- Hi everybody. Sorry for the slow start there. This is Dr. Joseph Mikhael. I'm the Chief Medical Officer of the International Myeloma Foundation and with me is my dear friend and colleague, Dr. Gurbakhash Kaur.

- Hi!

- From UT Southwestern. She's an assistant professor there and really is becoming a world expert in so many of the new therapies that we have in multiple myeloma. We'll come back to that in a second. But I wanna to welcome our Facebook community here for our Facebook Live. We are live broadcasting from Boca Raton, Florida, where we have one of our four flagship education programs for the year. And we call these our Patient and Family Seminars. This is an opportunity to spend pretty much two days with the IMF crew and learn all that you wanna learn about myeloma in two days. We had most of the day yesterday, on Friday, where we went over the basics of myeloma, we talked about Myeloma 101, we talked about advanced care planning, financial considerations in myeloma. We really had an extraordinary afternoon together. And today we've been focusing on many other aspects of myeloma that I'm gonna come to in a moment. But we are experiencing Myeloma Action Month. In fact, today kicks off the second half of Myeloma Action Month. And so we appreciate all of you in the social media world who have been using the hashtag #MyelomaActionMonth as we try to increase awareness of myeloma, but not just awareness, but action. And talk about action, yesterday, we had the March for Myeloma. Do you see the double entrendre there? It was March, but we were also marching. We had a 5K run and walk yesterday. I may be still a little bit sore from it, but Dr. Joe ran, and we had several people running here in Boca Raton as well as virtually, across the whole world. In fact, we had participants from Paris, France, we had participants from Malta, so thank you for those who participated yesterday to raise more awareness and to raise funds for what we do at the IMF. So we're very thankful to be here in Boca Raton and I wanna ask Dr. Kaur a little bit about what she was discussing today. So I mentioned, yesterday, we sort of laid the foundation of what are the basics of myeloma, how do we think about myeloma, what is this disease, and we really had a wonderful reception altogether last night. But today we wanted to dig a little bit deeper and the crowd was split into two and those who were newly diagnosed went into one room and those who had relapsed myeloma came in to this room with Dr. Kaur. So Gurbakhash, maybe tell me a little bit about what you covered in your talk today.

- So, today during my talk, first of all, thank you Joe, for having me. I've had a great time here so far, I'm really enjoying with the patients and you and the rest of the IMF staff, so it's so awesome, so I appreciate that. My talk was mostly focused on relapse myeloma. We talked about what is the classification of my relapse disease, what kind of relapses are there, biochemical versus actual clinical, the nature of the disease and how do we sort of parse through the many options that we have in myeloma, how do we decide when a patient gets an oral option versus an injection? So there's different regimens, as you know, in myeloma. So the first half of my talk was talking about conventional therapies that we have, which include myeloma antibodies and proteasome inhibitors and how do we pair them together and and what factors go into deciding on that treatment. And the second half of my talk was on immunotherapy. We focused on CAR T-cell therapy by specific therapy, the differences between them, the approved agents that we have, the side effects that are associated with them, and what sort of the future holds for myeloma. So that was the, in a nutshell, that's what my talk was about.

- Wow, that's a lot. So let's break this down a little bit. So one of the great things about Patient and Family Seminar is that we really get a chance to dig a little bit deeper. Now we have about 250 attendants here at the Patient and Family Seminar. Many are patients, many are their care partners. And one of the great things we get to do is spend a lot more time digging in deep in myeloma and having a lot of time for question answering. I gotta tell you, after your session, there were so many questions that people wanted to ask, which is great 'cause it gives us an opportunity to dive a little bit deeper. But let me ask a couple of questions myself. So you talked about CAR T-cell therapy, and which is ironic when your last name is Kaur. I know you spell it differently, but I think that's wonderful. But, just, can you go over the real basics of CAR T-force? Like what is this all about so that we can do that? And while she's answering that, those of you are listening, you are listening of course, but I wanna remind you that you can submit your questions into Facebook and my trusty partner here in crime, Alana Kendall, is with me and she's gonna be feeding us those questions. So I get to ask the first one, but you guys come up with the subsequent questions. So the question is, again, Dr. Kaur, just give us a bit of an overview. How does CAR T-cell therapy work?

- Sure, so over the last 10, 15 years, we've harnessed the power of the immune system and we realize how do we use the immune systems to attack the cancer cells actually? So CAR T-cell therapy is where you take the patient's T-cell. So there's a process where the patient gets hooked up to a machine, take the T-cells and send them to a lab. In the lab, cells are engineered to recognize some kind of gateway, or a door, such as, in this case BCMA, because that is what's currently approved. And we engineered to chart the T-cell to express, to target the myeloma cell. And that engineering takes about four to five weeks, at minimum. Sometimes it could be longer, it just depends on the robustness and the healthiness of the T-cells. And then those T-cells get infused back into the patient. And that's a long, so there's a lot of logistics that get involved when it comes to CAR T-cell therapy. The patients, once the cells are infused back into the hospital, is very closely monitored by the healthcare team for the side effects, such as cytokine release syndrome, which is overactivation of the immune system. or the neurotoxicity that's associated with that overactivation of the immune system. So the healthcare team closely watches the patients in the first couple weeks. So that's sort of the process of CAR T-cell therapy. But CAR T-cell therapy has revolutionized blood cancers in general, in lymphomas and now in myeloma, it's made great waves.

- That's incredible. So, I mean, had you and I have been doing this Facebook Live about 10 years ago, it would've sound like a Star Trek movie, right?

- Yes.

- So, basically, what you're saying is I can take white cells out of a patient that are kinda like soldier cells that we can train, we train them to attack the patient's own myeloma, we actually multiply them in the lab, and then give them back to the patient. I mean, that concept is amazing. One of the things you talked about in your lecture, too, was one of the reasons why, as I think you used the word revolutionize, what we're doing is the response rates to CAR T have been, you know, dramatically higher than pretty much anything else we've ever seen in myeloma reading. Will you comment a little bit about that?

- Yeah, so, traditionally, whenever we've had a drug come into the myeloma space, we look at the single agent. So how is that drug doing on its own? And the responses, the response rates by themselves is, like, 20%, 30%, max 40%. And here we have a treatment that was introduced in the late relapses, where the disease is very aggressive, and we are getting response rates of 80%, 90%. And not only that, but those responses are actually durable. So that means patients are staying in remission longer and they're also having treatment free time, away from the doctor's office. So, you know, that time toxicity that we talk about, you know, cutting down the visits where patient's quality of life is improved. So CAR T-cell has, that's why it's revolutionary because we're not only getting great responses, but we're also getting very durable responses.

- I mean, that's fantastic. I talked about that today, that my favorite drug to give patients is nothing, nada, right? And so after someone gets CAR T, they can actually go off therapy for a period of time. So that's just a single example of the kinds of things that we have time to dig into a little bit more here at the Patient and Family Seminar. So don't forget to send in questions. All right, Alana, start firing questions at me. What do our amazing friends in Facebook want to know about myeloma treatment?

- [Alana] They have lots of questions. Is CAR T treatment less toxic for the patients than the treatment of SCT?

- Okay, so the question is, is CAR T-cell therapy less toxic than getting a stem cell transplant? And, well, maybe I'll get you to answer that. Why don't you answer that, 'cause I know you do both.

- Yes, that's a really good question, actually. They both come with their own flavor of toxicity. So, honestly, it is up to you when you hear and have a discussion with your doctor about the pros and cons of each therapy. I do think that, with stem cell transplant therapy, you have to, the conditioning therapy, chemotherapy, which is Melphalan, can be very toxic. There's a lot of GI side effects. And patients, you can't really take frail patients to stem cell transplant. However, when it comes to CAR T-cell therapy, you can even take frail patients through it, of course, depending on the side effects and which CAR T you end up choosing. But they just have a different side effects profile, right? Like I said, there's CRS and ICANS that's associated with CAR T-cell therapy and there's, we're still very early in this stage. We have to have longitudinal data to truly understand the long-term side effects that are associated. Where the stem cell transplant is tried and tested, right? It's been around, we've known how to give Melphalan, we know how to deal with the side effects that are associated with it. And now we also have long-term data of the side effects that happens when you give someone Melphalan plus the longitudinal maintenance therapy that comes, that's Revlimid, right? So I think it's, one is a tried and tested approach, one is still very early in infancy. But, you know, you mentioned earlier, because we are having these therapies where side effect profiles getting tweaked, stem cell transplant may, may, it's a big may. I'm a transplanter, I still like to do transplants. So it may not be done as much as it's being done right now in, let's say about five years, when we have even better therapies around.

- Well I think I'm really glad that that question was sent to us 'cause it really is such an important question. I agree with you. I mean we have patients who are aren't really eligible for transplant, but can get CAR T. It just reminds us of the importance of having that conversation with your healthcare team. And we also know, one of the talks that we had here at the Patient Family Seminar that I gave was on health disparities. Because we know that, historically, there have been individuals who have been disadvantaged in getting access to things like stem cell transplant and CAR T-cell therapy as well. So as we evolve and improve the therapies that we're giving, we really hope that we can make more accessible. All right, Alana, I'm ready for another question, then I gotta talk a little bit more about our Patient Family Seminar.

- [Alana] Okay, we have a lot of questions about CAR T. Is it possible that bispecifics replaces CAR T-cell immunotherapy?

- Great question. So, I'll answer this one. So we talked a lot about CAR T-cell therapy. We also talked about the latest approved therapies, which are called bispecific antibodies. So very quickly, to explain that, Dr. Kaur explained so beautifully that CAR T-cell therapy is we take T-cells out of a patient, we train them to fight against the myeloma, and we give them back to the patient. So that's a process, it takes time, it's very effective, as we've said. But we've also introduced this concept of bispecific antibodies, which is a bit of a smoother process, maybe not quite as effective, but it's the notion of, we call it bispecific for a reason because these are drugs that have two arms, if you will, they're bispecific. So one arm hooks onto the myeloma cell and the other arm hooks onto a local T-cell, which, we're even developing kind of bispecifics that hook onto other cells. But for now, it hooks onto the T-cell. So it's kind of like a matchmaker is the word you use, you know, makes me think of "Fiddler on the Roof," matchmaker, matchmaker make me a match. And so it matches these two together and it so called engages the T-cell. So now we don't have to collect cells, we don't have to wait for the manufacturing, we just give this drug directly to patients and it links together their myeloma cells and their own T-cells and triggers those T-cells to destroy the myeloma. We've seen really remarkable response rates in about 60, 70, sometimes over 75% of patients respond to these bispecifics. So to answer the great question, will bispecifics replace CAR T, you know, my answer, my favorite answer to almost any question is all of the above. So I'm gonna say instead of replacing one, we want as many therapies as possible. In a disease that we have not yet cured, I want as many things on this buffet as possible. Because, for one patient, CAR T may be better. For another patient, bispecifics may be better. And we also sadly know that, although these drugs work really well, we've not seen a cure from them. And so, inevitably, even though someone gets a deep and a durable response from CAR T, their disease will come back and often will use them sequentially and use the bispecific there. All right, Alana, let's get one more question from you.

- [Alana] Okay, if someone has myeloma, should their children or siblings be screened for MGUS or smoldering myeloma?

- Well we've got a very informed crowd here today. We had a bit of a session yesterday where I addressed the issue of familial myeloma. The short answer to the question is we do not have guidelines that would tell you to go and screen family members here. That being said, we know that there are some families that have multiple patients with myeloma. One of our attendees yesterday was explaining to us that both he and his brother have multiple myeloma. And any one of us, like Dr. Kaur, myself, who see a lot of myeloma patients, we inevitably see some families that have several members with myeloma. And in that situation, we may consider testing other people in the family. But that also has to be preceded by a conversation. Because, you know, testing comes with consequences. It could affect health insurance, it could affect life insurance and other things. At the same time, what the IMF is working very hard on, and one of our research initiatives, is to really understand familial myeloma. We've just supported this incredible screening project of over 80,000 people in Iceland to understand the family connections. And I really think we're gonna learn a lot more about familial myeloma or what puts people at higher risk within families for multiple myeloma. We know that patients of African descent, like myself, are at greater risk of myeloma. We know that myeloma happens a little bit more in men than in women. But when it comes to family patterns, we still have a lot to do. All right, Alana, bring us another one.

- [Alana] All right, this is a good one. How does yesterday's ODAC outcome impact patients?

- Oh wow. So, I know you're very familiar with what happened with ODAC yesterday, so maybe I'll just quickly explain the process and you talk about the outcome. So the ODAC, or Oncologic Drug Advisory Committee, is a group that is called on by the FDA. So the FDA has a responsibility, of course, to keep us safe. We support that. And there were some concerns about whether or not we can use CAR T-cell therapy in earlier lines of myeloma. So myeloma, right now we can only give CAR T-cell therapy when someone has had four lines of therapy. But a lot of great trials were done in earlier line therapy. And so this ODAC committee is called, as sort of expert reviewers to say is it safe, is it worth doing? And that conversation happened yesterday. So I'll turn it to you, Gurbakhash, to tell us a little bit about what the outcome was. What do you think it might mean for myeloma?

- Sure, so currently there's two FDA approved CAR T products. One is ABECMA, the other one is CARVYKTI. And they were, there's two trials. One is KYMRIAH, that's for the ABECMA product, the other one is for CAR T four and that's with CARVYKTI. Both of their data was presented yesterday, whether this should be moved up. For CARVYKTI, the votes were 11-0 in moving it up earlier. For ABECMA, it was eight to three. But the vote is still favorable. And we don't know the official answer yet, but this is, the FDA usually takes into account ODAC's recommendations heavily when it makes its decision. I do see CAR T will move up as a result of that, I do see that there will be a future that CAR T-cell therapy moves up. Now, will everyone get access to it at first relapse? I don't think so. Like you said, there are disparities. We've had stem cell transplant for ages. Yet we have disparities about that and that's gonna be probably one-third the cost of CAR T-cell therapy. Now imagine that with a drug that's expensive and then there's also this lag time and manufacturing process. I do see that it's gonna move forward, it's gonna be, the patients who are gonna need it the most are gonna be the high-risk patients. And that's my take on it. Other people may differ. The high-risk cytogenetics or the functionally high-risk patients, I would see that they're gonna get priority in terms of getting it first relapse. We still really have other good options as well, such as, you know, the monoclonal antibody paired with a second generation proteasome inhibitor such as CARFILZOMIB plus dexamethasone, right? The CKD versus DKD. I think those are, that's a giant, it's hard to beat that data. So they're still gonna be to, not everybody's gonna get CAR T, as much as we like to give it. We have to be practical and be in touch with reality.

- But we also, I mean, I agree, I'm very happy about what happened yesterday. There was overwhelming support. You know, it is so important. I always say safety is paramount. We wanna look at every signal and make sure that what we give our patients is safe. And of course, every drug and every approach comes with risk. But I think yesterday was a sentinel day for myeloma patients to see that we're very likely to be able to have greater access to CAR T-cell therapy and it just widens those opportunities, as you said. Yes, pragmatically, not everybody will get it, but we think many more patients will get it. This is the sort of thing that we even discussed yesterday. So we kick off our Patient and Family Seminars with what we call Hot Topics in Myeloma. And it's a privilege for me to be able to share what's hot and what's the latest in myeloma. I got to present Hot Topics in myeloma 20 minutes after the first vote at the ODAC committee yesterday. So, talk about being timely. And that's what we seek to be at the IMF, of course. Not just in conjunction with Myeloma Action Month, here in March, but we hold four Patient Family Seminars over the course of the year. So right now, of course, we're live broadcasting from Boca Raton in Florida, but we want to encourage you to attend one of the three upcoming Patient Family Seminars. So we have one in San Francisco in April, we have one in Minneapolis, Minnesota. I'm a little bit biased towards Minneapolis 'cause my wife is from Minneapolis, so I'm sure there'll be like, you know, chicken pot pies or something provided there. But we're gonna do one in July in Minneapolis. And then we're have in our home city of Los Angeles for the IMF, we'll be in Los Angeles in August for a Patient Family Seminar. And you can go to the myeloma website, myeloma.org, and hear more and read more about these Patient Family Seminars where, as I've mentioned, we really try to spend two days with patients where we get to share with you and their partners, share with you the latest and greatest in myeloma. And this year in particular, we've really made a huge change to our curriculum at the Patient Family Seminars. We're doing shorter talks, more interactive talks, covering more topics, and having breakout sessions. So this morning, when Dr. Kaur was talking about relapse therapy, we had, in another room, Dr. Peter Voorhees from the Levine Cancer Institute in Charlotte talking to us about newly diagnosed myeloma. 'Cause we know different patients are at different parts of their journey along the way and we wanna make sure that we provide opportunity for them. Soon after this, Gurbakhash and I are skipping lunch to do this Facebook Live, but right after lunch, we're also gonna do a breakout where we have one room for patients only and one room for care partners only so that we can ensure that, you know, myeloma's often a family sport or a team sport, isn't it, where the partner, a family member, a friend, whoever it is that's supporting that myeloma patient through their journey, they have needs too, they have responsibilities, too. And so we wanna make sure that we have that opportunity. So wherever you live in the US, hopefully it's not too far from one of our Patient Family Seminars and hopefully you can attend in the not-so-distant future. All right, let's turn it back to Alana for another question.

- [Alana] So a lot questions about stem cell transplant versus no stem cell transplant. What do you do?

- Wow, so, that is a question of questions and I'm more than happy to let Dr. Kaur answer that.

- That's a very, well, it's a straightforward yet complex question, right? Because it's each individual care home. We're at that point in myeloma therapy that we actually can say that you, can defer transplant. We weren't always in this space, right? 20 years ago, transplant, it was it. When you didn't have these novel image or proteasome inhibitors. But that being said, I think several factors play a role in deciding whether transplant is the way to go or to defer transplant or actually no transplant. One is age and comorbidities. If you have the physical health status to actually go through transplant, that's a major factor, right? And the second is patient preference. And the third is actually the genetics of the cancer. If there's high-risk cytogenetics, this is the one, I think that is also an unmet need in myeloma. In this space, I feel that very rarely you will get me to say you should defer transplant. I will always recommend transplant unless you are at an extreme age where it's not safe for me to do so, right? So cytogenetics and the risk status of the disease plays a role. But if you have standard risk disease and you're young, let's say you're in your fifties, and you're not really up to doing a transplant right now, but you do have standard risk disease, I would say yes, then there is a possibility of differing transplant because you get five, six years and then you need transplant, you'll be 56, still be in good shape. However, if you're in the later sixties and early seventies, the decision to do transplant is now. Because, after this, you're gonna be much older and you may not have the ability to tolerate the transplant. Keep in mind, in the trials, 20% of the patients who deferred transplant were not able to get the transplant later on because of either disease-related toxicity or treatment-related toxicity that they experienced. So it's a very individual discussion, this is between you and your doctor. The genetic, the cytogenetics and the high-risk status plays a big role and the rest is, you know, what's the support system like, do they have the time, can they actually take off time from work? So many factors at play, right, that help you decide.

- Absolutely, I think it's not an absolutely yes or no.

- Yes, exactly.

- But I'm gonna quote a little bit from Dr. Asmati. So Dr. Asmati, today, gave us an extraordinary lecture on what he sees as the future of multiple myeloma. He wasn't able to be here in person for several reasons, but we were very glad that he was able to join us on the screen and gave us a talk on the future of myeloma. And I think, you know, you said it so perfectly, Dr. Kaur, that we have a tried and true therapy that works. But we have seen this evolution in myeloma where we're moving to more immunotherapies and newer treatments. And it's quite likely that maybe we wouldn't take it entirely off the table, but that we're gonna be doing a lot less transplant in the future. Now we're doing many of these clinical trials. In fact, I know even at my site, we have a clinical trial open where patients either go to CAR T or transplant after their reduction therapy. And I think we're gonna learn a lot about this in the coming, years to come. So I'm gonna turn to Alana for one last question. Believe it or not, we're getting close to time to wrap up. Let's take one more before we wrap it up.

- [Alana] How important is using DEX?

- Ah, this is one of my favorite questions. How important is it to use dexamethasone? So dexamethasone is a steroid drug and we talk a lot about dexamethasone here at the Patient and Family Seminar. I often think of it, and I even show a picture in my clinic, I think of it as, like, the booster rockets on the shuttle. It really helps boost almost every treatment we use in myeloma. But the reality is, after a while, you want those booster rockets to fall off. And there has been this movement that I've entitled #DownWithDEX. And we really want to see this take hold where, many years ago, an individual who worked with the IMF, Mike Katz, convinced one of our large myeloma committees to say, "Why don't we do a clinical trial that compares a lot of DEX to lower dose DEX?" We used to give a ton of DEX, we're still giving a lot of it. And we showed, unequivocally, that lower doses of DEX were better. Well, I think we're gonna even go lower now. And so dexamethasone is important, it's important to talk to your provider about the dosing, but many of us now are using a strategy where we choose the correct dose, what we think is the correct dose, and really only give that for a couple of months and then start to reduce it. And why? Because it comes with lots of side effects. It effects people's sleep, their mood, their blood pressure, their blood sugar. It can have a lot of negative effects. So it's the drug we hate and we love. And so we really think in the future, even as we design clinical trials now, we're starting to see a lot less dexamethasone being used because of many of the great agents that Dr. Kaur has shared with us today. Well, believe it or not, it's time to wrap up.

But I wanna thank everybody in our Facebook community, sorry we couldn't get to all of your questions for streaming in. But thank you for engaging with us today. Hopefully you've learnt a little bit more about myeloma, you've learnt a little bit more about the IMF, and you've learnt a little bit more about our flagship program here, the Patient and Family Seminar. We hope to see you in either San Francisco or Minneapolis or Los Angeles in the near future. Otherwise, please always feel open to engage with us at the website of myeloma.org, we have an info line, we have over 160 support groups across the country, lots of ways to interact with us. And lastly, I want to thank you very much, Gurbakhash, for joining me today, sharing with us your expertise, your experience in myeloma, and your passion for myeloma patients and their providers. I'd like to also thank our sponsors, 2seventy Bio, Amgen, Binding Site, Bristol Myers Squibb, GSK, Johnson and Johnson, Karyopharm, Pfizer, Regeneron, and Sanofi for supporting our work here at the Patient Family Seminar. And don't forget, you still have a half month left to celebrate Myeloma Action Month, #MyelomaActionMonth. Make sure that you get involved and support the work we're doing so that every patient can live better with myeloma to their full health. As our President and CEO shared with us in his President's Address today, that that really is the goal. As we seek to find a cure, we want our patients to live their best lives. Thanks again and appreciate your attendance.