14th International Myeloma Workshop

Hot topics at IMW 2013 - interactive discussion

Professor Philippe Moreau – Centre Hospitalier Universitaire de Nantes, France
Professor Jesus San Miguel – University Hospital of Salamance, Spain

Welcome back to Kyoto, day three of the Multiple Myeloma Workshop. Today we will have an interactive panel discussion and we received many, many questions on the website so it means that people outside Japan are interested by the discussions here. I will ask Professor San Miguel, who joins me today, some questions regarding the treatment of elderly patients that we received. We received one considering the standard of care of elderly patients, so for fit elderly patients what, in your opinion, is the current standard of care, frontline treatment?

OK, let me, Philippe, tell you that I suppose that I’m not going to be here only to answer the questions, I will ask you some questions as well. I think we have already two standards of care, particularly in Europe, and both of them are based on melphalan and prednisone and are MPT, melphalan, prednisone plus thalidomide, and melphalan, prednisone plus lenalidomide. In the United States, not yet approved in Europe…

MPV – melphalan, prednisone and bortezomib.

So plus bortezomib, yes. In the United States, not yet approved in Europe, up front another standard of care is lenalidomide-dexamethasone. There is one very interesting trial that hopefully we will have data very soon, the MMM20 trial in which MPT has been compared with len-dex, either a fixed period of time or continuing len-dex with maintenance. Probably at the next ASH meeting we will have data on this important trial to know if len-dex is superior to MPT and, if it is superior, if it is superior based on the maintenance or not, which is going to be a huge difference. Regarding MPV, the only thing that I can say is that the consolidated data after five years’ follow-up for the shortest follow-up of the last patient in, there is one year, thirteen months, advantage for MPV as compared with MP and it’s really robust data as a good standard of care. Nine seconds.

Thank you, so this is really very clear. What is your current thinking of the future use of daratumumab? So can you give us some possibilities, let’s say?

Yes. As I said yesterday in the symposia, for many years myeloma doctors have had a dream and this dream was to have a monoclonal antibody similar to rituximab that they have, the lymphoma doctors. And probably this dream has become reality, first with elotuzumab that is showing impressive results in combination with lenalidomide and dexamethasone and there are phase III randomised trials in newly diagnosed as well as in relapsed refractory patients. I think we expect, all of us, that the trials are going to be positive for the combination. Daratumumab is an obvious monoclonal antibody because CD38, together with CD138, are typical plasma cell markers. They are not specific of plasma cells but are very characteristic in plasma cells because of the intensity of the expression. What is fascinating to see is that a single agent, daratumumab, is showing approximately 40% of patients responding to this single agent in a reduction, more than partial responses or at least minor responses, half and half partial and minor responses to make a total of 40%, in patients that had been refractory to other agents. Then why I am really interested in monoclonal antibodies is because the mechanism of action is different and then will allow you to do many combinations. We are almost ready to start a clinical trial combining VMP, one of the standards of care that you asked me before, plus daratumumab, it’s going to be a pilot study.

Can you tell us briefly about the toxicity of daratumumab?

The toxicity has been demonstrated mainly with infusion reactions and it’s not a strain, if you are talking about monoclonal antibodies, humanised monoclonal antibodies, but usually they were controlled with corticosteroids.

So your thought is that maybe we are going to combine this monoclonal antibody that is not toxic with other well-known combinations.

Lenalidomide-dexamethasone plus MPV, whatever it is. Yes, I think we are going to face a situation very similar in that has been observed in the lymphoma.

OK. That’s also very, very interesting. We had a lot of discussion regarding smouldering myeloma and are we ready now to treat high risk smouldering myeloma? So in this situation your group, the Spanish group, performed a very interesting trial. So can you summarise this study, the results, the main results, and the outcome following these results?

Yes. Probably I would like just to go back to you after I answer this question about the criteria that we use for diagnosis of multiple myeloma because I think that this is going to be very important. What we have done is to identify a sub-group of smouldering myeloma that are the high risk smouldering myeloma. Our personal view is that these are not really smouldering, they are early myeloma because they have high chances to progress within the first two years. In these patients our position is that we wanted to test a convenient treatment, not a combination, associated with low toxicity in order to see if an early intervention may delay the progression and, at that time, as a secondary objective it was overall survival. The good news of this trial with a mature follow-up of more than 45 months shows that there is a very significant difference in time to progression to symptomatic myeloma with a hazard ratio of five points.

So we are delaying the onset of symptomatic myeloma?

Delaying the onset of symptomatic myeloma and when you are talking about symptomatic myeloma in this population we are not talking… what I expected was anaemia.

Yes.

The most frequent complication is bone disease and renal insufficiency. And don’t forget that these patients were followed up, the follow-up in these patients was monthly. And in spite of the monthly follow-up, we were facing these complications.

You had some patients with renal impairment.

And the other important good news is that the overall survival is significantly better and now it’s consolidated.

In my opinion this is a most important finding.

This is an important one, this is an important one. We waited one year, we reported one year ago already a benefit in overall survival but we decided to wait another year just to see if this was just a trend or if it was consolidated. And what we have observed is that this is clearly consolidated. I think this opens really a new panorama about the treatment of myeloma early.

The study was not a study for the approval of the combination in smouldering high risk.

No.

It means that… do you think that it will translate into clinical practice very soon or we have to wait for the confirmation with another study? I know that there is another study that is going on in the US in the same population of patients.

Yes, I think we need to wait a bit more. I think we need to wait a bit more but I would confess to you that we are just in the process to activate a new trial in high risk smouldering, but in the young population, the transplant candidates. And the endpoint is going to be [?? 8:25] negative at five years.

You are telling me that you want to perform an autologous stem cell transplantation in high risk smouldering?

Yes, this is going to be… it’s going to be run almost in parallel to the symptomatic patients with the same approach – triplet induction, autologous transplant, consolidation and maintenance.

With the goal of achieving [?? 8:49] negativity and maybe curing?

Maintain it and maybe curing. And I think, unfortunately, we talk about chronic disease and we talk about…

Second line of treatment…

Cure, but we are, I think, far away. And probably if you look today at symptomatic myeloma, the best results are for stage 1. If you look for pulmonary cancer or breast cancer, the best results are for early disease, early intervention. And probably by delaying the treatment you are assuming the risk of more aggressive clones to emerge.

But nevertheless we’ve heard today a very good talk from Gareth Morgan indicating that at the stage of smouldering with high risk you have many, many clones so maybe the disease is already there and very heterogeneous and maybe it will be difficult to cure these patients.

We have looked to the high risk smouldering and the profile is exactly the same as the multiple myeloma. Then the point is why wait if it is there? May I ask you something?

Yes, for sure.

Let me ask you about the diagnosis. Today I was a bit shocked with the presentation of Ola Landgren with CRD in high risk smouldering because he has said as an exclusion criteria we use CT/PET. If CT/PET is positive, the CT showing clear lenticulations, disease already.

Yes, in fact I think that maybe Ola today anticipated future definitions of multiple myeloma with imaging techniques. We all know that as soon as the MRI is positive in a smouldering myeloma it seems that these patients are not yet smouldering, well not symptomatic but a true multiple myeloma. I think that they are anticipating on the role of PET/CT in the future and we had some questions regarding PET/CT in symptomatic patients. One question was that we’ve heard a lot about the prognostic value of PET/CT, how do you think that it could be translated into the clinical care in the future?

Let me follow the previous question and I will join the current question that you are asking me. In the previous one I would say that I have been very conservative in the diagnostic procedure for myeloma and I stick always to the plain X-ray. But it is true what I heard today and what sometimes patients told me: “Why do you ask me to do thirteen X-rays, don’t you have something more convenient and particularly more sensitive to detect?”

More sensitive, for sure.

More sensitive to detect, why the lymphoma patients, why other patients have more sensitive techniques and you are sticking to very old techniques that require 30% lost in the body mass just to show [?? 12:06]. And probably we are delaying the diagnosis. And this was the same as one patient told me, “Treat me now that I am stage 1, don’t wait until I have a big [?? 12:18].”

“I don’t want to wait to be symptomatic to be treated.”

To be treated. But regarding PET as a prognostic marker for symptomatic myeloma, I think we are now a bit back as compared to the lymphoma doctors. The lymphoma doctors were faster than us in the monoclonal antibody and I think they are ahead of us in the use of PET but they have learned something, that PET requires strict rules for interpretation.

Yes, standardisation.

Standardisation, the timing that you do, the [?? 13:00] that are hard to measure and I think myeloma is far away, still, from that.

So we need to reach a consensus regarding standardisation.

No doubt, no doubt.

How to interpret a bone lesion, what is the SUV and so on.

I think it’s the time just to have a group of myeloma experts to work with nuclear medicine experts just to start to do similar to what has been done in the lymphoma.

That’s really interesting. So I would like to thank you, Jesus, for these interpretations and proposals. So thanks again.

It’s been a pleasure.

And see you soon. Thank you very much to all of you and we will welcome back very soon again for future discussions. Bye bye.