Denosumab or zoledronic acid for bone disease in multiple myeloma

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Published: 25 Jun 2017
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Prof Evangelos Terpos - University of Athens School of Medicine, Athens, Greece

Prof Terpos speaks with ecancer at EHA 2017 about the comparative trial of denosumab and zoledronic acid for skeletal disease in new multiple myeloma diagnoses.

Prof Terpos describes how, from a randomised trial of 1718 patients, the progression to skeletal disease at 15 months was equivalent in both arms, with denosumab meeting its non-inferiority goals.

Those receiving denosumab were also found to have reduced renal toxicity, and, in an exploratory assessment, progression free survival was also favourable.

ecancer's filming has been kindly supported by Amgen through the ECMS Foundation. ecancer is editorially independent and there is no influence over content.

Can you tell us about the presentation at this year’s conference on denosumab versus zoledronic acid?

I think that this is a very important study because for the first time we have a face to face comparison of two bone-targeted agents - zoledronic acid, which is the standard of care, and denosumab, which is a novel anti-RANK ligand molecule with a totally different way of action compared to zoledronic acid. So zoledronic acid, let’s say, induces the apoptosis of the osteoclast while denosumab mainly inhibits the osteoclast function without killing the osteoclast. So this one of the biggest differences.

The second difference is that one drug, zoledronic acid, is given intravenously and of course all physicians know how to use it. Denosumab is administered subcutaneously so this is also another difference that may make a difference in our clinical practice.

The study is a double blinded study, randomised one-to-one to zoledronic acid plus placebo or placebo plus denosumab and it includes more than 1,700 patients. So this is one of the largest studies in the field of multiple myeloma. We had also stratified the patients according to the use of novel agents as front-line therapy or non-novel agents; to their autologous transplantation eligibility or not; to the stage of the disease, 1, 2 versus 3. Also we had a stratification according to the previous skeletal related events, present or not, and the region – Japan versus all other areas – in order to have also a better representation of the patients globally.

So the result of the study is that the primary endpoint, which is a non-inferiority regarding the time to the first skeletal related event was met. So denosumab was found non-inferior compared to zoledronic acid regarding the time to first on study skeletal related event and this is very important because if you see the data you can see that after the third month where we had the vast majority of the skeletal related events then we see a difference and we took a landmark analysis on month 15 in order to have one year after the first three months where the majority of the SREs happened. We found that in this 15 month landmark analysis that denosumab managed to have a lower number and also time to the first on study skeletal related event.

I’m going to present to this meeting that all SREs were reduced in denosumab after these 15 months compared to zoledronic acid, meaning that the prolongation of denosumab administration leads to a reduction in skeletal related events, pathological fracture, need for surgery, need for radiation and spinal cord compression. In the three categories, pathological fracture, need for radiation and need for surgery, we had a 20-50% reduction of the skeletal related events after month 15 with denosumab.

A second very important finding of this study is the safety profile. We’ve seen that denosumab has a better renal safety profile, mainly in patients with a creatinine clearance between 30-60ml/minute. We’ve seen that denosumab produces twofold lower renal problems compared to zoledronic acid, 13% versus 26% with zoledronic acid. But within the whole population denosumab reduced 10% of renal adverse events compared to 17% with denosumab. So the renal profile which is very good and this is very important for the myeloma patients that many of them have renal impairment as a primary feature of their disease.

The third, very important also, observation of the study is the progression free survival. Although this was not the primary or secondary endpoint of the study, it was an exploratory endpoint, we’ve seen that patients who received denosumab compared to those who received zoledronic acid had an approximately 10-11 months progression free survival advantage. This is something very important. We checked all the different subcategories of patients, those who received bortezomib-based therapies up-front, an IMiD based therapy or bortezomib and an IMiD and we’ve seen that this hazard ratio is the same across all subgroups meaning that these results are irrespective of the therapies which is logical because we had a lot of stratifications initially: patients who received transplant or non-transplant, received novel agents versus non-novel agents. So I think that this is something important. Of course we understand the statistical limitations because of the exploratory analysis and not the primary or secondary endpoint but this is a very important observation that everybody takes into account as we do know that denosumab is more potent than zoledronic acid.

This is also seen by some adverse events of the drug – it has a little bit more hypocalcaemia, a little bit more osteonecrosis of the jaw, although this is not statistically significant, mainly for osteonecrosis of the jaw in the study, for hypocalcaemia it is. This means that this is a more potent drug and we’ve seen that from the reduction of skeletal related events after the first year and also the progression free survival and because we do know that the osteoclasts support the myeloma cell growth and survival.

So in order to summarise, the major finding of this study is that the landmark analysis after 15 months showed that denosumab is more potent than zoledronic acid with a prolongation of the administration in reducing skeletal related events. We do know that, at least as a primary endpoint, it is not inferior to zoledronic acid according to the time to the first skeletal related event. The renal safety profile is better, we have a prolongation in PFS and although this is an exploratory endpoint I have to mention that. Of course 11 months, 10.6 to be honest, is something extremely important for the everyday clinical practice. I believe that with all these three important observations denosumab will be another standard of care for the treatment of myeloma related bone disease.