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There are significant advances being made in multiple myeloma - more so than in any other cancer. Join us for this annual HealthTree Podcast for Multiple Myeloma with Robert Orlowski, MD, PhD of MD Anderson Cancer Center as we discuss the recent findings from the American Society of Hematology (ASH) meeting, key innovations being developed in myeloma and what patients can expect to see in 2023.

The show will review immunotherapy options, optimal combination therapies, targeted treatments and key learnings from top myeloma investigators.  

Thanks to our episode sponsor, GSK

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Jenny: Welcome to today's episode of the HealthTree Podcast for Multiple Myeloma, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. We'd like to thank our episode sponsor, GSK, for their support of this program.

Now, before we get started with today’s show, I have a few announcements about recent updates we have going on HealthTree. We have a new HealthTree Coach website that has just been launched with a new site design and new features. If you are looking for a mentor, as a patient or a caregiver, please check that out and myelomacoach.org, or you can always go to healthtree.org/myeloma, and find it in the menu bar under apps and programs. You can choose your own coach who can work with you for a short time or a long period of time. You can find coaches with specific areas of expertise, or whatnot. Feel free to include or to use that program because it’s amazing and the coaches are fabulous.

I also want to remind you about our journaling feature, which allows you to journal your myeloma story by video, audio, or in text formats. You’ll see that come out in our newsletter, different ideas that you can keep journal topics on. You can keep that journal private for you and your posterity or share those posts on social media or by email. I’m a huge historian. I wish I had had this available at my diagnosis, so I could go back and look at my 12 years of myeloma experiences, but I’m using it now. That’s always good.

Lastly, I want to give you a heads up about two new programs, you’ll see us releasing in the coming days and weeks. The first is a complete software refresh at HealthTree Cure Hub, to make keeping track of your myeloma labs more automatic and so much easier. You’ll see us make a major announcement in the coming days about that.

Second, we'll also be launching our own social media platform inside of HealthTree called HealthTree Connect. If you belong to our HealthTree chapters, this will be a great way to connect with other chapter members on specific topics or in your geographic region. That's coming soon in the next few weeks. Obviously, we have a lot going on, and more announcements to follow. We'll keep you posted on that as soon as we release these updated and new tools. Now, on to our show.

This is our annual review of what we can expect to see in 2023. It's my favorite show of the year. With so much innovation happening in the myeloma space, we need to stay as current as possible as patients and caregivers. Now, we expect this to be a fast-paced show covering a lot of different topics, but Dr. Orlowski is the best at making these topics easy to understand. We'll have a full show transcript that you can reference at a later time, and we'll end the show with a few minutes of Q&A. Write your questions down before the end of the program. We will go a little longer than our normal hour for today's show if Dr. Orlowski's schedule permits. Dr. Orlowski, welcome to the program.

Dr. Orlowski: Well, thanks very much, Jenny, for inviting me and hosting this show. I wanted to take the opportunity to wish a wonderful new year for all of the patients, and family, and caregivers out there, and hopefully 2023 will be the best year yet in your myeloma journey.

Jenny: We hope so. It's exciting to start a new year. Let me introduce you before we get started. Dr. Orlowski is Director of the Myeloma section and Professor of Medicine in the Departments of Lymphoma/Myeloma and Experimental Therapeutics at the Division of Cancer Medicine at MD Anderson Cancer Center. He's been honored with the endowed Florence Maude Thomas Cancer Research Professorship. He's also Disease Site Liaison for the International Center at MD Anderson. Dr. Orlowski serves as Chair of the Southwest Oncology Group, and is a member of the American Society for Biochemistry and Molecular Biology, member of the Editorial Board for Expert Review of the publication, Hematology, a member of the NCI Steering Committee, member of the Medical Advisory Committee for the LLS, a Scientific Advisory Board Member for HealthTree, reviewer of the ASH Abstract Review Committee, and member of the AACR Clinical Trial and Translational Cancer Research Grant Scientific Review Committee.

He's also an author on over 420 articles, abstracts, or book chapters. Dr. Orlowski has received many awards over a number of years including the Leukemia & Lymphoma Society Scholar in Clinical Research, the LLS Man of the Year Award, the Emil Frei III Award for Excellence in Translational Research from MD Anderson, the Waun Ki Hong Mentor of the Year Award, and most recently, the Gerald Bodey Award for Excellence in Education, and the 2022 Giant of Cancer Care in Myeloma. Congratulations for those wonderful awards. But you can find news and information from his daily newspaper that he uses on Paper.li called Myeloma Daily or find him on Twitter @myeloma_doc.

We have a lot to talk about. Maybe we just want to start with early precursor conditions. I think some of the important questions that I saw coming out of this last year's ASH, and also what we have to look ahead of in 2023, are just different. How do we stratify patients into patients who might progress or not progress? Do you want to start with that? Then, I'll let you go and cover whichever topics you'd like on these precursor conditions.

Dr. Orlowski: Yes, definitely. I think MGUS is a great place to start, because it's the most prevalent of these conditions. For folks who have a certain level of maturity, shall we say, anywhere from 3% or more of patients will actually have MGUS. Fortunately, most of them will not progress. But we need to get better in identifying who will and who will not. I think one of the interesting abstracts at the ASH meeting was from a group at Arkansas, where they narrowed down their previous gene expression studies to a ten-gene panel, which they thought was very predictive of progression from MGUS to active myeloma. That's worth remembering because gene expression profiling is available for patients but isn't routinely used. In a study that we've done at MD Anderson, where we're also following precursor patients, our early data seem to confirm that gene expression profiling may be the best approach in trying to risk stratify folks with MGUS.

Jenny: Interesting. Gene expression profiling, interesting that that would be a way. They did narrow down because they had more. They had a 70-gene panel, didn't they?

Dr. Orlowski: Correct. Originally, the Arkansas panel was a GEP 70 or 70 genes. The Europeans have their version called SKY92, which has, of course, 92 genes. We still need more validation, before I would say that every MGUS patient should get this, but I think it's definitely worth thinking about. The other thing that's interesting about MGUS is that there is more information coming out about the potential role of things like body mass and risk of progression to myeloma.

Now, we've known for many years that obesity, especially during early adulthood, is a risk factor for developing myeloma itself. In fact, it's pretty much the only risk factor that we can do something about, but now, there are some studies that suggest that at the MGUS stage, if you have a higher body mass, you have a higher risk of progression to symptomatic multiple myeloma. Actually, one of the studies that was presented also suggested that may be especially true in women.

What we don't yet know is if you do some kind of intervention, let's say that you have the MGUS, and you are on the higher end of body mass index, if you lose weight by diet and exercise, will that help you to reduce your risk? We don't know the answer to that yet. But there are more and more studies that are associating a Western type diet, meaning lots of carbohydrates, lots of processed foods, with a higher risk of progression. There are some suggestions of that a "healthier" diet, including less processed foods, less sugar, less carbohydrate, and perhaps more of a plant-based diet may be better. That's not surprising, because similar findings have been found in other cancers. Some of our own studies looking at what may predict for progression, suggest that if you have a weakened immune system, that may predispose you to progression. We do know that obesity and some of the dietary aspects of the Western diets do increase inflammation. These factors may contribute through that mechanism to a risk of progression.

Jenny: As patients, if there's something that we can do about it, then we can. It's the start of a new year, so I will just have a shout out that we have now plant-based diet recipes on the website under healthy recipes. I, myself, I'm trying to move more that direction, although it's not the easiest thing to do, it's a good thing to do. Worth the effort, for sure.

Dr. Orlowski: I definitely would agree with that. Which other tests did you want to talk about?

Jenny: Maybe circulating tumor cells or single cell sequencing type tests?

Dr. Orlowski: Yes, definitely. Circulating tumor cells are interesting. Most people think of myeloma as being in the bone marrow, which is definitely true. But we can detect small numbers of myeloma cells in the circulation in most patients who have not received therapy. Although these tests are not yet routinely available at most clinical locations, we do have studies that show that circulating tumor cells, if they're increased, are associated with a greater risk of progression. One of the exciting things is that these circulating cells, if we do what you mentioned, which is single cell sequencing, and we now have the technology to even take one individual myeloma cell, and sequence the DNA in that cell, and even look at what genes are turned on and what genes are turned off, many studies now show that the mutations present in those circulating cells are pretty much the same as what are present in the myeloma cells in the bone marrow.

The reason that's helpful is that we may, in the future -- I don't think we're there yet -- but we may, in the future, be able to do diagnostic and molecular testing just on these circulating blood cells, rather than on bone marrows. Therefore, maybe, we can get away with these aspirants and biopsies. I do hedge, because we do know that the peripheral blood assays are ten to 100 times less sensitive. One of the studies that was presented at ASH that looked at MRD testing at a peripheral blood level, actually took 50 ml of blood in order to reach the level of sensitivity of the bone marrow. For those of you that get blood testing, if you think about that, each blood tube is maybe five ml, so you're talking about ten tubes of blood, just for that MRD assay. Never mind actually looking at the chemistries in the M protein. Clearly, we need to get a little bit more sensitive than taking ten tubes of blood every time we want an MRD assay, but at least, it's moving things in the right direction. I think that's an exciting area for further research.

Jenny: Yes, absolutely. Is that something that can be done at the MGUS or smoldering myeloma stage, or is that more inactive myeloma where you have more cells present?

Dr. Orlowski: Yes, definitely. You can do it in precursors as well as active myeloma. In general, as you would imagine, patients with active myeloma have more circulating cells than patients with smoldering. Smoldering patients typically have more cells circulating than MGUS patients. But with these single-cell techniques, we can get even information out of ten or 20 circulating cells. The other advantage of being able to do that single-cell analysis is that we get a better idea of how different the myeloma cells are. Even though myeloma starts out with one bad, nasty, ugly cancer cell, as it grows, there are different clones, not all of them behave the same. Some may have a mutation and RAS, some may not, for example. RAS is an important gene in myeloma. By being able to look at each individual myeloma cell, we're able to get a better view of the differences between the myeloma in each patient. I think in the future, that will help us to pick better therapies for patients.

Jenny: Just to follow on what you're saying, I know that in smoldering myeloma, it was identified that you could see some of these gene signatures that you would have in active myeloma, in a smoldering setting. But is that true in the MGUS setting too, or no?

Dr. Orlowski: You're right, that it seems the gene mutations that are present in active myeloma are pretty similar to the ones that appear in smoldering disease, which suggests that it's probably not those mutations that cause progression. With MGUS, the challenge is that because there are so many fewer cells, you have a more difficult time identifying the mutations. But a lot of studies do show that even in MGUS, the same mutations are already present. This, again, gets back to that possibility that we're working on, that maybe it's a weakening of the immune system by the cancer that allows the cancer to grow, rather than that it's some new mutation that makes the myeloma cell more aggressive.

Jenny: Would you go over that a little bit more about your work, about what you're doing there, because I think this is fascinating.

Dr. Orlowski: Thanks for the opportunity to talk about that. We have a Moon Shot in high-risk myeloma here, which was led by one of our faculty, Elisabet Manasanch. She is directing the effort to try to understand some of the immune changes that happen in people who progress from precursor stages. Some of those are now leading to clinical trials about therapies that hopefully will reverse those changes. We just finished enrolling to a vaccine study. Although we don't have the final results of that trial, we do see that we can raise immunity in patients with myeloma against proteins in the myeloma cell, which would be a first step to get more immune attack against the patient's own cancer.

We also, of course, have other clinical trials like looking at isatuximab with lenalidomide and dexamethasone, as well as other possibilities in the setting, with the goal being that if we reduce the myeloma enough, we will at least be able to delay progression. Ultimately, we'd like to prevent progression altogether. But even if we just delay progression by say, five or ten years, if you have progression down the road, we're going to be much better at treating the myeloma then, even than we are now, and that's even though we've got really wonderful therapies now, but the more time that we buy, as it were to learn how to treat myeloma better, the better will be the outcomes.

Jenny: Yes, absolutely. I think that's so interesting. What are you finding about raising immunity, like you mentioned?

Dr. Orlowski: Some of these approaches use the CD38 antibodies like daratumumab or isatuximab. Many of them involve immunomodulatory drugs. There are other approaches that people are taking as well. I'll give you one example of something that was updated at ASH since this is a post-ASH meeting. But there was a European study called GEM-CESAR. This was a trial where patients got carfilzomib, lenalidomide, and dexamethasone stem cell transplant, then more carfilzomib, len, and dex, and then after that, they got maintenance with len and dex.

What they reported is that the MRD negative rate at ten to the minus six was about 50% on that trial, and ten to the minus six is a really sensitive level, which means that this regimen was very, very effective in producing some of the highest quality responses. That's the good news from that trial. The somewhat frustrating news from that trial was the patients were still progressing to active myeloma. It was a 62% progression-free survival at 70 months, which still means that 38% of patients had progressed, so that therapy doesn't yet rise to the level of what we would call a cure, but if we can delay your progression by almost ten years, or five to ten years, let's say, again, you'll be in a better situation with more effective therapy available down the road.

Jenny: I agree that that's such an important point, because the technology is moving so fast, the diagnostic testing is getting more sensitive, and the drugs and treatment combinations are getting better. You could buy yourself a lot of time by doing that. That was the approach that I was thinking about too, as a newly diagnosed patient. Let's just buy time until other things can be developed. Wow. Over the last 12 years, amazing, amazing developments. I think that's not a bad strategy at all.

Dr. Orlowski: Definitely. There were some developments in newly diagnosed disease as well. We could cover some of those next, if you think that would be appropriate.

Jenny: Sure, absolutely.

Dr. Orlowski: One thing that many in the field are, I think, recognizing is that probably, if you're newly diagnosed, you should get a combination with a CD38 antibody. Right now, for the most part, that would be daratumumab, because it's approved there. But there were a number of studies at ASH with isatuximab, which is the other anti-CD38, which is coming to the newly diagnosed setting. Those trials really did show that adding that antibody had a big impact in improving the MRD negativity. It does so without really a big increase in side effects. I used to use these four-drug combinations, mostly for patients with high-risk disease, and for patients with a high disease burden. But frankly, we're now using this for all patients with myeloma.

There are still exceptions, because there are some folks who have other medical problems, or may be too ill or frail to receive four drugs, in which case, a three-drug combination is still very appropriate. But to me right now, the four-drug regimen is probably the standard of care.

One of the questions that is now being asked, and we don't yet have the answer to this, but one of the questions is about stem cell transplants versus CAR T. We have some data coming from the KarMMa studies. These are trials with the Abecma brand of the BCMA targeted CAR T, and then CARTITUDE-6 is with Carvykti, the other brand of BCMA CAR T. several of these are still very early, and nonetheless, are showing what look like better response rates in earlier patient populations, if you use the CAR T's sooner. I think that's certainly very encouraging.

Not unexpected, for two reasons. First of all, if you give a treatment earlier, myeloma is less drug resistant, because it hasn't been exposed to so many different therapies. But probably even more importantly, because both of the current available CAR T's use the patient's own T-cells. If you take T-cells at an earlier time, that haven't been exposed to so many drugs, their health and robustness is probably better, which means that they will work better against myeloma. CARTITUDE-6,  in particular, is looking at whether CAR T will be better than stem cell transplant as a consolidation after the initial chemotherapies. It's going to be a little while before we know what the results are, but at least if you look in the B-cell non-Hodgkin lymphoma space, there already are results of randomized studies that show that the CD19 CAR T's may be better than a stem cell transplant in terms of long term outcomes. That doesn't guarantee, of course, that the same thing will be true in myeloma, but it certainly makes it very encouraging that that will be the case.

Jenny: I think that the idea of this better immune system and using it earlier upfront is a really important concept. I have a question about that. If you use CAR T upfront as a newly diagnosed patient, would you still do like dara RVd or RVd as an initial therapy to drop the tumor burden, and then you would go to CAR T. But are you still doing the lymphodepleting chemo that they do during CAR T? How would that process work? I'm just curious about that.

Dr. Orlowski: Those are great questions. First of all, most of the trials include some amount of induction chemotherapy like the dara VRd that you mentioned. That's for a couple of reasons. First of all, the manufacturing for the autologous CAR T's can take a month or two from the time that the T-cells are collected. If somebody presents with symptomatic disease, you don't want to wait a month or two without doing anything until the CAR T's are manufactured and ready to put back in. Starting with some chemotherapy is very reasonable. The second reason why you probably want to give some chemotherapy first is that all of the CAR T's have some risk of what's called cytokine release syndrome.

There's also neurotoxicity, which is called ICANS. The reason these occur is that when the T-cells are infused, and they find the myeloma cells, they become activated, and they release these proteins called cytokines, which cause inflammation. Probably the best example is people who've had the flu, or unfortunately, now people who've had COVID. As you know, sometimes, you have fever, you have malaise. All of those things are due to cytokines. The more myeloma you have, when you get your CAR T-cells back, the greater is the chance of the cytokine release syndrome. The second reason to give some chemotherapy before the CAR T, other than buying time for the manufacturing, is that the less myeloma you have, the greater will be the safety with a lower risk of cytokine release.

You also asked about whether you need the lymphodepleting chemotherapy, which is usually with two drugs, one of which is fludarabine, the other of which has cyclophosphamide. Right now, the answer is that yes, all patients who get CAR T still need the lymphodepletion. The reason to do that is that even though these are your own T-cells that you're getting back in your body, they've been modified with this new gene that leads to expression of this CAR, or chimeric antigen receptor, which is a new protein on your T-cells. Your immune system is trained to recognize new proteins. If your immune system is going gangbusters, it may attack those CAR T-cells and get rid of them sooner than you want, which would reduce their efficacy. The point of the lymphodepleting chemotherapy is therefore to get just a little bit of immune suppression so that you don't get rid of the CARs right away, because you want them to hang around long enough that they can kill off the myeloma cells.

Jenny: Well, thank you for explaining that. That's new information to me. I didn't I didn't really understand it. I know some people who are getting CAR T right now are getting the bridging therapy, so they might be getting dara RVd, or RVd, or something like that to bridge them to that point. Thank you for explaining that. Appreciate it. It makes a lot of sense.

Dr. Orlowski: The bridging therapy, by the way, you're right, the bridging therapy is meant more to buy time because, again, with the manufacturing of the CAR T's taking a month or two, some people have myeloma that's growing slowly, and they don't need anything during that interval. But other people have myeloma that's growing very rapidly. In those cases, they may need bridging therapy to knock the myeloma back a bit so that they can wait a month or two for their T-cells to come back. Lymphodepletion really is needed to be given to everybody. Not everybody needs bridging, but everybody does need lymphodepletion.

Jenny: Okay, so on CAR T for newly diagnosed patients. I had a question for you. Do you think bringing CAR T to the forefront for both high-risk and standard risk patients is going to be equally impactful? Is there any way stratifying that?

Dr. Orlowski: Well, you're right, that CAR T-cells really should care only whether the target protein, which again is mostly BCMA, is expressed on the surface of the myeloma cell. BCMA seems to be pretty equal on the surface of both high-risk and standard risk myeloma. Theoretically, these CAR T-cells, and I know we'll talk later about bispecifics, they should work as well against high-risk and standard risk. We don't really have enough data yet to say whether that's the case, but I do think that because the high-risk patients have shorter benefits from standard therapy, it will be quicker to show that hopefully, CAR T makes a big difference for them, compared to no CAR T. But I'm sort of confident that CAR T will also be better for standard risk patients versus no CAR T in the newly diagnosed setting, but we won't know for sure until the trials are actually done.

There's good news and bad news here. But good news is that patients now with newly diagnosed disease are doing much better than ever. As an example, I would say that the survival for a standard risk patient right now is in the 10 to 15-year range. The good news is that patients are doing better. The only wrinkle in that is that it takes much longer to see whether a new therapy for newly diagnosed patients is working, because you need to wait years and years to see if the people who got CAR T do better than the people who did not.

But that's an area where something we talked about earlier, the MRD testing, could be helpful, because in general, if you are MRD negative, you do better than MRD positive. there are many people trying to make MRD what's called surrogate marker for new drug approval. What that would mean is that we could use MRD testing to see if a drug works or not, and get it approved sooner, rather than waiting for overall survival, because patients with myeloma are living so much longer. That's still not an endpoint, but many people are working to try to get that to happen.

Jenny: Are you an advocate for that? I think it would be so important to speed up trials in any way that we can, right?

Dr. Orlowski: I definitely agree. We're doing wonderfully well with patients with myeloma now, but we're still not curing the disease. I think once we're at the point that we're curing patients, then we'll of course be a lot happier. But until we get to that point, anything that speeds up new drug availability is going to be a positive, because I'm going to want to get the newest and best therapies to patients as soon as I can.

Jenny: Right. You're doing so many trials to understand those questions. It's so important to not have to wait eight to ten years until a trial reads out with their overall survival data more. It's so important.

Dr. Orlowski: Exactly.

Jenny: You mentioned earlier in the program that when you have a newly diagnosed patient, if they were high-risk, you would do their RVd or something like that. But now, you're using it for standard risk patients. Is there any other way that you stratify treatment for a newly diagnosed patient?

Dr. Orlowski: Right now, we do not have specific therapies that are directed against one subtype of myeloma over another in the newly diagnosed setting. The one exception is there's a drug called venetoclax, which is a BCL-2 inhibitor. BCL-2 is a protein that helps, in this case, myeloma cells to survive. We have drugs that block that protein. We're now designing a study -- actually, I mentioned Elisabet Manasanch earlier, since she's our leader for smoldering disease, she's going to do a trial where she's looking at adding venetoclax to newly diagnosed patients, who are going to get three and four-drug regimens. I think that's an example of where we would like to go in the future, where we have a common core of drugs that we give to all patients, but then we add additional drugs that are specific for their particular abnormality.

We actually just sent in a proposal to the Multiple Myeloma Research Foundation on newly diagnosed high-risk disease, that has some ideas that we would like to test about other therapies that will be good for specific subtypes of high-risk myeloma. The goal, really, is to develop what I like to call designer drugs, because again, they're meant for a particular subtype, and that hopefully, will improve outcomes in those types. We are trying to personalize myeloma therapy, in terms of using the best therapy for each individual patient, but we're not quite there yet.

Jenny: On the 11;14 study that you're opening, is that open already?

Dr. Orlowski: That's still being designed. It will be a multicenter study, though. Hopefully, once it's open, there will be the ability for patients all over the country to access it.

Jenny: Okay. I would love to add a link or something to that study, when it becomes open. I think this is such an important idea to tailor the therapy to each individual patient. With that being really the only genetic feature that we know of that has a targeted drug for it. It seems to be that would be an excellent -- I would join that if I were a newly diagnosed patient with 11;14.

Dr. Orlowski: Well, I'll definitely let you know when that becomes available. We've talked for a couple of years now on the show about deletion 17p myeloma. 11;14 patients usually have a good prognosis. Of course, it's always better to make it even better than good. But deletion 17p patients have, unfortunately, a less than average prognosis. We do now have a drug that based on laboratory studies, seems to work better against deletion 17p myeloma than regular myeloma. This is a drug that doesn't have a name yet, but it's called HDP-101. It's now in clinical trials for relapsed and refractory disease. But if we get good results there, we would be very excited to move it earlier.

This is what's called an antibody drug conjugate. It's a Trojan horse, if you will, because it's an antibody that binds to a myeloma cell. It's got a drug attached, which is then released inside the cell, after the myeloma cell takes up this antibody drug conjugate. The drug that it's attached to is especially active against deletion 17p myeloma. I know you were wanting to talk about belantamab in the future about relapsed refractory disease, but so far, with this new drug conjugate, we have not seen any ocular toxicity, which is the keratopathy, or dry eyes, or blurry vision that was really a big problem with belantamab.

Jenny: Here's a question about deletion 17. What's the difference in the diagnosis? When you see the newly diagnosed myeloma, what's the frequency and the severity that you're seeing in newly diagnosed myeloma versus highly relapsed refractory myeloma?

Dr. Orlowski: Most of the studies done on this suggests that about 10% of patients with myeloma have a deletion of 17p in the newly diagnosed setting. But as you get later and later in the disease, that proportion seems to go up. In general, what we know is that patients with that abnormality have a shorter time in remission than people without it. However, if you're in that group, there are some nuances. Don't be anxious right off the bat. The reason is that there are different subtypes of deletion 17p. Some of them actually have a good prognosis. Those are people -- because we have two copies of each chromosome 17, some patients will have a deletion of one, but the other copy is normal. Those people do actually very well.

The people who have more of a problem are those where one copy or both copies are lost, and one copy is lost or the other is mutated. You don't just need FISH to know if you're high-risk, you also need sequencing. That's why getting evaluated at a place that has not just the FISH available, but also sequencing and maybe GEP is important. If you have deletion 17p on your bone marrow, I would recommend definitely that you get a second opinion at an academic center where they can do sequencing, because that may actually give you a better prognosis than what you would otherwise expect.

Jenny: Oh, absolutely. I want to emphasize this point as a patient advocate, you just you need to know what kind of myeloma you have. This is a warrior fighting, and you need to understand the enemy. You need a myeloma specialist in your corner. There's data from two major academic centers showing that you live longer if you have a specialist on your team. University of North Carolina and Mayo Clinic both. It's so, so critical. Anytime you're making a treatment decision, in my opinion, whether you're newly diagnosed, or relapsed, or relapsing again, you need a myeloma specialist to give you some guidance.

Also, I had a question on your study that you have, the HDP-101 study for relapsed/refractory patients. When you say that -- some of these deletion 17, there's some stratification inside of that. Are you taking all comers, all deletion 17 patients, in that trial?

Dr. Orlowski: That particular study takes all patients with multiple myeloma because the drug does work against normal 17p myeloma. It just seems to work even better against deletion 17p, but we are collecting information about the mutation status. At the end of the study, we're going to compare, and hopefully, what we'll find is that the ones that did have deletion 17p will do at least as well. Who knows? Maybe they'll do even better than patients who don't have it, but it is open to all relapsed and refractory myeloma patients.

Jenny: Oh, okay. Wonderful. I would love a link to that study. that's the only open at MD Anderson, right?

Dr. Orlowski: No. That's actually a multicenter study. I don't know all of the centers, but you can definitely look up the link, which I'll send you, or for those of you that are interested, you can also look on clinicaltrials.gov, which is another good location to find where trials are available.

Jenny: Right, and we have a clinical trial finder tool also just for myeloma trials. I will include that link in there too, so people can find it. That's a wonderful, wonderful study. Well, thank you for mentioning it.

In newly diagnosed myeloma, are there any other strategies for, let's say, you have all these high-risk features or more than one high-risk feature when you're newly diagnosed, are there other approaches like more of consolidation therapy, or different kinds of maintenance, or other things that you are finding that are helpful for newly diagnosed patients?

Dr. Orlowski: Definitely. First of all, through SWOG, which is one of the cooperative groups funded by the National Cancer Institute that does clinical trials across the whole country, we're designing a study where we're going to compare four drugs, which is the dara with VRd as the standard, and we're adding a fifth drug, which is called teclistamab, a BCMA bispecific, with the hope that we'll get even more patients to achieve MRD negativity. That's one approach.

Also, many experts in the field, if you get a stem cell transplant, or recommend a more aggressive maintenance, and that would be at least with an immunomodulatory drug like lenalidomide and a proteasome inhibitor. There were a couple of studies at ASH from European groups that looked at consolidation, even after a transplant, with three and four-drug regimens, including an anti CD38 antibody, and they really did support the possibility that more aggressive therapy for these high-risk patients will produce better outcomes in the long run. Essentially, you have to whack-a-mole even better against high-risk disease, and keep those clones down to as low a level as possible for as long as possible to get the best outcomes.

Jenny: Yes, much harder, I would think, to get it under control, once you've gotten it under control, in a high-risk situation than just keeping it under control.

Dr. Orlowski: I think, again, looking for clinical trial opportunities, as we discussed earlier, looking at CAR T's, looking at bispecifics, these are all very novel and exciting therapies, that hopefully, will make a big difference. If you've got high-risk disease, you really want to look for something more than just the standard of care therapy. It's like if you go to the ice cream store, and you want some sprinkles on your ice cream. That's what you want here too.

Jenny: For sure. On your SWOG study that there are VRd plus the teclistamab, which is a bispecific antibody, do you just stay on that treatment until progression, or is there a fixed duration of any of that, or you just stay on it?

Dr. Orlowski: Good question. The current design does maintenance based on the response. If you are MRD negative, you have less intensive maintenance than if you're MRD positive. That really determines the duration of therapy with the bispecific antibody. We also have MRD testing involved there. I think this is the way we're going to be treating myeloma in the future, both for standard and for high-risk patients, meaning that we're going to be checking MRD, and we're going to be deescalating, meaning decreasing treatment for people that are MRD negative. For people who switch from MRD negative to MRD positive, we're probably going to go back up on the intensity of therapy. But the good news is then that not everybody will get every drug all of the time.

Jenny: Well, that's such a nice approach, because it's so much for patients to stay on therapy all the time at maximum doses for a really extended period of time, both just physically and emotionally, and cost-wise, and everything else. The more that you can do to determine who can come off, or who can lower their dose, or whatever, is just so much appreciated by the patients.

Dr. Orlowski: There were studies presented at ASH talking about dexamethasone and the fact that you may be able to reduce or even get rid of the steroid component of some of these therapies. For those of you that have not been on therapy, most people think that it's the chemotherapy or immunotherapy component which is the worst in terms of side effects. Certainly, for some people, that's true. But I find more of my patients have more side effects from the steroid part than from the rest of the treatment. We used to do steroids because they were one of the only things that we had available. But now, with many of the therapies we have that rely on immune cells, too much steroid is actually bad, because steroids are immune suppressive. For any of you that are on CAR T-cells, or that are getting bispecifics, you know that the goal is to hopefully avoid giving steroids while you're on those, unless you have a particularly severe form of that cytokine release or neuro toxicity. I think, in general, that's the direction that the field is going, which I know patients will be happy about is to try to reduce the steroids as much as possible.

Jenny: Oh, patients are going to be so excited about that. Because dex is that drug that makes everyone else stupid. Spouses everywhere will thank you. They will love that. Absolutely love it. Well, should we move on to relapse and refractory disease? Is there anything else that you wanted to share about in the newly diagnosed setting?

Dr. Orlowski: I think we can move on to relapsed and refractory, and we can always get back to newly diagnosed as other questions come up later.

Jenny: I think a lot of patients have questions in a relapsed status. Should I do maybe a bispecific antibody now that one is approved, teclistamab? Should I do clinical trial with a bispecific antibody? Should I shoot for CAR T? What should I do first at relapse? I'd like to know what you suggest as a leader in the space?

Dr. Orlowski: Definitely. Well, I think that both the bispecifics and the CAR T-cells are really exciting therapies that are better in advanced disease than anything that we have seen before. Sometimes, the disease itself may dictate what we need to do. What I mean by that is if you have myeloma that's growing, but it's growing slowly, you may have time to do a CAR T. As I mentioned earlier, it can take a month or two for the CAR T-cells to be manufactured because they have to collect them from each patient, send them off, they have to have this new CAR gene put in, they have to be expanded, and then they get sent back. Whereas, a bispecific is an already made antibody that's off the shelf. You skip past that one to two months.

If you have a very aggressive myeloma that's growing very rapidly, you may be better served by a bispecific because it's something that you can do right now, as opposed to wait a month or two. Although we did talk earlier about bridging therapy. That's always an option to buy some time while your CAR T-cells are being made. If you have myeloma that's growing more slowly, you may prefer to do the CAR T-cell. One of the advantages of the CAR T-cell is that it's what I like to say a one and done therapy, because you get the lymphodepletion, you get your T-cells infused back in. There's usually a monitoring period of a few weeks when there is a risk for the cytokine release and neurotoxicity. But after that, at least as of right now, you don't do any more therapy. Oftentimes, you can be off of treatment for months to even a couple of years. For many people, that is a period off treatment that they have not had for a long time. People always enjoy being off of therapy.

Before you get too excited about that, there are trials looking at adding maintenance or other treatments to CAR T-cells to see if they work better. It may prove that they do. But at least for right now, there's no maintenance. The big difference with bispecifics is that because they don't stay in the body for a long period, you wind up getting that dose on a regular basis. Most of them start off with a couple of small doses before you get a full dose. Then, they go once a week for a period, and then eventually, some of them can be given less frequently. Some of them, teclistamab in particular, can be given subcutaneously, but there is still this risk of CRS and ICANS, and so you don't have that one and done feature because you do have to come back in on a regular basis. I think those are some of the pros and cons of the two approaches. I think if you have slow growing disease, probably if I were a patient, I would prefer to get a CAR T-cell, because of that possibility to be off of therapy, but there are fewer slots available for CAR T-cells, whereas, with the bispecific there should be greater availability. At the end of the day, you have to do what will most rapidly get rid of your myeloma.

Jenny: Yes, absolutely. Sometimes, they're not always available. What you would love to have might not be available at the time. I know they're working on that with CAR T. Maybe we should start with CAR T, and availability issues, and things like that, and then some other CAR T approaches. I'm seeing these dual fast CAR T's like doing two targets, and with a faster production of just a few days, and allo-CAR T's. Do you want to just review what you see as most important happening in the CAR T space?

Dr. Orlowski: There's a lot of really exciting things in the CAR T space. We've talked mostly about BCMA as a target, but there are other myeloma cell surface proteins that seem to be good targets. GPRC5D is one example. The interesting part there is that we may be able to use a CAR T against one target, and then if patients relapse, we may be able to use a CAR T against a different target after that. That's the exciting thing there. The FAST CAR T that you talked about is a dual CAR where it goes after a BCMA and CD19. CD19 is a B-cell protein, but there are some suggestions that a myeloma stem cell is around at a low level and may be CD19 positive.

The theoretical advantage of hitting BCMA on myeloma cells, and CD19 on myeloma stem cells, is that you may have a longer time in remission. We don't know yet if that's the truth. But so far, the data with that approach look good. The fast portion of that is that they have much more rapid manufacturing. Of course, that is really exciting because it gives you more options rather than having to wait one month or two months. We may wind up just like we currently use chemotherapy drugs in combination, we might wind up using CAR T-cells against several targets, and hopefully, wind up with better efficacy. We don't know that yet, but that would certainly be an exciting possibility.

You also mentioned allogeneic CAR T's. Those are a little further back, and none of those have yet gotten FDA approval. But there's a couple of theoretical advantages to an allogeneic CAR. Allogeneic, of course, means that the T-cells that are used are not from the patient, but from a normal donor. A couple of main advantages. Number one is that because the donor has not had chemotherapy, the T-cells should be much healthier, because they haven't been exposed to a variety of treatments. The other benefit is that because these T-cells are already available, you can expand them, and the T-cells can essentially be off the shelf, and you don't have that one-to-two-month manufacturing period. The downside is that because these are different T-cells than the ones that you have in your body, some of them require more lymphodepletion or more immune suppression. But the fact that you can get them more rapidly and that the T-cells are healthier will hopefully win out. We don't yet know if those will be routinely available, but I think it's definitely a very interesting and promising approach.

Jenny: Yes, wonderful. Well, it'll be interesting to see comparing the autologous versus the allo over time. That will be really interesting to see. Definitely nice to have something off the shelf and ready to go. Should we talk about bispecific antibodies? There's so many of them. I had no idea that there are new ones popping up. I mean, there's teclistamab. I didn't know that BMS had a new bispecific antibody. I did not know that. There's one from Regeneron, there's one from AbbVie, there's one from Pfizer, elranatamab, there's tell talquetamab which is Janssen's second bispecific antibody. Do you just want to review those and help us differentiate a little bit?

Dr. Orlowski: Sure. Well, a bispecific antibody is similar to a regular antibody. If you think about it, a regular antibody has two binding sites. Both of them recognize the same protein. We talked earlier about daratumumab, which has two binding sites. You can think of them as like Velcro. Both of them bind to CD38. With engineering, you can make an antibody where one of those sites binds a myeloma protein. Another site, usually in this case, would bind C3, which is a protein on T-cells. It's a way to use the T-cells already present in the patient's body, but bring them right next to a myeloma cell, and activate the T-cells and make them angry, and then the T-cells attack. It's like using your own T-cells as a car. That's why you've got this off the shelf approach. You mentioned that there is teclistamab, which is already FDA approved, which is a BCMA bispecific. You mentioned talquetamab. That's also a bispecific, but against GPRC5D and not yet FDA approved. Many of the others that you mentioned are BCMA bispecific, so elranatamab is from the Pfizer folks, and you never know how the timing will work out, but it seems like that will be the second bispecific approved. You mentioned Regeneron, which is linvoseltamab, and then there are others as well.

The interesting thing is that all of these have a response rate of about 60% to 70%. The fact that they're all pretty similar would suggest that it's probably the same 60% or 70% of patients that are responding. We don't yet know why there's that 30 or 40% of people who do not respond well, but one possibility is that those are people whose T-cells are not particularly healthy, and can't be made angry, and won't attack myeloma cells. I think one of the challenges in the field is, first of all, can we identify which 30& or 40% of patients that will be? Can we do something for those patients to help make the T-cells angry, so that they attack the myeloma cells better? There's a lot of research going on around that, including at MD Anderson. But we don't have an answer yet. Although, I'm actually pretty confident that we will be able to improve upon that 60% to 70% response rate.

Jenny: Well, that would be wonderful. Maybe that's combinations, like you talked about the SWOG trials combinations. That'll be really interesting to see --

Dr. Orlowski: Well, exactly. Just like you can get a CAR T that goes after different targets. We may wind up -- we're already doing this in trials, we're already combining bispecifics against different targets, to see if that may work better. The reason that's a possibility is that sometimes, myeloma cells may express very low levels of, for example, BCMA or GPRC5D. If that's the case, then those myeloma cells are essentially invisible to the bispecific. Having two different proteins that you go after makes it less likely that both of those will not be present, and therefore, improves the chances that every myeloma cell is going to be able to be targeted. The only potential downside is that if you over activate the T-cells, then that can result in T-cell exhaustion. If your T-cells are not working well, then a bispecific approach is also not going to be very successful.

Jenny: That's where maybe you go look to an allo approach or something like that when your own system isn't working right.

Dr. Orlowski: Exactly, or look for approaches that will make the T-cells more active.

Jenny: How's that done?

Dr. Orlowski: Well, we don't know that yet, but there are other drugs that have been used in other cancers that help to reverse T-cell exhaustion. Examples of those include immune checkpoint inhibitors. Some of those have been tried in myeloma before, but they may work better now in these new combinations.

Jenny: Can I ask you too about sequencing types of therapies, immunotherapies? You read about infection rates, and you alluded to cytokine release, and the ICANS, and neurotoxicity. But some of the side effects to have CAR T and the bispecific antibodies are infections. If you are sequencing these things, like let's say, you get a CAR T, and then you progress, and you go on a bispecific, or maybe you add another bispecific or you combine them like you're saying, how do you manage the infection risk seeing that myeloma patients, many times, die of infections, and that's a big concern for myeloma patients. How do you manage that?

Dr. Orlowski: Well, you're definitely right. Sadly, infection is one of the most common reasons that myeloma patients die, because first of all, myeloma is a cancer of the immune system. Many of the therapies including CAR T-cells, bispecifics, all of the things we've talked about, attack, not just myeloma plasma cells, but also normal plasma cells. The job of normal plasma cells is to make antibodies, which help us to fight off infections. First of all, one thing that can be done is, especially in patients that have a low IgG level, and sometimes 400 is used as a threshold. If the IgG is below 400, you can get gamma globulin replacement therapy (IVIG), and this helps to increase your antibody levels. That's definitely something to consider.

Most of these patients need to be on antiviral preventative measures. That would mean acyclovir, or valacyclovir, or another drug in that category. Many folks are now adding anti-bacterial antibiotics as a prophylactic in the settings. We are trying to come to a point where we have a uniform set of recommendations about what prophylactic drugs to use. Patients also need to be careful. I definitely recommend to all of them that they monitor their temperatures regularly, and get in touch with us if they get any temperature of 101 degrees or higher. If it's a little bit lower than that, but they're having shaking, chills, or other symptoms like that, we often will bring them into the hospital and give them intravenous antibiotics. Most of them have relatively low level of viral infections, but every now and then they have unusual infections. We've seen things like adenovirus, cytomegalovirus, of course, fungal and bacterial infections. This, again, is where it helps to be at least nearby a large center that has expertise in these infections, because these are not the typical things that your average cancer patients have been getting.

Jenny: Right, absolutely. That's a good thing for patients to watch out for. If you're on these different immunotherapies, just be extra cautious, and ask your doctor lots of questions, and make sure that you know who to call if you see any problems. Some other questions on a few other different types of drugs. Maybe you want to cover those quickly. I want to leave some time for questions, which I'm not doing a good job of. But can you cover maybe CelMoDs and the Blenrep status on that, and maybe, if you want to cover anything else for relapsed refractory before we head to questions?

Dr. Orlowski: Sure. CelMoDs, there's two of them. One is called iberdomide. The other one is called mezigdomide. These are drugs that have some relationship to lenalidomide and pomalidomide, but they seem to be more potent, can be active, even if patients have myeloma that has progressed on those prior immunomodulatory drugs. One of the interesting things about mezigdomide is that our early trials suggest a nice response rate in patients with extramedullary disease or EMD. That means myeloma that is outside the bone marrow, which unfortunately, usually doesn't respond well to treatment, but there may be something particularly helpful about mezigdomide. There are large studies of both of those drugs that are currently ongoing, and hopefully, will lead to their FDA approval, and definitely look for those. Mezigdomide also can be active and patients with prior CAR T therapy. Look for that.

You mentioned belantamab mafodotin. This was the antibody drug conjugate that was previously FDA approved. More recently, there is a process started to withdraw the drug. For those of you that are still on it, or maybe will want to be, it's important to keep in mind that this process of withdrawing it is not because there was a safety concern about the drug different than what we already knew. What happened is that whenever you have a drug approved with just a single-arm study, the FDA requires a randomized trial to confirm the activity be performed.

In this case, the randomized study compared belantamab to pomalidomide and dexamethasone, and it turns out that the two drugs were maybe the same as belantamab. That doesn't mean belantamab is a bad drug. it means that it has to be given in the right combination. There are combinations that are being tested that look good so far. I think it actually will be available again in the future. You can still get it right now on an expanded access basis. There are a few more hoops that you have to jump through, but I do think that it's still an active drug that should be considered for some patients. Those are, I think, some of the other drugs to consider.

Jenny: Great. Is there anything else for extramedullary disease patients that you mentioned the CelMoDs, and that's great, but for patients who are having that issue, is there any other thing that's stands out to you?

Dr. Orlowski: We often like to do alkylating agent-based therapies in those settings. Those are drugs like cyclophosphamide, sometimes radiation can be helpful if there is one location. We are looking at may be different ways to give CAR T-cells that hopefully will be effective, because at least so far, the way we do the CAR T or the bispecifics routinely, the folks with extramedullary disease seem to benefit a little bit less. But right now, I think that either the CelMoDs, or alkylating agents, or radiation, these are all things to consider in those settings.

Jenny: Okay, great. Well, thank you so much. You answered so many of my questions. I want to open it up for a few of our caller questions. If you have a question for Dr. Orlowski, you can call 347-637-2631, and press 1 on your keypad. While we are waiting for people to do that -- let me go to our first caller. Go ahead with your question.

Caller: Hi there. My name is Rose, and I'm a patient at MDA. My question has to do with weight loss. During COVID, I began to acquire a lot of weight. I've gained more weight than I need to. The question is, what is your feeling about going through a weight loss therapy? Maybe Lap-Band or something like that?

Dr. Orlowski: Well, thank you very much for your question. I think many of us gained a little bit more weight during COVID than we wanted to. You should, of course, consider any kind of surgery in the context of advice from physicians who know your case well. We talked earlier about the potential role of weight in progression from MGUS to full blown myeloma, and the fact that we don't know for sure that weight loss will make a difference in that risk. Similarly, in more advanced disease settings, we don't know for sure that weight loss will be a benefit. Although if you asked me, is it healthy to do that? I would say probably, you will be better off with some amount of weight loss. But you really do need to consult with an expert to find out how much weight you should drop. If you do a surgical approach, make sure that you maintain other aspects of good nutrition, because you want to make sure to get enough good protein and vitamins in there so that your immune cells are as healthy as possible, and can help to fight the myeloma.

Caller: Okay, yeah. That answers my question. I do have an upcoming appointment with my doctor at MDA. I will discuss this with the stem cell doctor when I see him next week, I believe it is. I appreciate your advice. Thank you so much.

Dr. Orlowski: Take care, Rose.

Jenny: Thank you for your question. Appreciate it. Okay. Go ahead with your question.

Caller: Well, thank you very much, Dr. Orlowski. This is fantastic information. Jennifer, you are doing a wonderful job. It's riveting. I had a stem cell transplant June of '22. I'm now on dara maintenance, in combination with nothing else, because I unfortunately experienced some pretty severe DVTs due to the RVd cocktail on the front end, more than likely due to the Revlimid. My numbers are great. I wanted to ask, what would be a suggested enhancer to the dara during my maintenance to improve things for my future? Secondly, I just started Zometa yesterday for bone strengthening, and what is the recommended dosage sequencing for that given that there is a jaw necrosis risk associated with that drug?

Dr. Orlowski: Definitely. Good luck on fully maintaining a remission for a long time, and congratulations on getting through the transplant.

Caller: Thank you very much.

Dr. Orlowski: In terms of the duration of daratumumab maintenance, we don't have a lot of information about shorter periods. I think the habit has been to continue until progression. You had you mentioned DVTs, and I don't know if you had a PE as well when you started on Rev-based therapy at the beginning, it is used to --

Caller: There was a tiny PE in one of my lower lung lobes.

Dr. Orlowski: It's true that some people have a predisposition to thromboembolic complications, and then Rev alone may be enough to push them past the edge, but we also know that the risk of these blood clots is greatest in the newly diagnosed setting. Once the amount of myeloma is reduced, oftentimes, that risk is no longer there. One option for you, even though you had a bad Rev experience before, would be to get a workup to make sure that you don't have any inherited condition that predisposes you to blood clots. If the answer is you do not, then what you could do is maybe some kind of blood center, there are oral blood centers now available drugs like apixaban, and then you could still add a low dose of lenalidomide. However, I could understand that you and your physician may be a little leery nonetheless.

And then, other options could be to add a proteasome inhibitor. The reason I hedge and say could is that there isn't really any data yet about a CD38 antibody and a proteasome inhibitor in maintenance, although we know that those combinations work pretty well when you give them in the relapsed refractory setting. Finally, if you're on dara, and you have standard risk disease, and you are in remission, and hopefully MRD negative, you may not need another drug. The option there would be to stick with dara. Now, going quickly to the Zometa question, if you just started it, hopefully you had a good dental exam before you began it to make sure that you don't have an abscess, because if you do, you have to get cleaned up first.

Caller: Yes, I did.

Dr. Orlowski: Excellent. In terms of how long you should be on it, first of all, I usually dose this every three months, because that probably reduces the risk of ONJ. I would probably give no more than a total of 12 doses, meaning over three years, and then stop at that point.

Caller: Is there any advantage to moving from three to four months intervals?

Dr. Orlowski: Well, I say three months, because there was a large, about 1,700 patients study a few years ago that compared monthly Zometa to every three months. There was no difference in benefit to the bone. It hasn't been looked at every four months, so I would probably stick with every three months, because we at least have those data. But if you have some logistical reason why every four months works better, I think that's fine, especially since you are not in the newly diagnosed setting anymore. I think that would be fine quite frankly.

Caller: Okay. I am on apixaban and my father did have blood clots.

Dr. Orlowski: Ah, the plot thickens. No pun intended.

Caller: Yeah. I'm being treated at UCSF. You probably know some of the folks there, I would imagine.

Dr. Orlowski: Sure. Did they do a hypercoagulable workup on you to see if you had an inherited thrombophilia? Because the fact that your dad had a clot also doesn't guarantee anything, but it certainly makes it more concerning that you may have some inherited condition whether it be a Factor V Leiden, or protein S, or protein C abnormality, or Factor II, or other things.

Caller: No, they did not. What happened I was on a 14-day cycle on RVD for four cycles, and then, I was increased, even though my numbers were almost zero at that point. I was increased to a 21-day cycle for two more cycles just prior to my stem cell transplant. The DVTs popped up when I was in the middle of a second cycle. I don't know if that additional Revlimid made the difference or not, or if it was already in process, the DVT. My leg pain was through the roof. I went right to the emergency room, and they put me on apixaban right away after they did the proper Doppler ultrasound scan, and the CT.

Dr. Orlowski: Well, it may still be worth looking at whether you have one of these inherent thrombophilias, because if you have kids, it may be helpful that they be screened if you turn up positive just for their own future medical care.

Caller: Yeah, great. Great. Thank you very much.

Jenny: Thank you for your question. Okay, we have five minutes and we have a hard stop. The show will end. I'm going to just do as many more questions as we can possibly fit in, and then we'll be finishing up. Go ahead with your question.

Caller: Hi. Thank you, Dr. Orlowski, for some great information. On the website thing in the introduction, it says, there are significant advances being made in multiple myeloma, and more so than any other cancer. I'm curious why there are more advances in multiple myeloma than in other cancers. We're happy about it. I'm just curious why that's going on.

Dr. Orlowski: Thanks for your question. Because I specialize in myeloma, I can't say honestly for sure if that's the case, but if you go by the number of new drugs that has been approved, certainly, myeloma is among the leaders. Part of that is because if you go back 15 and 20 years, which many of us remember very well, we had relatively few drugs that were available. We started off in a situation with not much available, and therefore, there was a lot of room for improvement. One reason is that. Second is that in the laboratory, our models for studying myeloma, both cell lines, animal models, and access to patient samples, made research a lot easier.

It was therefore easier to identify targets and new approaches, and validate them, compared with what used to be the case 20 and 30 years ago. The old models for research in cancer was that there was a list of drugs that were new and available, and you just went down the list and tried whatever drug was there. Sometimes, those drugs did not work. Now, with better models in the lab, we can test these drugs there first. Although there's no guarantee that if a drug works in the lab, it will work in people, most of the time, if it doesn't work in the lab, it's certainly not going to work in people. Therefore, I think we've done a better job in collaborating with industry, and patients, and advocacy groups, and the FDA to make sure that only the most promising drugs get out to trials. Therefore, I think our success rate has been better than in other cancers, although there are still drugs in trials that don't make it, so not everybody benefits from a trial.

Jenny: Okay. Well, great answer. We have run out of time. I'm so sorry. We have at least five more questions, but our show is going to end technically. I better just say, if you have a question for Dr. Orlowski, you can send me an email, jenny@healthcare.org. Dr. Orlowski, I know sometimes, you share your email if patients have a question for you. If you want to go ahead and do that.

Dr. Orlowski: Yes, I do. Yeah, please, feel free to shoot me an email. My address is rorlowski@mdanderson.org. Usually, I can get you an answer back within a day. Please feel free to reach out. Also, MD Anderson physicians have now been licensed in not all 50 states but in many of them. Some of you may live in areas where you can access a second opinion from one of our specialists using telehealth approaches, so that you don't have to schlep here. Although for those of you that live further north, I should point out that it's been in the 80s here today. It might be a nice break for you from where you are now.

Jenny: Very, very nice. Fabulous. Telehealth, I think, opened up a whole new realm for us. I want to thank you. I especially want to thank you because you were our very first show. This is our ten-year anniversary. Here you are again ten years later with so much to talk about in multiple myeloma. I just thank you for everything you're doing and all the work that you're doing on behalf of patients. Thank you so much.

Dr. Orlowski: My pleasure. I'll be lifting my virtual glass of wine and toasting you for another ten years.

Jenny: Well, thank you so much. We hope myeloma is cured by then. But with people like you, it will be.

Dr. Orlowski: Definitely.

Jenny: Thank you so much for joining. Thank you for listening. We look forward to having you learn next time what's happening in myeloma research and what it means for you.