Robert Z. Orlowski, MD, PhD
MD Anderson Cancer Center
Interview Date: January 22, 2021
The myeloma landscape is ever growing with more therapies coming to the clinic. In this exciting review. Dr. Orlowski shares new treatments for patients with MGUS and smoldering myeloma, newly diagnosed multiple myeloma and relapsed multiple myeloma, covering a wide variety of treatment types and combinations. He shares the immunotherapies such as bi-specific antibodies, antibody drug conjugates and CAR T treatments, targeted therapies like venetoclax and selinexor and new treatments coming up for approval including melflufen and new tools to combat high risk disease like del17p. This show is a favorite of the year and gives myeloma patients hope that such exciting development is in progress.
Thanks to our episode sponsor
Jenny: Welcome to today’s episode of Myeloma Crowd Radio, a show that connects patients with myeloma researchers. I’m your host, Jenny Ahlstrom. We'd like to thank our sponsor for this episode, Karyopharm Therapeutics. We're very grateful for their support of Myeloma Crowd Radio.
Now, to me, it's truly fascinating to see the progress that's been made in myeloma over the last 10 years since I was diagnosed. We are very excited to have with us today, Dr. Robert Z. Orlowski, for this annual forward-looking show to review what patients can expect in 2021.
Now, both our guest today and his father, have worked on myeloma advances for several decades, starting with the development of bortezomib, and now you can just look at how far we've come. While this might be a fire hose of information in today's show, it will reflect the great number of advances that have been made and the hope that we should have in myeloma today, and there's no one better to explain it all to us. So, Dr. Orlowksi, welcome to the program.
Dr. Orlowski: Thanks very much for having me. It's always a great privilege and a lot of fun to do this every year.
Jenny: Yes, it's fun. I love this show. Let me introduce you before we get started. Robert Orlowski is Chairman and Ad Interim, Director of Myeloma, Professor of Medicine in the Departments of Lymphoma and Myeloma and Experimental Therapeutics in the Division of Cancer Medicine at MD Anderson Cancer Center in Houston.
Dr. Orlowski earned his doctoral degree in Molecular Biophysics and Biochemistry from Yale University and his medical degree from the Yale University School of Medicine. He did his internship and residency at the Barnes Hospital at Washington University in St. Louis. After his fellowship in Hematology at Johns Hopkins, he joined the faculty at University of North Carolina in Chapel Hill. In 2007, he came to University of Texas, MD Anderson Cancer Center to lead the Myeloma Section in the Department of Lymphoma and Myeloma.
Now Dr. Orlowski is an investigator on numerous myeloma clinical trials. He is the appointed Myeloma Committee Chair for SWOG, which is the Southwest Oncology Group that is part of running national clinical trials. Dr. Orlowski is also on the editorial board of Hematology and the Journal of Clinical Oncology, while contributing to numerous publications. He is the principal investigator for the MD Anderson Cancer Center High-Risk Multiple Myeloma Moon Shot program and the Leukemia and Lymphoma Society Specialized Center of Research in High-Risk Plasma Cell Dyscrasias.
Dr. Orlowski is also working on the development of several new immunotherapies for myeloma in his lab, which I hope you'll cover at the end of our show. Thank you again for joining us. We have a possible outline covering everything that is new. This will be kind of a different show because it's a lot of different topics all in one. Maybe we'll just start with the precursor conditions, and you can share what's coming or what we should look forward to in 2021.
Dr. Orlowski: Sure. Thanks again very much and happy to be doing this show. We can start with MGUS and smoldering multiple myeloma, where I think the standard of care for most patients is still probably a watch-and-wait approach.
There were a couple of studies more on the biology side that were presented at ASH in December that I thought were interesting; one which was presented by Elizabeth Manasanch who's from MD Anderson, and she's the leader of our precursor disease effort. This was an oral presentation that looked at changes, not just in the myeloma cell, but also in the microenvironment, in the bone marrow when patients had progression.
The important thing that was found is that there were significant changes in the immune microenvironment that were associated with progression from these precursor states to full-blown myeloma. It actually turns out that the genetic changes in the myeloma cells themselves appear to maybe be less important, and it's, if you will, a weakening of the immune system or of what's called immune surveillance that may allow outgrowth of myeloma and to develop clinically active disease. I think that's an important insight, and others have found similar findings as well. This adds to it.
The other important part is there are really two things we hope to be able to get out of this. Number one, we hope to be able to better predict who will progress and who will not. That's, of course, important because we could reassure the people who we think will not progress. Whereas, the people who we think will progress, would be people we could treat with some available therapies.
The second important implication there is, because some of the immune changes that we detected can actually be modified now with various immune treatments, for those people who we may predict would progress, we now may have ways to strengthen their immune response or take the brakes off their immune response so that hopefully we would reduce the amount of myeloma, and they would never progress.
A second paper that I wanted briefly to cover in that area, looked at really whole genome sequencing, and they really were able to find that there was progression of myeloma in association with certain genes being expressed. One of these were the APOBEC family of genes, and these have been talked about for a little while in myeloma. These genes actually play an important normal role, for example, in the ability to protect us from viral infections, but sometimes, when they are not correctly regulated, they can lead to increased mutation in cancer cells.
What the sequencing that they did, this is Bénedith Oben and colleagues, they found that if these APOBEC genes and some family members in particular, if they were increased, there was a greater risk of progression. Whereas, the people that did not have up-regulation of those genes actually had a very low risk. So if we put these two pieces of information together, the important news is that we're getting better and better at predicting, we hope, who will progress and who will not, and what treatment we may be able to give to those people who do progress.
You probably know right now that the current criteria for stratifying patients into high, intermediate or low-risk of progression from smoldering disease involve things like, is there 20% or more involvement of the bone marrow with plasma cells, is the monoclonal protein two grams or more, or is the involved to uninvolved free light chain, 20 or more? These are important clinical criteria. It's probably one of the best systems, but there are other features that we may be using in the future; for example, the immune profiling and the molecular profiling that I mentioned, and other things that we may be doing in the future. We'll be using things like, are there myeloma cells circulating in the peripheral blood? That may be helpful.
I hope, with time, we will refine these criteria. Because even among the high-risk smoldering categories now, there are people who do not progress; and among the low-risk, unfortunately, there are people who do progress. We clearly need to be better, and I think we're going in that direction.
Jenny: Let me ask a couple follow-up questions before we go onto the treatments. You talked about the genetic changes. I remember hearing something in ASH, talking about some of the genetic changes being found early in these precursor conditions. That's my first question.
Dr. Orlowski: It does appear that a lot of the molecular changes in the myeloma cells at the time that people are diagnosed with smoldering myeloma, for example, are the same ones that are present when the myeloma is fully clinically active and needs treatment. That's why I think that looking at these immune cells that are around the myeloma are important. Because if the mutations are already present, that suggests that what you really have that promotes progression is a weakening of the immune response to the myeloma.
Jenny: That was a very intriguing thing you said about we could just boost the immune system and avoid progression in the first place. I just want more detail about how you thought that that was possible.
Dr. Orlowski: Well, there's a lot of studies being done in this space. I'll briefly put in a shameless plug for what we're doing at MD Anderson. One study that we have, which again, Elizabeth Manasanch is leading, is a vaccine study where we sequence the genome in the myeloma cells, we find the mutations, and then we pick peptides that we can use as vaccines which would generate a response just to those mutated proteins which are only present in myeloma and not in the patient's normal cells.
We've been doing this for a little bit. We are seeing, now, responses in the immune system where we can detect that after the vaccination, there is greater immunity against the target proteins. We're now doing the vaccine in combination with lenalidomide or Revlimid with the hope that we'll be able, once again, to strengthen the immune responses, and that we'll be able to get nice clinical responses.
Others are doing studies with some of the bispecific antibodies, and we'll get to those when we get to the relapsed/refractory setting. I think that daratumumab and isatuximab, which are anti-CD38 antibodies, are also being tried, both alone and in combination, for patients with smoldering disease. These have worked very well in the relapsed and newly diagnosed setting. I think the hope is that when you give it to people with an earlier disease state, that perhaps there will be even a greater benefit.
Jenny: Thank you very much for mentioning that study because that's a really fabulous smoldering myeloma study. It’s wonderful.
Dr. Orlowski: Moving then to newly diagnosed myeloma, when folks already have disease that requires treatment, we do divide folks up into standard-risk myeloma, which fortunately is about 80 to maybe even 85% of patients, and then there are still 15 to 20% of patients that have so-called high-risk disease. That's something that, if you've just been diagnosed, you should find out what risk group you're in because it does influence the prognosis.
Both patient groups respond very well to chemotherapy, but it looks like the patients with the higher risk variants of myeloma don't stay in remission for quite as long. I still think that right now, the optimal therapy for all of these patients is the VRd combination or Velcade with Revlimid and dexamethasone. There was a recent trial that was published and led by the ECOG folks, this is one of the other cooperative groups, that showed that KRd or Kyprolis, Revlimid and dexamethasone, was not necessarily better, although there are other comparison studies like that ongoing.
I think the other big question in this space is whether adding a fourth drug is of benefit, and probably the fourth drug that people would most want to add is daratumumab or DARZALEX. This is an anti-CD38 antibody. The reason to add it is that it really adds very little increase in toxicity or side effects, but the benefits that it gives are quite dramatic in most settings. We're beginning to see data that the VRd with daratumumab combination looks like it should be better than VRd alone. There is a larger, randomized study of that comparison now ongoing.
Whether you should get the four drugs now, I think, is an open question. If you have high burden disease, in my feeling, and to me high burden would be, for example, if you have more than 50% involvement of the bone marrow or if you have a very high monoclonal protein; to me, because it's tougher to get somebody into complete remission if you have a high level of disease to start with, I think if you're at that level, trying to get that fourth drug is definitely worth it. Although, keep in mind, it's not yet FDA-approved with that combination and so sometimes insurance may not be easy to get approval for.
I think high disease burden and I think high-risk disease is something where there could be a benefit to dara. I kind of hesitate a little bit there because there are some studies that suggest it does benefit and others that don't. To me, anything that deepens the response is probably going to be a plus, and I think dara is definitely in that category.
Jenny: Everybody was so curious to see the KRd versus VRd. I think everybody thought KRd would be more effective, so that was so interesting when you talked about that earlier.
Dr. Orlowski: It was a little bit disappointing because, of course, we hope that every trial that we do, improves patient outcomes. When that turns out not to be the case, that's a disappointment. I did mention that I don't think that ECOG trial is necessarily the last word. There are other ongoing studies comparing those two. KRd may still turn out to have a usefulness, but for right now, VRd is the way to go.
The other thing to mention is so-called MRD or minimal residual disease testing. Right now, probably most of you are followed for your myeloma levels by measuring the protein in the blood and/or the urine. That's certainly very good, but MRD, usually on the bone marrow, is a more sensitive way to detect how much myeloma may be left. I do use MRD testing in newly diagnosed patients.
For example, if somebody achieves a complete remission with their initial therapy, and they are MRD-negative, and they have good-risk, molecularly, disease; I actually think that people like that should have the option to have their stem cells collected and stored away, but not necessarily do a transplant right away. They could go just on maintenance Revlimid, and maybe do the transplant only if they relapse.
Whereas, if they are MRD-positive, meaning there is still detectable disease, or if they don't achieve a complete remission, or if they have high-risk disease, then I think adding the transplant is of benefit. This is not something we've proven yet because we need large studies to know how to use the MRD data in the best way, but this is one way that I use them. There are others in the field who do the same.
Jenny: In general, MRD testing, especially at first line therapy, is being looked at for what can we hope to achieve through overall survival, right? I've heard some of that.
Dr. Orlowski: Correct. MRD is generally associated with a better progression-free survival, which means longer time in remission, if you're MRD-negative than if you're MRD-positive. Usually, it's associated with a longer overall survival. It makes sense because less cancer is always going to be a better outcome than more cancer.
I think the challenge is still, to the MRD testing, is that right now, we still do it mostly on the bone marrow because that is more sensitive right now than peripheral blood tests. As our technology becomes better, I think we hopefully will soon have an MRD test on the blood that is just as sensitive as the bone marrow. That will make everybody happy because you won't have to have quite so many bone marrows, and then I think the usefulness of the MRD testing will be increased.
Jenny: When you talked about VRd with or without dara, as that being an open question, are there clinical trials that you're looking at, for newly diagnosed patients, that you think are the most intriguing or the most promising, if you were to go a clinical trial route?
Dr. Orlowski: Yes, definitely. I think there are many trials in this setting, and one of the best resources to go for is a website called clinicaltrials.gov. Every trial that is run in the United States and also abroad has to be registered in that database. You can go in and search it by diagnosis. You can search it by drug type, if there's a particular drug that you're interested in. You can even search it by geography. You can, for example, put in your zip code. If you don't want to drive more than 50 miles, you can put that in the search, and it will only find trials that are open at places within 50 miles.
I think some of the really interesting studies in the newly diagnosed setting for high-risk patients, there are studies that are looking at adding CAR T-cells, which I'm sure we'll talk about a little bit later. These are so-called chimeric antigen receptor-guided T-cells. Because the high-risk patients yet still don't do as well with newly diagnosed myeloma and current therapy, adding something like an immune therapy or a CAR T-cell would be very exciting. Also adding some of the new antibodies and bispecifics would be very interesting there as well.
Jenny: Interesting. Also, just as a note, we have a product called HealthTree, and we also partnered with SparkCures, which many of you might be familiar with. If you have a HealthTree account, you also have access to SparkCures, which you can find a little bit easier than going to clinicaltrials.gov for trials, but I'm a huge advocate for clinical trials. I think you should consider them at every stage of your disease.
Dr. Orlowski: The nice thing about HealthTree is, if you want to, once you set up an account, you can upload your own laboratory data, your own pathology data, and that makes it easier if you want to get a second or a third opinion from somewhere else because the physician at that location can log on and look at all of your information, get graphs, see what your protein numbers have been doing. That really gives them a great idea of what your options may be, rather than having to pore through, in some cases, hundreds of pages of records where maybe 99% of what's in there is not as helpful as the 1%.
Jenny: Yes, that's hours worth of work on your end. Thank you for mentioning that.
Dr. Orlowski: Now, there's a lot going on in the relapsed and refractory setting because even though people with newly diagnosed myeloma are doing better than ever with their front line therapy, they are still relapsing. Now, there's such a wide array of new drugs that are coming, that I think there's reason for great optimism. It's never, of course, good news to hear that you are relapsing, but we have a lot of great things.
One category that we could start with are some of the new drugs that bind to cereblon. You may know that cereblon is a protein which is the target for the so-called immunomodulatory drugs. These are thalidomide, lenalidomide and pomalidomide. There are newer generations of drugs that are being tested though, and one is called iberdomide. The other one doesn't yet have a name. It’s CC-92480. Both of these have, at recent meetings, shown good activity, including in people whose myeloma was previously progressing on drugs like Revlimid and in some cases, Pomalyst.
These are, of course, oral therapies. These days, in the era of COVID still being around, certainly going with an oral therapy route for convenience and having to travel less is a good idea. So, if you are looking for novel treatment options, new combinations based on one of those two drugs are available out there, and I would definitely look into them.
Jenny: Those are called cell mods, right?
Dr. Orlowski: Correct.
Dr. Orlowski: Yes, exactly. Sticking with the oral therapy route, there is selinexor or Xpovio. This is a drug that previously was approved in the relapsed/refractory setting by itself with a little bit of dexamethasone added, but more recently, there are new data with that drug in combination with Velcade. That now is FDA-approved.
It was an interesting study design. It was the so-called Boston trial. What they did is that the experimental group got the Velcade once weekly, and the selinexor was given once weekly. Whereas, in the control arm, the Velcade was given twice weekly, which is the more common way. That's a little bit of a handicap, as you can imagine, because if you reduce the frequency of one of the drugs, you would think that the combination might work less well. In fact, the combination of the once weekly selinexor and Velcade with dex, beat out the twice weekly Velcade with dex, and there was less neuropathy associated with it, which of course is great because neuropathy can be a problem with Velcade. So, definitely, that's something to think about. Some of the GI side effects of selinexor which were seen when it was given at twice-a-week dosing were also substantially better when it was given at just once per week.
The other drug to keep in mind, there wasn't that much about it at this year's ASH, but I still think it's worth remembering is venetoclax. This is a drug that is particularly effective for patients that have the 11;14 translocation. This is a test result from something called FISH testing or fluorescence in situ hybridization. It's done on the bone marrow. It's present in about 10 to 15% of patients with myeloma. If you have amyloidosis, it can be 30 to 40%. It's also present in Waldenstrom. It's a worthwhile test to get and to know the result because some of the combinations with venetoclax have had response rates of 80% or more, and the benefit has been truly dramatic.
I think this is another example, beyond what I mentioned earlier, of needing to know if you're high-risk or standard-risk when you're newly diagnosed. Here's an example where, if you have that 11;14 translocation, then venetoclax is an important option for you in the relapse setting. The studies that were done looking at all myeloma patients found that people who did not have the 11;14 translocation did not benefit, so it's unfortunate for those people that they didn't benefit. The good news is that we now have a targeted therapy for one particular group of myeloma patients, and we hope, as we move forward, that that will continue so that we'll be able to have, if you will, design or drug combinations for each of the different sub-types of multiple myeloma.
Jenny: Yes, this is really the first time that that's ever been used in terms of one therapy for one type of myeloma.
Dr. Orlowski: Correct, and that's exciting because we’d really like to personalize treatment.
Jenny: I just want to emphasize your point. If you don't know what kind of myeloma that you have, you should go talk to your doctor and make sure, at a minimum, they have this FISH test performed. That's the most basic genomics test in multiple myeloma that everyone should have done. If you’ve gotten treated and you no longer have any detectable myeloma, you're never going to know what you had, what type of myeloma you had, because all the cells are gone. So, please go ask your doctor about that before you start getting treated. It can change over time, so you can get it performed at relapse again, and then you have one or two or more just to look at, to see how your myeloma is behaving.
Dr. Orlowski: Even if you've had the FISH test done but, let's say, it's been a few years and your myeloma has relapsed in the meantime; it sometimes can be helpful to repeat that testing because the myeloma isn't the same in every patient at every time that they relapse.
I'll give you another example of how we may be able to personalize treatment with a new drug that is going to be in the clinic in the first half of this year. Deletion 17p is one of the sub-types of myeloma which is in the high-risk category. Most of the novel agents that we have, do improve outcomes in that group, but they don't change high-risk into standard-risk.
There is a drug, doesn't have a name yet. It's called HDP-101. It's an antibody-drug conjugate. We actually will talk about that next. This is essentially like daratumumab in that it's an antibody. This one binds BCMA or B-cell maturation antigen. An antibody-drug conjugate means that the antibody molecule is there, and linked to it is a drug which is often released inside the cell when the myeloma cell takes this antibody up. The drug then kills the myeloma cell from the inside. I like to tell people, it's kind of like the Trojan horse. The myeloma takes this thing up because it thinks, hey, this looks okay. Then when it's not looking, it gets killed from the inside.
The reason this drug, it’s called HDP-101, is interesting is that the drug that is attached to the antibody is even more effective against deletion 17p myeloma than against regular types of myeloma. It probably will be very active in all relapse disease, we hope, but it would be particularly good for deletion 17p.
Jenny: You say it will be potentially approved this year? Because that would be amazing.
Dr. Orlowski: No, sorry, not approved, but it will start clinical trials later this year, probably within the next three to four months, fingers crossed.
Jenny: That’s fantastic.
Dr. Orlowski: It might be a couple of years before we get approval, but if the data look really fantastic, it might be sooner.
Jenny: Oh, yes. Well, deletion 17 patients need something, so this is so needed. I'm super excited about that.
Dr. Orlowski: Yes, definitely.
Jenny: Thanks for sharing it.
Dr. Orlowski: The other antibody-drug conjugate that we already have approved is called Blenrep or belantamab mafodotin, if you want a tongue-twister. It's also a BCMA antibody but with a different drug attached. It previously was approved just as a single agent, but at this year's ASH, there were a number of abstracts showing that it works even better in combination, including with Velcade, and also some nice data with Pomalyst. These are not yet FDA-approved, but it may be possible for you to get the combination. Definitely, the antibody, by itself, you can get from your local hematologist, oncologist.
The main things to watch out for is that it can cause some thrombocytopenia or a decrease in platelets. There can be eye complications with dryness or blurry vision. People do have to see an ophthalmologist or optometrist before they start and then before each subsequent dose, but the data with the drug, especially in combination, look really good. It's easy to get because it's, what we call, off-the-shelf, meaning that the drug is there. It’s not having to be manufactured individually for each patient, like the CAR T-cells are.
Jenny: Yes, but going after, primarily, the same target.
Dr. Orlowski: Correct, yes. Now, continuing in the theme of antibodies, there are what are called bispecific antibodies. Most of the antibodies that we have now and that I've mentioned, are antibodies that bind only one target, but you can engineer the antibody so that it can bind two different targets, and in some cases, even three. If it's two, it's called a bispecific. If it's three, of course, it's a trispecific.
The reason that can be helpful is that if you make a bispecific, you can have one arm of the antibody bind the protein on the myeloma cell, for example, BCMA, and then you can have another arm bind to a protein on your T-cell. Usually CD3 is the target, and it kind of acts as a bridge to bring the T-cell and the cancer cell right next to each other. It also activates the T-cell. It makes it angry and that then attacks the myeloma cell and kills it. So, it uses your own T-cells to get them angry and kill the myeloma cells.
There's a number of these now that are in trials. None of them are yet FDA-approved, but they all have 50 to 70 or 80% in some cases, response rates, even in very advanced and difficult-to-treat myeloma. The only side effect to watch out for is something called cytokine release syndrome or CRS. That happens when T-cells become activated. It's like having the flu, if it's relatively mild. You can have a fever. You can have some inflammation and body aches. Although, in more severe cases, there can be elevated liver enzymes, there can be increased heart rate, and some people can get neurologic complications. Fortunately, those are rare, but the efficacy of these drugs is very high.
The trispecifics, where you bind to three different proteins, are also quite interesting because there's one class that provides additional activation of the T-cells. There are also bispecifics that bind what are called NK or natural killer cells, which are a different type of immune cell that can kill myeloma.
Two things that were really exciting at ASH in this category, most of these products have gone after BCMA. There are many BCMA-targeted therapies. The challenge with that is that sometimes myeloma can become tricky, and it can stop making BCMA on the surface. Then those BCMA-targeted therapies are no longer effective because they can't latch onto the myeloma.
There were two abstracts that looked at different targets. One was against a target called GPRC5D, and that looks like it also is predominantly expressed only on myeloma cells. Then there was another one that looked FCRH5 as a bispecific, and both of those showed very good activity.
The reason I think those are exciting is that, just like chemotherapy drugs now are used in combination, I think in the future, we'll be using these immune therapies in combination. Probably combining a BCMA-targeted bispecific with one targeting either GPRC5D or FCRH5 may be interesting in the future. That may be, hopefully, something that gets us closer to a cure for myeloma. So, again, if you have relapsed or refractory disease, do look for clinical trials with these bispecifics.
By the way, heading back to the earlier disease states, there are single center studies of some of these drugs looking at their efficacy in smoldering myeloma. For example, we're going to have a study of belantamab. That's the Blenrep, the BCMA antibody-drug conjugate for smoldering myeloma.
Probably, within the next four months, we're going to have a so-called window study of one of these BCMA bispecifics for newly diagnosed myeloma so that instead of chemotherapy, you're going to get only immune therapy. If the response is really good, you may not have any chemotherapy for your newly diagnosed myeloma. It may be all immunotherapy with these bispecifics, so we're excited about that one to get opened.
Jenny: Yes, that's what struck me, I guess, at this year's ASH, was all these immunotherapies and people wanting to bring them up earlier and earlier and earlier in the process. Because you know you can go back to some of the regular chemo therapies, but you're not curing either, so it's great to see these new approaches.
Another comment on the bispecific antibodies, can you comment on just the sheer number that are in development and the fact that they're off-the-shelf, because these are also off-the-shelf, and I was blown away by how many companies are really in the space.
Dr. Orlowski: Well, you're definitely right. It's an exciting area. There are tens of trials and tens of compounds which have different companies supporting them. I think that we have room for probably at least a few of them, hopefully, to get FDA-approved. For example, we, right now, have three immunomodulatory drugs and three proteasome inhibitors that are FDA-approved. So, hopefully, we will have at least a couple of these bispecifics that wind up being available.
It will be a little bit tough to tell who's the winner, unless a couple of them have really much better response rates, durability of response, and decreased, hopefully, side effect profile; but it's definitely an exciting area. If you are looking for a trial with a new drug for relapsed myeloma, the off-the-shelf part, as you mentioned, is important. That compares to CAR T-cells, which we briefly mentioned earlier.
Right now, the challenge with CAR T-cells, most of them are autologous CAR T-cells, meaning that you have your own T-cells taken out from the blood. These are different cells, by the way, than stem cells. For those of you that have had stem cells collected, those, unfortunately, are not the same and can't be used for this process. Your T-cells get taken off, they get sent to a laboratory where a new gene is introduced, which expresses this receptor, and the receptor is a protein that allows the T-cell to recognize the myeloma cell better. Again, usually, BCMA is the target.
The only challenge with the CAR T-cells is that, with the autologous cells, it takes two to four weeks to do the manufacturing. In the meantime, your myeloma, unfortunately, may be progressing. Most of the trials do allow what's called bridging therapy so that you get some kind of treatment to knock the myeloma back a little bit while the T-cells are being made. That's one approach that you can take if the myeloma numbers are going up, but the response rates with that therapy have been quite high, sometimes up to in the 90% range.
We actually hope to have the first BCMA CAR T-cell approved in the first three months of this year, and that would make it commercially available. This is the one from BMS and Celgene called ide-cel, or some people may know it by the older name, bb2121. The big plus to the CAR T-cells is that it's what I like to call a one-and-done therapy, meaning that once you have the T-cells reinfused and you get past the first about week or two weeks which is when you're most likely to have some of the symptoms, like cytokine release syndrome; you then don't have to, right now, take any additional therapy. For many people with multiple relapsed disease, this is sometimes the first break that they've had from continuous therapy for years, and as you can imagine, they really love it.
Jenny: Yes, definitely. There might be another one approved this year, too, right?
Dr. Orlowski: Later on in the second half of the year, there may be a second one. This is called cilta-cel, which is from Janssen. Some of you who follow the field may remember that this particular CAR T-cell started out with a Chinese company called Nanjing Legend. That one also looks very active and hopefully will be, as you point out, may get approved by the second half, probably in the fall to winter range, depends of course on the additional data that will be needed. Certainly having one or the other or both would be great for patients.
Jenny: Then when it comes to CAR T, I know you talked about the autologous, what's being developed in terms of the off-the-shelf for an allo CAR T.
Dr. Orlowski: Great question. The allo CAR T’s are, of course, the same concept in terms of the chimeric antigen receptor and the T-cell part, but instead of getting the T-cells from the patient, you get them from a normal donor. The advantage of that is that those T-cells are presumably healthier than someone's T-cells who's been through years and years of chemotherapy, and therefore, they should be more active and kill more myeloma cells.
The danger, as you can imagine, is that someone else's T-cells may recognize your cells as being foreign, and attack, so they do have to be engineered. They usually do is knock out the T-cell receptor or other portions of the cell that are important so that you don't get what's called graft versus host disease. These are interesting for two reasons. Number one I mentioned already, which is that they should be more active because the T-cells are healthier. Number two, as you pointed out, these are off-the-shelf because these are donor cells that are already just sitting there. You don't have to wait the two to four weeks for manufacturing; and theoretically, it should be cheaper because you can get many patients’ worth of T-cells from just one donor.
There were data at this year's ASH, showing encouraging results from some of the early allogeneic BCMA-targeted CAR T’s. I do think that, definitely, looking at that, as well as an autologous, would be a good approach to think about.
Jenny: Let's talk about also strategies that you're seeing to extend the remission length of CAR T.
Because you mentioned some of these patients were on therapy and then -- I've had friends who have been on 12, 18 lines of therapy, a crazy amount, and then the CAR T worked great for them for a bit.
Dr. Orlowski: Yes, the one thing about the CAR T, so far, is that it seems that the majority of patients do wind up relapsing. Unlike in non-Hodgkins lymphoma where there was a good fraction of patients who were cured, that doesn't seem to be the case in myeloma.
Right now, the average progression-free survival ranges, depending on the product that you are looking at, from about 12 months out to maybe 24 months. A lot of that appears to be that the T-cells don't hang around for as long as we would want for them to. Therefore, there may still be some so-called myeloma stem cells around, that, once the CAR T-cells are gone, start to churn out new myeloma cells.
So, there's a couple of things that are being looked at there. First of all, you may be able to re-treat because many of the relapses have the same BCMA protein still being expressed. Also, depending on how you put the gene into the T-cells, you may be able to make more, what are called, memory cells. The memory cells tend to hang around a little bit longer.
Other people are looking at combining these T-cells with things like Pomalyst or some of the checkpoint inhibitors so that hopefully, again, you get a longer duration of the T-cells that's called persistence, so that they don't disappear very quickly. The longer those T-cells would be around, the better the chance they would have, of course, of killing off any remaining myeloma cells that have the nerve to try to start growing again.
Jenny: Well, it's so fascinating what's happening in the immunotherapies, like you were talking about earlier, combining immunotherapy, combining either two different bi-specifics. Are there other strategies that you can think of? You're doing vaccine work and smoldering myeloma. I guess the combinations are really unlimited.
Dr. Orlowski: Well, you could do the same thing for CAR T-cells where you would have either one batch of T-cells that would have two different receptors against different proteins, or you would have different batches where one batch of T-cells, for example, would be against BCMA and another batch would be against GPRC5D, and perhaps having both together would be better. There are some animal studies that have suggested that that would be true. Of course, right now, most of the trials have looked at only targeting a single antigen, but there are some that are beginning to look at combinations as well. Ultimately, it will depend on how much benefit you get versus how much of an increase in side effects, of course, you see, which you may, in some cases, do.
Jenny: Right. Now, I want to move onto caller questions, but I did forget to ask you about melflufen. Can you discuss that a little bit?
Dr. Orlowski: Definitely. Melflufen is another drug that we hope to soon have available. It may be FDA-approved in the first half of this year. It's a drug which is a conjugate between a peptide and melphalan. The theory behind it is that it seems to be concentrated in myeloma cells. Many of you have had stem cell transplant where high-dose melphalan is given, and you know that it not only wipes out myeloma cells, but also the normal cells.
Because this is a peptidase-activated drug, it seems to concentrate just in cancer cells, which means that it has much less of an effect on the normal blood cells. There are nice data with melflufen in combination with dexamethasone. Also it, as you would expect, is being used in other combinations as well. Plus, it's going to be looked at as maybe a way to improve upon the benefits of stem cell transplant compared to just melphalan as a single agent.
Jenny: Yes, so there's so much going on. It's unbelievable. If you have a question for Dr. Orlowski, we're getting to the end of our show, you can call 347-637-2631. Press 1 on your keypad so I know you have questions, but we still have other things we need to talk about before we do that. Did you have anything else for relapsed/refractory? Because there's a lot going on there.
Dr. Orlowski: I think those are probably the main areas to cover. Probably these days, no discussion would be complete without having some mention of COVID. I did want to say that if people have access to the vaccine, they should definitely avail themselves of it. We do worry that people with myeloma, because it is a cancer of immune cells, even if they're not on therapy, but especially if they are on therapy, that there is the possibility that they may not respond as well to the vaccine compared with somebody who does not have myeloma, but there shouldn't be an increased risk of side effects to the vaccine. Even if you only get 50% protection, compared to a person without myeloma, that could be enough to either prevent the infection if you get exposed, or to at least make the severity of the infection less, compared to if you did not have the vaccine.
I usually recommend that for people who are on treatment, they try to get the vaccine during a week off of therapy so that they have the best chance to respond as possible, but it depends a little bit on your situation. If you have very aggressive disease and you need to be on treatment all the time, that may not be an option for you. Of course, taking care of the myeloma is number one on the priority list. Whereas, if you're, for example, just on maintenance therapy or you have a very low disease burden, then taking a week off or even maybe an extra week off, usually is not that big a deal. Although, as always, consult with your local hematologist oncologist for more personalized recommendation.
Jenny: Well, we didn't cover maintenance therapy. I'm not sure if there's anything you want to address because I know a lot of patients have a question like, how long should I be on maintenance? Is there anything broad you want to say about that before we move to caller questions?
Dr. Orlowski: Two things on maintenance. Number one, -- I'm glad you brought that up -- there was an update of the so-called FORTE trial. In the maintenance setting, they looked at Revlimid versus Revlimid plus carfilzomib. The group that got the Revlimid and carfilzomib had a better progression-free survival. That may mean that, at least in some patients, an IMiD and a proteasome inhibitor are the best way to go, and we do that routinely for, again, patients with high-risk disease.
Your question about the duration of maintenance is a more difficult one because we don't have as much data yet. We do know that even people who are MRD-negative can relapse, so we still recommend, at this time, that maintenance be done until progression. We are now looking at this question more formally in, for example, the SLOG current maintenance trial has Revlimid versus Revlimid and daratumumab, after transplant.
After two years, if you're consistently MRD-negative, there will be a second randomization to either stop maintenance or to continue on maintenance. Hopefully the group that stops has just as good an outcome as the group that continues, which could support that we could stop the maintenance in some folk, but it'll be a few years before we know that result.
Jenny: Well, it's such a fascinating topic. We want enough therapy, but not too much, if we can at all help it. That's really fantastic. We covered so much, and you did it so clearly. That's why I love this show so much.
We're going to move to caller questions. Do press 1 on your keypad if you're calling in by phone. Okay, caller, go ahead with your question.
Caller: Hi, can you hear me?
Dr. Orlowski: We can.
Caller: I was just diagnosed last week with what they say is a rare non-secretory multiple myeloma. I was interested in what you think the regimen should be, or the therapy.
Dr. Orlowski: Well, non-secretory myeloma, for those who may not have heard about this, is a type of myeloma that doesn't make a protein that can be measured either in the blood or the urine, and would typically also not have serum-free light chains. Have you had the serum-free light chain assay done?
Dr. Orlowski: Okay. So, that is unusual. There's probably 1% or less of patients with that particular presentation. We would normally recommend the same therapies in that setting. We unfortunately don't have enough patients with this rare sub-type to do separate trials, and they're often not included in trials because there's no protein to measure. I would still recommend going with one of the standards of care, which would normally be either the VRd combination or think about also the daratumumab with Revlimid and dexamethasone combination.
Caller: Okay, thank you.
Dr. Orlowski: Good luck to you.
Caller: Thank you.
Jenny: Thanks for your question. Okay, next caller, go ahead with your question.
Caller: Hi, Dr. Orlowski. Thank you so much for a very informative talk. I have a question. I recently had BCMA CART T done, the bb2121. I responded, one month out, the markers were down by 75%. Unfortunately, it seems like, two months out, they're starting to -- the myeloma markers are moving up again. My question is, what do you think might be a better idea now, another target, CAR T maybe using GPRC5D, or the other target is FHR5 with the CAR T, or maybe a BiTE using -- what would you try next? I know it's a question of availability, but in the best world, what would you try next?
Dr. Orlowski: Well, thank you for the question. I'm sorry if it turns out, of course, that additional tests show that your numbers are increasing because some patients get a longer benefit from the bb2121. What you should do next -- influenced by what you've had up to now. Without knowing that for sure, it's tough to say, but I would definitely think about a therapy that targets a different protein.
My bias is that if one BCMA-targeted therapy for you is not going to work, then a second BCMA-targeted therapy would not be a good idea. I do think that looking at something targeting GPRC5D or FcRH5 would be probably a good thing. You can also look at maybe if some of these other therapies that we've mentioned, the venetoclax, if you have 11;14 translocation, the selinexor. You can think about melflufen. These would all be possibilities for you to consider if another immunotherapy was not an option.
Caller: Makes sense. Regarding other targets, these other proteins that you mentioned, other BCMA, do you find that a CAR T or a bispecific might have a better chance of success?
Dr. Orlowski: A great question and we don't yet have a great answer because they tend to be different modes of therapy. In general, the main difference appears to be that the CAR T, as we've mentioned, is kind of a one-and-done, and you don't need any additional therapy afterwards. Whereas, the bispecific tends to be given regularly. Now some of them are given IVs. Some of them are now available subcutaneously. The schedules are either once a week or in some cases, every two weeks, but the bispecific usually is more continuous therapy, along the previous paradigm with standard therapy.
It's really tough to say whether a CAR T or a bispecific would work the best. If you really pinned me down, I would say, at this point, that the best CAR T data look a little bit better than the best bispecific data, but we're still so early in our understanding and optimization of how these things work that, next year, if I'm invited back to do the show, I may have a different answer about that.
Jenny: Of course you are.
Caller: This is the last question, do all myeloma cells express all of these receptors? Or is there an assay that may show you what percentage of the myeloma cells express one or the other of these proteins?
Dr. Orlowski: There are some of these assays in development. Right now, it does seem that essentially, 100% of patients with myeloma express BCMA, and the same thing seems to be true for GPRC5D. Now, that may change after therapy. For example, unfortunately, if you really are progressing, there's a reasonable chance that the myeloma cells that you have now progressing may be BCMA-negative, and that may be why the bb2121 didn't work as well for you. That, I think, is where the assays will be helpful. Because for people who relapsed after prior BCMA-targeted therapy, I think looking at whether they still express BCMA or not would be important because then you would know whether a second BCMA therapy would work or not.
Caller: Makes sense. Thank you.
Jenny: Okay, great question.
Dr. Orlowski: Also just briefly, I did want to say, for those of you who don't get to ask a question, my email address is email@example.com. You can feel free to email me, and I usually can get you back an answer within 24 hours.
Jenny: Okay, that's awesome. How much time do you have? Do we have time for a few more questions?
Dr. Orlowski: Oh, I have a little more time. We can keep going.
Dr. Orlowski: It’s not Happy Hour here yet :).
Jenny: Next caller, go ahead with your question.
Caller: I have two questions. The first is, you mentioned venetoclax, and are you recommending that in combination with other drugs? My second question has to do with Blenrep. I've been on a study and just had Blenrep for two years. Is there a reason, now that it's been FDA-approved, to combine that with other therapies?
Dr. Orlowski: As to the first question, yes, the venetoclax is particularly effective in people with the 11;14 translocation. I would probably try to use it in combination simply because the combinations appear to work better definitely with dexamethasone; and if it's an option, I would probably add Velcade onto that as well.
As far as Blenrep, right now, the approval is still just for Blenrep as a single agent in relapsed/ refractory disease. The reason it's being studied in combination is that usually, if a drug works well on its own, it often can work even better, especially if it's given to earlier patient populations. That's why it's being looked at in combination. Until we get to the point that 100% of people are cured, we still have to look at other combinations. Because Blenrep is also an antibody and drugs like Pomalyst may make antibodies work better, that's another rationale for that particular combination.
Caller: You also noted that this could be repeated, even if someone's already been diagnosed with 11;14 translocation. How often would you say to repeat that?
Dr. Orlowski: The 11;14 translocation tends to hang around, so if you've had that before, you probably will still have it on a repeat. Deletion 17p is an example of an abnormality that sometimes is present at such a low level at one point that it may not even be detected, but then, because those cells tend to be more aggressive and hang around longer, they can become a larger proportion of the population later on. So, I wouldn't do this every time you have a bone marrow necessarily, but if it's been a few years, then it's a consideration.
I also like to get it, if the behavior of the myeloma has changed. Let's say, for example, your myeloma is always, when it's progressed, sort of gone up very slowly over the course of many, many months, and all of a sudden now, it's behaving much more aggressively, and the protein is shooting up much faster than it did in the past. Something like that would tell someone like me that, oh, the myeloma is behaving a little bit differently, and we need to take another look at it.
Caller: Thank you very much, and thank you for all this excellent information.
Dr. Orlowski: My pleasure, thank you for calling.
Jenny: Thank you, great questions. Caller, go ahead with your question.
Caller: Just a minute. I have a rather unusual case. I was diagnosed in 2002. I was at MD Anderson with Dr. Wang. Then I had a stem cell in 2005, but I went San Antonio with another doctor because he was my former student.
Dr. Orlowski: Oh, wow.
Caller: Well, if you know Fred, he was in my Honors English class, and he said that “I dropped out.” I said, “Well, thanks a lot.” He said, “I was tired with being with all those smart people. I felt like I needed to be with regular people,” which I think is probably one of his strongest suits. He is he's just a marvelous person, as well as an excellent doctor.
Now, I have had multiple myeloma, stem cell transplants, and now I have myeloma on my skin. I emailed him, and he said, “Well, that's unusual, but not rare.” I Googled it, and there doesn't seem to be a treatment. I just thought I needed to talk to you and find out what you thought about it.
Dr. Orlowski: Well, first of all, congratulations on the very good outcome with myeloma that you've had so far, if you're 19, almost 20 years into it, that --
Caller: I’m 83, and we just keep doing stuff. We try to do everything that comes down the pipe.
Dr. Orlowski: There you go. Hopefully that'll be an inspiration for people that are just starting their journey, and they know that you can have a good long life, and hopefully you've had some good quality along the way.
Skin involvement is something that we do see, and the typical approach approach is, it depends a little bit on what areas are involved. If you have just a few spots and there's no evidence of disease elsewhere, and frankly, that's unusual, but what the heck, we’ll cover even the unusual, if you've got it just in one other area, and let's say a PET scan doesn't show disease anywhere else; one option is to just radiate that one area. Radiation is usually quite effective.
Usually, though, if you have cutaneous disease, that's a manifestation and an indication really, that there is disease elsewhere, and I would typically switch therapies. What I would use would, in part, really depend on what you've had before. For example, something like Blenrep might be a good idea for you to try at this point because it's fairly well-tolerated and can be quite effective, even after other therapies no longer are.
Caller: Okay. Well, I know I do have it elsewhere because I've got places on my left leg and in my back. My oncologist says, “Well, let's get a PET scan and see what's going on.” I know I need radiation again. I've had it several times over the years at MD Anderson. I'm in Columbus, Texas, so it’s not inconvenient for me to go in and do things like that. I have a scheduled PET scan with MD Anderson. I'm sure I'm gonna need lots of radiation. Now what was that you said I should try maybe? What drug? Blenrep?
Dr. Orlowski: Blenrep, yes, ma'am. That's the BCMA- antibody drug conjugate. I would just say that if you have multiple areas of the skin that are involved, unless there is one dominant area that is causing you discomfort, there's probably less of a role of radiation because it suggests that there probably is microscopic disease elsewhere. I would be probably tempted, of course, I don't know your case more than what you've told me, but I might be tempted to avoid the radiation and just go with the Blenrep.
Caller: Well, I’ll suggest that to my oncologist, but some time, I think, maybe I’ll see you. It's not inconvenient. I actually have seen you one time, but it's been several years ago.
Dr. Orlowski: Oh, gosh, well I'm happy to see you again.
Caller: Well, I may do that.
Jenny: Okay, thank you so much.
Caller: All right, thank you.
Jenny: Okay, I've got to say two more, even though we have more. Caller, go ahead with your question.
Caller: Great. Thank you for taking the call, and thank you for the presentation, doctor. Question I have, looking at different options, I have relapsed after two and a half years, post-stem cell transplant, on maintenance Revlimid only. There’s obviously a wide variety of different options at this early point that I've discussed, but two that are specifically interesting. One is venetoclax because I do have t(11;14) translocation, and whether that has a place, early on, or not.
The second is a trial that is available to me, using the cilta-cel, CAR T-cell that you mentioned, which has now been opened up for people with only one to three prior treatments, and is being looked at as something to happen early on in the treatment with perhaps better results than than what had been seen in the 12 to 24-month, you mentioned, where it's typically been people with 5, 10 or more prior treatments. That's interesting. I didn't know if you had any thoughts on that type of approach versus more traditional next steps.
Dr. Orlowski: Well, there's nothing good about a relapse, but you are in a pretty good situation, nonetheless, because with 11;14, venetoclax-based combinations would be great. Actually, I'm a little bit of an outlier among the myeloma academic community because when my colleagues and I get together and discuss this, many of them seem to feel that leaving venetoclax for later is fine. Whereas my rationale is, this is the perfect drug for 11;14, and let's give it as early as possible. So, I would definitely think about doing the second line venetoclax.
However, in this case, if you have an option to go onto the cilta-cel trial, I do think that, because the results with that study, as you point out, in relapsed/refractory disease have been really bang up and hopefully your T-cells will be even healthier because you haven't had that much therapy; I think the opportunity for a long treatment-free interval with a really effective one-and-done treatment, to me, would be probably the way that I would go. I might steer you more in that direction, but this is like having your cake and ice cream too. You've got great options, no matter which way you go here.
Caller: Okay, thank you. I appreciate it very much. This is perfect timing because I've got a short decision window on the trial. I sincerely appreciate your input. Thank you.
Dr. Orlowski: Good luck, no matter what you decide.
Jenny: Thank you. Okay, our last caller, go ahead with your question.
Caller: Hello, Dr. Orlowski. I've enjoyed this. You just about described me in part of the show. I was diagnosed with multiple myeloma in April of 2020. I didn't have any symptoms, but I went for a typical wellness check in March. My blood work was a mess, and they sent me to a hematologist. I was diagnosed then in April through a bone marrow biopsy.
They did testing. I had the lambda light chains. They were over 3200, had some genetic abnormalities with t(14;16) and a gain1q. So, my oncologist started me on the RVd, and when lambda light chains came back, he added the dartumumab. I can never get that word right. He did four rounds.
In July, I went back to my myeloma specialist. I had a second bone marrow biopsy, and he still saw I had fibrosis. He didn't feel that I was a candidate for stem cell transplant at that time. He recommended to do another four rounds of the VRd plus Darzalex. I did that. Actually ended up doing five, had another bone marrow biopsy, the first of December. Two of the high-risk factors are no longer detectable in my marrow, and my lambda light chains are down to 21, putting them in standard range.
Now, my conundrum is, I have a meeting with my myeloma specialist next week on the 29th. Do I move forward with a stem cell transplant, or do I -- essentially with the drug -- or do I hold off and try to stay in maintenance? My concern primarily is where COVID is right now. Is there any problem holding off till maybe September, with everything going on?
Dr. Orlowski: Yes, those are all difficult and important questions. It sounds like you've done well with the VRd and daratumumab, and the disappearance of those FISH abnormalities is a good sign. One question about the 1q21, do you remember or were you told whether there were three copies of 1q21, or four copies?
Caller: I don't know.
Dr. Orlowski: This is one of those nuances. It turns out that if you have four copies or more of 1q21, that is probably an even higher risk group than if you have just three copies. Sometimes if you look at the original FISH report, it will tell you. They don't always do that, but some of them do. To me, especially if it turns out that you had four or more copies, although you could do quite well -- unfortunately, the average for the so-called ultra high-risk patients is short. If it turns out that you're in that category, I would probably recommend, despite COVID, to go ahead and do the stem cell transplant.
I don't know where you are, but we here at MD Anderson now do all of our transplants, inpatient. We actually used to do quite a few outpatients, but with COVID, of course, we no longer do that so that people are not going back and forth and increasing the risk of exposure. If you had standard-risk disease, I would be 100% fine with you going and just doing maintenance until September, but two things. Number one, you've got that molecularly, probably high-risk disease, and it sounds like your myeloma didn't respond all that well, just to VRd. You had to have dara added. That's also a little bit of a factor that would, to me, argue to do the transplant.
Caller: Okay. I'm in Ohio, and I'm going to Cleveland Clinic. They do it inpatient.
Dr. Orlowski: Well, yes. Plus, you wouldn't want to be outdoors in Cleveland these days right now anyways, considering how cold it is out there.
Caller: Right, right. Okay, that's very, very helpful because I've been reading a lot, done a ton of research. I’m a registered dietitian. I've eaten plant-based, most of my life, didn't eat red meat for 40 years, and I exercise since I was age 12.
Dr. Orlowski: Wow, great.
Caller: This has been, how I ended up with this diagnosis, I have no idea, and then to be super high-risk or ultra high-risk.
Dr. Orlowski: Well, unfortunately, cancer doesn't care whether you've been a wonderful person and done everything possible to stay healthy, in many cases. That's one of the frustrating things.
Caller: Right, right. This has been very helpful. I appreciate it. Thank you.
Dr. Orlowski: Good luck.
Jenny: Okay, thank you so much for your questions, great question. As you can hear all these, it's so difficult sometimes for us as patients to navigate this, and this is why we need a myeloma specialist on our team, like Dr. Orlowski. Thank you, Dr. Orlowski, for your time. Thank you for being so generous with your time. It's unreal.
Dr. Orlowski: My pleasure.
Jenny: I'm thrilled at what you're working on, at MD Anderson. The level and extent to which you shared everything that's new, we have so much to look forward to, and you helped describe it in such a nice way. Thank you so much. Very, very informative show.
Dr. Orlowski: Well, take care of everyone. Have a good rest of your Friday and weekend, and stay safe out there, and get vaccinated.
Jenny: Okay, thank you so much. I know patients are trying like crazy to do that. Thank you to you again, and thank you, for our listeners, for listening to Myeloma Crowd Radio. We invite you to join us next time to learn more about what's happening in myeloma research and what it means for you.
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