EHA 2016

Meta-analysis of overall survival in multiple myeloma treated with lenalidomide

Dr Philip McCarthy - Roswell Park Cancer Institute, New York, USA

Today we presented the results of a meta-analysis that examined the use of lenalidomide maintenance after autologous stem cell transplant for newly diagnosed multiple myeloma patients. In the past there have been three major studies that had looked at lenalidomide versus a placebo or a control and these were the IFM 05-02, the French study, the American Study, CALGB 100104, and the GIMEMA trial which was lots of literature, RV-209. What we saw in the past is the French study there was a PFS benefit as the same in the US and the Italian trials but there was not an overall survival benefit in the French trial whereas there was in CALGB and there was a trend towards one in the GIMEMA trial. So what was necessary was to do a meta-analysis looking at all three trials using primary data from all three studies. Since all three studies had been reported it allowed us to be able to do this analysis and look at whether or not lenalidomide maintenance truly was associated with an overall survival benefit.

What we were able to show is that, as I mentioned, all PFS endpoints were met and we were able to show that there is an overall survival benefit for the use of lenalidomide maintenance but it took a while. So in other words, the control arm had a median overall survival of about 84 months. It had not yet been reached for the lenalidomide maintenance arm, showing that these patients live a long time now. Which is a good thing for our patients but it’s harder for studies because you have to look several years afterwards to see benefits, sometimes many years after the original endpoint has been met, in this case it was PFS. So what we were able to see is an estimation based on a hazard ratio of 0.74 that we see about a 2½ year increase in overall survival estimated with the use of lenalidomide maintenance when compared to no maintenance.

We were able to pool about 1,200 patients in half receiving lenalidomide, I think it was about 605, and 604 receiving placebo. So this is a large number of patients pooled from those three studies. The GIMEMA trial had both a transplant and a chemotherapy arm so we only looked at the transplant arm. And both the French and the American studies looked at lenalidomide until progression. Of note, there are a couple of things that came out that were unexpected. Number one there was a second primary malignancy signal that was seen in both the French and the American studies and we found this to be related to the use of lenalidomide maintenance. However, when we did a cumulative incidence risk analysis we were able to see that even though there was a higher incidence of second primary malignancies in those patients receiving lenalidomide, there was a higher incidence of either progression or death in the patients who did not. So the risk of a second primary malignancy is outweighed by the benefit of receiving lenalidomide maintenance.

I think that we now see lenalidomide following stem cell transplant as a new standard of care and we’d like to see this being available for all patients worldwide. What will be of course interesting would be to combine this now with newer agents. There are several planned trials that are going to ask this question: there’s the MN trial which looks at lenalidomide with a consolidation question. That just was reported at ASCO, we’ll have to see more long term how that factors in, especially with the use of consolidation.

What we’ll need to see is combining new agents, so there is a planned US trial looking at ixazomib len versus len that is currently planned. We think there are some other very attractive agents such as daratumumab, elotuzumab, both monoclonal antibodies, the proteasome inhibitor ixazomib, which is oral, potentially carfilzomib, which is intravenous, as well as some of the newer agents – there are HDAC inhibitors on the horizon, there’s a nuclear transport protein inhibitor that is currently in clinical trials. These are all very interesting molecules that we potentially would want to incorporate into future maintenance trials, the most important thing being is they have to be well tolerated because patients do get treatment fatigue with prolonged toxicity, even if it’s low grade. So these have to be drugs that have to be well tolerated by the patient and easy to administer.

The checkpoint inhibitors are also very interesting as single agents. They don’t have too much activity but when you combine them with an IMiD they seem to work better. Then, of course, it would be very attractive to potentially combine a checkpoint inhibitor both with daratumumab or elotuzumab, both of which have different mechanisms of action but combined with the checkpoint inhibitor we may see synergy. This is very exciting. What we don’t know is can we now generate something that’s equivalent to R-CHOP in lymphoma. I don’t know if we’re going to be able to do that or whether or not we have to have patients on prolonged therapy to control disease but these are great questions to be able to have to answer for our patients and hopefully it will allow us to be able to allow patients to live a very long time with control of their disease. The one thing that is a problem is that some of these studies have to stay open for several years so what we really need to do is develop early endpoints, whether that’s immune profiling to allow us to figure out which patients have better control of their disease based on their immune status or minimal residual disease testing. These are all questions that we need to answer over the next few years.

What we’re very happy to see is that finally we’re seeing a signal in all three studies that supports the use of lenalidomide maintenance and in particular the fact that we see an overall survival benefit.