Carfilzomib represents potent, effective addition to standard multiple myeloma therapy in phase III study

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Published: 7 Dec 2014
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Prof Keith Stewart - Mayo Clinic, Scottsdale, USA

At a press conference at ASH 2014, Prof Stewart presents his findings surrounding the use of carfilzomib in the treatment of multiple myeloma.

Read the news story and watch the interview for more.

This was a large study, it was conducted in 90 centres in 20 countries around the world and accrued 792 patients. The two arms of the trial are shown here; the reference treatment is Revlimid and low dose dexamethasone weekly. The experimental treatment is the same combination of drugs with the addition of Kyprolis. Kyprolis is given in the same schedule for one year following which the frequency of dosing was reduced and, importantly, after eighteen months it was discontinued.
The primary endpoint of the study was the duration of time that patients were free of disease, or progression free survival. This was highly positive in favour of the combination therapy arm. The median progression free survival for Kyprolis with Revlimid and dexamethasone is unprecedented in first relapse myeloma at over two years, 26.3 months, versus the control arm which did exceptionally well as well at 17.6 months. This is a difference of 8.7 months, the hazard ratio is 0.69. You will note that the maximum separation of the curves is at 18 months at which point the carfilzomib was discontinued as pre-planned by the study.
One of the secondary objectives and the second important take-home message from this study is that overall response rate was also significantly higher for the triplet combination than for the doublet, 87% versus 67%. Even more impressively, the complete response rate was more than three times higher for the patients who took three drugs instead of two drugs.
At this time the median overall survival for both arms of the trial has not been met and did not cross the pre-specified boundary set by the statisticians when the trial started. However, there is a trend in favour of the triplet Kyprolis-containing combination with a hazard ratio of 0.79 and a p-value of 0.018. At two years the Kaplan-Meier overall survival is also trending in favour of the triplet combination.
We’ll talk about side effects just briefly. This is actually another very encouraging aspect of the results we’ll report which is that despite adding a third drug to the cocktail of treatment that the patients were undergoing, adverse events were essentially the same in both arms of the study both for overall side effect profile, the number of patients who had serious side effects. You’ll notice that the number of patients who discontinued treatment at the bottom of this slide due to adverse events was actually slightly higher in the control arm of the study. Importantly, number of deaths due to adverse events was identical in the two arms, this despite the fact a third drug had been added and despite the fact that people on the triplet combination stayed on therapy for 88 weeks compared to the control arm which was on therapy for around 52 weeks.
Another secondary objective I think is worth noting is that we measured health-related quality of life, global health status, for patients participating in the trial. As you can see here on the curves, almost immediately we started measuring this patients on the three drug combination reported a better global health status which persisted for the full 18 months they were on Kyprolis Revlimid and dexamethasone.
So there are five take-home messages here. First, the primary endpoint of time without disease progression was met as we have already discussed, with an unprecedented median time of 26 months. Secondly, there is a trend towards an overall survival advantage although that has not yet been confirmed. Third, the overall response rate is significantly higher and there are three times as many patients in complete remission on the triplet combination versus the doublet. Fourth, despite the fact that we added a third drug and patients were on treatment significantly longer, there was really a fairly well balanced ratio of patients who had to discontinue treatment due to side effects. It’s important to note that both cardiac and renal events which have been reported in some studies of heavily pre-treated patients with Kyprolis in the past were marginally higher in the three drug regimen but overall were very consistent with or even lower than had previously been reported. Finally, patients in the KRD, Kyprolis containing treatment regimen, reported a superior health related quality of life throughout the study.