What we’re presenting here is the first presentation of a very large double-blind randomised trial comparing the use of zoledronic acid, which is kind of the standard of care for the treatment of myeloma related bone disease, to denosumab which is a monoclonal antibody directed against RANK ligand. It is the first time we are presenting this dataset; it is one of the largest multi-centre international trials of close to a little over 1,700 patients actually, so one of the largest international trials that we are presenting in myeloma. The other nice thing about this trial is all of these patients, in fact, the eligibility was that these are newly diagnosed patients comparing standard of care of zoledronic acid with denosumab as bone targeted treatment for myeloma.
What methods did you use?
Like I said, this was a double blind randomised trial; we have over 1,700 patients in this trial. It was a one to one randomisation with half the patients getting zoledronic acid plus placebo versus the other half getting denosumab, which was the experimental arm, plus placebo. It was blinded to the investigator, it was blinded to the study sites as well as patients. Our primary endpoint here was looking at time to first SRE. We did have secondary endpoints and the secondary endpoints were time to second SREs and time of overall survival. We did have an exploratory endpoint and that was essentially looking at progression free survival in these patients. The way we randomised these 1,700 patients was we did a little bit of risk stratification so that we looked to see whether patients were getting novel drugs versus non-novel and the way we defined novel drugs was IMiDs and PIs, proteasome inhibitors, versus others. We also controlled for whether they were supposed to get a transplant versus not a transplant and then we risk stratified based on the international staging system for myeloma.
What were your findings?
What we found here was, like I said, 1,700 patients randomised in a one to one way, we found that SREs in both arms, there was no difference in SRE rate in both denosumab versus zoledronic acid, our secondary endpoint. So we found equivalence in the study with respect to SREs; we did not find any superiority but what was very striking in the study was we found a huge progression free survival benefit in the experimental arm. So patients getting denosumab had a close to ten month improvement in progression free survival in our patients who were being treated with these bone targeted agents.
What were the implications?
This is something which is akin to what has been presented by the MRC IX trial and the big difference here is this very striking difference in PFS. We don’t yet see an overall survival benefit and I think part of the reason we don’t see that is the follow-up is short. It’s a newly diagnosed study with a median follow-up of about 17 months now and we’re going to need to wait a little bit longer. The fact that we see such a dramatic PFS benefit can only mean two things: one is that you actually have denosumab having a very significant anti-myeloma activity and, unlike the MRC IX trial, this is being compared to another very potent antiresorptive. So zoledronic acid, unlike the MRC trial which compared it to clodronate, is a very potent antiresorptive despite which we are seeing a very marked difference in progression free survival. So that has been striking and actually quite surprising to all of us.