18th Congress of EHA

Advances in Multiple Myeloma from EHA 2013

Prof Michele Cavo - University of Bologna, Italy interviewed by Prof Philippe Moreau - Centre Hospitalier Universitaire de Nantes, France

Welcome to ecancer.tv. We are here in Stockholm for the EHA meeting, June 2013. My name is Philippe Moreau and I’m working in Nantes in the Haematology Department. I’m joined today by Michele Cavo who is a very famous expert in multiple myeloma working in Bologna, a member of the GMMR group. Michele, maybe we can discuss together on the role of autologous stem cell transplantation in young patients, newly diagnosed. We heard during the meeting in some symposiums that there is really a consensus regarding a triplet induction. What, in your opinion, is the best regimen, the best triplet induction prior to autologous stem cell transplantation?

There is a general agreement that induction before a transplant should be bortezomib based and there is also general agreement that a third agent should be added to bortezomib. We have several phase III clinical trials showing that combining thalidomide or doxorubicin to bortezomib significantly improves the complete response rate, progression free survival and, in a single study, also overall survival in comparison with a control group. These are the results based on phase III clinical trials, there are other possibilities to use triplet bortezomib based regimens. In these regimens lenalidomide or cyclophosphamide are given in combination with bortezomib. Unfortunately we have no phase III clinical trials supporting this regimen and showing the benefit in comparison with the control group.

So in your opinion VTD, well established, phase III data and VCD, or RVD, only phase II studies. But you are running a very important study comparing early versus late autologous stem cell transplantation, you are still enrolling patients in this study, newly diagnosed young patients, with the EMN consortium, and you decided to use the VCD regimen. You are trusting, maybe, the results and you think that it could be equivalent to the VTD regimen?

At the time when we started to discuss we had already robust data supporting the use and the activity of VTD. At that time there were preliminary data supporting that cyclophosphamide combined with bortezomib could equal the results of VTD although there were, at the time, no head to head trials comparing the two regimens. But the main reason supporting the choice of VCD was to avoid an IMiD as induction and to place the IMiD as part of consolidation therapy.

Consolidation, for sure. I understand that, let’s say, in the majority of the countries, not only in Europe but also in the US and Canada, we are using triplet induction and you were mentioning the role of consolidation. We had a very good discussion during one of the symposiums at EHA about the role of consolidation. Round the table we heard from the Nordic group, that they were using, outside clinical trials, consolidation. In Italy you are also using consolidation following high dose. In France the French recommendation is to use a VTD consolidation, two cycles following high dose, also in Greece, Dr Dimopoulos mentioned this point. So, in your opinion, consolidation is now routine, well it’s a standard of care following high dose?

Probably at this time not yet. We have already published the results of a phase III clinical trial comparing bortezomib as a single agent, as consolidation therapy, versus no consolidation showing an improvement in comparison with the control groups in terms of VGPR rate and extended progression free survival. Generally speaking, all the trials using one or more novel agents have shown that consolidation therapy increases the rate of high quality responses and in several of these trials this advantage translated into a prolonged progression free survival from the landmark of starting consolidation therapy. So my personal feeling is that consolidation is an important phase of the auto transplant sequence. Probably we need to confirm in currently running phase III clinical trials the role of consolidation therapy. I think that we have already quite robust data supporting the use of a combined regimen as consolidation. The lesson coming from induction can be replaced also to consolidation and, for example, if you combine a proteasome inhibitor with an IMiD the advantage in terms of extended progression free survival is more remarkable than that achieved, for example, using bortezomib as a single agent. Although several issues are still not yet addressed, for example, the optimal number of cycles to be given to increase as much as possible the rate of CR, the rate of patients with MRD negative disease.

We can maybe summarise, indicating that to date a large consensus is in favour, in fact of consolidation using maybe the same regimens as the one used as part of the induction treatment. And my understanding is that we are not ready for maintenance, in fact. Let’s say maintenance is not ready for prime time, neither with bortezomib nor with lenalidomide. Maybe we’ll have more data with lenalidomide maintenance but my understanding is that the drugs are not approved but we don’t yet have this strong overall survival advantage in favour of the maintenance. What is your opinion regarding this?

I would like to go back to consolidation since I agree with you. When you use a short-term induction probably there is no need to switch to another class of agent as part of the consolidation. The same regimen should be given as induction and as consolidation. Regarding lenalidomide, we have at this time two large trials exploring lenalidomide as maintenance for patients receiving autologous stem cell transplantation. In both of them a significant advantage in terms of extended progression free survival in the 43-44 months range, one of them showing an overall survival benefit and the other no difference at this time signal although, in my opinion, quite low coming from SPM but probably due to the SPM signal. We need to have an overall survival advantage or at least to have evidence that there is no significant impairment in patients’ quality of life. Due to this reason the agency have not yet approved the lenalidomide and probably due to this reason in Europe. I think in the US the landscape is different, that in many centres lenalidomide is already part of maintenance. In the US, probably in use, lenalidomide is not yet part of daily clinical practice.

And another very important question, a burning question let’s say, is the comparison of early autologous stem cell transplantation as part of front line treatment in the context of novel agents or performed at the time of the relapse, the first relapse. In my opinion the two most important trials have not yet been published and reported yet; you have this EMN study comparing early versus late with the VCD induction. We have, in France and in the US, the IFMDFCI study with this RVD plus or minus autologous stem cell transplantation. These two studies are the most important ones but we’ve heard about the results of the Italian study looking at RD as an induction and then patients are randomised to receive either a tandem autologous stem cell transplantation or an MPR regimen. So can you comment on this interesting study? One problem that I would like to emphasise is that you did not use, in this study, bortezomib or a proteasome inhibitor as part of induction. We discussed previously that Vel-dex should be the backbone so maybe patients were under-treated in the conventional arm without frontline high dose treatment. Can you speak about this, although the follow-up is already short?

Yes, we can discuss about the design of the study. I agree with you and the quite low CR rate after double transplant, in the 20% range, might support the possibility that these patients were under-treated or did not receive the optimal treatment in the context of a double transplant procedure. Anyway, the study was designed to compare transplant up front versus transplant delayed until the time of relapse. At this time there is a significant difference in PFS favouring patients receiving double transplant in comparison with those receiving transplant at the time of relapse. The follow-up is very short, we need to confirm the results of this study with the two on-going clinical trials, both of them using bortezomib as part of induction before autologous stem cell transplantation.

Let’s move now, very quickly, to conclude in the relapsed setting. Not many new data right now with carfilzomib, we know that this drug is effective but at ASCO and during this meeting at EHA we’ll hear about the results of this MMO3 study in very, very advanced patients comparing pomalidomide and low dose dex versus high dose dex. So what is your opinion regarding these results and the role of pomalidomide in very advanced patients?

Very, very active; both second generation proteasome inhibitors and second or third generation immunomodulatory drugs hold promise to be very effective especially for those patients who are refractory to bortezomib and lenalidomide. These patients probably are and will be the mathematical need in the next few years. Both the pomalidomide and carfilzomib are very active, are able to overcome resistance to bortezomib and lenalidomide in approximately 30% of patients. The results of the phase III clinical trial comparing pom-dex versus high dose dex are very promising, not only in terms of extended progression free survival but also in terms of a significant improvement in overall survival. And, again, these patients before pomalidomide and before carfilzomib had no chance to receive any active agent for the treatment of a disease in a very advanced phase.

So, in my opinion, the study is also very important because it will lead to the approval of pomalidomide in Europe. We had a good signal from the EMA very recently and the drug will be definitely approved by the end of August. So that’s really a plus for the patients. For carfilzomib we have to wait, in fact, for the results of the on-going FOCUS study comparing carfilzomib versus best supportive care in very, very advanced patients.

Yes, I agree. My personal opinion, I would like to also know your opinion, is that, at least in Europe, we need to be conservative, we need to use pomalidomide after lenalidomide and not as first line therapy because all the advantages are after a prior lenalidomide therapy. Do you agree?

Yes I agree.

Because I do not know if it will happen in the US.

Well, in the US probably the drug will be used very often off-label and early in the course of the disease.

In earlier phases, yes I agree.

Maybe in first, second relapse. I think that we have to respect the labelling of the approval of pomalidomide and, as you mentioned, the activity of this drug is clearly demonstrated in patients refractory or progressing on lenalidomide and bortezomib. So we have to respect the labelling of the approval.

The data are very impressive. I mentioned the significant advantage in terms of overall survival, it is also impressive to see that there is no difference in terms of a PFS duration for patients in the whole group population and patients who are refractory to both bortezomib and lenalidomide. This means that our drug is very active.

Yes, you’re right, that’s really important. So that’s all for our discussion; maybe you would like to add something? I think that we covered the field of autologous stem cell transplantation.

I would also like to remind that the role of double transplant still remains open and probably it needs to be addressed in the context of randomised clinical trials and in the currently running EMN study. Patients in the high dose therapy arm will receive not a formal randomisation but a randomisation by country and they will receive a single or double autologous stem cell transplantation. It may be we need to address this issue prospectively, that double transplant may have a role especially combined with novel agents in patients with very high risk disease due to cytogenetic abnormalities or other prognostic factors.

So in conclusion, we have discussed the role of induction prior to autologous stem cell transplantation with triplet combination. We also discussed about the impact of a consolidation therapy following autologous stem cell transplantation and maintenance with some on-going issues on the role of maintenance in young patients. And we have discussed on the role of pomalidomide and carfilzomib in very, very advanced patients in the relapsed setting.