ASH 2015

ENDEAVOR: carfilzomib new standard in multiple myeloma?

Dr Keith Stewart - Mayo Clinic, Rochester, USA

You’ve been looking at the relapsed refractory setting in multiple myeloma, what was it you particularly wanted to investigate?

At this meeting we’ve seen an update on a clinical trial that was called ENDEAVOR. ENDEAVOR took patients who had had one to three prior relapses and randomised them, a very large study, over 900 patients, to receive the standard of care, bortezomib dexamethasone or the investigational arm which was carfilzomib at relatively high doses, 56mg/m2, along with dexamethasone.

So what did you do in the study, how many patients did you have and how did you conduct it?

There were over 900 patients randomised, it’s one of the largest randomised controlled trials in multiple myeloma to date. It was a direct head to head comparison of bortezomib, which is well known to our community, and carfilzomib, which is still in the regulatory approval processes in many countries.

So two proteasome inhibitors, what happened?

The carfilzomib containing arm dominated and out-performed the bortezomib containing arm. Progression free survival was almost doubled from over 9 months to over 18 months for the carfilzomib treated patients which was an even better performance than most of us expected. Toxicity was really not a big issue, there is a slight increase in toxicity in the carfilzomib arm given at that dose compared to bortezomib but there is no neuropathy with this drug which is a major advantage. Depth of response was higher, overall response rate was higher and, as we’ve already said, PFS, time without therapy, was better with the carfilzomib arm.

It sounds as if we ought to be seeing something about a change in overall survival, was there any?

Not at this stage. That is too early to look for overall survival advantage at this point and so we don’t have data on that. We’ll have to look at that and report that in subsequent years.

So what are the clinical implications coming out of this do you think?

The clinical implication is that most patients at diagnosis receive bortezomib today and when they relapse the question was do you go back to that drug or do you use carfilzomib, a novel proteasome inhibitor. The answer to this trial is definitively carfilzomib is the drug of choice in this situation. Now, there are other drugs, as you know, that have just recently been approved by the FDA in the United States and soon elsewhere that have to be built into this mix but for cost and economic reasons as well as convenience use of a doublet therapy where there’s only one expensive drug such as carfilzomib has been shown in this trial to probably be equivalent to most of the triplet therapies using new drugs.

What about earlier in the disease then? Do you think this proteasome inhibitor could be used elsewhere?

Carfilzomib has already been studied in newly diagnosed patients in phase II clinical trials with very impressive results but is not approved in that indication yet and has not been subject to randomised phase III trials. But those are now underway.

So what’s the bottom line coming out of your announcement here at the American Society of Haematology for doctors?

The bottom line is the doublet therapy of carfilzomib dexamethasone at one to three prior relapses is really the proteasome inhibitor of choice.