ASCO 2010 Annual Meeting, 4—8 June 2010, Chicago

Roundup of the 2010 ASCO conference

Interview with Professor Gareth Morgan (Institute of Cancer Research, Sutton, UK)

Results of the multiple myeloma study comparing zoledronic acid to clodronate

What did you present at ASCO 2010?

I was fortunate enough to be able to present in the meeting the results of a 2,000 patient trial we carried out in multiple myeloma.  Basically, one of the randomisations was to look at the function of aminobisphosphonates compared to first-generation bisphosphonates.  Patients with myeloma have real problems with bone disease, and so this can impair quality of life and survival.  So, we wanted to ask, would this drug, Zometa, reduce the incidence of skeletal-related events?  Would it improve progression-free survival?  And would it improve overall survival compared to the drug clodronate?  The study ran over four years and now has a median follow-up of four years.  It recruited 2,000 patients from 120 centres around the UK.  We showed that both drugs reduce the incidence of skeletal-related events, but Zometa was more effective than clodronate and there was a 25% relative reduction in skeletal-related events in the patients receiving the IV Zometa.  But what’s really exciting, I think, is the fact that the patients treated with Zometa lived, on average, five and a half months longer than the people treated with clodronate.  This is a study with effective treatments in it, and provides evidence to suggest that most patients with myeloma should be treated with an IV bisphosphonate in the form of zoledronate.

The other important thing with any sort of drug, I guess, is its side effect profile.  There have been two things that have worried people about bisphosphonates, the first of which is osteonecrosis of the jaw has been a big potential problem, but I think for a variety of bias reasons the rates of osteonecrosis of the jaw have been over-reported.  So, in this population-based study, there was clearly a significant difference between the two bisphosphonates.  But, it was only 3% in the one arm and nothing in the other, and most of the cases were mild, self-limiting, and didn’t need any form of intervention.  So, I think you can say now that it’s safe to use Zometa and it’s highly effective.  This idea of balancing risks between osteonecrosis of the jaw and skeletal-related events, I think disappears to a large extent.  People were getting 50% SREs in the past in control arms and with this it’s right down at about 30%.  So, it’s a huge reduction in the amount of SREs.

Was the trial age dependent?

This was a trial for all patients, so it came in two pathways, one for younger, one for older patients.  But the benefits were there in both cohorts in the studies.

So, if you break down what the SREs were need for radiation to bone, surgical intervention and fractures, and all of them seemed to be reduced in an equivalent fashion.  So, I think it’s really quite important news.

It becomes the state-of-the-art, doesn’t it?

Yes, absolutely. And the other sort of very interesting thing about it is it’s not just in myeloma where you start to see effects on survival.  There are two big breast cancer studies, one in post-menopausal, one in pre-menopausal women, where improved progression-free survival was associated with the Zometa.  So, I think it there is an anti-cancer effect of the newer bisphosphonates.

And prostate as well?

I’m not sure of the prostate.  I think that’s coming out in the near future.

And what’s the next sort of question?  I mean, there’s another challenge or to Zoledronic acid, denosumab which was reported here as having certain features which might be better?

I think it’s interesting, yes.  I’ve only seen some of the abstract data, to be fair, but if you look at the patients with myeloma that were randomized to Zometa versus denosumab, there was no survival effect in the denosumab-treated arm.  So, it seemed to be looking like, for survival, Zometa was a better drug.

So, the denosumab might be better at preventing skeletal-related events, but there might be a survival advantage for the zoledronic acid down the road?

Yes.

Of course, denosumab has not been studied in a 2,000 patient trial yet, but it’s an antibody and it’s different.

For me, it’s very different and, I mean, equally exciting that it specifically goes for RANK ligand.  So, you’re just breaking one of the feedback loops.  Maybe the Zometa works in  some other stimulatory routes as well as directly killing the tumour cells by impairing  for instance the mevalonic pathway in protein prenylation.

This is a fascinating area.  We could talk about it for a while, how about the interesting extracellular matrix effect in the tumouricidal mechanism of action of zoledronic acid?

There are all sorts of things that the drug does- it stimulates gamma delta T cells in their anticancer effect; it inhibits both cell lines from mouse models of myeloma at least.  So, I think there’s a sort of building body of evidence that suggests they are effective.  I don’t think it’s the absolute solution, but if you’re given the choice between a drug to prevent bone disease and/or something that improves survival, then you would go for the one that does both.

I have to confess that I was involved in early studies of a bisphosphonate from Leiden when I worked in Amsterdam in the 1980s, and they said then that this bisphosphonate group had anti-cancer effects.  They weren’t taken very seriously!

Thank you very much indeed.