Torben Plesner, MD Vejle Hospital, Denmark Interview Date: September 28, 2016
Dr. Plesner was involved in the earliest work on daratumumab (Darzalex). He describes the story of its beginnings and the slow start to ensure maximum safety in early clinical trials. Dr. Plesner shares tips about using daratumumab in the clinic and a new finding that daratumumab can eliminate regulatory cells that are putting the brakes on the immune system, freeing them up to do their job. This may be why daratumumab aids in longer-term responses. He suggests that dexamethasone is a good daratumumab companion to reduce infusion-related reactions. Dr. Plesner shares how daratumumb can affect the loss of blood typing while patients are on the drug and how daratumumab can also can affect monitoring of a patients' level of disease. Doctors and patients must be aware that it can appear as if there is residual disease when there may not be. He shares his thoughts about the best possible combinations and uses of this new drug.
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Jenny: Thank you for joining us on today’s show on Myeloma Crowd Radio, I’m your host, Jenny Ahlstrom. It’s blood cancer awareness month and there is much you can do to help spread awareness for myeloma. You can share articles and information from the Myeloma Crowd website and you can invite your friends and family to donate to research. The Myeloma Crowd Research Initiative is funding two therapy research projects that are cutting edge to help all myeloma patients - but especially those with high risk. You can take a look at the research initiative on the Myeloma Crowd site and share with your friends and family during blood cancer awareness month. We’d like to thank our sponsor Takeda Oncology for their support of the show and we’d like to thank all listeners for getting up so early to be able to listen to a renowned myeloma specialist Dr. Torben Plesner who joins us from Denmark, which is the reason for the early hour of this show. So Dr. Plesner welcome to the show. Dr. Plesner: Thank you very much for inviting me, it’s a great pleasure to be with you. Jenny: Well thank you so much for joining us. Let me give a brief introduction for you before we get started and then we can launch in with our questions for you today. Dr. Torben Plesner is Professor and head of the Department of Hematology at the Vejle Hospital in Denmark. He is the founder of the Clinical Research unit at the hospital and participates on the council, board, committee and networks for the European Hematology Association and the European Myeloma Network. He is on the council and board of both the American Society of Clinical Oncology, or ASCO, and the American Society of Hematology, ASH. He has helped evaluate research and early clinical trials for daratumumab and you are really the point person for daratumumab and its very inception so we are thrilled to have you as the daratumumab expert. So maybe you want to give us just a little bit of background about how you got involved in working with daratumumab and its early progress and where we are today. Dr. Plesner: You know I think I’ve been very lucky to get involved in this field. Way back, I met people from the small Danish company, Genemab, I developed 20 antibodies for lymphoma and CLL and I signed with them and conducted clinical trials of the CD20 antibodies and they were pleased with the quality we provided during the trial and then they had developed this interesting new antibody, the CD38 antibody which is now known at daratumumab. It was in those very early days back in 2007 where they approached me with this idea of using CD38 antibodies and I must say I warned them against this idea because I thought this would potentially be dangerous. The reason being that the CD38 molecule is very widely expressed in the human body, I don’t think you can mention any cell in the body that doesn’t have CD38 on it so you could enact all sorts of dynamic spiking an antibody to CD38 to a patient. For instance, the central nervous system, the heart, the muscles, lots of cells in the body, the hematopoietic cells, the platelets, red blood cells, white blood cells, they all have CD38 so we were really interested about this idea by Genemab but they had pre-medical data from their lab in Holland where they showed very high killing activity by this antibody. They wanted to move ahead so we decided on a very careful Phase I program of the antibody where the antibody was applied for the first patient in extremely low doses as close as you could get to pure water as you can imagine and the patients were observed very carefully, they were dosed once and observed for three weeks to see if there were any signals of side effects and then they had the second dose and then we could continue on the weekly dosing as we do now but only after some period of observation we were allowed to take the next patient into the trial so we were confidant there was nothing bad happening for the first patient. And then the second came in and after a while the third but it was really, really slow progress because we had this safety issue over our heads so we had to be moving very, very carefully and we did that but gradually we could gain confidence that at least at lower dosing it was not harmful so we could gradually increase the dose of the antibody and still there was no signal of activity because we were still working at very low doses and people were losing their spirits because nothing really was happening to the patients, no harm but also no sign of activity until we passed two milligrams per kilo of body weight, after this dose level and onwards up to four, eight, and sixteen, we started to see signals of anti-myeloma activity by the dosing of this antibody and as soon as that happened the scene changed totally from this feeling of having an antibody that could be harmful and is probably not efficient and everybody could see that this was something that could be really big. And the work was speeded up and included the dose of the single agent antibody which was used in the first trial daratumumab alone with nothing else and then adding dexamethasone to address infusion-related reactions. About this time point around two milligrams per kilo we planned on a combination study because it was evident that one single agent, one single drug will not of its own be able to do something lasting for myeloma so we had to think about combinations and the first combination was combination of daratumumab, lenalidomide and dexamethasone. The reason being that the preclinical data from the experiment that Genemab has in Holland showed the synergy between daratumumab and lenalidomide. So that was the first partner to combine with. The second one we were thinking about was bortezomib and which has now been taken through Phase I, Phase II and Phase III trials. The combinations have been used in refractory multiple myeloma and these combinations have been explored in the newly diagnosed setting being diagnosed with other patients. It has been a long but very, very rewarding trial run of daratumumab. And I must say that we had these very, very solid preclinical data and ideas coming from Genemab and I must also say that they are experts in producing antibodies, they produce antibodies of extremely high quality and they are fully human, so it’s not humanized, it’s fully human from the starting point. But this is a small Danish/Dutch company they don’t have the muscles to take a drug into Phase III clinical testing. It takes a lot of financial background, structure, to do the clinical trials, so they partnered with Janssen and that has been a great, great partner in this development. Janssen is strong, they have expertise in myeloma, they are a very open and academic pharma company. They are really listening to innovators, listening to observations, listening to new ideas and interacting with us in a very open manner so we have been able to make very significant progress due to this partnership between pharma, academia and the clinical setting. As you may know, preclinical studies have shown that daratumumab can kill myeloma cells together with complement (cytolytic serum factors), with natural killer cells ADCC (Antibody-dependent cell-mediated cytotoxicity) and by antibody-mediated phagocytosis where myeloma cells are eaten and destroyed by macrophages, - in all three cases by binding to the CD38 molecule on myeloma cells and activating these various mechanisms of killing. But one very important, very recent observation is that daratumumab eliminates some regulatory cells that put the brake on the immune system So these regulatory cells, they are eliminated because they also express CD38 and thus we release a break that is holding back cytotoxic T cells. So what we see in patients treated with daratumumab is an increased number of cytotoxic T cells and they are expanding with what we call clonal spikes. We can see they are really active and they are going out into the hunting fields so to speak and we think they are anti-myeloma T cells. We believe that this activity may explain why we have long-lasting disease control with daratumumab treatments so this is a very important new observation just recently published in Blood coming from a very strong collaboration between Janssen as a pharma company and academia. Jenny: Well to me this is just a perfect example of the process from inception, I mean you said it was from back in 2007 and we’re in 2016 so it takes a long time to go through that process, that discovery process and the testing process and the validation and the clinical trials and you’ve used this drug as a single agent and in combination so it takes time and the partnership handoff. Dr. Plesner: And rewarding trials. Jenny: Amazing, it’s completely amazing but this is why it takes a long time because you have to be careful and you obviously have been. Dr. Plesner: When we embark on new clinical trials, patient safety is always the first concern so you cannot do harm, you must be sure that you’re not doing harm. Jenny: And I think a lot of times by the time you enter clinical trials you have a pretty good idea, don’t you, of it being effective? Dr. Plesner: I think the first patients that went into the first trials, Phase I of daratumumab were extremely brave because they were told that we were dosing at extremely low doses so it would probably not be efficient, could potentially be dangerous, possibly very dangerous, but they accepted anyway. So going through the trial, to let us dose them, and pave the way for other patients that could benefit from this treatment. So we are standing on the shoulders of many, many idealistic patients who really got themselves involved in this trial or set of trials and paved the way for the progress we are seeing now. Jenny: Amazing, it’s amazing, the effort that it takes both from the scientists and the pharma companies and the patients too to be able to join. So let’s talk a little bit about the combinations. You mentioned the combination of lenalidomide and dexamenthasone with daratumumab, I’ve heard other doctors say, that lenalidomide has an immune system-boosting effect and then I’ve also doctors say that dexmanethasone has an immune system repression effect, so can you talk about the effect on the immune system with daratumumab combined with lenalidomide and dexamenthasone? Dr. Plesner: I’d be happy to. There’s been a lot of worries about the possible antagonistic effects of giving dexamethasone when you want to use an antibody and immune mechanisms that complement to kill myeloma cells. You would think that dexamethasone would be not good but on the other hand for infusion related reactions – when you give an antibody you need to give steroids – dexamethasone or prednisone or some other steroids to cope with these reactions to the infusion. So you cannot completely avoid the steroid. Singular dara needs some steroid so you can’t get rid of it. Actually, we have no signal that it has been harmful. And on the other hand if you look at the combinations of lenalidomide and dexamethasone or bortezomib and dexamethasone, when you add dexamethasone, to lenalidomide or bortezomib, then you have a doubling of response rates. So dexamethasone and the other steroids are really efficient anti-myeloma agents by themselves. It could depend on the dose level, but they are really anti-myeloma agents and can contribute very significantly to the killing of myeloma cells. So you have two initial effects of the steroids – you are to have the control of the infusion related reactions and you have the anti-myeloma effects that contributing to what you achieve with daratumumab and lenalidomide or bortezomib. Jenny: That’s so interesting because I know a lot of patients would like to get rid of dexamenthasone, but every time we ask that question it’s so effective it’s not really a good idea eliminate it. Dr. Plesner: What I do in clinical practice is that I start out with what we call the full dose of dexamethasone to achieve a response. So if I have a good clinical response, I would start listening more to the side effects the patient is complaining about so we start out with full dose and then we can negotiate an amount. I actually have patients now who started out on the combination of daratmumab, lenalidomide and dexamethsone and are in stringent CR (complete response) and after two years they start complaining about side effects coming from lenalidomide and dexamenthasone, so I take them off of that and I just give them daratmumab and a little steroid for the infusion. So that’s possible, but you should achieve a good response, good disease control before you release the speed. Keep going with the full program then have a response and then you can negotiate. Jenny: Well that’s a really good point that you’re making is that when you’re on treatment of any kind, you can talk to your doctor about dosing at all times to see if there’s any flexibility in what you can ask them to do if you’re having major side effects so I think that’s a key point you’re making. Another question is, what other combinations is daratumumab being considered in, especially now that checkpoint inhibitors are coming out and things like that. What other types of strategies are you considering? Dr. Plesner: Actually we have a clinical trial coming up now sponsored by Celgene where they are planning to combine daratumumab with durvalumab, an anti-PDL1 antibody and if the patients don’t respond to the daratumumab and durvalumab treatment in combination, then we must add pomalidomide to the combination. You should be aware of the fact that the activity of these antibodies are completely different. We know that daratumumab can kill the myeloma cells via activation of complement and by interacting with natural killer cells or macrophages but recently it was also found that daratumumab can also release a brake which has been imposed on the immune system by the myeloma cells. The brake consists of so called regulatory cells that inhibit the growth and activity of cytotoxic T-lymphocytes. When the brake is released by treatment with daratumumab the cytotoxic T-lymphocytes grow and become active and we think that this reactivation of the immune system is important for the long-term disease control seen during treatment with daratumumab. The checkpoint inhibitors are a group of antibodies that can inactivate a protective shield around the myeloma cells by binding to either the PD-1 molecule on cytotoxic T-lymphocytes or the PD-L1 molecule on myeloma cells. When either the PD-1 or PD-L1 are covered by antibody the myeloma cells can no longer kill approaching cytotoxic T-lymphocytes but are killed themselves by the T-lymphocytes. Thus by both releasing a brake on the T-lymphocytes with daratumumab and protecting the T-lymphocytes from being killed when they approach the myeloma cells the myeloma cells may be effectively eradicated. The feasibility of treating patients on the same time with two different antibodies, daratumumab and anti-PD-1 or PD-L1 is now being explored in clinical trials. So the myeloma cell has a shield around itself where it can kill T cells that approach it and this part of the mechanism is eliminated by the checkpoint inhibitor process and the anti PDL-1, anti-myeloma antibody. So you have by daratmumab a release of the brake of the immune system so the T cells can expand and approach the myeloma cells and then you protect the T cells from being killed by the myeloma cells with the checkpoint inhibitor antibody. So in theory, the combination of a checkpoint inhibitor and daratmumab could really be interesting. It’s currently in clinical trials. So for other combinations I think pomalidomide would be evident as a partner for daratmumab, a very effective proteasome inhibitor, carfilzomb, may be an interesting partner for daratmumab. We need to see the safety of this combinations. But if you think about how the survival has improved for myeloma patients you can imagine that in the community of medical doctors and clinical sciences the lives patients are also increasing rapidly so people are starting to talk about a cure for multiple myeloma. And trials are being designed now to try to approach this situation where we can really think about curing myeloma patients and I think for trials people will think about daratmumab, carfilzomib, dexamethasone and lenalidomide and dexamerazone. Those combinations, they’ll be very strong. Jenny: And what kind of therapy? Sorry. Dr. Plesner: High dose therapy and autologous transplant. Jenny: Oh, ok. Dr. Plesner: Which is not so popular in the United States anymore but still it has not been beaten in the younger patients by the novel agents. In Europe we still feel like for younger patients high-dose melphalan and autologous stem cell transplantation is priority treatment. Jenny: Yes, I think transplant is still a core treatment. So two questions about that, are there any clinical trials with daratumumab and carfilzomib together at this point? Dr. Plesner: I don’t know if the first patient has been enrolled, but there are very exact plans for this and I think it could probably be ongoing already. I went to the meeting with the European Myelom Network over the weekend and we were presented a very specific plan for a trial for the younger patients and we chose that for them and there will likely be another trail coming soon. I know that the Spanish myeloma group are very active and they have been planning on this with several companies for awhile so it could be ongoing now. So, very, very soon. Jenny: OK well we’ll look into it because we’ve partnered with a clinical trial finder called Spark Cures and it helps myeloma patients in the United States find clinical trials easier because it’s in plain language and simplified for people to be able to find and join clinical trials and I think one of the reasons we started this show was to advocate participation in clinical trials because if we have patients who want to get to conclusions faster that’s a great way to help people like you do that. So we will post a link to that if we can find one that’s open. When would be the best time to use daratumumab with transplant? As induction therapy or after the transplant or…? Dr. Plesner: In the plans I’ve seen, it would be used as part of the induction treatment such as dara, carfilzomib, lenalidomide, dexamethsone for four courses followed by high-dose melphalan and then consolidation similar to induction with four courses of dara, carfilzomib, len, dex and then for maintenance either dara alone or dara and lenalidomide. I think that would be an extremely strong combination. Jenny: And let’s talk about maintenance therapy for a minute since you mentioned it. So, you were saying daratmumab could be used as a single agent maintenance therapy, I know a lot of times Revlimid is used as therapy so would you combine those two and maybe do a doublet for maintenance therapy as a strategy? Dr. Plesner: I think the combination of daratmumab and lenalidomide is an extremely strong combination and I think if you imagine that you have patients that have passed induction therapy, high-dose therapy and consolidation entering into maintenance then my best advice, from what I know, it needs to be explored in trials of course, but my advice would be to give dara, len, dex for two years. And then stop len/dex and continue with dara.It needs to be proven through clinical trials, but I think that arm would be the winner. Jenny: That would be your betting guess and as an expert in daratmumab that would be a pretty good guess. I know clinical trials validate all of that but that’s great to understand and hear. And I know when all those new drugs were approved last November and daratmumabmab was includedthat in November of 2015 it became a little more challenging for myeloma experts to know what to use and in what order, what timing and what dose and what combination so that’s a great suggestion. Let’s talk about daratmumabmab also in smoldering myeloma. What do you suggest and how is it being tested in clinical trials in smoldering myeloma? Dr. Plesner: I think smoldering myeloma is very difficult category of patients to deal with and very challenging to run clinical trials on because you have to be extremely careful about your definition of the trial population to be able afterwards be able to separate to the general population and give advice about who should be treated and who will not benefit from treatment so my feeling is that this field of smoldering myeloma is a very difficult one but that being said, a lot of work has been done recently to try to identify patients with smoldering myeloma who are in high-risk of progression to actual myeloma. And there has been a desire to avoid this progression by treating early, so we could potentially benefit from early treatment but it’s still a bit uncertain and we’re still working on clinical trials to show who to treat and who not to treat. Our patients with smoldering myeloma that have not just been treated for just followed for ten years or more are doing fine and not in treatment and some are progressing in a few months, so it’s really a difficult field to approach with a trial because the way you select the patients for treatment or the control arm, no treatment, that will determine the outcome of the trial. Well, one side of the assay we are very interested in now to determine the risk of progression from smoldering myeloma to active myeloma is diffusion-weighted MRI. I think this is a technology that carries promise for the future. We still need to learn more about the information we get from this type of technology but we do it for patients with smoldering myeloma at the time of diagnosis and the consensus is that if there is more than one lesion in the bone marrow then you should treat but even those that made these recommendations, I don’t think they do it in clinical practice but they follow the patients and they repeat the MRI and if there are new focal lesions coming in the bone marrow, if there’s a progression in the bone marrow then they will start treating the patients. You need to see some sort of development in the situation before you jump to treatment if we are outside of clinical trials. Jenny: So another question that I have is when you use daratmumabmab I know there are certain things that patients need to be aware of and I know a lot of patients are now aware of the longer treatment times of the first few infusions and then that tapers off and the reactions that you were talking about that were calmed down by some of the steroids at the very beginning of infusions and not further infusions, but there’s also a blood type loss. Maybe you want to talk about that and what patients need to think about when they start daratmumabmab. Dr. Plesner: Yes you have that problem with daratmumabmab which is coming from the fact that it’s a small amount of C38 which binds to the red blood cells. You have daratumumab which is a human antibody molecule of IgG type binding to the red blood cells in very small amounts. It doesn’t cause any harm. If it was found in great amounts you will see destruction of the red blood cells, you would see development of immune and other problems, but that’s not what you’re seeing you’re just seeing this subtle binding of the antibody to the red blood cells but that very subtle binding can cause confusion when the blood bank is working to find the optimal blood for transfusion because they are fooled by this presence of an antibody that seems to be something irregular that precludes you from using blood product from a certain donor. So you have this seemingly incompatibility which is not a real finding but a finding caused by daratumumab. So you have to be very careful with your blood typing before you start daratmumab. Without any trace of daratumumab, you need to have your blood typing done. And you need to carry information about your blood type for future use if you are in need of blood transfusions. This problem from daratumumab will continue through the whole period of dealing with daratmumab and half a year after the treatment has been terminated, you will still have traces of daratmumab on your red blood cells that will still cause trouble for the blood bankers. But if they are informed about the fact that you are receiving daratmumab then they can circumvent the problem by certain chemical treatment on the red blood cells to get rid of the found daratmumab so they can do the typing. So it’s just a matter of being informed. The patient should be informed, the clinical doctors in care of the patient should be informed and the blood bank must be informed about this problem and how to manage it. And I know that Janssen, they’re doing a good job to really get this information disseminated and integrated into their clinical practice so this is being done and taken care of in the proper way. Jenny: So patients need to know their blood type and what you’re saying is up to six months after treatment they won’t be able to do the blood type unless they get that special blood test you were talking about. One thing that I think our website will offer is a charm or something you can attach to your keychain that you can purchase one that has your blood type on it and that’s important to keep your blood type with you. That’ll help because people forget what kind of blood type they have. Let’s also talk about daratmumabmab and disease monitoring. So I understood that it interferes with some of the tests like the SPEP test so can you talk about what it interferes with and how that works and how you get around it and I know Janssen is working on a new test to help monitor better. Dr. Plesner: I would be pleased to do that. Daratmumabmab is in essence an IgG human immunoglobulin and many myeloma patients that have an M component that is exactly of the same IgG type immunoglobulin so there is great chemical similarity between the tumor and the M-compoent of the patient’s serum about half of the patients hve an IgG type myeloma. And in this group of patients there is the potential to be a problem of defining when you have got rid of the disease because we are measuring the success of the treatment by monitoring the level of the M-component, a myeloma protein M component which we can see by serum electrophoresis and identify and measure. So what you want to see happening is that with continuous therapy you will see a gradual decline of the M-component to zero. We’d like to see it come down to zero. But if this is achieved and treated with daratumumab, you’ll still have a small amount of an IgG type antibody circulating which looks like an M-component so the doctors are fooled to think there is residual disease in the patient. We did not achieve a complete response. We have residual disease and we do not have full control over the disease. You should be aware of the fact that if you get down to very low levels of this M-protein then you need to perform a special test to see if it’s residual M-component coming from the myeloma cells and a sign of residual disease in the patient or if it’s due to the treatment and that can be done now because Janssen has developed a test where they add a reagent to the patient’s sample that interacts with daratmumab and shifts the daratmumab away from the place of the M-component. So by doing this and running this, you can see if the traces that you’re seeing in the patient’s sample are due to the M-component or due to daratmumab. If you can show that it’s daratmumab and not M-component then you need to go one step further because to formerly prove that you have achieved a CR complete response you need to take a bone marrow and show that you’ve gotten rid of all the myeloma cells. Jenny: So this is really critical. We have a smoldering patient, Dana Holmes, who has created a Facebook group that I will share a link with you later, that you might want to join because patients are just discussing their experience with this drug and some patients, they have doctors who don’t know this and they are being pulled off the drug because it looks like it’s not working. And so this is critical for patients to know that it may still look like there’s residual disease even though that M- protein level went down. So when you say you need to get a bone marrow biopsy if patients are in complete response, is that the MRD test or what specific test is that that looks at that level? Dr. Plesner: No I think we are working on a lot of MRD assessments nowadays but the definition of complete response is that by simple morphology, by looking at the bone marrow in the microscope you can see that the abnormal myeloma cells that have accumulated at the time of diagnosis have disappeared. The serum numbers or plasma cells in the bone marrow. That would be the test – simple examination of the bone marrow in the microscope. Of course you can refine the strata and that is being done now in clinical trials and also sometimes outside of trials by different methods that are being explored such as flow cytometry which has proven to be successful in many centers, but also a new technology called next generation sequencing is gaining popularity and becoming more and more used at least in clinical trials. I think it will be more and more obligatory a part of clinical trials to look for this MRD assessment, flow cytometry or next generation sequencing. Still you should be aware of the facts that when you take a bone marrow sample out to examine it by flow cytometry or next generation sequencing for in situ myeloma cells, this is a sample from one part of the body you’re taking out and you cannot exclude with certainty that there couldn’t be myeloma cells somewhere else in the body that could escape even with a very sensitive technology. So therefore people are also discussing to what extent imaging technologies should play a role in the assessment of CR (complete response) and here we are talking about a technology called diffusion-weighted MRI which could show that the bone marrow has normalized it’s appearance. People are also working on PET-CT. Many patients with myeloma have PET-positive lesions at the time of diagnosis. We want them to disappear, with treatment, so imaging technologies could give you a global view of what’s going on in the body as opposed to the local sample you are taking for MRD assessment by flow cytometry and next generation sequencing. Jenny: So what you’re saying is that people are looking at a whole body assessment instead of just looking at one factor. Dr. Plesner: We need to take all of these technologies into use to really be sure that we are doing our best to assess if this patient needs more treatment. One thought for the future could be that if you have one patient who has a normalized MRI and normalized his PET-CT, has undetectable myeloma cells by MRD assessment by flow or NGS, then perhaps after some years of maintenance therapy he could think about stopping therapy and observing if the disease showed signs of recurrence and then could start treatment again. A bit of that approach has been taken with chronic myeloid leukemia inhibitors of this kind have been given to bring the disease level to very, very low levels and then and then perhaps after some time after some years of treatment you could stop treatment and watch carefully to see if there are signs of reoccurrence. We really need to take different methods into use to assist the patient probably. Jenny: And do you have any indication - I know Janssen was working on a specific test that could be used in the clinic so the doctors could use that easier to see that the protein was either the daratmumab or the actually myeloma cells, do you know when that is anticipated to be available? Dr. Plesner: I think that Janssen has committed themselves to make this available to the community so I think doctors that are treating patients with daratmumab should approach a local representative of Janssen and ask for an address. That way they can send samples to this if they have a patient they think who could be in a complete response. They could be looking at the daratmumab in the patient sample then they should be all ready now to send a sample to a reference lab appointed by Jansen. I think that should be in play now. Jenny: OK that’s a great suggestion. Now I have one last question, I know we have a lot of caller questions and a lot of people in the daratmumab group and I’ve written their questions down in case they’re not online I can ask their questions for them, but, we read an article about ATRA possibly helping out with daratmumablab. Can you speak to that? Dr. Plesner: Oh ATRA, the ATRAa story, that investigational. It’s interesting because what has worried people of course why are some patients refractory to treatment with daratmumab and we’ll have some responding for a while but losing their response to progressive disease. So what is the mechanism behind the failure to respond and can we do something about it? The clinical research group in Amsterdam led by Niels van de Donk, Henk Lokhorst, Tuna Mutis, and Jakub Krejcik. They have discovered that ATRA which is used as treatment for a special type of leukemia, can increase the expression of CD38 on myeloma cells, so the idea is to take patients who have failed daratmumab and to treat them with a combination of ATRA and daratmumab with the hope that ATRA will increase the expression of CD38 to a level where daratmumab becomes effective. So that is being explored right now in a phase one clinical trial in Amsterdam and we will be invited to take part in the Phase II and when we can expand to a certain dose level to learn more about the activity of this combination, it’s still being confirmed. Jenny: OK, So a work in progress it sounds like. Dr. Plesner: I think so, yes. Jenny: OK well I would like to open it up for caller questions and Maureen I know you are on the phone. Anyone who would like to ask a question of Dr. Plesner and sometimes people get shy about asking him so I can ask them for you but it would be great if you asked him yourself so press one on your keypad if you would like to ask Dr. Plesner a question and if you are listening by computer you can call into 347-637-3631 and ask your question. So Maureen we will start with you, go ahead with your question. Caller: Thank you doctor. I have had myeloma for 15 years and have been resistant to thalidomide and Revlimid, they just didn’t work and I am on daratmumab, the first patient my doctor had on daratmumab. I’ve been on it for four cycles and after two cycles (I’m on it alone, nothing else besides the dex). My protein which is IgG lamba in the beta region went down 0.5 as did my IGG went down 6 or 700 but they saw a possible monoclonal antibody in the gamma region I have no gammaglobulin to speak of but in that region and the doctor has no idea what that means and I’m wondering if it could a function of the daratmumab or if I’ve developed a new clone? Dr. Plesner: It could probably be the daratmumab, it could then be IgG kappa. You said your M-protein was IgG lamba. You can discriminate between your own M-component and the dara component by the light chain. So dara would be IgG kappa and and that can be seen by the immunofixation procedure associated with the electrophoresis. So you can ask the doctor for typing of the M-component so that your own M-component would be IgG lambda and dara would be IgG kappa. So the new M-component could be dara G kappa. Caller: Dara G kappa OK, thank you very much. Jenny: Thanks so much for your question. OK our next caller, go ahead with your question. Caller: Hello doctor. Dr. Plesner: Hi. Caller: I just have a quick question which is a little bit off the subject. You know in the United States there’s a lot of usage based on the POLUX study of using dara together with pomalidomide and some dex and then there’s been some discussion of using biaxin in the combination together with the pomalidomide. Now I know you didn’t talk too much about the pomalidomide, but have you heard of that being done and do you have any opinion about it? Dr. Plesner: My expectation is that pomalidomide would also be a very effective partner for daratumumab. We have less experience with the combination of daratumumab and pomalidomide but if I had a patient with renal failure, I would prefer using pomalidomide rather than lenalidomide because pomalidomide is not dependent on the renal function, so I would definitely use the combination of dartumumab and pomalidomide but I think we need clinical information from trials – it’s less extensive. The dara plus pomalidomid plus dara/lenalidomide. I think it’s very useful that would be my expectation. Caller: Very good and the biaxin part, have you heard that discussed at all? Dr. Plesner: Yes I heard that there’s a lot of interest about clarithromycin or biaxin, what you call it. We did actually right now terminate a clinical trial prematurely here in Denmark which was a randomized trial with clarithromycin or biaxin early because we had a number of gastrointestinal infections that were assigned to the antibiotic treatment of clarithromycin. So there have been rumors and Phase II trials suggests that clarithromycin could be effective. There have been people telling us that it could be because increased the level of dexamethasone simply by giving more steroidal exposure to patients that receive clarithromycin or else have felt that it was an effect by the clarithromycin on the myeloma cells, but there has not been definitely the proof and we tried to explore that in a Phase III trial that was randomized and it and it has showed I think beyond doubt an increase of side effects in patients that received clarithromycin. Caller: And one other quick question is, this patient has been taking the dara let’s say taking it for months and their on every other week or once a month, is there any other reason to take dexamethozone on the off weeks? Dr. Plesner: No, if the patient is receiving daratmumab every second week or on a monthly basis you just give steroids when we give infusion, just to get rid of the infusion related reactions. It is not very problematic beyond the second and third infusion. We don’t see infusion related reactions, but we would still be giving steroid and antihistimine and the daratumumab, but nothing between the infusions. Caller: Thank you very much. Jenny: OK great, thank you so much for your question. So Nancy had a write-in question and she was part of the daratmumab group, her question was how long are people staying on the daratmumab after they have reached remission? Is it once a month for an X number of months or is it stopped as soon as remission is reached? Dr. Plesner: If I got your question right, the standard dose schedule is that we treat patients on a weekly basis for eight times, that’s two months, every second week for four months and then on a monthly basis until progression, so that will hopefully be several years. If I were on daratmumab as a single agent and there was signs of treatment failure, I would add in lenalidomide or pomalidomide on top of the daratmumab and continue daratmumab in combination and I would expect to see responses in a substantial number of patients. And the reason being that even if your myeloma cells are refractory to lenalidomide and pomalidomide if you have been exposed to that before and you are refractory, still that would have an effect by boosting the immune system for better collaboration with daratmumab so the effect of inhibition could be on the immune system rather than on the myeloma, but still it could benefit. Jenny: OK and so what you’re saying is it’s not over when you think it might be over, keep trying different combinations and it might activate something else. Dr. Plesner: I think that especially the combination of darautmumab and pomalidomide is very powerful. Jenny: OK, great, that’s good to know. OK, we have another question, go ahead with your question. Caller: Yes, I’m on combination with darautmumab and Revlimid and dex so I’m wondering when you get to the period where you’re just, you’re getting a monthly one are you still taking the Revlimid 21 days and one week off during that period also or does that get discontinued and you just take the dara? Dr. Plesner: I encourage my patients to stay on the combination as long as they can tolerate it. Often if you are not very young and strong you will have side effects and you’ll need to reduce the dose of lenalidomide from 25 to 15 or 10 milligrams per day but I would encourage to continue the combination of daratumumab and lenalidomide and dexamethasone if possible for a minimum of two years. You could then adjust the dose along the way but at least continue as long as you can with the combination. If you are in very good remission, stringent complete remission, after two years of the combination treatment then you could possibly stop len and dex and continue with dara alone as maintenance therapy that is what I have been doing with patients who have been on clinical trials and that seems so far to be useful. Jenny: OK, thank you so much for your question and Dr. Plesner for your answer. We have one more, a write-in question from Laurie whose husband is on daratmumab. So he was diagnosed in 2013 and had multiple treatments including a transplant, RVD, Revlimid maintenance and has since done carfilzomib, pomalidomide, dex. cyborD, and is now on dara, pom and dex. So with rising numbers he’s on once a month with pom and dex and she’s wondering if this means it’s run its course, he’s got 4;14 and deletion 13, so would you consider adding anything else? And this sort of begs the question for me, is daratmumab appropriate or have you seen in retrospective studies to be better for certain genetic features over others? Dr. Plesner: That information is being collected right now because all of these assays have been included in the recent trials such as CASTOR and POLLUX and that will be published very soon but we don’t have the published evidence now. The early trials coming established by the Genemab in the first part of the development of daratmumab did not include genetic studies such as the ones you are mentioning here. So we don’t have the information at this time but my feeling is that daratmumab would probably overcome many of the negative what is considered by our standard treatment to be a negative prognostic factor. Daratumumab is very much like a shotgun approach to get the myeloma cells. Jenny: Yes and with her question, and her husband having been on multiple therapies, would you add something different like Velcade or something that he’s previously been on in combination like you mentioned earlier? Dr. Plesner: What we know right now is that Velcade is a good partner for daratumumab. IMIDS such as lenalidomide and pomalidomide are good partners for daratumumab. What we have not explored extensively, but what is being done now is the combination of carfilzomib and daratumumab which should be a very, very potent combination but we need to learn more about safety before we go out and recommend it. Jenny: OK, we have a few more calls and questions. Go ahead with your question. Caller: Thank you doctor. I was diagnosed at 74, a pain in my hip they discovered it had to be partially removed, I had myeloma, I was put on Revlimid which I had for 20 months and then my kappa light chains moved up dramatically and so I went on to CyborD and Velcade for about 31 months which is where I am now. Now my light chains seem to be moving up again, the question is, what would be the next treatment? Would it be pomalidomide with daratumumab or daratumumab by itself or some other combination or perhaps trying to increase the potency of the Velcade? My light chains are at about 22.5, 19.4 being normal, my PET can was normal but it shows a progression, what do you think the next step would be? Dr. Plesner: I think you have several options. You have pomolidomide and dexmethasone as one option, you have carfilzomib/dexamethsone, carfilzomib/cyclophosphamide, (you’ve had lenalidomide so that’s not an option) but pomlidomide and daratumumab could be an option as well as daratmumab as single agent, so I think there are plenty of options for you. Carfilzomib is a very potent drug. Caller: So that might be the next step. Dr. Plesner: Depending on your age and situation, I think that pomalidomide is a very benign treatment and many patients are doing fine on pom/dex for a couple of years. Caller: Does it make sense to add dex to the Velcade and see if that boosts the potency? Dr. Plesner: It does make sense yes and it does for a while and after that you still have these other choices that I mentioned before. Caller: Very good, thank you doctor. Jenny: OK thank you so much for your question. Another caller, go ahead with your question. Caller: OK, I’m a smoldering patient currently on a clinical trial with daratumumab and I was on the intermediate arm which is essentially an eight week cycle followed by bi-monthly treatments. Following the eight-week cycle I was having a really pronounced response with my M spike reducing by 50% and my involved kappa being reduced by 50% and over the course of the last four to five months while on the bi-monthly infusions my M-spike is increasing as well as my kappa and I’m just curious to know is that an indication that it’s not working anymore, what is the recommendation since it is a clinical trial they can’t just introduce additional medication. Dr. Plesner: We cannot introduce anything extra than what you are doing now because you are participating in a trial, but if you are nervous about your own situation and feel that you are in any sort of danger you should tell your doctor you want to quit the trial, you have many options to go from. Caller: OK, so you would recommend just continuing with the trial even though my numbers are increasing? Dr. Plesner: Yes, to a certain extent yes. The important thing is that there is no organ damage, the CRAB criteria is you don’t have any lesions coming so you may ask your doctor to check for osteolytic lesions, anemia, no renal failure then you can stay on the trial but as soon as you see any sign or signal of these then you should stop the trial. And I should mention that CT scans are much better for detection of lytic lesions in the core part of the body such as the spine and pelvis. You see much more by CT scans compared to conventional X-ray, so if you’re going to be assured for stoping the therapy or to make sure nothing is developing please ask for a CT scan rather than an X-ray. Caller: Is there historically any potential for there being a bit of rollercoaster having the M spike increase and then with time having it reduce again? Dr. Plesner: I think if you remain on the same therapy, you may see a gradual increase of the M-component when you decide to leave the trial and our feeling is that dose increase does matter with daratumumab, so giving it on a every seond month may be too little and that means also that if you leave the trial and come back another time on commercial daratumumab, you can change the kind of treatment and have a response. Caller: Thank you so very much. Jenny: OK, thank you so much for your question. We have two more questions that we’ll take. Caller: Yes I had tandem transplants over six month ago and my numbers are creeping up now my kappa and lamba to IGG as well as the M spike so my oncologist recommended to have daratmumab single agent treatment next month. Do you have any data to show the effectiveness of this daratmumab as a single agent either as an induction or maintenance therapy after transplant? Dr. Plesner: We that even in heavily treated patients including patients that have received single or double transplant as least one third of the patients will have a response and more will have prolongation of progression free periods so you are in a good situation to choose daratumumab also because the double transplant you received was exposing you very heavily to alkalytors so you have a burden of treatment on your bone marrow. That means when you go out for something else for the treatment, you’d like to use something that is not causing any damage to the bone marrow such as daratmumab, I think it would be a good choice for you. Caller: OK, thank you so much. Jenny: OK thank you so much and our very last question and I apologize for us going over. Please our next caller quickly. Caller: Hi, good morning Dr. Plesner, thanks for taking my call, I’ll make my questions really quick, try to get to the point. I understand that the daratmumab can give false positives within the heavy chain, just the IGG, would it also increase potentially, give false positives in the kappas? Dr. Plesner: No not in the free kappa light chains, you will see a very minor addition to the IgG like .5 g/liter which is not what you are used to thinking about but it’s very low levels of IgG you see coming from daratumumab. Caller: Oh thank you that was actually going to be my next question what the actual value was. Dr. Plesner: About .5 grams per liter. Caller: OK wonderful. Dr. Plesner is there any test to test the cells for robust CD38 expression to determine if that would actually be effective? Dr. Plesner: No I don’t think you can predict if dara would be effective but you can test for CD38 expression through flow cytometry and there is a correlation between the level of expression and the responding of that but even if you don’t have high levels of expression I would recommend a clinical trial for it. Caller: OK, I know that you’ve been working with dara for a very long time and I’d like to know what is the longest time that you’ve actually seen it continue to be effective? Can some patients actually continue on it and respond long-term? Years even? Or will it eventually stop working in every patient? Dr. Plesner: We don’t know that yet. We have patients that are in stringent CR in the moment on years of treatment and if that lasts we don’t if we have cured some of them we don’t know we are continuing treatment. Caller: OK, if dara is not effective alone, which drug if a patient was refractory to let’s say the iMiDs and the proteasome inhibitors, which drug would you add back first? Is it a pattern? Would you go with the iMiDs first and if no response then either switch to a proteasome inhibitor or add a proteasome inhibitor? Is there a method to that? Dr. Plesner: I’m very impressed by the activity of carfilzomib. We have seen that patients may respond to a combination of carfilzomib and dexamethasone. If they lose their response to this combination we add in cyclophosphamide. There has been a publication from of a Phase II trial from a group in Italy adding cyclophosphamide to carfilzomib can get very nice responses. And we have seen actually patients that carfilzomib/dex response and when we add in cyclophosphamide, on a weekly basis then we see they regain their response. Caller: So that’s Cytoxan, yes? Dr. Plesner: I would add Cytoxan and yes, if that doesn’t work I would add an iMiD – lenalidomide or pomalidomide to carfilzomib and dexamethasone. Caller: OK because I have a member in my Facebook group, the dara group that actually was on dara and Kyprolis but she had to stop the Kypolis because of side effects and then her dara was every other week and then her numbers started climbing again. So she’s at a path now and they’re wondering what they should do next. What would you recommend in a case like that? She obviously can’t get back on the Kyprolis. Dr. Plesner: I think that’s a difficult case you’re mentioning here, you really need to delve into the details of the her situation. Doxil could be worth considering. Caller: Could a patient’s hematologist actually reach out to you if they had any questions about either the dara response or the dara combos? Dr. Plesner: Yes. Caller: They could? OK that’s good, we’ll encourage our patients in for that too. Dr. Plesner: You may yes. Caller: OK, great, very good. Jenny: Well Dr. Plesner I know we are beyond our time for our show with you but I just want to thank you so much for joining us, about being so clear about daratumumab and its use we’re very, very excited that it’s not available and being used in the clinic and look forward to other opportunities to learn more about it so thank you again and for your participation we really, really appreciate it. Dr. Plesner: It has been a pleasure talking to you and to the patients calling and thank you very much for allowing me this opportunity. Jenny: Well thank you for joining us, we just so appreciate it, so valuable to us and thank you for listening to Myeloma Crowd Radio, you can find us for future shows to learn about the latest in myeloma research and what it means for you. Thank you very much.
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