early proactive way with that, if a myeloma patient does test COVID positive. Maybe you can comment on that and maybe Rafat, as well. What do you think about that?

- Well, you know, so again, go by the guidance of your institutions. So we've had a few myeloma patients who've not required hospitalization, because they had mild symptoms and we treated them at home. There were others who we hospitalized. And at least at our institution, if your oxygen requiring, you end up getting Remdesivir. The monoclonal antibody cocktail, which Dr. Durie is mentioning is more an outpatient approach, which we did use in a subset of patients who did not need hospitalization. But I would really go by what is being considered at your institution, what your guidelines at that institution are.

- [Rafat] Agree.

- Do you recommend that patients use a pulse oximeter or have an Apple watch where they can follow their oxygen level?

- So we've done that, and what we've had out here, Brian is, you know, early days last year, Boston obviously was in a lot of trouble. But we created in our cancer center, a system called the rack system, which is a respiratory sort of screening system. And if you have symptoms of cough, cold, et cetera, we actually do see you. We monitor, we test you, and we then triage you. If we're triaging you home, then absolutely we have a home kind of monitoring system, which includes using these remote monitoring devices for your oxygen saturations, your temperature, and essentially how you're feeling. And we keep in close contact with you. And if you need hospitalization, obviously, all of that is done in house.

- Right. Right, right. So, Rafat, any comments on this topic?

- No, no, I just wanna bring in issue that I saw questions that people are staying on Dexamethasone for a long time.

- [Brian] Right.

- I think once the disease under control, and you're almost in remission, or you just have a little disease, I think one need to discuss the steroids long term with their physician. Because I think data suggests that longer exposure to steroids does not really improve the outcome, but may actually impair your immune response.

- Right. Yeah, I think a very good point. And maybe a link to that. Someone asks here, when we were saying, do not burn bridges, someone wants to know, well, what exactly does that mean when we say that?

- I'll take that because I said that, Brian. So a few things I think is really important to remember. You know, if you choose not to get a transplant upfront, which is perfectly reasonable, don't stay on an ImID indefinitely, because that's gonna interfere with your stem cell collection. So have those stem cells collected and stored, which you may or may not use later on. The other thing is, think about if you're using now that we have all of these BCMA directed strategies. It's really important to try and figure out which BCMA directed strategy you want. Because especially on a clinical trial, before all of these are approved, if you get a prior BCMA, you get excluded from a specific clinical trial. So I think talking to your physician. And if your physician is not necessarily somebody who does myeloma all the time, touching base with somebody who has that myeloma expertise who can sort of walk you through these different options, I think is a good idea.

- Yes. Thank you for that, yes. Still more questions about COVID. Rafat, you answered one of the questions on this. Do we have any indication that if you get the vaccine and then now we're recommending that patients would get like three doses, that there's any indication that this could trigger myeloma? And this is a concern, not just for patients with myeloma, but maybe patients with smoldering myeloma, or something like that. But to my knowledge, we really haven't seen any actual triggering of the myeloma. Would that be correct in-

- [Rafat] No, no.

- Kevin you can chime in on this as well. I mean, if you're checking the free light chain, sort of immediately after you get the vaccine, it may be, you know, slightly elevated, in the next two to four weeks after the vaccine. But if it does come back down to normal, the following test. So I really don't react to a patient who get vaccinated and the light chain goes up just when reading. 'Cause you know, it's just, you're stimulating the immune system and you're stimulating any plasma cells. So you may get a low rise, but it does not really cause sort of reason for relapse of the disease, it does not do that.

- Right. Right, right. Yeah. I haven't seen relapse. Noopur, or Kevin, have you seen patients where there's been a concern of a new disease? I haven't really heard of that at all. The light chain things, a number of patients have commented on that.

- Right? I have not seen that, but in the same respect I will, I always tell patients, we don't put any value, like Dr. Abonour was saying, we don't put any value in two numbers. You can't draw a straight line between two numbers. You need a couple of data points to make anything out of this.

- Yeah, and I would just add don't be afraid of the vaccination, I think it saves lives. It's gonna save, even if you end up with COVID post vaccination, that COVID is gonna be milder. So we haven't seen any data that suggests that the vaccination in itself causes myeloma. There's data, which has come out from the Greeks, which have looked at the incidence of myeloma pre-COVID and during COVID, and really there is no difference in the incidents pre and post.

- All right. Very, very good. So one other thing, just a small point is that in the scheme of things we've also been looking at MGUS versus smoldering, and active myeloma. And it seems that patients with MGUS are really not at particular risk related to COVID as compared to other people of the same age, and other medical status. So that I think good news is that if you have MGUS really that doesn't confer a high risk, or risk of problems that we do see with myeloma. Just a comment.

- And they develop an immune response too, to the vaccine.

- Yes, yeah, excellent response. Yeah, very, very good. Important, yes, definitely. There's a question about CRISPR. CRISPR, which is a technique for DNA editing. This is something for the future. Certainly something that can be used to help generate more tailored vaccines. And I think it may be used for that in the future with mRNA. We're also looking at CRISPR technology in our studies in Iceland. In Iceland, we're looking at populations who are at risk of getting MGUS and at risk for progression. And then there could be an option for CRISPR gene editing technologies there, but this is for the future.

But it's definitely, probably going to be an important technology. Then let's see one just practical point, which I think is a good idea. Someone says, "Well, how about making sure that family members, caregivers, and those that you are routinely in contact with get vaccinated? well also?" And I think that this is obviously a very good idea to encourage family members, caregivers, and friends, to be vaccinated, to help protect the group that you will be with mostly in your local activities.

- And I encourage the family not to be with somebody in the family, who's not vaccinated without a mask on. And try to avoid them.

- Absolutely.

- I have a patient who had COVID in the spring and come back, he was in Florida, came back to Indiana and his grandson does not wanna get vaccinated. And you know, the grandma and the patient are frustrated. And I said, "Well, don't be around him. And maybe grandma can yell at him," 'cause he will listen to grandma and get vaccinated.

- No, I think that you do need to take a tough approach on that, and really either not get together with them, or really be firm about the need for protection, yeah. So we don't have questions on this, but Noopur, I don't know whether you want to talk about it specifically. But I think that here in 2021 heading into 2022, we may have some cautions about some of these immune therapies. Maybe even the CAR T therapies where we may have some cautions related to COVID. And might have some special recommendations for maybe boosters or something like that to make sure for patients getting those more aggressive immune therapies are well protected. Do you have any thoughts on that? Or maybe you don't want to comment?

- [Rafat] Did we lose her?

- Maybe, Noopur's left us for now.

- [Assistant] She lost connection.

- Hm?

- [Assistant] She lost connection.

- Oh, she gone. She had to drop, oh. So Rafat, I don't know whether you want to comment on that. I feel like we should need to have a degree of caution.

- Say it again, what was the question?

- Just when we're using CAR T therapies, or maybe a quadrupulet with Dara or Isa, you know, that we might want to be a little bit more cautious.

- Yeah, no, I think, you know, obviously monitoring the patients, especially after any BCMA therapy, using monoclonal antibody, you need to make also, paying attention to their normal IgG. 'Cause this patient, they become hypogammaglobulinemic. They become immune deficient. And they will probably need to get intravenous immunoglobulin. I think we should not underestimate that. I love plasma cells. I love them when they make good antibodies.

I hate them when they become malignant, but we should not ignore that normal plasma cells, that's why we live 80, 90 years, we need them. So we need to respect them. We need to find a way to protect the normal plasma cells. And if they're not working, how can we sort of generate a response similar to normal?

- Right? Absolutely. Along the same lines. There was a question about getting other kinds of vaccinations right now. And my suggestion is for the next two or three months, if you're getting your booster, et cetera, I wouldn't take any other vaccinations right at the minute. So to try to enhance the COVID antibody response. Actually there's another question from Jack, which I think is a good one and maybe we can all answer it.

You know, I think we all really do want desperately to get back to face-to-face meetings, however, especially with this Delta variant, and the fact that even people who are fully vaccinated can get infected and can even transmit the infection. I am quite cautious about resuming face-to-face meetings. And so we're not rushing to do that even through the end of this year. So Rafat and Kevin, what feedback are you getting on that?

- Yeah, our local support group here is still not doing face-to-face meetings.

- [Brian] They are doing them.

- We are not doing them, excuse me, not.

- They're not doing them. No, no, no. And Rafat, I mean, I think that we're looking at no face-to-face meetings probably for the balance of the next several months, probably for a while. That's what I think.

- We were thinking about having a picnic, a family picnic for all of myeloma patients here in Indiana. But we are probably not gonna be able to do it, because of the recent spike in the number of cases.

- Right. Right. Well, we just don't want to be putting people at risk.

- No.

- Yeah, yeah.

- I wear my mask everywhere I go. I'm vaccinated. In Indiana, you don't have to wear a mask when you go places, but I'm not gonna take a chance. I'm going wear my mask.

- No, no.

- And I'm not gonna sit with anybody I don't know without a mask.

- No, no, I wear my mask wherever I go. Yeah, definitely, definitely. Okay. Well I think that we have really covered a lot of ground. There are some questions, I don't know. I can touch on just a couple that are just small. Someone wanted to know if they should take contrast if they're getting an MRI and they have kidney problems. We don't need to use contrast with MRI anymore. So don't take contrast when you're getting an MRI done. We can analyze the MRI without using a contrast. And then a lady was wondering whether she needed to delay her mammogram right now, if she's gonna get a COVID vaccine. It's probably safe enough. I mean, I think that it might be good to, depending on, I know that some-

- Let me answer this, Brian. The reason for that is that when you get a shot in your arm, you may get the swollen lymph node in the arm pit. So when they do the ultrasound, they may find it, and then they go crazy and they do all the stuff and they may biopsy it. So I will definitely wait on the mammogram for a couple months.

- Okay. Thank you for that. Get the mammogram first and then-

- [Rafat] First, and then get vaccinated, vice versa, yeah.

- Right, right, right. Okay. And then I think that's probably, oh, one last thing, I guess, which I guess is important. A gentleman's asking if he's had a autologous stem cell transplant, he was vaccinated before the transplant. But probably he should go ahead and get vaccinated again after the transplant. And Rafat, you mentioned that possibly we could do that a little sooner than the 100 day point, maybe after two, three months go ahead and get re-vaccinated just as we do for other vaccines, right?

- [Rafat] Yeah.

- Okay. Well, thanks to everyone for participating. Thanks particularly to Rafat, Kevin and Noopur for giving our guests really expert presentations, bringing everyone up to speed. And thank you to everyone for excellent questions, which actually help everyone learn as we try to give answers as best we can. And so appreciate this. This is a webinar where we will appreciate your feedback. We always want to know what else would help to make this worthwhile, and the best that it can be. The only other closing remarks is that we, again, thank our sponsors. The first time around, I did not mention Karyopharm, which for some reason I missed it among all of the others. But we definitely appreciate the support from all of our sponsors. And those are all of the others that I mentioned at the beginning of the presentation today. So I think that with that, we will close for this Saturday. And thanks to everyone.

- [Rafat] Have a good weekend.

- [Noopur] Thanks for having us.

- Thank you for joining us.

- Thank you so much, thanks. All right, enjoy the rest of your weekend.