EHA 17

Emerging advances in multiple myeloma; expert roundtable at MM CTP 2012

Professor Thierry Facon – Centre Hospitalier Universitaire, France

Professor Pieter Sonneveld – University Hospital, Rotterdam, Netherlands

Professor Hermann Einsele – Medizinische Klinik II, Wurzburg, Germany

Professor Javier De La Rubia – Hospital Universitario La Fe, Spain

TF:            Welcome to ecancer.tv. It’s now the beginning of summer in Western Europe and just we had recently the ASCO and EHA meetings and it’s a good time to summarise new results in the treatment of multiple myeloma. So the participants today for this ecancer.tv meeting are Dr Hermann Einsele from Germany, Dr Javier De La Rubia from Spain and Dr Pieter Sonneveld from the Netherlands and we will discuss together the main issues in multiple myeloma as well as novel agents in the treatment of the disease. My first question for Pieter is that we discuss every year which are the treatment goals in multiple myeloma and if all these treatment goals are now different, now they’re different in elderly patients and in younger patients in fact.

PS:            Thank you, that’s many questions. I think the ultimate treatment goal first should be to relieve symptoms in the patient and then try to achieve a rapid response. Then, as regards the depth of the response, currently most experts would agree that CR, the complete remission, or complete response if you want, is what we would like to achieve because that correlates with a longer progression free survival and maybe even overall survival. So this should be the treatment goal in both the younger and the older patients, however, the way to get there might be different.

TF:            And we have heard also about new techniques regarding the assessment of response, especially Spain is one of the major countries in the field, especially minimal residual disease assessment and also looking at emerging techniques, we have now PET scanning. So, Javier, do you think that these techniques have to be implemented into routine practice, yes or no, and would it be the case in the future, for example?

JD:            Yes, we have now much more effective treatments so it’s easier to reach better quality of responses. Despite this, there are some patients that relapse even with biological good complete response. Maybe this is because we are not refining the quality of response, not only in the marrow but also outside the marrow. In this regard, I think new imaging techniques, as you say PET scan but also MRI, probably are going to add some value in order to better define a global response, not only biological but also extramedullary response. However, I think that for the time being it’s too early to incorporate these techniques as a routine practice but, for sure, they are going to have a very important prognostic impact in the next future.

TF:            So we agree that it is still investigational but that will probably be important in the future.

JD:            Absolutely. Yes, for sure.

TF:            On the other hand, another main topic, of course, is the concept of consolidation and maintenance so we have some results with Velcade-based consolidation, lenalidomide-based consolidation and maintenance, both in the transplant setting and in the non-transplant setting. So, Hermann, do you think, how can we address the issue of consolidation and maintenance in the younger patient in the transplant setting?

HE:            What we have learned is that a patient who achieves a complete remission probably has the longest time until he progresses. Therefore, one of the major goals that was already addressed in one of your questions before is to achieve a complete remission with a first line treatment. We know that not all, only part of the patients undergoing autologous stem cell transplantation, even when they have received novel agents during induction, will achieve a complete remission. Therefore the idea is to do something in addition to improve response quality also after transplantation and that is consolidation. I think there are increasing data from small studies still that by giving additional treatment after stem cell transplantation you can actually improve quality of response and, probably coming out from a few studies, also prolong progression free survival. So I think consolidation will be a big issue in the future, in future trials, and in some countries actually, according to their guidelines, consolidation therapy is already administered. The second point is maintenance, maintenance means not really improving on quality of response but maintaining the patient in complete remission or in a very good remission and there are different strategies that have been tested in the past, it has been interferon, steroids, conventional chemotherapy and none of them has really improved progression free, and especially overall, survival. But with the novel agents we now have available we can either give thalidomide, bortezomib or lenalidomide post-transplant. We had a discussion very recently about  especially thalidomide and the feeling in the group was that thalidomide can be given and was shown in six studies to prolong progression-free survival and in three studies also to prolong overall survival but that is probably a small proportion of patients that are benefitting from thalidomide maintenance, mainly patients that do not show high risk features and patients that are tolerating the drug for a certain period of time and also patients that have not already achieved a very good partial remission post-transplant. So thalidomide is an option but probably only for a proportion of patients. With bortezomib we know, especially from the HOVON German study, that maybe even a high risk patient population might benefit from long-term application of bortezomib; I think this will have to be studied in further trials. And lenalidomide we have very clear data on prolongation, a significant prolongation of progression free survival from the IFM and from an American study but we don’t have enough data to really see that it’s also prolonging overall survival. So lenalidomide is very effective in prolonging progression free survival but we need more data and probably a slightly longer follow-up.

TF:            Do you think, Pieter, that the issue of consolidation, and especially the issue of maintenance, is different in the elderly patients? That’s my first point and the second point is that could you comment, we know that the EMA has reached a decision on lenalidomide maintenance very recently in the transplant setting and also in the non-transplant setting. Could you comment on this and this decision?

PS:            Yes, I think the road to a cure is very long in the elderly patient, in the non-transplant patient, so as long as we cannot achieve cure we should try to achieve a long progression free survival which in the elderly may be 75% of the lifetime that he still has. So every attempt should be made to get a good remission again, a CR, with the first treatment. One example of consolidation has always been that once you achieve the maximum response in a patient you give two or three extra cycles which can be regarded as a consolidation kind of treatment. Later, like Dr Einsele explained, thalidomide has become available but only for a short time span and not in all patients, patients with poor cytogenetics may have a disadvantage from using thalidomide. As you mentioned, more recently lenalidomide has been used in clinical trials both in the transplant and non-transplant setting, both as an early treatment after conventional treatment which can be regarded as consolidation, and then continuing as maintenance in the elderly and the younger patients. PFS has been improved dramatically in all the trials that we have seen so far but so far no overall survival advantage. The data have to mature and so we cannot routinely recommend lenalidomide maintenance at this point but looking at the data it’s very likely that in two or three years from now we will see a definite advantage in favour of lenalidomide maintenance also translating in overall survival advantage and hopefully this will further improve the outcome in these patients.

TF:            And this is in line with the three papers recently published in the New England Journal with the lenalidomide maintenance as well. So looking forward to probably the next EMA decision for myeloma we have the sub-cue Velcade which will likely be approved in a few months. What can you say about sub-cue Velcade? Do you think that we will switch from IV Velcade to sub-cue Velcade in all countries and very rapidly or..? Pieter, could you…?

PS:            Well, I cannot speak for all countries but I think the main advantage of sub-cue Velcade is that it’s more easy to administer, may be administered at home, and it’s probably better tolerated by the patient because it is associated with less polyneuropathy. This is the main advantage. We do not, at this time, know the exact outcome in terms of efficacy of sub-cue versus IV but all the data point in the direction that, at least in the relapse setting, the efficacy is similar between the two administrations. So in my view, and this will also be the case for the European Myeloma Network Trial, we will switch from IV to sub-cue but keeping to the same schedule, twice-weekly.

TF:            And is the situation different in Spain or do you anticipate that, for example, the VMP will be VMP with sub-cue Velcade for all patients, for example?

JD:            Yes, I think so in Spain. In fact, in some centres it’s already being used sub-cue, bortezomib, although it is still not approved. However, I have some concerns regarding the widespread use of sub-cue bortezomib, especially in younger patients. I think there are still not enough data to show superiority, I mean to show the same results in the front line setting with sub-cue versus IV, So from my point of view, before changing to sub-cue formulation, especially in younger patients or even patients with more aggressive disease, with severe renal failure, very high extramedullary disease, we’ll be more cautious before recommending the general use of sub-cue bortezomib.

HE:            I think the pressure is really coming from the patients now because I often see patients and when I advise them to have a bortezomib-based treatment, they say, “We have learned and we have seen the literature…”

TF:            “We’re OK for sub-cue.”

HE:            “We want to have sub-cue, we don’t want to have IV.”

TF:            No, you are right, that’s correct.

PS:            One big difference may be if the patients tolerate better, have less polyneuropathy, you may be able to continue the treatment for longer than with IV. So even if efficacy is a little bit less, on the other hand continuation will be better and so the overall outcome may be the same.

HE:            Yes, and especially if we think about long-term application like in your study with giving bortezomib for two years, I think it’s a big advantage to do it at  home and to have less toxicity.

JD:            Yes, at least in Spain, although we are going to have sub-cue bortezomib, we are not allowed to administer it outside of hospital. So the patient still needs to come to the hospital to receive the drug. And, on the other hand, in our previous BTD trial for younger patients receiving BTD as induction therapy, only 7-8% of the patients had to reduce dose of bortezomib due to polyneuropathy. So I think that is going to be much more useful for elderly patients or even patients who have relapsed and had previously received bortezomib and had developed some grade of neuropathy.

TF:            Another still important topic is high-risk myeloma; is there any change regarding the definition of high-risk myeloma or is that the same we had last year or…?

HE:            I think what we increasingly have learned is that especially the 17p deleted patients have a  very poor outcome and I think there’s only one study, and that’s the HOVON/GMMG trial, where really with the long-term administration of Velcade one could have changed the prognosis of the patients. In all the other studies I think the 17p deleted patients are really the patients with the worst outcome and there’s also increasing knowledge about extramedullary disease and that extramedullary disease already at the first presentation means that the patient has a very bad prognosis.

TF:            And a plasma cell leukaemia.

HE:            And, of course, plasma cell leukaemia as well. I think these are probably the three situations where the situation of the patient with all conventional treatment is rather poor.

TF:            Would you say that the novel agents we have today make a difference in (4;14) patients and in patients with deletion 17p? Yes or no, basically?

PS:            I think it’s yes and no. Because in the HOVON trial, as was mentioned, the 17p deletions, they improved with bortezomib but not completely to the level of patients without 17p. In other trials it was not so clear and (4;14), which we expected to benefit from the bortezomib treatment, did not so in terms of PFS and overall survival in our trial as in some other trials. So there’s still doubt and we have to do a meta-analysis of all the trials to see with larger numbers of patients what the outcome with and without bortezomib will be. As for other agents like lenalidomide it’s even less clear at this time.

TF:            And Javier, would you say that we have to treat differently patients with high-risk disease and standard risk disease, I would say?

JD:            Ideally we should develop strategies specifically for defined subgroups of patients, one of them is those with high risk disease. Unfortunately we still have not the therapeutic tools or even yet to discriminate so well which patients are going to benefit from which treatment. So up to now maybe the only exception is to consider the early use of allogeneic transplantation in younger patients with very high risk disease. But apart from this, I still think that we must administer the same treatment to every patient regardless of prognostic factors and see how to do the adminstering.

HE:            I think the problem is at the moment, with all the therapeutic options we have, we only cure probably a very small minority of patients even among the good risk patients. Therefore, whereas in other diseases where you have a very high rate of cure, like in Hodgkin’s disease, you can actually decrease the intensity of the treatment but in myeloma, unfortunately, we haven’t really reached the stage where we can say we can reduce it because even in the good risk patients we are curing only small proportions. We should offer all risk categories the best treatment options we have.

TF:            And back to the recent ASCO and EHA meetings, in your opinion what are the most important results presented at ASCO and EHA? And probably this is a question for all of you.

HE:            I was quite impressed about some of the new antibodies that are coming along and I think the anti-CD38 antibody…

JD:            Daratumumab.

HE:            Daratumumab, that was tested in the Netherlands and then also in Scandinavia, I think those results are really impressive.

TF:            Yes, because it was active as a single agent which was really not the case for the previous one.

HE:            Elotuzumab, yes. And maybe the antibodies are offering or opening a new window of treatment opportunities for myeloma patients.

PS:            Yes, and in addition I think also the new proteasome inhibitors like carfilzomib, but especially also the oral ones like Millennium 9708, are really promising. They have been used mostly in the relapsed refractory setting so far but even there I think good responses are observed. Also these agents can be used in combination with IMiDs and steroids to have a full oral effective regimen which can be used both for the older and the younger patients.

TF:            That’s true. And Javier?

JD:            No, I would like to stress the forthcoming of the third generation immunomodulators like pomalidomide that also look very promising, even in patients relapsing after lenalidomide treatment. So I think we have now several realistic options to rescue more patients.

PS:            And in addition I would also like to add both at ASCO and EHA in the last half, we see more and more efforts to really get to the biology of myeloma, to the molecular analysis of what’s driving the disease are the changes from the diagnostic samples to the relapsed samples and we see on an individual basis, for example by whole genome sequencing or whole exome sequencing, we see changes at relapse that were not present at diagnosis. So if we can incorporate this information in our therapeutic decision making, hopefully we can make a step forward.

TF:            That will have some impact on treatment decisions probably and then treatment strategies as well. So, OK. Would you agree to say that, looking at ASCO results and EHA results, we have now a lot of novel agents including some monoclonal antibodies, some new proteasome inhibitors and new IMiDs which will be very important for the treatment of myeloma, both for the elderly and for the younger patients? And all these novel agents will be incorporated into treatment strategy,into induction, into consolidation and probably in the maintenance setting as well. OK, thank you very much for your attendance.