2010 American Society of Hematology Annual Meeting 3rd - 7th December

Interview with Prof Pieter Sonneveld - Erasmus University Rotterdam, Netherlands

Key multiple myeloma research from ASH 2010

KS        Keith Stuart

PS        Pieter Sonneveld

KS        So, Pieter, give us your thoughts on what’s exciting in myeloma here at this meeting.

PS        Well, first of all, I think we see the new drugs coming through now in first line therapy, including the proteasome inhibitors, the next generation of those drugs, with exciting results there I would say.

KS        Do you think there are any particularly combinations that got you excited at the meeting?  Were there updates on trial regimens?  I heard there were some studies that suggested that you couldn’t really distinguish too much between the cocktails; they were all very good.

PS        Yes.  But still, if I may mention our trial from the HOVON in Europe, in Holland specifically, we compared, let’s say, bortezomib for injection phase as standard and then transplant and then thalidomide maintenance over bortezomib maintenance.  What we observed there is a highly significant improvement of progression-free survival and also survival in favour of the bortezomib treated patients and this may be partly due to the maintenance that we added for two years in this regimen. 

KS        How did you give the bortezomib in that regimen, as maintenance?

PS        It’s an easy regimen.  Bortezomib, IV, just one injection every two weeks for two years.  It’s well tolerated, no drop offs for toxicity, especially no neural toxicity, so that’s well tolerated. 

KS        How big a difference was there between bortezomib and thalidomide maintenance?

PS        Well, thalidomide maintenance is less well tolerated.  Almost 70% of the patients have to stop thalidomide maintenance, even at 50 mg per day during that maintenance period, but for the bortezomib more than 50% are able to continue until the end of maintenance.  So there is a difference there.  And in terms, for example, of progression-free survival, it’s median follow-up of 40 months.  The difference is 36 months for bortezomib and 27 months for thalidomide progression-free survival.  So there is definitely a difference.

KS        I’m presenting at this meeting also on a thalidomide maintenance trial from the National Cancer Institute of Canada and in that trial, thalidomide improves progression-free survival very substantially, but does not improve overall survival, and I wonder if you have any overall survival data from your trial?

PS        I think you have a good point there.  Thalidomide is improving definitely as a maintenance treatment after, let’s say, the standard therapy.  We also see 10% more CRs, more very good PRs with thalidomide maintenance for two years, but I doubt whether it results in a better overall survival in our trial, given the difference between the bortezomib maintenance and the thalidomide maintenance. 

KS        How do you think, given the revlimid maintenance studies that will also be presented at this meeting, showing also very good improvement of progression-free survival with the three drugs.  Do you have thoughts on which is optimal or should they be put together in combination?  Where do we go from here?

PS        Yes, it’s an interesting question.  Our trial was the first one which presents, let’s say, a significant number of patients with bortezomib maintenance, so it’s too early to say if bortezomib is really the maintenance therapy of choice.  Thalidomide will not be the treatment of choice for me because too many patients have to quit thalidomide because of neuropathy.

KS        Yes, we found the same thing. 

PS        Yes.  So in the end I think we should also be able to prefer lenalidomide, but I would like to do a head to head comparison between bortezomib and lenalidomide.

KS        Or maybe both together.  One of the themes, I think, that is emerging is using more drugs earlier and using them for longer, particularly in combination, so it seems logical to use both perhaps?

PS        Absolutely.  Maybe even combine.

KS        No another study, a big study, that’s being presented at this meeting involves the use of allogeneic bond marrow transplant, a North American trial which is being presented tomorrow and suggests that it does not improve outcomes in patients, in fact maybe slightly worse than standard risk patients.  Do you have any thoughts on that study?

PS        Well, I’m not surprised.  This trial that you mention is a big trial.  Over the years we have done three successive randomised trials with auto-allo tandem transplantation in each of the three trials and if you take the data together, they’re worse than single auto or even tandem double auto.

KS        Right.  So you would... in your smaller trials, you would have predicted the outcome of the larger trial?

PS        Yes.  It’s along the same line and even more disappointing is that we expected that with allo, we would reach a plateau phase survival or in progression-free survival, and that did not happen.

KS        So do you think allogeneic transplant should be abandoned completely in myeloma, which is my own bias?

PS        I think in its current way, yes. What we have been trying to do and are doing now is to add lenalidomide after allogeneic transplant in order to, let’s say, stimulate the immune system, NK cell activity and so on. 

KS        Would the message be, yes, as part of a clinical trial, but probably not outside of a clinical trial?

PS        Absolutely, but in the context of reduced intensity conditioning and then doing the allo and trying to play with the lymphocyte  infusions and, let’s say, modifying the immune system by adding certain drugs like lenalidomide.  We expected that we could play a little bit and improve the results of allo, but even there, the results don’t seem very promising.

KS        So, just very quickly, to end, there were a couple of other very interesting studies I wanted to get to.  One was on the use of bisphosphonates and particularly in the use of zoledronic acid from the United Kingdom, and there’s some very provocative results I believe which suggest that patients who get zoledron on a continuous basis actually live longer by about six months, if I recall.  What are your thoughts on that study and how it will change our use of bisphosphonates? 

PS        Well, I think everyone is impressed by the results – excited is too much, but impressed yes.  In my view, the comparison arm is not the optimal arm.  Clodronate, an oral drug, which is...

KS        There’s some suggestion that may have inhibited their ability to take other oral drugs by causing GI distress.    

PS        Yes, that is one issue.  The other issue is that clodronate by itself is very poorly absorbed in the intestinal system.  But anyway, in the end, the outcome is that by adding a bisphosphonate you can add six months of life for these patients and this is, I think, for the first time that somebody has shown that.   On the other hand, people are trying to downgrade pamidronate infusions, like the [unclear] group has done, from 90 to 30 claiming the same results.  So I think there is some way to...

KS        What will you do in your practice, going forward?

PS        At this time, we are still giving pamidronate, but I think zolendronate is tolerated very well, so based on the UK data, we will probably change to zolendronate.  We still have to discuss whether you should continue for life on that drug because it’s another expensive drug that adds to the cost of treatment in these patients.

KS        Of course.  There’s not pamidronate made to the same... I guess it hasn’t in previous trials produced overall survival, so maybe it’s something unique to zolendron...

PS        No.  The trials that have looked at that were negative, not only in myelomas but in breast cancer and...

KS        So, last question – there were some exciting updates on new drugs.  Do you have thoughts or comments on which of the drugs that have been presented are most exciting and which...?

PS        Well, if I can name one without having a preference, but I have seen the results of carfilzomib in frontline treatment.  The trial is still ongoing, there’s a dose escalation ongoing, but the CR rates are astonishing, close to 70% just in the induction phase of treatment, and this is very promising.  So I’m looking forward to that.  We are working ourselves with carfilzomib in frontline combined with thalidomide and dexamethasone in transplant candidates.

KS        We also have a frontline trial for next year, but so far it looks very promising.

PS        It looks good, yes. 

KS        What about pomalidomide?  Do you think that has a future? 

PS        Yes, well, if you look back to pomalidomide as it was used a couple of years ago, the results were good at the time, but there was more toxicity.  Now we are starting just a trial, so I have no personal experience, but it’s one more example of a drug that has a specific effect and can be used in combination.  And maybe for the future carfilzomib and pomalidomide is the best combination.

KS        It’s going to be a very attractive combination.  We will be updated our pomalidomide results from the Mayo Clinic here and it continues to look very promising, particularly exciting that it works in people who’ve failed bortezomib and revlimid.  So both of those drugs, I think, have a bright future.  Well, Pieter, thank you for your time.  That was fun and...

PS        Thank you, Keith, for the discussion.  I liked it too.