EHA 2015
EHA 2015: Expert opinions on new treatment standard in multiple myeloma
Prof Pieter Sonneveld – University Hospital Rotterdam, Rotterdam, Netherlands
Prof Antonio Palumbo – University of Torino, Torino, Italy
Prof Gordon McVie – European Institute of Oncology, Milan, Italy
Prof Thierry Facon – University of Lille, Lille, France
GM: Welcome to a round-table at the European Haematology Association meeting in Vienna. Very exciting, very busy, very hot. We’ve got a very distinguished panel, multinational panel, and we’ve got Sonneveld over there and Palumbo in the middle and Facon here. So you’ll be telling us, one by one, what are the highlights of this meeting. Particularly exciting is multiple myeloma, of course. Pieter, why don’t you kick off?
PS: At this meeting, indeed… by the way it’s the twentieth anniversary meeting of EHA and again we have reached a large audience at this meeting here in Vienna. It’s not for nothing that we are seeing exciting news. In the field of multiple myeloma, especially clinical studies, I think we have seen at this meeting a couple of very promising results or updates of results that were presented before. I would like to start with the first trial, which is a trial for patients that are not eligible for a transplant programme and who need treatment for a diagnosis of multiple myeloma. Dr Facon, from Lille in France, he published a paper in the New England Journal about the first results in this trial. So, Dr Facon, can you elaborate a bit on what the trial effect was and what the updated results really bring to the audience.
TF: Yes, as you say, the trial was designed for elderly patients with myeloma and these patients are… the majority of myeloma patients are elderly patients in fact. So the study was designed for newly diagnosed myeloma, as you said. So basically the comparison was melphalan prednisone and thalidomide, which was a standard of care for these patients for some years, versus lenalidomide and low dose dexamethasone given either for a fixed duration or continuously. At the time of the first publication we said that basically lenalidomide and dexamethasone was a better regimen, it was true for the progression free survival, it was true for the survival as well at the time of an interim survival analysis. So at this meeting we presented an updated analysis for PFS and for survival as well. So the results have been fully confirmed. What I can tell you is that looking at the progression free survival there is not a lot of difference between this analysis and the previous one. The median progression free survival is 26 months for the continuous lenalidomide and dexamethasone arm; it’s around 20 months for the two other arms. Looking at the survival, and this is still an interim analysis for survival, the median survival for the continuous lenalidomide dex arm is approximately 5 years, so that’s 59 months. I think that’s the take home message. The take home message is to say that nowadays with this regimen, and that’s true for some other regimens as well, you can get 5 years median survival in elderly newly diagnosed myeloma patients. We also did a sub-analysis according to age and so we will present the updated analysis according to age for PFS and survival. The good news is that for very elderly patients, so patients over 75 which represent approximately one third of myeloma patients, these results are still valid. So there is a PFS advantage and there is a survival advantage as well, which is approximately a one-year difference for survival in favour of the lenalidomide versus the thalidomide. Regarding safety, there is not a lot of difference for safety between patients 65 and 75 and patients over 75. So the conclusion is that this lenalidomide and dexamethasone regimen is now a standard of care for elderly newly diagnosed myeloma patients. This is also true for very elderly patients so that’s [?? 4:17]. And the good news is that this regimen has been approved by the FDA and EMA some months ago so this will be an available regimen for European patients basically.
PS: Thank you. So we will come back to that later. I would like to ask Dr Palumbo who really was one of the first to think about elderly frail patients, what to do with those patients, whether we can treat them in the same way as, let’s say, people below 75 or without frailty. What’s your opinion about the results in this update?
AP: They’re certainly very important. I think the results presented by Thierry are showing basically, I would say, two concepts: one that continuous therapy is essential to prolong progression free survival and the second the use of an oral administration to very easily deliver lenalidomide and corticosteroids can be superior to a three drug combination like MPT with a survival of 5 years. Today it’s very important to differentiate among all the elderly population the fit from the frail. The fit could probably take advantage of a three drug combination, bortezomib plus lenalidomide, bortezomib plus alkylating agents, while on the other hand the frail population might take, probably, more advantage of a two drug combination including from one side lenalidomide, from the other side bortezomib.
PS: So for many people who are listening or watching this, they now face a choice - what is the preferred regimen for the non-transplant eligible patients? Will it be RD continuously or a bortezomib based regimen like MPV or bor-dex with cyclophosphamide? These are questions that have to be answered in some way. Dr Facon, maybe I know your answer but please…
TF: No, these are difficult questions, honestly, and I would not put bortezomib against lenalidomide. I think the first statement is to say that these two regimens are good regimens for elderly patients. So then it’s partly a discussion between physician and patient. Looking at efficacy, the efficacy of the VMP and lenalidomide and dex is probably quite similar. What is true is that, as said by Dr Palumbo, it’s easy to administer lenalidomide and dex because it is oral but the VMP is still a standard of care for the elderly.
PS: So if we look to specific subgroups, like the patients with adverse cytogenetics if they are available. Do you think that might influence the choice of treatment?
AP: Personally not. I don’t think that today we do have a specific treatment for high risk patients, for patients with chromosomal abnormalities. Unfortunately the poor prognosis is still poor prognosis in multiple myeloma and we do need, certainly, specific treatment for a patient carrying chromosomal abnormalities but today we do not have it.
PS: So a question to both of you: is melphalan no longer the standard for the elderly patients?
TF: I think that what has been shown in the first trial is that an alkylating agent free regimen can be better than an alkylating agent containing regimen. So that has been done in the context of this particular study. On the other hand we say that the VMP or the VCD are still good regimens for the elderly and, as you know, we have ongoing studies still based on melphalan. So we have the carfilzomib, melphalan, prednisone study, we will have a VMP daratumumab study. So I would not support too much the fact that melphalan has been killed by the first trial. So that’s a statement for some of our US colleagues. But what is true is to say that we have now and we will see more regimens not based on an alkylating agent and some of these regimens will be extremely active.
PS: So do you think this will be beneficial for the patients also in terms of late effects?
AP: Absolutely, yes. I think that, in my opinion, the real difference is probably the three drug or a more dose intense treatment for the fit patient, the two drug or a less dose intense treatment for the frail patient. Then according to your choices for the three drug you can combine IMiD with proteasome inhibitors or proteasome inhibitors with alkylating agent and probably with time cyclophosphamide will come out as a better tolerated drug than melphalan. But I agree that today to say that melphalan is dead is probably too early.
PS: We also have seen abstracts and presentations on three other drugs that are not yet approved but are promising in Europe – carfilzomib, elotuzumab and daratumumab. So let’s start with carfilzomib. Dr Facon, do you think carfilzomib will be the new drug replacing bortezomib?
TF: Looking at the ENDEAVOUR study which has been presented at ASCO and again at this meeting, I think the study has shown a significant PFS benefit in favour of carfilzomib moving from 9 months to 18 months which is a huge difference. I would agree to say that carfilzomib is likely a better proteasome inhibitor than bortezomib to make short a long story. I am still a little bit concerned by the… I am not sure the toxicity profile of carfilzomib is as good as the toxicity profile of bortezomib but that’s my personal opinion. For sure this drug will be approved and will have to play a role in myeloma. I would like to see a little bit more data in elderly and very elderly patients with carfilzomib and possibly different regimens with carfilzomib as well.
PS: Can you comment on that? Do you have personal experience with trials?
AP: I would say that in a brief comment carfilzomib is a second generation proteasome inhibitor; it certainly has a major advantage that is the lack of peripheral neuropathy. There is a small signal in terms of cardiac toxicity, mainly hypertension after infusion that I think with time will be probably less relevant than we might think today. On the other hand, we may have different dosing of carfilzomib that might represent also different opportunities for different patient populations. So certainly a lower dose of carfilzomib, 27 or 36, is probably very well tolerated in the elderly patients; a higher dose of carfilzomib, 45, 56, might be delivered in younger patients. And certainly there is a significant increase in terms of complete response rate. So we are putting together the lack of peripheral neuropathy and an increase in complete response rate.
PS: Two other drugs have been presented here and that’s the antibodies. So there’s elotuzumab and daratumumab. If we start with elotuzumab which has been around a little bit longer than daratumumab. What do you think, Dr Facon, what will be the place of elotuzumab in the future?
TF: It’s difficult to say exactly what would be the place of elotuzumab but the ELOQUENT-2 study is basically a positive study. So the study was designed for relapsed refractory patients, the control arm was lenalidomide and dex and the other arm was lenalidomide, dex and elotuzumab. They had two primary endpoints, so the response, which is better with elotuzumab, and the PFS, which is also better with elotuzumab. So you may want to discuss the magnitude of the PFS benefit. But anyways there was a PFS with a clear and rapid separation of PFS curves. Looking at efficacy across subgroups, so elderly versus younger patients, standard cytogenetic versus high risk cytogenetics, there was a benefit for elotuzumab and the safety profile was quite good as well. I think this is a good study and this is a good drug. Things are moving so fast in myeloma so it’s difficult to say exactly what will be the role and what will be the place of elotuzumab in terms of sequencing. But what is true for sure is that this drug will be approved and this drug will be used for myeloma patients.
PS: So am I wrong if I conclude that this is a valuable addition to the therapeutic arsenal that we have? We of course also wait for the results in the first line treatment with ELOQUENT-1. So thank you for these comments. Then, moving to daratumumab, an anti-CD38 antibody, what is your comment there? Lots of studies going on now, what may we expect from daratumumab?
AP: We are in the early development of daratumumab but certainly there is a great excitement because we have been waiting our R-CHOP and been jealous of our lymphoma colleagues for years. Probably we now have the opportunity to combine our standard treatment with antibodies and certainly daratumumab does represent one of these options. The CD38 antigen is the antigen for myeloma plasma cells and these antibodies might represent a major change in the treatment paradigm of multiple myeloma.
PS: Thank you. So, in addition, looking to all the technical developments like MRD molecular characterisation I think we may conclude that at this meeting the clinical studies had a great impact and will have for our patients in general in the years to come.
AP: If I can I would give a last word for another drug that is coming and is an HDAC inhibitor such as panobinostat that might have a role specifically in patients resistant to bortezomib. This is another novel agent coming. So more difficulties for us in how to choose the right treatment but certainly much more options.
GM: It’s a very rich time and we haven’t even started on the anti-PD1 or the anti-PDL1. It’s about the only area of solid tumour oncology where they’re a little bit ahead of the haemato-oncology people. It’s really encouraging to see now that the clinical triallists are taking this into account. But as well as the elderly issue you guys are bombarded with riches. You’ve got proteasome inhibitors, you’ve got antibodies coming out of your ears. I take my hat off to you because you’re really doing very well organised, well disciplined, well logically planned clinical trials. Therefore the evidence is coming out and is improving patient outcomes. 5 years for multiple myeloma. I saw 20 years’ worth of Medical Research Council trials where we were talking about the same 37 or 38 months and now this is just transformed totally. And we haven’t really mentioned stem cell transplants may just be going away. I hope that melphalan personally goes away and I hope that cyclophosphamide goes away and all the cytotoxic drugs go away. So thank you very much indeed, both Pieter and Antonio for taking up that side of the argument and for Thierry for a really nice presentation and congratulations on that nice trial. Thank you very much indeed, that’s all we’ve got time for in Vienna and I’m signing off. Thanks.
