(Guest Lecture ): Know Your Myeloma Therapy: Carfilzomib (Kyprolis) with Dr. Harsh Parmar

to Dr. Parmai. The topic for today is Know Your Myeloma Therapy, Carfilzomib, or commercially known as Kyprolis. This year in the relapse refractory myeloma patients chapter, we're going to be inviting myeloma specialists to come speak about different medicines that are found in the myeloma arsenal used for relapse and refractory patients. We want you to better understand their mechanisms of action, their approvals and combinations, and their side effects. We are excited to talk about a commonly prescribed treatment, Carfilzomib, again known commercially as Kyprolis, here with you today. The multiple myeloma specialist that has agreed to speak to us today is Dr. Harsh Parmar, and I'd love to introduce him. He specializes in the treatment of patients with multiple myeloma and other plasma cell disorders such as amniocardial adenosis and Waldenstrom's macroglobulinemia. He chose to specialize in the care of patients with these diseases because there are no current treatment options that result in a cure, and there are opportunities to make advances in the management of these cancers. He joined John Thurick Cancer Center at Hackensack University Medical Center in 2020. When he meets new patients, Dr. Parmar takes a caring attitude and treats them with compassion. The treatment of these cancers may extend over years, as we know, as patients go into remission and then relapse. Dr. Parmar enjoys getting to know his patients, including their preferences and goals of therapy. In addition to standard therapies, he is interested in clinical trials of innovative therapies that hold promise for extending patients' lives. Dr. Parmar received his medical degree from Seth G.S. Medical College in King Edward Memorial Hospital in Mumbai, India. He continued as an internal medicine resident at Jersey Shore University Medical Center, completed a hematology oncology fellowship at the University of Connecticut Health Center, and had additional training as an advanced hematology fellow at the Mayo Clinic. He is also a member of the American Society of Hematology and the American Society of Clinical Oncology. I wanted to read his entire bio to you so that you can get to know what a great man he is and how qualified he is to speak on this subject. So Dr. Parmar, we're looking forward to your presentation today, and the time is now yours. Thank you, Audrey, and thank you to the health tree for inviting me today to speak about the use of carfilzomib in the setting of relapsed multiple myeloma. I think it is very important for our myeloma patients to know about the different treatment options available to them, the side effect profile of all the different drug therapies that are out there, as well as effectiveness and what to expect in terms of the adverse effects as well. So with that, I will start my talk with introducing you to what multiple myeloma is, the treatment algorithm that we follow, which is quite standardized across the United States, and then talk about carfilzomib itself. So what is multiple myeloma? So if you look at the term multiple myeloma, you could actually, if you know a little bit of pre, you can actually figure out what it is. So myelos in Greek means the bone marrow, and oma means cancer. So cancer of the bone marrow is what this term implies, and multiple indicates the multiple sites of tumors that were initially identified on autopsy performed on the very first patient who was identified back in the 1890s, and this was in Chicago, at the University Medical Center. So multiple myeloma is a hematologic cancer or a blood cancer that develops in the bone marrow, which is the soft spongy center of most bones, and it typically occurs in the spine, the pelvic bones, the ribs, shoulders, and the hips. This is where the blood cells are produced. So myeloma tends to affect plasma cells, which are a particular type of a white cell. Their normal function is to produce immunoglobulins or antibodies that function to protect you against infections, but in myeloma, these normal plasma cells become cancerous, and they produce abnormal proteins, which are dysfunctional, and they are produced in large quantities, and they can affect your kidneys, they can affect your bones, weaken your bones, also weaken your immune system. They start crowding out other healthy cells, your bone marrow, so you can start becoming anemic. Your other blood cells may also drop your white cells or platelets. So next slide. Looking at the survival outcomes for our patients with myeloma, this has changed quite significantly over time. If you look at the curves, particularly the one on the right, which is the overall survival curve, back in the 1990s, this overall survival was very poor. At two years, only 50% of the patients were alive, but with time now, if you look at the transplant year between 2009 and 2013, at least 75% of the patients were alive, and now this has improved even further. So a lot of our patients are surviving longer than five years, over seven years, and now we're talking in terms of decades, and this is all attributed to the newer treatments which are now available to our patients. Next slide. So looking at the treatment paradigm for multiple myeloma, as I was saying, the treatment is quite standardized across the United States. The first step is to identify whether you are eligible for a stem cell transplant or not, and this really depends on your performance status, which means how strong you are. If you have any other comorbidities or any health issues, if you would be able to tolerate high dose chemotherapy, and if that's the case, then you get the stem cell transplant. Actually, you start with induction therapy for a few cycles, you get your myeloma under control, and then you get the stem cell transplant, and then about three months after, you are put on maintenance therapy, which tends to be single agent problem, and you enjoy a period of remission, and then the disease may come back, and that is called a relapse, and that will be the focus of my talk in relation to the carfilizoma. Next slide. So looking at the different myeloma therapies which are available to us, so the first group of drugs that I'll talk about is the steroids. The commonly used steroids are dexamethasone and prednisone. Then we have chemotherapy drugs, melphalan, which is used in the context of a stem cell transplant, cyclophosphamide, which is commonly used in combination with Velcade and dexamethasone for some of our patients in newly diagnosed selling. Bendermostene is not very commonly used these days, and then you also have the PACE chemotherapy, which we are moving away from. Then we have IMIDs, or immunomodulatory drugs, so there are three drugs which are available to us. Thalidomide was the very first one which was discovered in the 1990s. It was found to be effective against myeloma, and it had a lot of side effects in terms of somnolence and neuropathy. So the next generation of drug was discovered called Revlimid or lenidomide, which we use quite commonly now. And then lastly, pomalidomide, which is more efficacious than lenidomide. Then I'll talk about proteasome inhibitors, in particular carfilizomib, which is a second generation proteasome inhibitor, vortizomib, which is a first generation inhibitor, and hexazomib, which is an oral form of proteasome inhibitor. Then we have monoclonal antibodies. The very first one that we had was the elotizomab. Subsequently, we have teratomab, and most recently, isotoxamab. We also have BCMA-directed therapies, CAR-T therapy, IDA cells, the drug name, and then belantomab as well. And then there are certain other novel therapies, such as selenoxor, venetoclax, and vanavinostat. Next slide. So what is a proteasome? So this is the mechanism of how carfilizomib works. Proteasomes are protein complexes or structures that function like a recycled bin for your cells. So your myeloma cells produce a lot of proteins in large quantities, and they are long-chained, misfolded, or defective molecules. They are usually broken down into smaller protein fragments and removed by these structures, the proteasomes. If we inhibit proteasomes, then these long protein molecules, which are defective, they start accumulating inside your cancer cells. This causes toxicity and eventual death of your cell, and other terms, apoptosis. So that is how proteasome inhibitors work in general. Next slide. So as I was saying, we have three proteasome inhibitors available to us, vortizomib, carfilizomib, and exazomib. Vortizomib is a subcutaneous injection, carfilizomib is an intravenous infusion, and exazomib is a pill. Next slide. So carfilizomib is an irreversible proteasome inhibitor, and in a lot of studies, it has shown more effectiveness against myeloma compared to vortizomib, and I will talk about that in a little more detail. So the name carfilizomib is actually a term which commemorates the physician scientists, or not physician, but the scientists who discovered this molecule. His name was Phil, and his wife's name was Carla. Both of them actually succumbed to cancer. So in their memory, this drug was named after them, carfil, and then zomib actually stands for proteasome inhibitor, IB is the inhibitor. So that's carfilizomib. Next slide. So carfilizomib is actually approved for use in relapsed refractory multiple myeloma. It can also be considered in patients with newly diagnosed myeloma. There was a trial which compared the use of carfilizomib against vortizomib or Velcade, and the outcomes did not look any different, but there were certain high-risk features which were identified, which were found to be more beneficial if you use carfilizomib compared to vortizomib, and that includes 1p deletion and gain of 1q. Next slide. So the Modify Administration, as I was saying, the drug is given as an IV infusion. It is administered over a period of 30 to 60 minutes. We ask you to drink plenty of fluids, lots of water, at least 24 hours before you get the drug. And we also give you some fluids with the drug, about 250 to 500 cc's, because there is a theoretical risk of something called tumor lysis syndrome, which is where the drug can kill the cancer cell, and as a result, a lot of toxins are released from the cancer cell, which can damage your kidneys. We give you pre-medications to decrease the risk for hypersensitivity, and then the usual schedule for this drug is once a week for three weeks in a row and then a week off. Earlier studies used this drug as twice a week infusion, but we now know that once a week infusion is just as effective as twice a week. So for convenience sake, we've gone down to once a week administration. Next slide. So therapy at first relapse, we know from our experience and multiple studies that three drug combinations have always proven to be more effective and superior compared to two drug combinations, because they improve the overall response rate, and they also improve something called progression-free survival, which means how long your myeloma can stay under control before it starts to grow again. And there are several different options and combinations which can be considered at relapse, and that includes the commonly used regimen of teratumumab, lenolidomide, revlimid with dexamethasone, teratumumab, parmalest, and dexamethasone. The combination can also include teratumumab, typrolis, or velcade with dex, and then KRD or carfilizumab, or carfilizumab, pomalidomide, and dexamethasone. Next slide. So now I will talk about the data behind the approval and the use of carfilizumab in the relapse setting. I don't think it's very clear here, but I will try to guide you through this slide. So the FDA granted accelerated approval for kyprolis in July of 2012, and this was on basis of this particular trial on the top. And it evaluated the use of kyprolis as a single agent, and we found that the drug was very safe and it was fairly effective. The overall response rate was about 25%, and the progression-free survival or PFS was about four months. So another study was performed, it was a phase two study called the FOCUS trial, and again the response rates were roughly the same, 20%, and the PFS was around four months as well. These trials actually used carfilizumab at a very low dose, and that's why you don't see as much of an efficacy or as much effectiveness. But encouraged by the safety data from these studies, the Endeavor trial was then performed that compared the use of carfilizumab dexamethasone against the standard of care of Velcade and dexamethasone. And as you can see here, the response rates were significantly better, it was almost 80% compared to about 60% with Velcade. And the disease control or progression-free survival was also significantly improved. It went up from nine months to about 18 months, so the PFS was almost doubled. And then for convenience sake, the ARRO trial was performed that compared the use of once-a-week kyprolis against twice-a-week, and they found that once-a-week was just as good as twice-a-week. As twice-a-week, actually it might even be better looking at the PFS, which is slightly better as well as the response rates. And then we had the ASPIRE trial, which looked at the use of triplet therapy compared to doublet of Revlimid index. So you have the use of kyprolis with Revlimid dexamethasone versus Revlimid dexamethasone. And again, you can see the response rates were significantly better with addition of the kyprolis at 90% versus 70%. And the PFS was also significantly improved at 26 months versus 17 months. And then we had the CANDOR study, which looked at the combination of Darzalex with Carpalizumab dexamethasone. So Darzalex is immunotherapy. And as I previously talked about, it's also considered one of the options in the relapse setting. And a lot of us like to use that in the relapse setting in combination with Revlimid or Parmalist, but Darzalex with Carpalizumab is also a consideration. And as you can see, the response rates were also pretty good. They were 80%. And the PFS was not reached in this particular study, which means more than 50% continued to remain in some degree of remission, whereas about 50% of the patients progressed at 16 months with the use of Carpalizumab dexamethasone. And then lastly, we have the IKEMA study that compared the use of Izotuximab, which is the newest monoclonal antibody. It works similar to the Darzalex. And again, the response rates were similar to what we found in the CANDOR study with Darzalex. Next slide. So this is a graph that compares the outcomes as far as the PFS goes for patients who received Carpalizumab dex versus Velcade dex. This was the NDOER study. And as you can see, the PFS was doubled with the use of Kyprolis. Next slide. And this was the ASPIRE study, which looked at the use of the triplet drugs, which is the Kyprolis with Revlimid dex compared to Revlimid dex. And you can see that the PFS is again improved by about nine months. Next slide. So what are the other combinations which can be used for patients who are in the setting of relapsed multiple myeloma? So we use the backbone of Carpalizumab and dexamethasone. And then we have various other drugs that we can explore. So there was a phase one study which looked at the combination of Parmalest with KD. And it showed that the overall response rate was about 50% and progression-free survival was about seven months. So that is one consideration. The other consideration is the use of Venetoclax. This is a very interesting molecule. It's found to be very effective in certain other cancers such as lymphoma as well as leukemias. And we know that it works in myeloma as well, particularly in patients who have this genetic change, the translocation 1114. And the data is quite promising. It was just published about two months ago. The response rate was over 90%. And a lot of these patients achieved complete response, which was 40%. With the use of Carpalizumab and dexamethasone, the complete response rate was much lower, about 10 to 25%. So this was a significant improvement. And even when we talk about PFS, it was 24 months compared to 18 months with just the use of Carpalizumab and dexamethasone. Looking at the next molecule, it's called selenixor, which has a very unique way in terms of its mechanism against myeloma. So the myeloma cells like to produce certain proteins inside their nucleus and they remove something called the tumor suppressor protein. So these tumor suppressor proteins are supposed to suppress the multiplication of your myeloma. The myeloma cells find a way to overcome this issue. So they kick out the tumor suppressor protein from their nucleus by increasing the production of the XPO1, which is the exportin. So the selenixor actually inhibits that structure. So their tumor suppressor proteins end up staying in the nucleus and your myeloma cell is killed. So this particular molecule was evaluated previously with Velcade and dexamethasone and it was found to be very active. And now we have data which also suggests that selenixor in combination with chyprolis and dexamethasone is also quite active and it's safe with response rates of, I want to say about 80%. And the progression fee survival was also quite impressive at about 15 months. And lastly, you can combine cyclophosphamide, which is an old school chemo drug with chyprolis and dexamethasone. And the data comes to us from a Spanish study and they found that this was very effective, particularly in patients who progressed on revlimid based combinations. So that is also a consideration. Next slide. Looking at the various adverse effects in regards to carfilzomib, the most common ones tend to be fatigue, headaches, diarrhea. But the ones which we get concerned most about are side effects like heart toxicity, particularly congestive heart failure, hypertension, renal toxicity or kidney toxicity. The way this happens is the carfilzomib molecule as I was saying, it inhibits the proteasomes. And in particular, it can affect a certain cell that lines the inside of your blood vessels. These are called endothelial cells. Their normal function is to produce nitric oxide, which keeps your blood vessels open and intact. So when these cells become damaged, the nitric oxide production goes down. So they actually start collapsing and narrowing. As a result, the pressure goes up inside those blood vessels and therefore you get high blood pressure and hypertension. You can also have pulmonary toxicity in form of pneumonitis, which means inflammation of the lungs. There's also a risk for infections, particularly upper respiratory tract infections. There's also the risk for shingles reactivation, which is why you should be taking either acyclovir or Valtrex when you're taking chyprolis. And lastly, tumor lysis syndrome, which I talked about briefly previously, which is where the chyprolis kills your myeloma cell. The myeloma cell releases certain toxins and the toxins can go and damage your kidneys, which is why we ask you to stay well hydrated and we give you a lot of fluids while you're getting the drug. Next slide. So chyprolis or carfilzomib is one of the most effective treatments we have for myeloma, and it's approved as a part of three-drug combination in the relapse setting. It can also be considered in patients with newly diagnosed multiple myeloma. The risk for neuropathy is significantly less with carfilzomib, and this is a major issue with Velcade, which I didn't talk about. But back in the early 2000s when Velcade found that it was a very complicated drug, and then Velcade first came into practice, it used to be given as an intravenous formulation and that caused a lot of side effects with the neuropathy. And then we learned that we can mitigate this issue by giving it as a subcutaneous shot. But despite that, the risk still persisted. But with the discovery or rather the manufacturing of this new molecule, the risk for neuropathy has gone down significantly. It's virtually non-existent, but there is some risk for cardiac toxicity, although the risk is very small, and this needs to be monitored very carefully. Next slide. Any questions with that? I think I've completed my talk, and I'll be open to any questions. Thank you so much for your presentation. I loved it. I especially loved the slide with the chronological clinical trials that Kyprolis was tested in because you hear often about how it makes its way from phase one clinical trials all the way to clinic approval, but it was fascinating to see how it was combined with different things, how successful it was. So I appreciate you including that slide in your presentation. We're getting questions, which is exciting. If you are new to Zoom webinar, you click our faces, or let me stop sharing the screen so you can see our faces even more clearly, and then click the Q&A and submit your questions there. One of my questions for you, Dr. Parmar, you mentioned high risk characteristics that did better with carfilzomib versus bortizomib. Can you remind me what those high risk cytogenetics are? So the Endurance trial was not really designed to look at high risk patients, but they included certain high risk genetic changes in the trial, and those were deletion of 1p and gain of 1q. So that particular subgroup on retrospective analysis, and there are lots of issues when you perform such studies, showed that the KRD arm did a little better compared to the VRD. That's fascinating. Thank you for that, especially because those high risk patients are kind of limited in their options or in the research that what does work better for them. So thank you for sharing that. One of the attendees here today is asking, do any of your patients suffer taste disturbances from Kyprolis plus dexamethasone? So the taste issue doesn't really, I wouldn't think about Kyprolis causing that problem, but the steroids can sometimes cause these issues with the taste. So yeah, but in IMIDS, particularly Revlimid, also I've seen patients have had issues with taste changes. So these two drugs can do it. Usually, if you cut down the dose of the dexamethasone, that can help you with that issue. But then, as I was saying, dexamethasone is an integral part of the combination with all the other drugs. So if your myeloma is in remission, then you can cut down on the dexamethasone. If not, I would probably try to push through, particularly if taste is the only side effect. Awesome. Thank you. Geraldine is wondering, what is the difference between a 30 minute infusion and a 60 minute infusion of Kyprolis? And how is the decision made to choose one over the other? So, you know, again, it comes to tolerability. Usually, here at our practice, we do it over a span of 30 minutes. But I think the initial infusions, we try to do them a little slower. So your initial infusion would be 60 minutes to make sure you're able to tolerate the infusion well. And if that happens, then we can cut down the duration to 30 minutes subsequently. Okay, thank you for that. One of the other questions that I had was, do you currently prescribe DERA plus Kyprolis plus dexamethasone to relapse refractory patients? Because it seemed extremely successful. Yes, I actually do that quite often. And I try to do this for patients who've had aggressive relapses, which means, you know, post transplant, they've had a nice response. But then sometimes their myeloma comes back very rapidly. So their M-spike starts to jump or their light chains and other proteins start to jump up very rapidly. And anecdotally speaking, in my experience, when I've used this combination, I get a very nice and quick response. So this becomes particularly an issue when we talk about things like gastrofibromatitis, or if you have a mass which is compressing on the spine or other essential organs. So myeloma can manifest as a plasma cytoma, which is, you know, a mass of myeloma cells. So in order to rapidly decrease the size of the mass or rapidly reverse gastrofibromatitis, you know, gastrofibromatitis means you have significant amount of light chains which are causing damage to your kidneys. So you really need to jump on it right away and try to reverse that as quickly as possible. So in such cases, combination of data, paraphils and Vandex seems to be very helpful because it achieves disease control very rapidly. Right, right. And just fascinating about the, they didn't even reach progressive or progression. Right, PFS. PFS was not reached, right. Yeah. That's fascinating. Is the risk of toxicities, particularly cardiac toxicity, gone once a patient has completed Kyprolis therapy? So once you are off Kyprolis therapy, it should not cause any significant cardiac issues. What we know from the dosing studies, and there was one particular study which looked at the endothelial cell dysfunction by measuring the flow of blood through brachial vessels. So these are the vessels in your arms. And they found that the effect of that endothelial dysfunction lasts until a certain period of time. And right before your second dose, that endothelial dysfunction issue, you know, doesn't happen anymore. So your cells recover by the time you get your second infusion. So if you're off Kyprolis, then the risk shouldn't be there, theoretically speaking. Okay. Thank you. Yeah. Theoretically speaking, and again, always talk to your treating physician. That is correct. Yeah. You know, if you are talking about Kyprolis and, you know, in combination with Revlimid, there is always a risk for blood clots, which goes up quite significantly. So you have to keep that in mind as well. So more than the heart disease, more than the heart, you know, things like blood clots in the legs, which may travel to the lungs, you have to be mindful of that. Yeah. Which is why we put you on aspirin or other blood thinners, like Xarelto as well. One of the attendees is wondering, are you seeing any cases of severe decrease in urinary output for a day or so post-treatment? Is this one of the side effects that you see? So, you know, one of the issues that you have to keep in mind when we talk about Kyprolis and I didn't put that in my slide, it's called thrombotic microangiopathy, which can, you know, which means your red cells can break up and they form small cells which can clog up different blood vessels and that can cause issues like kidney problems. So I don't know if there is any evidence of renal insufficiency or the creatinine going up, if that is causing problems with decreased urine production and therefore you decrease urinary output. If that's the case, I think you should be the physician, you know, we should be checking for this condition and we can actually look for it by running certain tests like tumor lysis labs like LDH, haptoglobin, particularly if the patient becomes anemic and the hemoglobin drops. So I think that's important to keep in mind. Thank you for that. And again, something to bring up with the doctor. Okay, so this patient is saying, I'll try to reword it so that it's more of a general question than a personal question, but they were on Dera, it didn't work for them. They are now on carfilzomib, cytoxin and dex, but it's experiencing a lot of side effects. Are they, what if you, what if you, the basic question is, are they able to go back and take DeraTumumab if it didn't work before in a different combination? Are you able to use it, whoever, are they able to use it in a new combination with different drugs if you were, if it didn't work before in a different combination? Does that make sense? Yes, yes. So, you know, I think it's important to identify the culprit here. So if the patients on carfilzomib, cytoxin, dex, it's important to know what sort of side effects they're getting and then attribute it to one of the drugs. Because, you know, if you're on these three drugs, you can always switch the cytoxin for an immunomodulatory drug like Revlimid or Parmalist. You can always certainly consider switching the cytoxin out and using the DeraTumumab, that combination can be effective as well. And again, if you have a translocation 11-14, or if you have BCL2 positivity on your bone marrow biopsy, and I think this is something that would be a discussion with the treating physician, then Venetoclax is also a consideration. And, you know, with Kyprolis and Nexamethasone, this particular combination is not yet listed in NCCN, so some of the insurance companies may give us a hard time getting this combination, but I expect that they're going to include it within the next few months on the basis of the study which was just published two months ago. There are various other options that can be looked at for sure. Okay, thank you for that. Cindy's wondering, with the cardiac risks, if a patient has AFib and of course is on proper treatment, would this render them not a good candidate for Kyprolis? So, no, I don't think that would be, you know, an exclusionary criteria for me to put that patient on Kyprolis. If the AFib is well controlled and if the patient is anticoagulated, then you can certainly consider the use of Carpolizumab. One consideration though is that you have to be sure that the patient doesn't have any heart failure. So, if you don't have any heart failure, then I'm okay. So, if your rejection fraction is adequate, say if it's over 50%, then I would be comfortable putting you on the Carpolizumab. But if it's less than 50%, I personally am a little hesitant, although we know from certain studies that even if your EF is low, if you get this drug, it doesn't necessarily mean that you're going to go into heart failure. There are a certain group of people who do end up doing that, but there are others who don't. But regardless, it's important to get a baseline echocardiogram to see how your cardiac status is before you start the Kyprolis because that way if you develop symptoms like shortness of breath or lightheadedness, then you're concerned about cardiac toxicity and, you know, at that point you get an echocardiogram and you want to see that change in the ejection fraction or the functionality of the heart. So, if you don't have a good baseline study, it's hard to know if there has been a change in the cardiac status. Yeah, thank you. Beth was wondering, are you aware of what the progression-free survival of Kyprolis dex and cyclophosphamide is? You mentioned it in your talk, but she didn't catch the progression-free survival. So, I want to say it was 26 months. Yeah, 26 months. Okay, thank you. This is interesting. One of our patients today is in the ICMA study in Spain, and they are wondering what is the most common pre-medication before having the treatment. And then they have a follow-up question, but let's go with that question first. What is the most common pre-medication before having the treatment? What is the most common, I'm sorry, treatment? Pre-medication before having Kyprolis. So, personally, I haven't used isotoxamab as much as daratumumab, but, you know, both are monoclonal antibodies with a risk for hypersensitivity reactions. So, for that, we typically use things like Benadryl, Pepsid, which is famotidine, and Tylenol. So, this is the hypersensitivity risk is high only in the first few doses, but with time, if you don't develop any of hypersensitivity issues, you can actually cut back. And after cycle one, I just stick with Tylenol. I don't give my patients Benadryl or Pepsid anymore after that. Okay. And- For the isotoxamab, I would probably have a similar approach, but personally, I haven't really used this drug as much. So, I won't be able to comment specifically for isotoxamab. Okay. Perfect. Are you aware of the Ikema study in Spain? Yes. Okay. They would like to know if you're seeing different results since the study's been given to more, like a large amount of people. Are we seeing different results? So, the results are similar to the study, which is the Candor study. The response rates, I believe, were close to 85 to 90%, which is what we've seen with the Candor too. That was about 84%. So, it's roughly the same. But I think what would be interesting to see is that if patients with high risk benefit with the Ikema study, because in our experience, when it comes to diatomamab, particularly in our newly diagnosed patients, we haven't seen significant benefit for the high risk ones. So, I'll be curious to see if there's any benefit for high risk populations. I think even with the use of isotoxamab in newly diagnosed setting, we haven't seen any improvement for the high risk patients. Except for I think translocation 1416, I believe the isotoxamab had some benefit over diatomamab. But again, they weren't compared head to head, but looking at the trial data, isotoxamab seemed to do better. Interesting. I think that's interesting too, when we're studying clinical trials that, okay, this wasn't our end game, but we're able to derive certain information from this. So, that's encouraging. Sheila is wondering, she's been on Kypolis for 17 months, is in complete remission. And you had mentioned earlier that in some cases, you are able to reduce the dexamethasone. How much of a reduction are we talking when somebody is using it as part of their high risk maintenance therapy? Right. So, that's a great question. So, yes, if you are in remission and if you are on 40 of dexamethasone, then there is certainly room to cut down from 40 to 20 milligrams, particularly if your side effects are very bothersome. If you're on 20, you can always cut down to 12 or 8 milligrams. But try to keep the dex as much as possible, because in my experience, if you completely get rid of the dex and if you just get the Kypolis by itself, a lot of my patients get a lot of side effects from the Kypolis. So, things like shortness of breath and whatnot. So, if I give them dex with that, that side effect issue goes away. And on top of that, dexamethasone by itself is quite active against myeloma. And when you combine dexamethasone with Kypolis, you get significant activity. And we know that from our experience in the trials as well. Yeah, it's kind of a catch-22, because which side effect would you rather have? It's a balance. If your myeloma is in remission, I would say you can try. I would be open to cutting down the dose of the dexamethasone, particularly if it's very high dose, like 40 milligrams. All right. One of Stephen's questions, he wants to know, he is in MRD remission. He's getting tested quite frequently because of the different high-risk characteristics of his disease. He's wondering, are there physiological symptoms that could indicate relapse, or is it always paying attention to those labs? So, occasionally, your myeloma can lose its ability to produce protein. So, when we talk about, say, biochemically looking at your blood, looking at your M-spike and night chains, majority of the times we pick it up if your myeloma is coming back or not. But if your myeloma doesn't produce these proteins, we may miss it if we don't do a full, thorough workup, and that includes a full body scan or a bone marrow biopsy. But if you're getting a bone marrow biopsy and if it shows that you are MRD negative, and if your blood also shows your M-spike is undetectable, your night chains are normal, then that's reassuring. But if you'd get symptoms like back pain or bony aches or pains, particularly focal areas of pain, I think that needs to be watched for and that needs to be imaged to see if there is any growth in terms of a plasma cytoma or a focal area of myeloma involvement. Yeah, that actually happened to a patient that I love. She was not feeling well, but her labs were indicating that she had a relapse, and it turned out that her M-protein became undetectable. She was actually experiencing relapse, so not common, but something to be aware of. Yeah, thank you for bringing that up. We have an attendee that I'll summarize their experience. They were taking Kyprolis for several years and they continued to lower the dose until it seemed the lowest you could get, basically, and then they relapsed on their labs. They tried different treatments. It wasn't working, so they went back to that Kyprolis and it put them in astringent remission. Did she ever ever technically relapse or was it just ... Do you understand? If the numbers indicate, and there are certain criteria that we go by, as you said, by the IMW group, if your light chains go up, say the difference between the light chain is over 100 from your best response or M-spike absolute increase is over a certain value, it's 0.5, then yes, that is a disease relapse. But anecdotally speaking, I've seen a similar situation where we cut down the dosing on the Kyprolis and then the patient's numbers started going up, so we re-challenged her with the higher dose of the Kyprolis and we were able to control the disease. How interesting. Wow. That's fascinating. You study amniocentesis as part of your career. Does the additional diagnosis of that call for a specific combination for better efficacy? What do you do with those patients who have that in addition to their multiple myeloma? Right. Yeah, that is a great question. With the amyloids, we have to be careful in terms of our satisfaction with the depth of response that they achieve. With amyloid, you really want to maximize the response. You want to get as deep of a response as possible because with amyloid, what happens is you have these circulating light chains and they undergo certain structural changes and that forms amyloid and the amyloid starts depositing in various organs and that includes commonly the heart, the kidneys, or even the nerves and once the amyloid sets in, it becomes very hard to reverse. So even if you get your myeloma under control and those amyloid producing cells under control, the amyloid which is already deposited may not go away right away or it may not just go away ever. So you will end up with certain degree of dysfunction always. So the idea here is to make sure that there are no abnormal light chains circulating in the blood because if that happens, those light chains are going to form amyloid and that's going to start depositing and worsen the organ failure and that's the heart and the kidneys which are essential organs. So we have to try to get as deep of a response to make sure that the light chains are normalized. Having said that, if the myeloma or amyloid becomes refractory to the treatments that we do, there are certain drugs like venetoclax which are very effective particularly in amyloid. So about 50% of patients with amyloid have translocation 1114 and that enables us to use venetoclax which is quite effective and we can actually achieve a complete hematological response. So normalization of light chains when we add to end that drug. So yeah I think it's important to obtain a CR, hematological CR when we talk about amyloid. So yeah I would encourage the use of venetoclax or any other drug if possible to get a complete response rather than stay in partial response or less than that. Okay thank you for that. In addition to that, Ivan is wondering if there are any studies on deletion 17 high risk that you are aware of and treatments you recommend in this case? So not that I'm aware of but we have two studies which is looking at the use of the CAR T cells in the upfront setting for high risk patients and at our center unfortunately those studies have closed. We have accrued patients but these studies looked at the use of CAR T in place of transplant for newly diagnosed ones. So particularly the ones with 17B deletion for 14 or 1416. So the high risk myelomorphish patients. Great thank you. Sandy is wondering if you can do a general definition of high risk for those that are unaware of what that is. Right so the high risk you know we there are three different staging system. There is the RISS, the ISS and then of course you have the high risk fish changes or the myelomorphish changes. So the RISS defines the high risk fish as certain genetic changes that includes the 17B deletion, translocation 414, and translocation 1416. And then we have identified gain of 1q as another high risk change in terms of your genetics. So this constitutes high risk myeloma. And then depending on the trial if they are conducting a high risk trial they like to include ISS stage 3 which means if your beta 2 microglobulin is over a certain limit then you become high risk in combination with albumin. And with the revised ISS you're looking at the fish as well on top of those variables. Awesome thank you and we can send more resources about that in the follow-up email that we send with all of our resources. We can give like a general definition of what is considered high risk. So thank you for taking the time to do that. And then Bruce is wondering the progression free survival on carfilzomibdex and Revlimid. Do we have that information? For in the relapse setting yes. It was the BFS was I had 26 months with the use of carfilzomib Revlimiddex compared to the Revlimiddex alone. Perfect thank you. One of the questions that I had as well is does prolonged use of Kyprolis run a risk of secondary cancers like Revlimid does? So not to my knowledge but I have to look into the literature and the latest data but as far as I know I have not I'm not aware of any secondary risk for the use of secondary malignancy risk. Wow this was such a great presentation I appreciate it so much. I appreciate your time in preparing and the questions were wonderful. So thank you again for taking the time. I'm going to finish up with just a couple of outro introductions. Do you have any closing statements before we finish? No I was I just wanted to thank you and the Milo Maitri and all of our attendees here today for having me and I'm happy to take any questions offline. I can send you my email if you have any questions I'll be happy to answer them. Okay perfect thank you so much Dr. Pramar. Thank you. Okay so to finish up today we just would like to invite you to join us next month in March as we continue learning about myeloma medicines. Next month we will be discussing how the use of daratumab commercially known as Darzalex has a role in treating high-risk myeloma patients so that's a little something that we talked about today but we'll continue that conversation in next month. We're still figuring out the speaker and the time but more details will be published shortly about this event and we look forward to seeing you there. You might be interested in other myeloma crowd community events that we have coming up on the 25th at 7 p.m eastern is the M. gas smoldering myeloma patients chapter. We will be hearing from Dr. Irvi Shah who has been studying the relationship between myeloma progression and diet. We will also hear from one of the patients in her study and hear what his experience has been like. On the 26th at 1 p.m eastern is our nutrition and wellness for myeloma chapter. We will be discussing how to navigate neuropathy through nutrition. This is a topic that many medical professionals don't talk about involving a debilitating side effect. Hear what we do know and come with your questions. And finally on the 27th will be our African-American myeloma community chapter. We will be discussing fitness tips for your winter exercise reboot with fitness expert Vanya. Willing to sign up for any of those events and even more events we have a lot of events on our site that I have not mentioned today is found at the bottom of the slide and will be sent out in the follow-up email within 48 hours of the event's conclusion. Another thank you to our sponsors Bristol Myers Squibb, Amgen Oncology, Genentech, Adaptive Biotechnology, Sanofi, Janssen Oncology, Karyo Pharm Therapeutics, Takeda Oncology, and Abby. And thank you to each of you. You had amazing questions today, great participation. Thank you for helping us build a strong myeloma crowd community. I appreciate you and hope that you have a great rest of your day. Thanks so much. And yes, I thank you Cindy. I said March. Next month is February. It's in February. We'll get that corrected before we go. Thank you so much everyone. Take care.