By Jennifer Ahlstrom | Posted - Nov 10th, 2020

 

 

 

 

Full Show: Venetoclax in the Multiple Myeloma Clinic for t(11;14) Patients with Jonathan Kaufman, MD, Emory University

Jonathan Kaufman, MD
Emory University Winship Cancer Institute
Interview Date: October 23, 2020

Thanks to our episode sponsor

GlaxoSmithKline

Summary

The quest for individualized myeloma treatment is one every multiple myeloma patient hopes to find. For patients with the translocation of t(11;14), one drug may be helpful - venetoclax. In early clinical trials, venetoclax was seen to have particular impact for t(11;14) myeloma. Currently, several trials are open studying the use of venetoclax with other standard of care myeloma drugs. Dr. Jonathan Kaufman has led many venetoclax clinical trials and shares a wealth of knowledge about this drug and type of myeloma. Patients with translocation 11;14 have more BCL-2 which acts a little more like a lymphoma compared to other myelomas. Additionally, while t(11;14) patients tend to do a little worse than "standard risk" myeloma patients, plasma cell leukemia patients with the t(11;14) tend to do a little better. Interstingly, the gene produced by this translocation (Cyclin D1) isn't the target - t(11;14) has different biology. Venetoclax is particularly helpful when used with dexamethasone because it increases BCL-2 expression. Doctors can tell immediately if their patients are responding to venetoclax. 

Venetoclax Trials in HealthTree

Dr. Kaufman on Myeloma Crowd Radio

Full Transcript

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 episode sponsor, Karyopharm Therapeutics, for their support of Myeloma Crowd Radio and this program. 

Now, before we get started on today's show, I just want to make a short reminder announcement about recent updates inside of HealthTree. You may have heard it in this last week's show, but it bears repeating. We now have new notifications and messages inside of HealthTree, so if somebody reaches out to you for a twin request or comments on one of your posts, you're going to see a little bell at the top of the screen with a red circle in it with your number of messages that you have. You'll also see twin messages in the chat icon so you can chat back and forth with your twins, and in the future, you'll also be able to chat with people directly, back and forth, like direct messaging, inside of the forums. We are listening to your feedback, and we're improving HealthTree to provide more functionality to you, over time. 

We also have a new feature in development, and we encourage you to enter your prior treatments and side effects to get ready for this new feature. I'm still going to keep you in suspense, but I know you're going to love it. We have a team ready at all times to help you enter your information. We can give you electronic ways to do it yourself, or we can do it for you if you prefer. 

Now, onto today's program. We hear about personalized medicine in cancer but really, what does it mean for us as myeloma patients? Top myeloma expert Jonathan Kaufmann of Emory University joins us today to discuss what could be considered the first true personalized medicine for myeloma patients who have the 11;14 translocation. We're very excited to learn more about this, so, Dr. Kaufman, welcome to the program. 

Dr. Kaufman: Great, Jenny, thanks so much for having me and looking forward to meeting with the Myeloma Crowd today. It's a lot of fun for me. I've never done your radio version before. I'm looking forward to sometime in the future where we get to all do this in-person again. 

Jenny: Yes! Dr. Kaufman participated in one of our roundtables in Atlanta, and you were just fantastic. We're just so appreciative that you're joining us for this particular topic today. Before we get started, let me introduce you.  

Jonathan L. Kaufman is Associate Professor and serves as Associate Vice Chair and as Director of the Division of Hematology in the Department of Hematology and Medical Oncology at Emory University School of Medicine, which is also part of the Winship Cancer Institute. He's board-certified in Hematology and Medical Oncology. 

Dr. Kaufman practice -- his practice includes treating myeloma and amyloidosis patients at Emory University; and as a network physician, he started practicing at Emory in 2005. He's also an active clinical and translational researcher in the fields of myeloma, amyloidosis and bone marrow transplant. He's a member of the Discovery and Developmental Therapeutics Research Program at the Winship Cancer Institute. He has memberships with ASCO and ASH, and his awards include Atlanta Magazine’s Top Doctor in 2015, ASPMT New Investigator Award, and ASCO and AACR Methods in Clinical Cancer Research Award, and additional awards. 

His work has been published in journals such as the Journal of Clinical Oncology, Science Signaling, Blood, Leukemia, Journal of Immunology, and many, many others. He has presented his clinical research on multiple myeloma at invited lectures, as well as national and international hematology and oncology conferences. 

Dr. Kaufman, I know you've been heavily involved in venetoclax clinical trials. Maybe we just want to begin with a broad overview for what is venetoclax and uses for venetoclax in myeloma patients in general? 

Dr. Kaufman: Great. Thank you so much again. So, venetoclax is a drug that targets a protein called BCL-2. I think it's important to let me just get to somewhere that -- I'm sorry, find a good way to talk about this is understanding what BCL-2 is in the myeloma cell. I'm going to spend a few minutes talking about really basic myeloma biology and really basic cancer biology. 

One of the things that we know about cancer cells, every cancer cell and every myeloma cell, is that they are very sick. The cell is sick, and it wants to die. Because there are so many signals within the cancer cell, the cell itself wants to die, but in order for it to turn into cancer, this very sick cell has developed a strategy to prevent itself from dying. It creates or over-expresses or modifies, in some way, all of these anti-death proteins that keep the cell alive. 

There are several anti-death proteins. One of them is the target of venetoclax called BCL-2. There's another one called MCL-1. There's another one called BCL-XL. All of these proteins are there to keep the cell from dying, and they work in a very complicated and coordinated fashion with each other and with similar proteins to keep the cell alive. Almost every myeloma cell is, in some way, dependent on MCL-1 to stay alive. There's currently a lot of clinical investigation, clinical trials, research into drugs that target MCL-1, but they're not really far in development at all. There's really very little clinical data about MCL-1 inhibitors.

BCL-2, in a subset of patients, is the protein that is really important in keeping the cell alive. Venetoclax is a drug that specifically targets BCL-2. The venetoclax basically removes the guardian of the cancer cell and allows the cancer cell to die because that's what it wants to do. It's really amazing technology, in terms of identifying these proteins that sit in this perfect little pocket to stop this protein called BCL-2 from working. 

Jenny: Okay.

Dr. Kaufman: Venetoclax is, it's an oral medication. Again, it's a BCL-2 inhibitor, and it's approved for several cancers. It's approved for acute myeloid leukemia. It's approved for chronic lymphocytic leukemia. It's very effective. I am very lucky to work here with one of my scientific colleagues, a scientist, Larry Boise, who, I would argue, is one of the top two, three world's experts in understanding what we -- the medical term is apoptosis, or the other name of it is cell death, but really understanding cell death in myeloma. 

We published an article in 2011, in the journal, Blood, where we looked at a drug like venetoclax, and we were able to identify and really understand the reason why certain cells respond to venetoclax, and certain, don't. I'll just quote you this quote that says,

“These data have several clinical implications, such as selecting the correct subset of patients to treat with venetoclax, as well as searching for agents that may synergize with this drug.”

So, we knew almost 10 years ago, that venetoclax was going to be a drug that was only going to work in a subset of patients. The question then becomes, the obvious question then becomes, well, who is that subset of patients? Isn't that what you were just going to ask? 

Jenny: Yes. Well, my question was actually about, in other cancers, you talked about AML and CLL. Is it effective, just broadly, or just for a subset of patients in those cancers as well?  Because that would give you an indication, right? 

Dr. Kaufman: That's a great question. That's a great question. You know how I mentioned in the beginning that most myeloma, almost all myeloma cells are dependent on the other protein, the MCL-1. It’s the exact opposite in AML and CLL, acute myeloid leukemia and chronic lymphocytic leukemia. They're almost all dependent on BCL-2. 

Jenny: Oh, it makes sense.

Dr. Kaufman: They don't need to do subset because they're the exact opposite.

Jenny: Interesting. Are the MCL-1 inhibitors the ones that are being looked at in the 1q gain, or do I have that wrong? 

Dr. Kaufman: Yes, that is true. The reason why people think that MCL-1 inhibitors might work more in 1q gain is because MCL-1 is on 1q, and so it all makes a lot of sense. If you have more of 1q, you'll have more of MCL-1. In theory, if you have more of MCL-1, then that cell should be more sensitive to MCL-1 inhibitors. 

Jenny: So interesting, okay. I didn't know the difference between the leukemias and myeloma. 

Dr. Kaufman: So, after that initial paper, we went and queried a whole bunch of cell lines with the drug. We have a protocol where we take patient samples, and we test the patient samples. What we found is that the cell lines at Harvard, the 11;14 translocation, and the patients who had the 11;14 translocation, were much more likely to respond in the laboratory than other cell lines and other cytogenetic abnormalities. 

Jenny: Why is that? What is it about 11;14 that just -- it just has more BCL-2 in it? 

Dr. Kaufman: No. This is just a great question. Why? Just before going into why the t(11;14)s  are more -- just, again, sort of understanding what t(11;14) is, and again, you guys probably already know this, but I'll just go through it again. We have 23 paired chromosomes in each cell, and they're numbered 1 through 22, and then either XX or XY. We know the different sizes of these chromosomes, and that's how we label them. What happens in the 11;14 translocation is that a portion of the 11th chromosome gets mixed and matched with a portion of the 14th chromosome, and that's the 11;14 translocation. 

Again, as a reminder, myeloma is cancer plasma cells, and plasma cell’s job in life is to make antibodies, and the gene for making antibodies is on the 14th chromosome. That's why, when we see all these cytogenetic abnormalities in myeloma, you'll see 14 come up over and over again, because 14 is where the gene that makes the antibody, comes. Again, we're going back to basic cancer biology. What makes the cell turn into cancer is if you put in a gene that makes the cancer grow or prevents the cancer from dying and then you put it right next to the portion of the gene that says, “I'm going to make you all the time,” so instead of all the time making an antibody, the gene is, all the time, making a protein that tells the cell to grow or tells the cell to not die or tells the cell that you can be resistant to chemotherapy or whatever it is that makes the cell go from normal to cancer. 

Jenny: I heard somebody talk about chromosome 14 as the promoter gene, like you're talking about.

Dr. Kaufman: Right, that’s exactly what I'm saying. 

Jenny: Like, “Okay, I’ve got the signal. I’m just going to go.” What does 11 do? 

Dr. Kaufman: That's a great question. What's on 11 is a protein called Cyclin D1, and Cyclin D1 is involved in telling the cell to grow more. So, the very first question that we asked, is, does the sensitivity to venetoclax, to BCL-2 inhibition in 11;14, have anything to do with Cyclin D1? We learned very early that it has nothing to do with the actual translocation. The sensitivity of venetoclax in 11;14 myeloma has nothing to do with the product of that translocation. So then we had to dig deeper and understand more. Again, that's this work we've done in the laboratory, and what we found in the laboratory is that it's these 11;14 cells that are much more likely to be associated with BCL-2 as the protein that's protecting the cell from dying, than other myeloma cells. 

The other thing that's really interesting about 11;14 myeloma, which we’ve actually known for a long time, is that 11;14 myeloma is a little bit different, clinically. A classic 11;14 myeloma cell is going to look different than another myeloma cell. It's interesting, and I think, Jenny, you might have picked up on this. The 11;14 myeloma cell looks a little bit more like a lymphoma or a CLM, just a little bit. The proteins that are on the 11;14 myeloma cell are more likely to be the lymphoid or the lymphoma-like proteins. We think that one of the reasons that a certain subset of 11;14 myeloma is more likely to respond, is because they act a little bit more like a lymphoma than a pure myeloma.

Jenny: Oh, that's so interesting.

Dr. Kaufman: I want to be very clear. Yeah, it’s still myeloma. It’s still 100% myeloma, but it acts just a little bit different. 

Jenny: Have other lymphoma or leukemia drugs been reviewed for 11;14 patients? 

Dr. Kaufman: Yes, but it's not enough like a lymphoma that lymphoma drugs will work. If you think about drugs like rituximab or ibrutinib and things like that, those have been tried and not to be effective, but that's a great question. The question is, can we -- it's not enough of a lymphoma-like to do that, but it's enough to make these cells potentially sensitive to drugs like BCL-2, drugs like venetoclax that target BCL-2.

Jenny: Interesting. When you think about 11;14, I know there are different types of heavy and light chain myelomas like IgG or IgA or IgM or whatever, and then 11;14 is typically considered lower risk. Do you want to go into any of that? Are there certain types that are found to be more sensitive or aggressive?

Dr. Kaufman: Yes that's a really important question. There’s a lot of data out there asking the question, how do patients with 11;14 do? Historically, patients with 11;14 translocation were not considered high-risk disease, were considered standard-risk disease. With the advent of drugs, all the new drugs we've had -- I say new, but now we're getting on almost 20 years old now -- all the proteasome inhibitors like Velcade and the IMiDs like Revlimid, those drugs really improve the outcome of patients with myeloma. 

It's interesting, if you look at our data, we recently published a series of 1,000 consecutive patients treated in a uniform way. We asked the question, how did the 11;14 patients do? The answer is that the 11;14 patients in our large data set, on average, didn't do as well as other patients with standard-risk disease. So we really think that there's a huge need for new drugs specifically in 11;14 myeloma because they don't benefit as much from what I call the pure myeloma drugs, drugs like Velcade and Revlimid. 

It's interesting, the other thing, clinically, about 11;14 myeloma is that the patients of 11;14 myeloma are more likely to have light chain only disease. They're more likely to have non-secretory disease. They're more likely to have plasma cell leukemia. There's a whole variation in 11;14 that makes it a little bit unique compared to other myelomas.

Jenny: I know non-secretory and PCL, those are considered more advanced and trickier diseases to work with.

Dr. Kaufman: Yes, certainly the plasma cell leukemia, but if you look at plasma cell leukemia patients, you can really divide them between if they have 11;14 and they don't have 11;14. Again, we have a publication that demonstrates that 11;14 myeloma patients who present with plasma cell leukemia are much more likely to live a long time than those patients with plasma cell leukemia that don't have 11;14. 

Jenny: Oh, interesting. Okay, so it kind of makes it better for them. 

Dr. Kaufman: Yes.

Jenny: Can we talk about bone damage as well, for 11;14 patients? Do you see a lot of bone damage, typically?

Dr. Kaufman: In general, you can, just like any myeloma can have bone disease, but it's not considered one of those where you have a high bone damage burden with 11;14. I'm not saying it can't happen, but it's not a classic feature of 11;14 myeloma. 

Jenny: Oh, that's interesting to know because I know some of the myelomas are slower growing but a lot more bone damage, and some are very limited bone damage and all that. That's so interesting.

Dr. Kaufman: Right. 

Jenny: We talked, at the intro, about personalized medicine. It's confusing in my mind because I've heard lately from different myeloma researchers that a diagnosis, you actually have thousands of mutations and then after treatment, you have 10X those thousands of mutations; so, targeting things directly with one type of drug or like a BRAF inhibitor or something like that might be challenging, but this doesn't seem to be the case in 11;14. It seems to be really pretty ideal. 

Dr. Kaufman: So, this is different than a mutation. We’re obviously, very aggressively, trying to develop personalized therapies based on mutations in myeloma, but myeloma is not a simple disease. The diseases where you can find that one mutation that controls everything, we just haven't found that yet, broadly, in myeloma, and we're continuing to work to see if we can find it. The thing about 11;14 is that the product of 11;14 isn't our target, but 11;14 is the marker that this is a cell with a different underlying biology. That's the difference. 

Jenny: That makes a lot of sense. Okay, well, thank you for clarifying that. Because I'm seeing so much efficacy in this particular targeted approach, and then the other part of personalized medicine just seems more challenging to me. 

Dr. Kaufman: Yes. Again, the 11;14, it's really what we call a biomarker. It's the marker that there's likely increased sensitivity to the drug as opposed to the target of the drug. Just like we do in all new drug development in myeloma, we had to do what's called a phase one study, and when you do a phase one study, you often treat patients where there are not other treatments available. So, this was a phase one study, and it was originally done, the original phase one study which has now been published, was done for any myeloma patient who had relapse disease and really didn't have any other options. Now, as I said, we've known for a decade here and we've been saying to anybody who would listen to us that what we really need to do is target this subset of patients. The whole study had 66 patients. You would predict that around 15% of the patients, in any trial, will have the 11;14 translocation. In this trial, of the 66 patients who went on the trial, 30 of them had the 11;14 translocation.

Jenny: That's almost half. Wow.

Dr. Kaufman: Almost half, and the reason that happened is because our center and a handful --once people started seeing the data that came from our center and a handful of other investigators started going away from not 11;14 patients and towards 11;14 patients. That ended up being about half of the trial had 11;14. If you look at the whole trial, the response rate was about 20%. If you look at the difference between the 30 patients who were treated, who had 11;14 versus the 36 patients who did not have 11;14, the overall response rate -- and this is single agent venetoclax, no dexamethasone, no combination, no nothing -- the response rate was 40%. 

Jenny: That’s much higher than normal. 

Dr. Kaufman: Yes. If you think about response rates for single agents; single agent Velcade in the phase one study was 30%, single agent Revlimid was 30%, single agent daratumumab was 30%. Because we understood the biology better, we were able to get a response rate of 40%. If you looked at the patient who didn't have 11;14, the response rate was 6%, which is also consistent with our data that suggests there are some non-11;14s that we predict would respond to venetoclax. Unfortunately, we don't have that biomarker completely nailed down. There are some thoughts about that, and the largest thought is those patients who don't have 11;14 but have very high BCL-2 levels, that those patients might respond to venetoclax. I would say that's much less known and a very intensive area of activity, I mean, of investigation. 

Jenny: Yes, how do you test for BCL-2?

Dr. Kaufman: It's a protein that's in the cell, and there are different ways to test the level of the protein within the cell. What we're doing, and we should be publishing shortly, is we've developed an assay that looks at the different proteins on the cell surface. One of our scientists, physician scientists here, his name is Vikas Gupta, has developed an algorithm that also selects for both 11;14 patients and non-11;14 patients that are more likely to respond to venetoclax.

Jenny: So fascinating that you can find them. That's amazing. 

Dr. Kaufman: Yes, that's our future. So, 11;14 is good because you can get from a 6% response rate to a 40% response rate, but what you really want is to have a biomarker that's so good that even if it's a smaller number of patients, you have 100% response rate. 

Jenny: Yes, definitely.

Dr. Kaufman: If we could predict, that's predictive medicine, which is, you don't say, the doctor doesn't say to you, yeah, there's a 30% chance of this working, there's a 40% chance, there's an 80% chance. We say, “You have this biomarker. Every single patient who takes this drug, responds.” That's precision medicine. 

Jenny: That's where those patients would like to see themselves. 

Dr. Kaufman: That will be great. That will be awesome. 

Jenny: Yes, for sure, before you take it.

Dr. Kaufman: Yes. That's Gleevec in CML. All those -- maybe it's not 100%. Maybe it's 98%. That's where we'd like to be with our precision medicine. 

Okay, so we got a 40% response rate and said that this is great. This is a signal. This is real. I will tell you, I remember going to meetings and saying, “I just cannot believe how excited -- because we had this one woman who was very young, and she was told there was nothing left to do. She came to us. She had 11;14. She went into a CR, and it's amazing. It's just really amazing. 

The next thing we want to do, and remember that opening statement I said, is we’ve got to figure out what the subset is, and we’ve got to figure out what the best partners are. Again, Larry Boise in the lab, and Vikas Gupta in the lab, and Shannon Matulis; all scientists went back to the drawing board and asked the question, what's the best combination? So we used all the standard combinations. People might not believe me, but the best combination with venetoclax was dexamethasone. 

Jenny: Oh, so interesting. Patients do not want to hear that.

Dr. Kaufman: This group of scientists were able to figure out exactly why. It's funny because I have one of my colleagues say dexamethasone is like bacon. It makes everything better. 

Jenny: Yes, it is.

Dr. Kaufman: I also say about dexamethasone is, always, dexamethasone is both our friend and our enemy, and we have to figure out how to manage that at all times. I think every myeloma patient knows that. The question we had -- so the reason why dexamethasone makes venetoclax better is because it shifts more patients to being dependent on BCL-2.

Jenny: Oh, really? Okay. I didn’t know that.

Dr. Kaufman: We figured out that we had this biology that we predicted, and with the one drug that was more likely to make more patients sensitive, at least more patients’ cell line sensitive to BCL-2, to venetoclax. Then we did a trial with -- we did two trials. The first trial we did, which was relatively earlier in the course of myeloma therapy, showed a 60% response rate. Then we did a trial where 90% of the patients were refractory to daratumumab. In that trial, combinations with dexamethasone, and all these patients were refractory to dexamethasone. There was about a 50% response rate. 

Jenny: That’s huge.

Dr. Kaufman: Yes. We're really looking at very impressive outcomes. Because if you look at drugs in patients with refractory myeloma, like pomalidomide and dexamethasone, the response rate in that setting is 30%. So, we're looking at a 50-60% response rate in a patient population that is already refractory to a daratumumab combination. 

Jenny: It feels a little scary, once you get refractory to daratumumab, and you've used everything. 

Dr. Kaufman: Yes. Okay, at this point, everybody asked the obvious question, which is, how come this is not available widely? Why is this still investigational? There's been a lot of research of combining drugs, the proteasome inhibitors with venetoclax. The rationale by using proteasome inhibitors is that proteasome inhibitors block, in theory, they have a way of blocking MCL-1. If you stop MCL-1 from being effective, and you stopped BCL-2 from being effective, then you should have a very potent combination. 

The preliminary research suggested that the combination of venetoclax and Velcade and dexamethasone was effective. That led to the BELLINI trial, and the BELLINI trial was a large international trial that compared relapsed myeloma patients. They had venetoclax, Velcade, dexamethasone versus Velcade, dexamethasone. The data came out that showed that the venetoclax arm, if you take the whole population, did better than the non-venetoclax arm. That's great. The problem was that there was an increased death rate in the patients who had venetoclax versus the patients who didn't have venetoclax. So, despite the whole group doing better, keeping the myeloma from progressing; the whole group, on average, had much more toxicity and that patients died. 

Jenny: What about it was halting the trial? 

Dr. Kaufman: That halted the entire development of venetoclax. It's that data that is why venetoclax, that, among other things, is why venetoclax is not available to all of us today, outside of the context of a clinical trial. There's a couple of things if you -- it looked like there was -- but remember that they took all comers. If you just looked at about 10% of the patient population consistent with what we'd expect, have 11;14; these patients did not, at least in these very small numbers, did not appear to have a worst survival; but these numbers are so small that you can't tell for sure. 

The data really looks like the problem was in the non-11;14 patients, and there's a couple of hypotheses. Maybe there was an increase in infection risk, and now all the studies are very conscientious about being on antimicrobials during treatments and making sure your vaccinations are up-to-date or getting up-to-date and things like that. Now, all the trials that are out there right now have stopped focusing on all myeloma patients and started solely focusing on the 11;14 patients. 

Jenny: Well, let's talk about some of those trials, if you don't mind.

Dr. Kaufman: Yes. Where are we now with trials? We presented at last year's American Society of Hematology Conference, the combination of venetoclax plus daratumumab and dexamethasone, this is patients who have never had daratumumab before, looks like to be a very potent regimen. We now have a randomized study ongoing that looks at two different doses of venetoclax with daratumumab versus Velcade plus daratumumab. We have a clinical trial with a control to make sure that we don't see that difference in survival, that decrease in survival. So, that, we have, and that study is led by Nizar Bahlis.

We have a study that's led by Luciano Costa, of the combination of carfilzomib, venetoclax and dexamethasone versus carfilzomib and dexamethasone alone. That study was presented, I want to say, in 2018, and hopefully we'll see some data, some further data later this year about that. That looks like to be a safe and potent combination. There's a large international, randomized trial of 11;14 only -- again, all these are now 11;14 only patients -- of venetoclax --

Jenny: That’s good.

Dr. Kaufman: -- and dexamethasone, venetoclax and dexamethasone versus pomalidomide and dexamethasone. That's an ongoing study. All these are ongoing studies. We have investigator- initiated studies here, looking at other rational combinations that we're trying to get opened to continue to investigate this. 

Jenny: Can I ask a question? 

Dr. Kaufman: Of course.

Jenny: I've heard other people talk about, when you start using more of the immunotherapies, that you may not want to use dex because it could suppress your immune system or whatnot. I've heard of some combinations trying to get rid of the dex. You're saying this is a really great combination for venetoclax, and you should keep it. How does that all play in, when you start doing trials like Velcade or venetoclax or dex?

Dr. Kaufman: Yes, it's a great question. I think, because there's a rationale for dexamethasone making venetoclax better, there's a rationale for having it there, at least in the beginning. What we try to do, I think once you get past the first couple of months of treatment, then based on tolerance, rapidly dose-reducing the dexamethasone because, while in the beginning, it's probably very important for a response, it's probably less important for maintaining the response. I think that's really the key. 

Jenny: Okay.

Dr. Kaufman: Because we don't think that the reason venetoclax works, is because of activation of the immune system, then I don't think we have the same concerns of using dexamethasone that you would have in a CAR T-cell or in a bispecific or something like that. 

Jenny: Yes, that makes a lot of sense, and it would make sense that you would start combining it with the things that are really well-known and well-used, like the proteasome inhibitors and the IMiDs. Are there trials, as well, using them with -- oh, you talked about the Velcade-dara-dex versus…

Dr. Kaufman: Yes.

Jenny: … Velcade-dara, right?

Dr. Kaufman: It’s venetoclax-dara versus Velcade-dara-dex. Right. 

Jenny: Oh, okay. Venetoclax-dara, okay, I wrote that down. There are other trials too, where they're using it, venetoclax-dara-dex, with or without bortezomib, right? 

Dr. Kaufman: Yeah, that study has modified into just dara-venetoclax-dex at two different doses of venetoclax versus dara-VELCADE-dex. We're not looking at the four -- we've pulled off from looking at that four-drug combination at this time. 

Jenny: Oh, got it. Okay. It's also being tested with ixazomib, right? I don't know what the difference is between ixazomib, normal ixazomib and ixazomib citrate, is it? That's what the study said. I don't know what the difference is. 

Dr. Kaufman: That's ixazomib. Again, just like looking at venetoclax with Velcade as a proteasome inhibitor and carfilzomib, Kyrpolis is a proteasome inhibitor, looking at it in combination with ixazomib, Ninlaro is a proteasome inhibitor also; it makes sense. 

Jenny: What phase of studies are these? They are all for relapsed refractory myeloma patients, right? 

Dr. Kaufman: Right. They’re phase one, phase two, and phase three studies. The study of venetoclax-dexamethasone versus pomalidomide- dexamethasone is a phase three study. That's a very large international study, looking at standard outcomes, including survival. The other ones are earlier. They're randomized, but they're still earlier, because you're still trying to figure out, is this safe, and is it good enough to do a phase three study?

Jenny: If you just have one phase three, they're still in earlier forms. How long do you think it will be before they start moving it up? Well, if things are in phase two and some in phase three, you already have the safety data, right? 

Dr. Kaufman: Yes. So, the venetoclax-dara versus venetoclax-Velcade, right now, it can be used as early as second line therapy. Again, that's as part of a study. I think we'll be able to see wider use, once we have a randomized study in 11;14 only that proves that there's no decrease in survival. That risk that we saw in the all-comers is not there in the selected population. 

Jenny: Yes, I remember going to a session on that. That was a couple years ago, right, when they were going through that?

Dr. Kaufman: Right.

Jenny: How many 11;14 patients are there, total, in myeloma? Do you develop that translocation at the beginning of your disease, even in the smoldering stage? 

Dr. Kaufman: Yes. 

Jenny: Can you develop it over time, or do you pick it up and… Yeah, well, let's start with that.

Dr. Kaufman: Great question. So, about 15% of patients have the 11;14 translocation, and it's early. It is part of the reason that the cell became a myeloma cell from a normal plasma cell. You can find 11;14 translocations in MGUS. You can find it in smoldering. Obviously, you can find it in myeloma. If you don't have 11;14 early, then you really shouldn't -- you shouldn't pick it up later. It's certainly possible that it wasn't identified early, and you only see it later, but you want to think about this translocation, like all of the 14-related translocations, as an early event.

Jenny: For your patients -- I mean, you have a lot of 11;14 trials running with these different combinations. 

Dr. Kaufman: Right.

Jenny: Do you just encourage your 11;14 patients, “Hey, you should always consider joining one of these trials”?

Dr. Kaufman: Exactly, that's exactly what we do. That's the only way that we're going to be able to get venetoclax to everybody is to -- everybody who could benefit from it, that is. When I say everybody, I'm just talking about the selected population of patients. The only way to get venetoclax to today's 11;14 patients and the 11;14 patients in the future is to participate in clinical trials. 

Jenny: Do you have any early indication whether -- because you were talking about when it was being used with bortezomib and things like that. You're not seeing a similar safety thing for the 11;14 patients. Do you have an idea of IMiDs versus proteasome inhibitors, which is going to be a better combination? Or do you just go with standard RVD or something like that and then get the venetoclax? 

Dr. Kaufman: Right now, the data we have is mostly with the monoclonal antibodies and proteasome inhibitors. There's just not a lot of data in combination with the IMiDs yet. 

Jenny: Venetoclax, by itself, do you see any particular side effects that patients need to be aware of, for venetoclax? 

Dr. Kaufman: Yes, great question. Venetoclax, again, want to be conscientious about infection risk. It can lower blood counts, and it can be associated with some GI toxicity, nausea or diarrhea. The other thing that's really important in venetoclax comes from the data that when it was first developed for CLL, and some patients with CLL developed fatal, what's called tumor lysis syndrome. The drugs killed so many CLL cells at once that all the cells died and the insides of all those cells came out and then damaged the organs to the patient. The patients actually died from what's called tumor lysis syndrome. 

So, now, in CLL and other diseases, there's a very, very cautious ramp up. You start at 50 milligrams, then you go to 100. Or even, you start at lower than 50. You start at 20, and then go to 50 and then 100 and so on, until you get to the target dose. This is in contrast to myeloma where, while it's still very effective, we have not seen serious tumor lysis syndrome. In myeloma studies, we either start immediately at 400 or 800 milligrams a day. Where in CLL, they start at 20 milligrams a day. I have patients that we treated that we can tell, have responded to a single dose of venetoclax at 400 or 800. We can tell they've responded in 24 hours. 

Jenny: Oh, my.

Dr. Kaufman: I know when I treat a patient, if they're responding, one day later. 

Jenny: Oh, that's incredible. I had no idea. How do you determine that? 

Dr. Kaufman: We've actually done light chains, the next day, and see patients’ light chains go down. Patients who have circulating plasma cells that don't quite have plasma cell leukemia, all their circulating plasma cells go away, kidney function gets better the next day. 

Jenny: That's incredible. 

Dr. Kaufman: Yes. 

Jenny: Let's talk about access for a minute. 

Dr. Kaufman: Okay. 

Jenny: I have a friend named Steve, and he actually submitted a question for a little bit later. He had 11;14, nothing was really working for him, and we had included venetoclax in HealthTree. He saw that as an option, went to his general oncologist, and he said, “Oh, no one would ever give you that drug.” He thought, well, I should probably go talk to a myeloma specialist. He talked that specialist, and the specialist said, “Actually, that would be a great option for you,” and ended up getting it and working with the oncologist to convince him that that was a good idea. He's been doing really well, ever since. How do patients access venetoclax? 

Dr. Kaufman: In theory you could get it, but I think, again, we have to be -- while I've seen really remarkable responses, we don't have the clinical trial data where we've proven without any doubt that the safety -- that the benefit outweighs the risk. We have to be honest about that. That's where we are today. 

Jenny: That’s the purpose of clinical trials.

Dr. Kaufman: Now you heard me talk about this, how excited I am about it, but I'm also honest about it and saying, if we knew that the benefits outweighed the risk, this will be an FDA-approved drug. That's how it works. So, in extremely rare circumstances that I would consider that. Primarily, the circumstances are that the person's not eligible for any trials and not eligible for any other therapy, and we've had a very frank and open discussion about the lack of complete data. 

Jenny: How long do you think some of those data will take to read out? Because if you said that it shows up early in the MGUS and smoldering melanoma stages, you would think that maybe you nip it in the bud at those early precursor conditions, by using venetoclax with dex or something like that. 

Dr. Kaufman: Yeah, that's interesting.

Jenny: In those early stages.

Dr. Kaufman: We're a long way from there. It's a great idea but, right now, what we have to focus on is the relapsed refractory patient population with 11;14. Let's prove safety, let's prove that the risk-benefit ratio is positive, and then start asking the wider questions. We have to just do the first step first and get the studies done that demonstrate that and demonstrate to the world and the FDA that this is a safe and effective medication in patients of 11;14. 

Jenny: Right. So, if there are four or five trials running in various stages, how long would you anticipate that -- I don't know. We're looking ahead, right, at things like CAR T, and we’re looking at --

Dr. Kaufman: Maybe two years. I’m going to try to say two years.

Jenny:  Ballpark it. 

Dr. Kaufman: Yes, I actually have no idea, but two years is my guess. 

Jenny: Okay. 

Dr. Kaufman: That is if it proves to be safe, if the risk-benefit ratio proves... 

Jenny: Right, and you just need the data before you know that. 

Dr. Kaufman: Yeah, and so I encourage everybody who has 11;14, who is relapse disease, is seek out one of these trials. Call me. Well, call Jenny, also call me to get on the study if it's appropriate for you. 

Jenny: Yeah, I think this is a really important point. We stress this on every program. Because this is how myeloma patients have the power to move research forward, is by doing these studies and learning.  

Dr. Kaufman: If we don't do these trials today and tomorrow, and if we don't do these trials in the next year, then three years from now, we're going to be having the exact same conversation, and we won't have the drug, if it's appropriate. 

Jenny: I agree, and just clinical trials, in general. The development in myeloma is happening so fast, and we could come to conclusions even faster if patients really thought about that as a treatment option. I know in this situation, it's really for relapsed refractory patients, but there are open clinical trials for every stage, whether you're -- even observational stuff in MGUS and smoldering, and even treatment in smoldering. 

So, I would just encourage all our listeners to think about clinical trials. Every time you make a treatment decision, think about them. We have tools in HealthTree, and we're linked to SparkCures in HealthTree, so you can find clinical trials that you are personally eligible to join. It's not as hard as going on clinicaltrials.gov anymore, and just doing the search on 400-plus clinical trials. We can connect people with investigators like yourself, to get people on study, so I highly recommend it for all myeloma patients.

Dr. Kaufman: Agree.

Jenny: Okay. Well, let's just give a couple minutes, if people have any questions. If you have a question for Dr. Kaufman, you can call 347-637-2631 and then you can press “1” on your keypad. Sometimes people are very shy, but I would encourage you not to be shy and just ask your question. Okay, we have a caller. Go ahead with your question. 

Caller: Hello, this Nathan. How are you guys doing today? 

Jenny: Good.

Dr. Kaufman: Great. How are you? 

Caller: I'm doing good. I've listened to the whole program. I appreciate that. I actually am wanting to get into the trial, but the problem is, and I've been talking to my doctor in Cleveland Clinic, I am not in complete remission. I'm also not where it was progressed enough. 

Dr. Kaufman: Right.

Caller: I can tell you that I had a stem cell transplant that the day I left University of Miami, my kappa numbers were higher than before. Every therapeutic drug that I've tried to do, just does not put me into complete remission. Thankfully, carfilzomib stopped my -- going from 21-day to the next week, going to 200, but at the same time, not a complete remission. The one thing I don't understand about what you had mentioned, which is that, going through a stem cell transplant, going through all of these therapies, my body is going to be worn down. I would much prefer, because I have the 11;14, understanding the full risk of what I'm doing. 

Because what I don't understand with some of the trials is that I have gone now five years, wearing my body down, and I would prefer if I could have done a trial like this, now, a year ago, two years ago, instead of keep on going through the chemo, waiting for my numbers to go up and then I'm even more worn down than before. I guess I'm trying to understand, why is there not a cohort or something for someone that cannot get into remission. I can never get my -- my lambda number goes off, my ratio number is off. I'm willing to do it because I understand the risk. I'm willing to do it because my body is going to be worn down at the time that they're taking the other patients. I don’t understand this going back and forth. I've emailed with Jennifer, a couple of months ago, of there's this cycle that myeloma patients are going through about the times that they progress, then their body can't take it. 

Jenny: Yes, great question.

Dr. Kaufman: I completely hear what you're saying. So, the entire structure of how we do trials for approval is all based on patient's myeloma not getting worse versus trying to make myeloma that's okay, better. Now, having said that, I think it's a very astute observation, which is, if you've done a treatment and you're left with a residual disease, we should be targeting that residual disease in a different way. Totally agree. Those types of trials are not the type of trials that are going to lead to drug approval, but you will find those types of trials -- at our center, we're currently building that exact trial, after treatment, seeing what's left and targeting what’s left. It's a great idea. If we ever have that trial that takes 11;14 patients and uses venetoclax to do that, I will let you know, and we'll make sure that's there. I understand, but your doctor’s right. You're not going to be eligible right now. You’re right, it's such a challenge to hit that perfect time where you're eligible but you're not too sick. It's a challenge. I think we all agree. 

Jenny: I love that question. Thank you so much for asking it. Okay, this will be our last question because we're at the top of the hour. 

Caller: Yeah, hi, this is Victor. Hi, Jenny.

Jenny: Hi, Victor. 

Caller: I came down, went down to Emory and got tested, and under the recommendation of Dr. Nooka, I'm on 800 of venetoclax and 20 of dex. Almost, for two years now, it's been working pretty well. I'm thinking about the future for me and wondering, what is the range of response times that you've seen? How long have people been on this, successfully? 

Dr. Kaufman: We have a patient...

Caller: The other question is, once it stops working, I've heard pitavastatin is a possible combination. I wonder if you could comment on that. The other thought is, if it also stops working, could you add something like dara or Kyprolis to it? Or would it be best to just abandon the venetoclax and move on to something else? 

Dr. Kaufman: Okay, three great questions in one. Perfect. Firstly, our longest patient, who is the young woman I talked about, is still on trial and still in complete remission. I want to say we started in 2004, so that’s six years. I'm sorry, 2014, it could be 2015. It's five or six years. So, it can be a long time. Secondly, there's probably, depending on your case, there's a lot of treatment options. I think you were talking about pevonedistat. That's one treatment option, but we don’t have --

Caller: No, it’s pitavastatin. 

Dr. Kaufman: I'm not sure what that one is. I might know it by the name.

Caller: It's a standard statin drug. 

Dr. Kaufman: I can't imagine that a statin drug would work as a single agent. 

Caller: No, no, combining it with the venetoclax.

Dr. Kaufman: Oh, I see what you're saying. That looks like it's effective in the laboratory. I do not recommend using statins with venetoclax, based on the laboratory data alone. While it's a good idea in a laboratory, there's no clinical data. If you need a statin for your cholesterol and you're on venetoclax, great. I would not take a statin, unless you needed it for standard reasons. The third question was, what we've learned is when venetoclax stops working, it stops working, and so adding things into it aren't the right thing to do. The right thing to do is switch. 

Caller: Okay, that's very helpful. Thank you. 

Dr. Kaufman: You’re welcome.

Jenny: Thanks for such great questions. Well, Dr. Kaufman, thank you so much for spending the hour with us. We are so grateful. I learned a lot about 11;14 myeloma today. 

Dr. Kaufman: You should talk to me more often.

Jenny: I should. It's awesome. Thank you just so much for participating. We're just so grateful there are people like you working on myeloma.  

Dr. Kaufman: Yes, no problem. I'm happy to do it. It's my life's work. 

Jenny: Well, we're so happy you dedicated it to us, and helping find a cure for even a subset of patients and beyond. We're just so very grateful. Thank you, and thank you for our listeners for listening to today's episode of Myeloma Crowd Radio. We encourage you to tune in next time for more about the latest in myeloma research and what it means for you. 

 
Jennifer Ahlstrom
About the Author

Jennifer Ahlstrom - Jenny A - Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical trials. Founder of Myeloma Crowd, Myeloma Crowd Radio, HealthTree and the CrowdCare Foundation.

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