What is the data coming out of ASH 2012?
It’s been a relatively quiet year at ASH this year for myeloma. I think most of the interesting work has been updates on use of new agents, for example, carfilzomib which was just FDA approved this summer in the United States and hopefully soon in Europe; a number of updates on the use of that drug, particularly in newly diagnosed patients in combination therapies with cyclophosphamide, with lenalidomide and with thalidomide. So very encouraging results – high response rates, deep responses, reasonable toxicity and particularly a notable lack of neuropathy, I think that has been one of the stories coming out of this particular ASH meeting.
The second drug is pomalidomide and pomalidomide, again, some updates on phase II trials essentially confirming activity in about a third of highly refractory patients. But most importantly for pomalidomide is the presentation of a phase III clinical trial called the NIMBUS trial, conducted mainly in Europe, which was a look at pomalidomide-dexamethasone versus supportive care or best standard of care. High dose dexamethasone which shows not only improvement in response rate but, more importantly, a significant improvement in overall survival in patients who had failed all other therapies and I think that bodes well for subsequent approvals worldwide for pomalidomide in a patient group that desperately needs new therapies.
So those were the main updates on new drugs that are most likely to come to the clinic soon.
What are the new therapies coming out of ASH 2012?
There were two particular categories of new agents which were of interest; the first were monoclonal antibodies. Unlike lymphoma and many other cancers, there is no monoclonal antibody yet approved for use in myeloma. We saw some very exciting updates on an antibody called elotuzumab used with lenalidomide and dexamethasone in relapse with very impressive overall response rates of 90% and, more importantly I think, a 27 or 28 month progression free survival which is almost double what one would expect from historical controls of lenalidomide-dexamethasone alone and that combination of elotuzumab-lenalidomide-dexamethasone is in phase III testing for both relapsed and for newly diagnosed patients. So that is quite exciting and hopefully in the next year or two we’ll get the results of that phase III trial.
Also daratumumab is an anti-CD38 monoclonal antibody; again in relapsed patients an impressive response rate. There was dexamethasone given along with it which may have contributed to some of that but I think what was compelling was that there is a dose response to the antibody suggesting that that is at least contributing to the activity of the combination. I think again this is an antibody that has some promise and we’ll wait for some phase II and then subsequently phase III trials to emerge. There are many other monoclonal antibodies that were described at the meeting but those are probably the two that are the most mature in their development.
The second class of drugs are essentially kinase inhibitors, we don’t have a kinase inhibitor in myeloma, we have proteasome inhibitors, steroids, alkylators and immunomodulators but we don’t have a kinase inhibitor. We heard about two single agent active kinase inhibitors at this meeting, one called the ARRY-520, which is a kinesin spindle protein inhibitor; it shows some activity in about 15% of patients when given on its own, highly refractory to other treatments. And then from our own group we described dinaciclib which is a CDK, but particularly CDK5, inhibitor which again has a 15-20% single agent response rate. So those two drugs are, to my knowledge, probably the only two that we heard about at this meeting that look like they have some activity and should move forward into the clinical trial arena.
What have been the most interesting abstracts on biomarkers?
The most interesting work on biomarkers, and there were maybe five, six or seven abstracts on this topic, was the target of thalidomide, lenalidomide and pomalidomide, the immunomodulators, which turns out to be a protein called cereblon. Cereblon is a protein that not much was known about; it was expressed in the brain, which is where its name comes from. It turns out it’s a very specific target for all three of those drugs; if the protein is not there the drugs don’t work, they’re completely inactive. So there were a number of presentations at the meeting looking at various ways of measuring levels of cereblon by immunohistochemistry, by gene expression, by RT PCR and then trying to correlate that with clinical outcomes and they all essentially have concluded that by measuring cereblon you can predict response to these drugs and you can predict survival as well. So there is no commercial test yet, this is the first run at this from a research perspective and I think we’ll hear more about this as the year is going on. Given the expense of these drugs and the fact that you may be able to predict which patients will respond and which patients won’t, particularly those who should stay on maintenance and for how long, I think that’s got a lot of legs and a lot of promise going forward.
There are a lot of big trials underway, what can we look forward to at ASH 2013?
Next year, I think there are a lot of big phase III trials that are maturing right now that will be very interesting next year. We have trials coming looking at a histone deacetylase inhibitor, panobinostat, in phase III trials; we have carfilzomib being used with lenalidomide-dexamethasone in a phase III trial; we have melphalan-prednisone-thalidomide versus lenalidomide-dexamethasone – a very large 1,500 patient study and I’m probably forgetting a couple. But I think it’s going to be a big year next year for phase III studies that will really tell us where the field is going and what new drugs are likely to help our patients.
What are the take home messages from ASH 2012?
The good news in myeloma is that we’re doing better. We’ve presented from Mayo Clinic our experience showing that both in younger patients but, more importantly, in the elderly population we’ve almost doubled survival in the last five years alone. What we need are probably less expensive and more convenient drugs going forward; for now all of our combinations are very expensive and they’re not that convenient. What is nice to see at this meeting was the arrival of some oral compounds, oral proteasome inhibitors in phase I testing which will help the convenience issue. Cost – the good news is we’re doing better, the bad news is it’s expensive.
How do you recruit onto trials and what median age do you look for?
The median age of myeloma diagnosis is around 70 so many of our patients are elderly and they find it difficult to travel for clinical trials. Nevertheless, I think in all of the studies we do you see patients in their early 80s and certainly many in their 70s participating, so that hasn’t really been a barrier. What traditionally we have done in myeloma is divide patients into the younger population who can go for transplant and the older population who require a less aggressive approach. It’s been interesting to witness over the past year or two a blurring of that distinction such that elderly patients now are getting a fairly aggressive therapy, almost comparable with the younger patients without the transplant and seemingly tolerating it well and are increasing their survival as a result.