EBMT 2016 Highlights: Expert discussion
Prof Paul Richardson - Dana-Farber Cancer Institute, Boston, USA
Prof Mohamad Mohty - President of the European society for Blood and Marrrow Transplantation – EBMT
PR: Good afternoon and it’s my pleasure to welcome you here to EBMT in Valencia, Spain. It’s my special privilege to introduce to you Professor Mohamad Mohty, who is not only the President of EBMT but the host of this year’s congress. We’re here to discuss some of the highlights of the meeting. So, Mohamad, perhaps you can share with me what has particularly struck you during this meeting in the space that you and I work in which is obviously, on the one hand, transplant and, on the other, multiple myeloma?
MM: Yes, well thank you very much, Paul, it’s really a pleasure being here. As you have noticed, this is definitely a very exciting meeting. It’s an amazing meeting because of all the novel issues that have been discussed. Myeloma has been like almost a superstar during this meeting and this debate about auto versus no auto-transplant in myeloma but we had also many sessions about the novel drugs. As you know, we had the opening lecture, which is the most prestigious lecture of the meeting, by Jesus San Miguel who made, I would say, the past, present and future history in myeloma.
PR: I agree, I thought Jesus’ presentation was quite superb. Speaking to that, what we were so privileged to have this afternoon with Professor Jean Luc Harousseau, and your and my discussion, was a framing that autologous transplant remains clearly an important option for younger patients who are eligible. But, as we look to the future, there was a consensus that whilst it is an option one size does not necessarily fit all. There may be patients in whom it can either be delayed or, in fact, there may even be patients we can identify in the future who might be spared some of the side effects of the procedure with the goal of achieving the same thing using some of the newer tools that we have, both in the context of assessing minimal disease and, at the same time, some of the most exciting new drugs. I think monoclonal antibodies were a real feature of this afternoon’s debate. What’s your take on what you’ve heard about both daratumumab, for example, and then some of the other monoclonal antibodies such as elotuzumab that have been recently approved?
MM: I think you’re right, the debate and the case for auto-transplant in myeloma is not closed. Both Jean Luc Harousseau and yourself made very good points regarding whether we should proceed or not. As usual, it’s never black and white, the truth is always in between. Obviously here we are in a European perspective and people are very convinced by the role of auto for several reasons – historical reasons, drug access reasons, of course, feasibility, safety etc. There is a long history of auto in myeloma and the recent IFM 2009 DFCI joint trial is in favour of auto-transplant, at least when you look to progression free survival. We do agree that there is no advantage in overall survival so it’s legitimate to ask the question is it really mandatory to everybody especially that we can maybe salvage them or we can delay transplant. So it’s rather, for me, a philosophy in your treatment than I have 100% argument in favour of this or that.
PR: I agree and I think the important message from this afternoon to me was that in the context of countries access to new drugs really matters because, in point of fact, that can determine your choices. For example, in a country which may not have access to optimal salvage regimens an auto-transplant early may be the best strategy for that particular patient in that particular health system. Obviously in the US we’re blessed with access to new drugs and a very different and more dynamic and more varied array of therapeutic options which changes the way we view this. I think another critical point, speaking to the data, is that, as you point out, there is no survival difference yet. With time that may emerge but the progression free survival benefit of transplant over no transplant early versus late was 8.8 months. I am very struck that lenalidomide maintenance as part of continuous therapy confers 2.5 years of progression free survival benefit, not just in one but several trials, and has been further validated by Dr Palumbo’s work. So in aggregate we’re left with really open questions. I thought today’s debate was very refreshing because Jean Luc and I agreed on pretty much everything and what was really nice, though, is that we both brought out differences.
MM: At the end there was an agreement. There was an agreement.
PR: Absolutely, and the US trial also for us shows a way to the future because it shows that in America by us partnering and running a parallel study to our French colleagues we’re able to ask actually importantly different questions but, at the same time, have a very similar and identical parallel track which will allow us to answer key aspects of the same question.
MM: Absolutely. Paul, you are raising here an important question which is the length and duration or duration of maintenance because definitely these results should be always read and interpreted in the context of the design. So if you have a relatively short period of maintenance it may be a totally different story than giving until progression. That might explain these differences so we have to acknowledge this. I would like to go back a little bit to the issue of access to drugs; this is also a very important point. However, it’s important for our community to acknowledge that this issue of access is extremely important. I think we should put all our energy and forces altogether, all stakeholders, to make all of the novel agents available to all patients all over the planet. This is our ethical responsibility. But we should be careful that this argument of access should not be an obstacle to the progress. It’s a dynamic field, everything is in movement there, therefore while trying to sort out these problems, and they may be different from one place to another, even in Europe - not everybody in Europe is within the same laws, same rules. I think we, as a myeloma community, we should really focus on how to design the best treatment that will ensure the longest overall survival with the lowest toxicity. This is very important to keep in mind.
PR: I agree and again we have to be also very realistic about differences in choices that patients face in different continents and different countries and different healthcare systems. But the fundamental premise of better access to all these exciting new advances is absolutely fundamental in my view. I think that that’s something that we as a research community are wholly committed to, as you know, from our international efforts and our strong collaborations. Changing gears a little, Mohamad, obviously you and I have been working very closely together on the development of defibrotide, talking of improving outcomes and reversing devastating toxicities. It has been particularly momentous for us together, as friends and co-investigators, to be here on this particular EBMT where we’ve had quite a series of landmark events. Perhaps you can outline for me what you think of the recent approval, the various papers, you’ve been a lead author on a key one. Perhaps you can comment?
MM: Yes, here you are raising another one important feature of this meeting. I think this is a fascinating story, really fascinating story. It was a true adventure and it’s a pleasure to see that after twenty years of huge important development this drug is now available and approved, both in Europe and in the US. All of us in the community are very pleased. This is an orphan complication, it will be very, very difficult to gather thousands and thousands of cases and actually we don’t want to have thousands of cases of VOD, by the way, because mortality is terrible, more than 80% mortality in cases of severe VOD. So I think now we have in hand a drug that can work and it is our responsibility to try to refine what is the optimal way to use defibrotide for VOD. The story is just starting because, when it comes to VOD or SOS, as you prefer, we’re talking about endothelial cell dysfunction and the endothelial cell dysfunction this is a wide spectrum of very rare complications. We are very familiar in the transplant field where we are a little bit lost sometimes, of course we always use steroids; when we don’t know we use steroids. But this is now rejuvenating the field and this is huge. One of the efforts we did, and you are a key player in this project, the new revised EBMT criteria for diagnosis and prognosis and grading of severity. These criteria will be published hopefully soon and they will represent a turning point because the idea in this complication, because of its very bad prognosis, to be able to intervene very early. If we want to save lives we need to intervene very early and if you want to intervene very early you need to have a very close monitoring and assessment and to be able objectively to evaluate the situation. I think we’re doing a good job, we owe this to our patients and I hope we will succeed.
PR: I agree and I think the journey with defibrotide has been one that has been long but thoroughly worthwhile because, as you so correctly point out, whilst the various syndromes that we’ve targeted, particularly VOD-SOS, with DF, are relatively uncommon, the endothelial platform is huge and that underpins so many other issues that can be so challenging for our patients. So one can envisage where defibrotide becomes a backbone agent that then provides us with both a preventative strategy in the future as well as something that can be used in combination with other new agents or even established agents such as Solu-Medrol to reverse syndromes that hitherto have defied our therapeutic efforts.
MM: And GVHD.
MM: Let’s not forget GVHD, acute GVHD.
PR: That’s almost exactly where I was going because.
MM: In the prevention trial published in The Lancet 2012 there was a clear indication that defibrotide may reduce the incidence of acute GVHD. It needs to be validated but I think this is a good start.
PR: It’s an extraordinarily important start because, again, no-one is arguing on its own but the point is that it becomes part of a combinatorial approach to reversing a variety of endothelial based toxicities of various stripes. In that note, the expansion of the therapeutic index has been very exciting to see. We’ve got the therapeutic opportunity of prevention coming but what was particularly exciting to me at this meeting was to see the enormous impact that defibrotide is having in children. The paediatric piece was remarkable and I thought at the session that you and I were part of, and it was a privilege to be part of with you, Mohamad, I was particularly struck by the contributions of our paediatric colleagues, Jean Hugues and, of course, Selim Corbacioglu. Very, very informative and very gratifying to see them.
MM: Definitely. I think here it’s very emotional when you listen to their talks about these very rare inherited syndromes.
PR: Yes, very raw for the patients and family.
MM: Absolutely, terrible situations. These are very high risk factors for VOD and being able to administer the necessary drug, I would say, for these patients, I think everybody would be happy.
PR: To me, one of the key moments of the whole meeting was that description from Jean Hugues of the poor child who succumbed…
MM: Three month baby, yes.
PR: The infant who succumbed without treatment and then the juxtaposition from Selim of a very similar, very ill child complete reversal, complete resolution and walking out of the hospital. For me this was just very, very striking.
MM: Definitely. I think we agree as part of this meeting we have the nice defibrotide story, we mentioned all the novel drugs in myeloma. We had also wonderful talks, for example in CLL, chronic lymphocytic leukaemia. We had ibrutinib and this is not necessarily our favourite topic but I’m very excited, we’re going to a chemo-free era.
PR: Yes, so biologically targeted therapies across all these diseases.
MM: Absolutely amazing. Lots of sessions about cellular therapies.
PR: Yes, I think a wave of the future and also in myeloma this will.
MM: Absolutely. We just had a session about faecal transplantation. Who can believe this, that faecal transplantation, whether autologous or allogenic can improve the outcome of GVHD? At least potentially, we still need to do the trials. But there are strong indications that you can improve the outcome of stem cell transplant using faecal transplantation. Absolutely, we are now exploring new frontiers.
PR: That’s a real new one.
MM: Absolutely, absolutely.
PR: But, you know, that’s very interesting because that does very much resonate with the microbiome story and the remarkable story from the German groups about the importance of antibiotic prophylaxis and what you use and when you use it. By changing the gut flora you can dramatically improve outcome. Fascinating.
MM: The key question is with our antibiotics, with the chemotherapy we use, actually we are de-regulating, we are creating a state of dysbiosis. The key question is now how are we going to restore a normal microbiome. One way of doing it is this faecal microbial therapy or transplantation. But I think the bottom message here is that it’s a fascinating area. If you look to all of these new frontiers that we are tackling…
PR: So as we look to this new era in myeloma therapy where we’ve got such exciting new treatments, there is a very real concern about late toxic effects. We’re learning a lot more about those; the good news is that secondary leukaemias do have a salvage rate but if we can possibly avoid them so much the better. I wonder, Mohamad, because at this meeting I’m struck that there is a concern that as our patients live ten, fifteen, twenty years, we really have to think about where we place our therapy and what we use because obviously we beat myeloma, make it a chronic illness for fifteen, twenty years, but then our patient in the middle of that process develops secondary leukaemia from prior exposure to melphalan. That is something we need to work to avoid. Thoughts on that, particularly in the context of today’s discussions?
MM: I think this is really more and more important, it’s even crucial. It’s not only about survival, we need to introduce and really consolidate the concept of complication free survival. It’s really important. We need life quantity but we also need quality. So we don’t want these late complications, late side effects. Second primary malignancies are one example because if you have an elderly patient, 70 years old, which can live for another ten years you may encounter these complications. Having said this, we should not forget from the other side that when it comes to myeloma, for example, all patients unfortunately, the first cause of death we know is myeloma. So we really need to find a sort of a balance while analysing carefully, monitoring the trials, looking carefully to the side effect, to the adverse events, calculating the incidence etc. We should be careful not to amplify or to create the situation of fear and avoid giving a good treatment to a patient. So it’s important to be aware, to assess the situation but also to know that the disease by itself is probably the most important cause of death.
PR: For the first time we’re now in a situation in myeloma, for example, where we can pick and choose. I think that’s an incredible thing that we can offer our patients is that, again, driving back to what we were talking about before, if we believe that one size does not fit all there may be distinct genomic, physiognomic patterns that we can identify in certain patients to spare them toxicities that perhaps other patients can tolerate and get benefit from. But for those who may be particularly vulnerable we can actually look to alternative strategies to get them to the same place but not then have to face the late consequences of, say, a genotoxic treatment.
MM: Actually, we’d still have a lot to do and this is with all the available agents this is now where the sequencing job will start.
PR: Exactly, and sparing and efficacy considerations accordingly. So as we think of the new spectrum of drugs in myeloma, obviously we’ve already touched upon the excitement around the monoclonal antibodies, we’ve got the ongoing excitement around the next generation IMiDs, particularly with the success of pomalidomide. Now, of course, we have next generation proteasome inhibitors and we have, on the one hand, carfilzomib which has shown such remarkable activity with tremendous improvements in progression free survival compared to be it lenalidomide-based therapy or bortezomib-based therapy. And, of course, now we have the oral ixazomib which in itself, a weekly pill, combined with an IMiD improving PFS with excellent tolerability. Thoughts, Mohamad?
MM: I cannot more agree. Actually, during this meeting we had only good news because we heard about the positive CHMP opinion regarding daratumumab in Europe, which is really good news for us after the US approval. First monoclonal antibody targeting anti-CD38, this is really a breakthrough achievement.
PR: I agree.
MM: We had also several talks, indeed, and several discussions about these second generation proteasome inhibitors because, as we all know, we lived almost fifteen years with the first generation, bortezomib, and now we have in hand second generation which are more potent and with a better safety profile. I think this is now changing the landscape. Carfilzomib, the data is quite appealing. Of course it’s IV so you may think an oral is better but I think there is room for all of these agents and we need to refine who are the best candidates. But I think the KRD, carfilzomib, lenalidomide, dexamethasone data published in The New England Journal which were discussed a lot during this meeting, about the triplet use of salvage therapy in relapsed refractory myeloma is very exciting. IRD, ixazomib, lenalidomide, dexamethasone, being able to deliver a triplet oral combination, ixazomib once per week, excellent safety profile, this is a huge progress for our patients.
PR: I agree and I think that one also mustn’t forget that this is not a zero sum game, it’s not one versus the other, that we have the advantages of bortezomib, its relatively powerful effects in renal disease and so forth, obviously neuropathy is a nuisance but it’s otherwise generally well tolerated. Given that the neuropathic signal can be so challenging, it’s great to have something like carfilzomib which is so non-neurotoxic but, again, we have to be a little careful there is this vascular signal from carfilzomib that we must be careful about. The flip of that is that ixazomib appears to have less neuropathy than bortezomib, doesn’t have the vascular signal that some of the other more potent proteasome inhibitors may have, so we now have choices. For our patients that’s wonderful because we can not only pick drugs on the basis of efficacy but also how they might best partner with a particular patient because of a side effect profile that may be favourable to that particular patient.
MM: Actually this is where you can guess the passion of medicine because this is where clinical judgement on a case by case, patient-tailored treatment, and actually you want to have all options available and then the clinical judgement will allow you to decide. First of all you need the clinical trials, of course, the procedure is there, but once you’ve got the approval then the real life effect will be seen. I think we are.
PR: I think that’s the perfect note to end on, to say that on the one hand we have extremely elegant bench to bedside science with small molecules, monoclonal antibodies and genotypic data really at the highest quality and the greatest technology. But we must never forget some of the most basic lessons that are staring us in the face. And on that note, Mohamad, it’s my pleasure to say thank you very much for being with us today.