Developments in proteasome inhibitors, transplant and myeloma research

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Published: 14 Dec 2011
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Dr Keith Stewart - Mayo Clinic, Scottsdale Arizona, USA

Dr Stuart Smith speaks with Dr Keith Stewart at ASH 2011 in San Diego on developments in myeloma research presented at the annual meeting.  Some developments in the field highlighted by Dr Stewart are a number of protease inhibitors in development, including one which is being used in a clinical setting. The most notable finding was the increased rate in complete remission. In addition to discussion on the progress of histone inhibitors from a phase III trial, where data was presented at the ASH meeting.  Dr Stewart notes that the focus of myeloma research now is on the sequencing, combination and scheduling of treatment, as well as transplant development.

2011 ASH Annual Meeting, December 10-13, San Diego, USA

Developments in proteasome inhibitors, transplant and myeloma research

 

Dr Keith Stewart - Mayo Clinic, Scottsdale Arizona, USA

 

Hello and welcome to the 2011 ASH meeting in San Diego. I am delighted to welcome Professor Keith Stewart from Mayo Clinic, who’s going to give us a bit of a perspective on myeloma at this year’s meeting.

 

Thank you, Stuart.

 

Keith, very welcome. Perhaps I can start by just asking your general feelings about some of the developments at this year’s meeting, from a myeloma perspective?

 

Well thank you. This meeting, myeloma continues to see remarkable progress due to many of the new drugs that have become available to us, particularly the proteasome inhibitors. At this meeting we will hear more results on carfilzomib, a novel proteasome inhibitor, in the newly diagnosed patient, which has shown, when combined with lenalidomide and dexamethasone, quite remarkable response rates including extremely high levels of complete remission, offering hope for the patients.

 

We’ll also hear about some very novel agents that we have been exploring, particularly vorinostat and panobinostat, which are histone deacetylase inhibitors. At this meeting, the results of a large phase III trial will be presented to see if vorinostat contributes to the response rate in patients who have received bortezomib. So these are some of the things that we’re really looking forward to hearing about. There is also a third proteasome inhibitor that sounds like it has some clinical activity from Nereus Pharmaceuticals; and we are getting further updates on some of the new immunomodulator drugs particularly pomalidomide. So these are the things together I think that show slow and steady progress, and better outcomes for patients.

 

And we were sitting through the myeloma education session yesterday, Ken Anderson was trying to give us an overview of emerging novel therapies in myeloma,  that was quite extraordinary the number of compounds that are coming through; I think he mentioned most of the interesting developments. Where do you see myeloma treatment going in terms of how do you choose the winners? How do you pick a winner in terms of best combination looking at different modes of action?

 

Well that will take more research to figure out which combination of each drug and how long and what schedule is optimal, but we now have regimens which consistently give close to 100% response rate; we have regimens on which the complete remission rate is extremely high. What the field is really focussing on now is what is the sequencing scheduling dose, much in the way in that with acute lymphoblastic leukaemia in children, once you have a portfolio of drugs, the trick becomes to figure out how to give them in combinations and for what period of time that results in cure, and that’s where we are with myeloma.

 

At that same education session Professor Sergio Giralt gave his overview of the role of transplant,  tandem transplant for example. What are your thoughts on that in terms of myeloma treatment?

 

In our own practice we continue to offer autologous transplant to most of our younger patients. We still believe it probably has some benefit in reducing tumour burden in the patient. Allogeneic transplant we have not offered our patients outside of a clinical trials setting. We have very rarely done tandem transplants recently because the complete remission rate with new drugs in the single transplant is extremely high.

 

People are beginning to challenge the notion that the transplant is as useful as it used to be. There is a large study going on between the French co-operative group and the Dana-Farber in Boston, to ask the question once more, is transplant really contributing a lot to these patients once they receive the best combination of new drugs. And that trial we probably will hear about in the next couple of years.

 

You had a presentation yourself, looking at cereblon expression, particularly in relation to IMiDs, I wonder if you might like to perhaps comment on that?

 

Well, as many of you will know, the use of thalidomide in myeloma was stumbled upon somewhat serendipitously by Dr Bart Barlogie and his colleagues and it was used because of its antiangiogenic effect. Subsequently, lenalidomide and pomalidomide have become widely used worldwide for the treatment of myeloma and other cancers. Unfortunately, what we knew about these drugs until recently was that they do a plethora of things to the immune system - they kill cancer cells but we never really understood why, which was amazing really when we think that these are drugs which are used worldwide in many, many patients; and we really had very little understanding of how they worked and what the key to the lock was. About a year ago a paper came out in the journal Science, showing that thalidomide binds to a protein in the cell called cereblon, and cereblon got its name because it had been linked to childhood mental retardation but very little was known about its function. It was an unexpected finding, and they showed in that paper that binding of thalidomide to cereblon was the reason that thalidomide caused such severe birth defects when it was given to pregnant women in the 1950s, 1960s. So when we saw that paper we concluded that this was probably the key to the lock for the cytotoxicity in myeloma cells. And so our paper today basically proves that hypothesis. Thalidomide, lenalidomide, and probably pomalidomide require cereblon to be effective. If cereblon is absent in the cell, the drugs have no effect whatsoever.

 

That has a number of implications for myeloma doctors and patients. Number one, you may be able to predict who will respond and who will not respond, based on whether cereblon is present or not in the cell, that’s a topic of future work. Secondly, you can now very accurately, I think, begin to decipher the exact pathway through which these drugs were working, and try and dissociate side effects from efficacy, develop better drugs that target, now we know what the target is. So I think for many reasons, this is a pivotal discovery that’s going to change, over the next number of years, give us a much better and deeper understanding of how myeloma cells grow and survive and what you can do to turn them off.