2011 ASH Annual Meeting, December 10-13, San Diego, USA
Update on the phase III VISTA trial
Dr Jesus San Miguel – University Hospital of Salamanca, Spain
This year we are seeing more consolidated data that were in the past year, not many new things but more consolidated results.
Could you update us on the phase III VISTA trial?
This is a very consolidated trial because we presented, many years ago, here at ASH for the first time after a median follow-up of sixteen months showing a significant benefit for the experimental arm that consisted of the combination of bortezomib plus melphalan prednisone over the control arm that was melphalan prednisone and the benefit was observed in terms of response rate, time to progression and overall survival. Now, in this ASH meeting, what we are going to do is to close the information about this trial with a median follow-up, now, of five years, minimum follow-up from the last patient in of 4.5 years. And the data is mainly focussing on overall survival and the incidence of second primary malignancies. As you know, overall survival has improved in myeloma but it’s sometimes difficult to demonstrate the benefit of an up-front line of treatment with novel agents due to the high efficacy of rescue therapies. Frequently the results that are positives in terms of progression free survival do not translate into an overall survival benefit due to the high efficacy of the rescue therapies. For this reason, although initially in this trial there was benefit in overall survival as well, we wanted now to see if this benefit in overall survival is consolidated after five years follow-up. In addition it should be taken into account that with a prolonged survival of myeloma patients they are at higher risk of developing second primary malignancies and nowadays, since this is important, it’s also important because we are using novel agents and we don’t know sometimes if the novel agent could have a carcinogenic effect. In this presentation we will address, for the first time as well, what is the incidence of second primary malignancies, on produce with bortezomib in combination with melphalan prednisone.
The results, after a median follow-up of sixty months, are highly positive in terms of overall survival. The median overall survival for the experimental arm, bortezomib melphalan prednisone, is 56 months as compared to 43 months in the control arm, this means more than one year difference in overall survival. This benefit was observed across all predefined sub-groups, in other words the benefit was also observed in patients over the age of 75, in patients with advanced stage and in patients with poor renal function. In addition, in this analysis we wanted to focus particularly in the subsequent therapies given to the patients at the time of relapse and the distribution of novel therapies used at the time of relapse are homogeneous in both arms, VMP and MP, with one exception, an obvious exception, and is bortezomib. Less patients in the VMP arm, the bortezomib arm, received subsequent treatment with bortezomib as compared to the control arm. The response rate to the rescue therapies was equivalent, for bortezomib a similar response rate with thalidomide rescue therapy, similar response rate with lenalidomide used as a rescue therapy.
I think it’s of particular interest, one sub-analysis that we have performed, and this analysis tried to address the paradigm of using MP up front and at the time of relapse being rescued with bortezomib to be compared with VMP up front. In other words, this is a recurring question, could it not be the same to use a more conventional approach up front and to reserve the novel drug for the time of relapse, as compared to using the novel agents directly at diagnosis and the results are clearly in favour of using the novel agents up front and not reserving them for the time of relapse. In addition, in this sub-analysis we have observed that the use of bortezomib up front is not associated with more resistant relapses.
The second part of this study focussed on second primary malignancies. What I can say as a summary is that the incidence of second primary malignancies was the same in the experimental arm as compared to the control arm and was a very low incidence, relative risk around 1, similar to what is observed in the general population of an age of 65-75 years of age. The number of second primary malignancies is very low, it’s 1% acute leukaemias in both arms, 5%, 3% solid tumours in both arms. In crude terms if you analyse by relative risk a hundred patients’ risk exposure, even the figures are lower. Then, I think, we have good news, really good news, because we have now a combination that gives you an overall survival benefit of more than one year over the conventional treatment and the second good news is that we have not an associated risk of second primary malignancies.
Finally I think it’s also important to mention that even in the control arm, now the patients live longer. In the past, trials using MP as control, the median survival was around 35-36 months, now in this trial I have talked about 43 months. This speaks about also the benefit of efficient rescue therapies.