Extending Outcomes with Continuous Myeloma Maintenance: Dr. Antonio Palumbo, MD, University of Torino
Learn about all myeloma happenings on the new Myeloma Crowd site: the first comprehensive site for myeloma patients and caregivers. Dr. Antonio Palumbo, MD University of Torino, Italy Interview Date: August 25, 2014 Summary Dr. Antonio Palumbo, MD of the University of Torino, Italy discusses his ASCO 2014 findings showing that continuous maintenance therapy can give on average an additional year of benefit for most myeloma patients. He notes that if patients have minimal residual disease, that continuing maintenance can help keep the myeloma down, improving their remission status over time. He cautions that even though patients may achieve a stringent complete response, it doesn't mean they are disease-free because there is always residual tumor. He wondered if giving continuous maintenance after the first remission would negate any benefit by making the myeloma come back in the second remission more aggressively, but found this wasn't the case; it still provided a year of benefit. He shares that only about 20% of patients will become refractory to the treatment with extended use. Dr. Palumbo describes when to stop continuous maintenance - when toxicities are above a grade 1 or whenever the patient feels that they are too much for an acceptable quality of life. Dr. Palumbo shares that Revlimid and bortezomib have been used as maintenance and both have shown the year benefit, although there have been no head-to-head comparisons between the two. He notes that out of all the indicators that may influence outcomes like disease biology and the patient response, the best indicator for outcomes is the duration of response. If patients have a longer response, they will have better overall outcomes regardless of remission status. He describes that with the wide variety of newer myeloma treatments, patients are now having not one or two remissions, but four, five or six remissions and while this is great news for patients, it makes understanding the impact of continuous maintenance more complicated to calculate. The live mPatient Myeloma Radio podcast with Dr. Antonio Palumbo, MD
Welcome to today's episode of mPatient Myeloma Radio, a show that connects patients with myeloma researchers. I'm your host, Jenny Ahlstrom. If you would like to receive a weekly email about past and upcoming interviews, you can subscribe to our mPatient Minute newsletter on the homepage or follow us there on Facebook or Twitter, and please share these interviews with your myeloma friends. For today's show, we are very fortunate to have with us one of the foremost world leaders in multiple myeloma, Dr. Antonio Palumbo. So welcome, Dr. Palumbo. Dr. Palumbo: Thank you very much for the invitation. Jenny: Well, thank you so much for joining us. Let me introduce you before we get started. Dr. Antonio Palumbo received his medical degree from the University of Torino, Italy where he served his residency in internal medicine and held a fellowship in hematology/oncology. Before his current position as chief of the Myeloma Unit of the Department of Oncology, Section of Hematology at the University of Torino, Dr. Palumbo was a research associate at the Wistar Institute at the University of Pennsylvania. In addition to membership in numerous professional organizations, including the Italian Society of Hematology, Italian Society of Experimental Hematology, European Society of Hematology, American Society of Hematology, and the American Society of Clinical Oncology, Dr. Palumbo is on the Board of Directors of the International Myeloma Society. He has authored more than 150 publications in peer-reviewed journals as well numerous abstract and several textbooks chapters. He specializes in malignant hematology and medical oncology and has clinical and research interest in plasma cell dyscrasia. Just recently, Dr. Palumbo was awarded the Robert A. Kyle Lifetime Award for 2014 from the International Myeloma Foundation for many, many years of service and discovery in myeloma. So Dr. Palumbo, thank you again for joining us. Dr. Palumbo: Thank you very much for your invitation. Jenny: Dr. Palumbo, one of the big reasons that we would love to talk to you, we have many reasons to talk to you as one of the world leaders in myeloma, but we are very fascinated about your paper, your ASCO paper of this year, about continuous maintenance therapy. So before we start with that, can you please give us a brief introduction about the Italian Myeloma Network? Dr. Palumbo: Yes. Basically, almost I would say 15, 20 years ago we started with the Italian cooperative groups called Gimema, and we put together several hematologic institutions throughout the country. This allowed us to start and with time have more and more clinical trials asking several questions. Just recently the Italian group joined with some other European countries to build up the European Myeloma Networks that hopefully will try to even prove that our current trial capability in order to make the study faster and probably better than. Jenny: Well, I very much appreciate the collaboration that happens in Europe. It seems to be a very collaborative group in the way that you're working together. Well, the continuous maintenance therapy, let's talk about that for a little bit. I know you had, before this ASCO paper, you had papers in 2012 and in November of 2013 with lenalidomide talking about some of the rationale behind that. Can you give us some background about the history of the rationale behind the idea of continuous maintenance therapy? Dr. Palumbo: Well, basically, this idea started many years ago when we had the randomized studies comparing treatment that was also given continuously and the progression versus a treatment that was given only for two months and the curves were very impressive because basically the major differentiation in terms of outcome basically was shown when treatment was stopped. So while patients were on treatment, the curves were very well-balanced and they were starting to diverge dramatically when in one group we stop treatment after a few months. In the other groups, the treatment was given continuously. So we started to think about the need of continuous treatment basically from this randomized study, and basically the two important concepts were that if in myeloma you do have residual disease after induction, you might need a continuous therapy to keep this residual disease under control. If you stop the treatment, that disease will come up quite importantly and quite soon. So this was basically the concept that keeps us evaluating this approach. Jenny: And do you want to share what you learned from what was in the ASCO paper? Because the specifics, it looked to me that the survival, the progression free survival with lenalidomide maintenance was 42.7 months compared to 17.5, which is a huge difference. Dr. Palumbo: Well, the ASCO paper was addressing, yes, this concept together with the idea of a resistant relapse. I will try to explain the issue. In oncology today, in myeloma specifically, but generally speaking do consider the treatment A is better than treatment B when the advance is a few months. With the continuous treatment, the difference in terms of remission duration has been constantly and basically in all studies around one year. So the first major concept is that the continuous treatment is prolonged in remission duration as a media value of one year. After that, the question becomes, well, okay, but if you prolong very much the remission duration and this aspect is a consensus that no one is discussing. But the next question was, well, if you prolong so much the remission, then the relapse may be quite aggressive. You might lose in the subsequent remission what you gain in the first remission. So in this study that we presented at ASCO, we basically not only evaluate the length of first remission but we also evaluate the length of subsequent second remission. So we put together the first and the second remission in the attempt to evaluate if the relapse after continuous treatment was short and in very much the subsequent second remission. And once again in a randomized study, the results show that when you put together the first and second remission, the advantage is still around one year when you compare first and second remission receiving continuous treatment versus first and second remission receiving just the short-term treatment. So the conclusion is that the delivery of a continuous treatment is not significantly shortening the second remission due to a more aggressive relapse. I hope it's clear because the concept is not always that simple to explain. Jenny: So you are basically trying to see if it extended both first and second relapse -- I mean remission times? Dr. Palumbo: Yes. Jenny: And that it had a year advantage. And then can you repeat what you said about the aggressiveness because I had some follow-up questions about just the aggressiveness. When it comes back the second time -- Dr. Palumbo: More aggressive and resistant because one of the questions being raised is that, okay, you prolong the first remission in one year but then you shorten the second remission of one year. At the end, there is no advantage. This assumption or, if you want, the question because if you give continuous treatment, the relapse that will occur and the treatment and the therapy. And at that point, that relapse could be much more resistant and aggressive. So the year you gain in the first remission may be lost during the second remission. This is actually not true. We could show that this remission advantage was kept also after the second remission. Jenny: So you are prolonging overall survival? That was one of your second questions, right? Dr. Palumbo: So that becomes even a more complicated question because overall survival is, let's say, two-thirds of the studies is prolonged. So you do see prolongation of first remission in 100% of the study. You see prolongation of first plus second remission up today 100% study. And you see overall survival prolongation not in 100% of the study but in, let's say, two-thirds or 70% of the study. How is this possible? There are several explanations for this. First of all, today myeloma is not one or two remissions; probably four, five, six different remissions. So the use of different drugs at subsequent relapse may alter the overall survival, and this is one of the reasons why in some studies we couldnt show but consistently overall survival advantage. But the other one is also toxicity and the ability to receive an effective salvage regimen. And this may also change the overall survival outcome. That's the reason why we wanted to get specifically involved in first and second remission to get close to the time period of the continuous treatment because if you go, you know, in the old days you only have one, two, maximum three-year remission duration. So it was very easy to translate the efficacy that was coming from the first remission to overall survival. Today, that fortunately we have four, five, six different remission duration. The overall survival might be coming from this point of view a more confusing employment because so many other treatments, so many other toxicities, so many different comorbidities, complications may occur during those four, five, six remission duration that this might -- I'm not saying cancer but create more confusion in the strict definition of remission duration and overall survival. Jenny: If I hear what you're saying, it just sounds like it might be blessing and a curse at the same time, a blessing to patients that the overall survival is longer now than with the newer drugs but more complicated to determine what is actually creating that extended remission. In running studies, it seems like it's a challenge because you have to have a much longer study to get the result that you want. Dr. Palumbo: Not only that but what my concept is that when in a given disease you have the six different remission durations, six different treatments, six different risks of toxicity during those six remission duration. It's very complicated to make a strict correlation between the efficacy of treatment given during the first remission and the overall survival because everything is getting mixed up by different risk that you might have, positive or negative, during the other five treatment lines and five remission durations. That's the reason why we try to put together what we called PFS 1 and PFS 2 because to clearly evaluate the efficacy of a given treatment and this was evaluated by remission duration and eventually the risk of a negative effect that is coming just after that treatment, not after six of those treatments. Jenny: Well, that makes a lot of sense. So it is very complicated to determine and narrow it down. Dr. Palumbo: The overall survival becomes more and more complicated to evaluate because we have more lines of therapy, more everything can be confounded by subsequent treatments. Jenny: Right. So the efficacy and the impact of the other treatments on your system and maybe on your myeloma. Dr. Palumbo: Exactly. Jenny: Now, at the beginning of this show, you mentioned that one of the studies was looking at patients who had some residual disease. So can we talk for a minute about who continuous maintenance might be appropriate for? And maybe we start by talking about the remission status of patients. Is it appropriate for all patients who have some residual? Is it appropriate for patients who have complete remission or a stringent complete remission? Could you inform us about that? Dr. Palumbo: That's a very important issue and I would say also something that needs some clarification. The outcome of the disease is the balance between the two, I would say, realities. One reality is how much the disease is sensitive to therapy and more the disease is sensitive to therapy, more the residual tumor is reduced. So no questions that with a given treatment, if you reach a CR or even a stringent CR, this is much better than achieving a PR only, a partial response only. But on the other hand, the other half of the moon is biology of the disease because if you achieve a complete response but the biology of the disease is very aggressive, the relapse might come very soon. On the other hand, if you are not very sensitive to treatment and you only reach a partial response but the biology of disease is not very aggressive and before the relapse will come after five years, this is of course a positive issue. So you always balance achievement a good response or a CR with the biology of the disease, and this is of course not easy to do. And the real end point is that remission duration. I would say that the length of remission duration is much more important. The amount of response you might achieve after therapy, if you achieve a complete response, the duration of the response is much more important than the achievement of a CR or of a stringent CR. But generally speaking, I do agree that the achievement of CR is generally better than PR, but this must be balanced with the duration of response. That might change from one subject to another and this is mainly given by how much the disease is aggressive and therefore how much is the relapse. On the other hand, the advantage of the continuous treatment is basically one: that with continuous treatment you might further increase the response achieved after induction and therefore prolong the duration of therapy, might increase the response rate, improve the response rate. On the other hand, as we were discussing before, the continuous treatment might delay the relapse because it is certainly controlling the cells that might be growing. Jenny: Okay. So there are so many questions out of what you just said. So I know you're trying to balance between the biology of the disease and then the remission response so some practical examples. If you had someone who had aggressive therapy and then hit, let's say, a stringent remission, has maybe one high risk feature, maybe not a deletion 17 but something else, how do you determine if the length of the remission duration is the most important? And they just came off therapy, would you suggest that or do you wait to see the length of their remission response thats not continuous therapy? Can you give us some examples maybe for different types of patients what you might do in those situations? Dr. Palumbo: I dont know if I understood correctly, but I think we have to clear out the concept. First of all, if you achieve stringent complete response in a given patient, we still have residual disease. This is not complete response and erradication of the tumor. So that's a method if we reach partial response, complete response, stringent complete response, even that minimal residual disease negative situation we always have residual disease. So we have to get rid of the concept that if I reach complete response, I'm cured because I get rid of the tumor; if I reach a partial response, I'm not because I still have tumor. There is always residual tumor. So from this point of view, you see the advantage of continuous treatment is always present because you always have residual tumors. From a practical point of view, what we do in our clinic, according to the research of the Phase III study, we decide that the given therapy is the best available treatment for that given patient and we give it to all patients. We are not changing treatment according to risk factors or achievement of response. We deliver what the Phase III studies have defined as best available therapy. And on that evidence, we deliver the same treatment to all patients. Jenny: And is that Revlimid right now, lenalidomide? Dr. Palumbo: Currently, I would say as a continuous treatment, we actually have Revlimid as continuous treatment but also proteasome inhibitors as continuous treatment today do represent an advantage over a fixed duration of therapy. Today, the evidence coming from the Phase III studies are both from IMIDs and from proteasome inhibitors that the continuous treatment significantly prolongs remission duration of approximately one year. We do not have a comparison of iMiDs versus proteasome inhibitors, and from this point of view we cannot say that A is better than B or B is better than A. We can only say that the continuous treatment is better than fixed duration therapy. Jenny: So at this time, you dont know if something like bortezomib would be better than lenalidomide as a choice. That's what you're saying? Dr. Palumbo: Absolutely, yes. No, we cannot say it because we do not have any head-to-head comparison of those two approaches. We know that from Phase III studies both bortezomib and lenalidomide gave an advantage of approximately one year in two independent randomized studies. Jenny: Do you think any of the risk factors would come into play? Because I know that sometimes they say bortezomib might have an impact on (4;14) patients over other types of patients. Would you take that into consideration when choosing a continuous maintenance drug? Dr. Palumbo: No, I dont, but I can tell you what, you know, that I should also say that depending on the reimbursement opportunity that they dont always give us the opportunity to give the best treatment. We do proteasome inhibitor as induction because this is a way to maximize as much as possible the response and to increase as much as possible the complete response because today only combinations including proteasome inhibitor could give without autologous transplantation a CR opportunity of approximately 30%. So we do prefer as induction proteasome inhibitors followed by lenalidomide as maintenance for two reasons: first, because we basically alternate the proteasome with the IMIDs; and second, to take advantage of the oral administration of IMIDs that is certainly a plus when you are planning a treatment that could be longer than two years. Jenny: I think that's a great choice because you to want to have a patient stay out of the clinic as much as possible, if possible. Dr. Palumbo: Absolutely, yes. And as I was saying, our approach is to take advantage of proteasome inhibitors that are certainly more effective than IMIDs in terms of increasing the complete response rate. And on the other hand, to take advantage of the IMIDs for a continuous therapy and the oral administration of the IMIDs that keep patients out of the clinic for a longer period of time. Jenny: Now, when you are talking about continuous maintenance therapy, can you share your opinion on dosage of that therapy? How do you maintain the best response with the fewest amount of side effects? What is your strategy to do that? Dr. Palumbo: Thank you for the question because I think that is probably one of the most important questions. This is a personal opinion. It's not given by any evidence. But my personal opinion is that maintenance and continuous therapy should be given provided they are not causing any toxicity. So my number one rule is continuous treatment should be delivered if all toxicities are minimal. And our policy is the moment we do see some toxicity, we eventually reduce or stop the therapy. We want to see those toxicities going back to a minimal toxicity, what we call grade one toxicities, and at that point we do restart at probably lower doses. So basically, our golden rule is to keep patient on treatment with the dose that is not causing any toxicity. If we do see hematologic toxicities, we reduce the dose from 10 milligrams of lenalidomide to even 5 and eventually we stop because we do believe that the quality of life and the absence of toxicity and even more important in the efficacy in terms of prolonging as much as possible the remission duration. Then here the results, so if you want a not very easy concept, the concept is if you keep going on a continuous treatment, you end up and you start to see some toxicities and you keep going, you will create a major toxicity that will end up in a clear discontinuation. So the two ideas are to minimize, to reduce the dose to keep patients on treatment as long as possible. But on the other hand, to completely avoid major toxicity because this has a major impact on quality of life from one side but also on the risk of the discontinuing therapy to excessive toxicities. Jenny: And a follow-up question, what specifically are you looking for when you look at toxicities? Are you looking for kidney function or what specifically are you looking at? Dr. Palumbo: First of all, I would say hematologic toxicity especially for both proteasome inhibitors and IMIDs are probably the most relevant. Infection is the second most relevant. But once again, when we do the workout that we look at hematologic condition that creatinine, the renal function, everything is not working properly is a good reason to reduce the dose. And this is especially important you mentioned the renal function for the elderly because the renal function is physiologically reduced in the elderly population, and therefore reduced dose of especially lenalidomide is almost mandatory. This is sad subject because the renal function cannot be 100% conserved and especially in those patients the dose reduction will be important not only for the kidney but also for the hematologic conditions. Jenny: And do you have any concerns about patients becoming refractory to a continuous maintenance drug? Dr. Palumbo: Yes, that is a concern. This is also happening, unfortunately. This is one of the major reasons why we ran the study pulling together in the first remission with the subsequent remission in order to evaluate if the resistance was creating a major damage for the subsequent remission. The data is showing that this is not in the practice is so true, that some patients do acquire a clear resistance to treatment but they are probably less than 20%. So the majority of patients are not acquiring a major resistance to therapy. And to some extent, when we balance the risk of resistance that is certainly occurring in 15%, 20% of patients versus the advantage you give, keeping the tumor under control with continuous treatment, there is much more advantage in keeping the tumor under control than the disadvantage coming from the occurrence of resistant relapse. Jenny: And it seems that you're always trying to take that balance: the maximum effective therapy and the minimum downside for the patients. Dr. Palumbo: Absolutely. I think this is the key issue; minimize the treatment and minimize the toxicity to maximize the treatment. I think this is probably rule number one. Jenny: So I have a question about newer therapies, with some newer therapies because there are so many different types now, all these different inhibitors and vaccines. Are there other therapies that could be used as continuous maintenance therapy like, let's say, for example, a vaccine? It might be too early for that - that doesnt have any side effects but might help boost the immune system and keep it going? In your mind, could any of those be used as continuous maintenance therapy now or in the future? Dr. Palumbo: We hope for the future. Today there is no evidence that vaccines can be used as a continuous therapy. We do need some clinical studies to show that there is a clear efficacy because vaccine could mean so many things and so many approaches and one slight difference in one approach over the other could make an enormous difference. But the main message today is we do not have any clinical evidence of efficacy of vaccine in myeloma. That doesnt mean that tomorrow this evidence will come. My concern is that the treatment should be delivered outside a clinical trial a clinical trial is a completely different story, but outside of a clinical trial when we do have evidence of efficacy. Today, there are some clinical trials evaluating vaccines. So if someone would like to test the efficacy of a vaccine, they should be included in a clinical study that will allow us to evaluate if this approach is effective or not but shouldnt use outside the clinical study because today we do not have any evidence. And we, on the other hand, need the evidence to show that vaccine is effective. They are a great hope for the future but once again we first need evidence and then we can use. Jenny: Well, maybe that's just my hopeful dream world of treatment without any side effects. But it is very positive what you said with 80% patients not becoming refractory to the therapy that's being used today. So that's very encouraging. So in looking at this, I know studies are difficult or a challenge because you have to do a study for a certain time period to find the results, and I know researchers dont want to do a study that is eight or ten years long because it takes that long to be able to announce your results. So can you take the data that you've already gathered and continue with that same patient group or cohort to extend the study to see as you give continuous therapy the results past maybe a three or a five-year period? Is that possible? Dr. Palumbo: Yes. I think that's another excellent consideration because you have to balance the time and the need of having announcements, not in ten years because it will be too long with the need of evidence. Today, I think this is the work that we should do all together -- patient, physician and probably also authorities -- try to shorten the period to get the signal. From this point of view, I'm very much in favor to find early signal that can allow us to say we do have evidence that this is effective, and that signal will then be confirmed with longer follow-up. So today, we still need randomized study to clearly show signal. We should probably start using early signal such as PFS. PFS may come in less than three years. Even response rate in the difference is very important it can come much less than two years after a study. So to have marker that in two to three years of time period can give us an early signal of evidence. This is, in my opinion, quite important and feasible today. It's less slightly more conservative from this point of view to immediately translate the experience of a study such as a Phase II study without a control arm and then there is more cohort of patients such as 20, 30 patients to immediately translate this evidence in clinical practice because in the past some states have done with this approach. So in my opinion, we do need Phase III, we do need early biomarker or signal to have an answer in two to three years. Jenny: And in your opinion, what else would shorten up this whole cycle of discovery for you? Is it more patient involvement? Is it structuring the clinical trials in different ways? With your experience, you have so much experience. In your opinion, what would shorten this up so we can discover new thoughts more quickly? Dr. Palumbo: I would say - certainly the ability to open and close those studies in a shorter period of time. I think that's probably the key issue and probably a better collaboration between investigators and authorities to design and to speed up all the bureaucratic procedures because today, to some extent, in our word we need standards. If you have a new drug, you should know immediately which is your standard study to do to have the approval, and you should immediately approve the drug if you reach that end point. So you dont have to go through discussion of things, things that should be more standard from a bureaucratic point of view and from a recruitment point of view. I think those are the two key issues. If authorities will have standards, they can certainly reduce the time required for approval. If the investigator has better facilities could probably reduce the time required for recruitment. This might, to some extent, reduce between 30% and 50% of the time to be required to get approval of a clinical trial. Jenny: Well, that's a huge timeframe. We're doubling the pace if we could eliminate that. And do you have a hard time recruiting for your studies? I know that Europe is different than the United States. Dr. Palumbo: No, but we are in a very good position. But generally speaking, another message is that the difficulties in recruitment is mainly due by the fact -- and this is if I can from a European perspective, add another very important message for patients -- the difficulties in recruitment is because the patients are treated in so small and different institutions. And to some extent, this is a major issue not only for recruitment but mainly for patients. Patients should remember the number one quality issue is the number of myeloma patients that a given physician sees every year. Myeloma is a rare disease. So if patients are treated by a physician who sees two, three, four patients per year, this is quality A. But if a physician sees 150 myeloma patients per year, this is quality B and A is completely different from B. So one issue is that, especially for rare disease, I know sometimes it's not so easy for geographical reason but the treatment should be driven by a physician who see at least 100 patients, unit patient, new patient per year because experience makes the quality on top of everything. And of course, if you start having a center who sees more than 100 newly diagnosed patients per year, also their recruitment will be increased because you will have more concentration. Jenny: Right. And to me as a patient, what you just said is just a no-brainer. My first oncologist that I saw, I asked him how many patients he had. He said maybe five. And then I went to two other specialists and at their facilities they were treating between 400 and 600 myeloma patients a year. It was very clear the expertise difference in those. Even though he was a good oncologist, he did not specialize in myeloma. And to me it wasnt worth it. So I completely agree. Dr. Palumbo: Absolutely. I think this is the number one message to give to patients. Always remember, in every type of a disease, what makes the difference is the number of patients that a given physician is seeing and the experience they might have. So even for surgery, for everything, the number one issue is the number of procedures or new patients you might see per year. That makes a great difference. Jenny: It's a great message. So I have so many other questions to ask you, but I know you need to end at our stop time and there are several callers. I'm going to open it up for caller questions. If you have a question for Dr. Palumbo, you can call 347-637-2631. Press 1 on your keypad and we will start with our first caller question. Please go ahead. Caller: Hi, Jenny. Thanks for doing this wonderful interview. And thank you, Dr. Palumbo, for being a part of this interview. This is Suzie Rose and my question, we are talking about continuous treatment and we're looking at the immunomodulator drug for continuous therapy. Do you have a perspective? I know this was not your trial, but do you have a perspective on using the proteasome inhibitors and putting that in the framework of what we were talking about with Jenny and refractoriness in terms of will patients become refractory if they're continued on proteasome inhibitor? And I'm thinking of that for patients who are in the high risk or cytogenetic. They have the translocations or deletion 17p or amplification of 1q. I'm really asking your perspective more so than -- because I know it wasnt part of your trial. So what are your thoughts there? Dr. Palumbo: That's a very complicated question. I'll try to give my best answer. We ran two different studies. One study was len maintenance versus no maintenance. The other study was another independent study and was proteasome inhibitor maintenance versus no maintenance. If you look at those two independent studies, no question the advantage was fairly similar in both studies it was around one year good prognosis patients did better than high risk patients in both studies. So the issue of high-risk was the highvrisk patient did worse in both with len than with proteasome inhibitors. Having said that, I'm in favor, without evidence, this is a personal opinion, certainly probably to use proteasome inhibitors in high risk because it has been shown and the proteasome inhibitors might be more beneficial than IMID in high risk patients and using this evidence together with the evidence that together with the no evidence because we do not have any evidence to show head-to-head comparison of IMID with proteasome inhibitor, I will be probably in favor of using the proteasome inhibitors in high risk patients. In terms of resistance, I actually do not know. I would not expect high risk of resistance from one drug in comparison to the other, but honestly speaking I do not know. Caller: Yeah, I asked that question because of the data that Dr. Lonial has now out of Winship where he -- well, I think it was more of a retrospective analysis where he looked at keeping patients on RVD after they were in the high risk population and he's seen a substantial increase following those patients in their survival. So that was kind of what prompted my question. I realized there's not a lot of evidence. But I appreciate your expertise and giving your clinical perspective. So thank you. Dr. Palumbo: Thank you very much. That's actually very nice. Thank you. I will completely agree with your comment because generally speaking, the more the disease is aggressive, the more intense the treatment such as VRD will be of course more beneficial provided it's tolerated. So I would completely agree with you and Dr. Lonial provided the treatment you are given is tolerated because otherwise we have to reduce the dose of that. Caller: That was the other concern that I had in terms of when we're doing continuous treatment like that, are we going to do it at the same pace and the same -- are we going to, you know, when you're doing like induction or when you're doing consolidation, typically it's twice a week, three times before three weeks in a row. Well, would we continue that or would we do once a week or would we, you know, you do maybe one year you get it twice a week and then the following year you go to once a week times three? I dont know and that's one of the questions because I think your core point is we have to sustain the MRD if we've reached it or continue to drive it down as much, you know, with this steady pressure of the drug. I dont know. Do you have thoughts on that? Should the dose intensity -- I know with lenalidomide they take you from 25 milligrams down to 10 or 5 milligrams for maintenance. Would you think we would do it with the -- because that's the thing. Even carfilzomib is up to 56 milligrams now. Do we back it back down for maintenance? What would your clinical perspective be? Dr. Palumbo: My perspective is, first, more is better if it's tolerated. So every time more is not tolerated, there is an excellent reason to go less. So this is number one. Caller: So dose limiting toxicity would be your parameter. Dr. Palumbo: For us we do re-challenge in continuous treatment if we have at least 1,000 or 1,500 neutopenic and at least 70,000, 80,000 platelet count. So if you start not having those parameters for us, this is a good reason to stop, wait, to reach those levels and reach that at the lower dose because, of course, if you had to stop, it's because the previous dose was not very well taken. So this is your rule number one. As a rule number two, I would use certainly no more than weekly bortezomib especially in a continuous approach. In our trial, we've honestly used bortezomib every two weeks. So our proteasome inhibitor was much lower when we gave it as a continuous treatment. Carfilzomib could be given more frequently because it has less hematologic toxicity and less neuropathy but still rule number one is if tolerated. Caller: Great. Well, thank you. Dr. Palumbo: Thank you very much. Thank you. Jenny: Okay, thank you for your question. Okay, we'll go to our next caller. Caller: Yes, hi. My name is Victor. I've noticed that clinical trials basically seem to be for relapsed refractory patients. I'm wondering whether it's possible to design any trials to try some of the newer drugs that are not approved yet like some of the monoclonal antibodies, for example, for people who are on maintenance. Has thought been given to that or would that basically just does not work because you wouldnt really be able to tell anything? Dr. Palumbo: No. Actually, what is ongoing is probably not so in the public domain. But what is ongoing now, our plan for all new drugs including monoclonal antibodies, are testing the maintenance phase. So basically, you are right. In the developing of a drug, first we test the drug in relapsed/refractory and then you need to newly diagnosed patients. And at that point, you at the same time offer a different study you address a question of maintenance. So the majority of the maintenance questions are in a newly diagnosed patients and in treatment administered to those patients. Caller: Okay. For someone who is on maintenance now, there dont seem to be any clinical trials available. You cant just sign up for one if you're already in a maintenance position. Dr. Palumbo: If you are already in a maintenance, no, I mean in the sense that a clinical trial can be delivered at the beginning of the maintenance. If you already started a maintenance, there is no clinical trial that will allow the inclusion of that person who already started maintenance because of course it would be difficult to evaluate the efficacy at this point. But on the other hand, I would also suggest if you are under a given maintenance, keep going. Dont mix that. You see, when you started treatment, the moment you make a decision, it's over. Dont change it in the middle of the way. Caller: No, I'm not going to. Jenny: Well, thank you for your question, Victor, we appreciate it. Okay, we have another question, please go ahead with your question. . Caller: I did have a question with the maintenance of Revlimid. Does that doctor suggests that dexamethasone is also a component in that regimen. Dr. Palumbo: You're asking me if I should add dexamethasone, yes or no. There is some evidence. They are not very strong honestly because the addition of corticosteroids might be useful. So you might add it. The study we have been running until now have been only comparing IMIDs or proteasome inhibitor without dexamethasone versus control arm. So the study we do have -- so the real strong evidence is without corticosteroids. There are some studies that they are adding corticosteroids to Revlimid. They do not have enough follow-up to make it a final conclusion. Early signal might say that there is an advantage so that's why I'm not so strong in saying yes or no because I'm strong in saying yes for len maintenance because we do have a strong evidence. For the addition of corticosteroids to len, we have some initial evidence. So my answer to you will be yes provided corticosteroids is not creating any trouble to you and probably even lower doses. Ten to 20 milligrams of dexamethasone may be good enough. So yes, provided it's not creating any trouble to you, knowing we have some early evidence, not strong evidence. Caller: Thank you very much, doctor. Dr. Palumbo: Thank you. Jenny: We have our last caller, please go ahead with your question. Caller: Okay, thank you very much for taking the call. It's been a great show today. Dr. Palumbo: Oh, thank you. Caller: Dr. Palumbo, you make a very compelling argument for a continuous therapy approach. A couple of questions around that. What is a quality of life issue that would stop you from continuing the treatment? You mentioned that the quality of life would be a significant factor. How bad would the neuropathy have to be or what would be the quality of life issue? You mentioned kidneys. What else would be those issues? I have a couple other questions after that. Dr. Palumbo: Well, I'm not going to detail because for me as I usually say, only grade one toxicity -- you know, all toxicity have been graded by one, two, three, four. So we usually accept grade one toxicities including fatigue. We do not accept more than that. So if you ask me the cutoff is grade one. That means minimal toxicities and you're on the point of quality of life you will decide that at the end of the story because you might find some minimal side effects very important and for me might not be the same. Especially for quality of life, you have to decide. My message to you is you have to -- you must have a normal life. Every time you feel something is not acceptable for you, I would discuss in detail what this means, but the final decision is on you. Caller: Thank you. The second question has to do with just the cost of continuous therapy. You mentioned sometimes insurance companies won't cover the ideal treatment. Are the insurance companies going to go along with the concept of continuous therapy or do you have any indication of this yet? Dr. Palumbo: This is something that is outside -- you know, I'm here in Europe so it's a completely different situation. I think the majority of the companies are covering the continuous therapy in United States -- in Europe it's still under discussion. The reimbursement should be coming soon -- what can I tell you? I dont know. Should be covered, in my opinion, but depending on the insurance, someone might not. Caller: Okay. Last week, the previous show was talking about the new heavy/light test and that test is kind of like a speedometer for the growth rate of myeloma. I believe it was Dr. Stephen Harding of The Binding Site that did that. Are you familiar with this test? And could some of these tests be used in combination with this continuous therapy as a more sensitive indicator of how the myeloma is or is not progressing? And maybe the concept of a patient dashboard, it's kind of a radical idea but as I've been listening to the show, some of these ideas are coming together in terms of how we can help improve the quality of care and the idea of monitoring at a more sensitive level is a very exciting one for me. Dr. Palumbo: Yes, I completely agree with you. We are testing several new approaches that are more sensitive. But from a practical point of view, we do not have any evidence on how to use it, for example, to stop the continuous treatment and eventually to restart or when to increase it - the dose intensity of a continuous treatment. So generally speaking, these are not the best that we can use today to make treatment changes. So from this point of view, I think they are still under investigation. They are more sensitive but they are still under investigation. Caller: Well, thanks again. Great insights today. I learned a lot. Dr. Palumbo: Thank you. Jenny: Okay, Dr. Palumbo, we are out of time and we could talk for another hour on your research. You've done so much with -- Dr. Palumbo: If you have another couple of questions it is a not a problem. Jenny: Well, I limited the time on the caller questions so we can end our time. So I apologize. I have quite a few questions about your treatment in the elderly and risk stratification. So maybe I'll end with one. During the International Myeloma Working Group that was videotaped by the IMF, you mentioned that it was needed to separate patients into more homogenous groups in order to risk stratify them and treat them differently. Are there any other steps that need to be taken to treat patients more specifically? Dr. Palumbo: Well, no, you see, I think there is a message but I think will come. Myeloma is at the end of the day a mix of three different diseases; the real high risk that is a disease completely different from the standard risk and the low risk patients. So I think there are today the tools to differentiate those three different groups that to some extent may represent the three different diseases, and what is needed in the future but might become more complicated for the need of numbers because numbers become of course smaller at that point, to have studies evaluating the high risk patient, the standard risk patient and lower risk patient separately. Today, we have made the mistake, if I can, but to pool everyone together and then starting to say this must be better than the other maybe comparing high risk versus standard risk. Tomorrow, I think the future would be to start the design trial only for the high risk trial, only for the standard risk. Jenny: Oh, I completely support that. You're comparing apples to apples and not apples to oranges and then you dont know what kind of result you're getting. Dr. Palumbo: So I think in the future, we are going there. But once again, it's a rare disease so the issue is mainly related to the rarity of the disease. Jenny: Okay. Well, if you have time, I'll add one more emailed in question from Jill. She just asked, "I noticed that in your studies you are moving away from melphalan to cyclophosphamide. Is there a reason for this, like less risk of secondary cancers? Can you describe the rationale?" Dr. Palumbo: Certainly, yes, I would say that the number one issue of melphalan is the risk of asecond cancer. So cyclophosphamide has a much lower risk of second cancer. So number one reason to move from melphalan to cyclophosphamide is the lower risk of cancer. The second reason is there is less hematologic toxicity with cyclophosphamide and this is another important consideration because at the end of the day, if you use melphalan extensively and the blood cell count is going down significantly, then there are difficulties in the liver salvage treatment. This is probably even more important than second cancer. Second cancer is fortunately a rare event. The risk of thrombocytopenia after significant delivery of a special melphalan much less high dose melphalan because it's a shot given once in the oral melphalan but also if you want with the high dose melphalan, the risk of thrombocytopenia may hamper the delivery of effective salvage treatment. This is in my opinion a good reason to move to better tolerated compounds just like cyclophosphamide. Jenny: That's very, very interesting. Is cyclophosphamide powerful enough to use it pre-transplant? Dr. Palumbo: Absolutely, yes. To some extent, you know, in the combination with bortezomib today we have two major combinations I would say, bortezomib plus lenalidomide and bortezomib plus cyclophosphamide. Of course, the first one is more active, certainly more expansive, and the second one is slightly more active than the combination of bortezomib and dexamethasone. Jenny: Okay. Well, that's very, very interesting. I think we'll see more on that later. Well, Dr. Palumbo, thank you so much for joining us today. We are so very grateful for your leadership in myeloma and your research to move the field forward as quickly as possible. Dr. Palumbo: Well, thank you very much for the invitation. I appreciate it. Thank you very much. Jenny: Oh, you've been delightful. Thank you so much. Thank you for listening to another episode of mPatient Myeloma. Join us for our next mPatient Radio interview as we learn more about how we as patients can help drive to a cure for myeloma by joining clinical trials.