At EHA this year we presented on behalf of my colleagues, particularly the first author Dr Giri who is one of our junior colleagues, a meta-analysis of the impact of daratumumab in the treatment of multiple myeloma patients according to cytogenetic risk.
We all know there have been multiple randomised phase III trials, both in the newly diagnosed setting and in the relapsed setting and in the newly diagnosed setting both in the transplant eligible and non-transplant eligible population that compare backbone multiple myeloma regimens with the same backbone myeloma regimen with the addition of daratumumab. So in the newly diagnosed setting we have ALCYONE, we had MAIA and most recently we had CASSIOPEIA in the transplant eligible patients. In the relapsed setting we have now CASTOR, POLLUX and more recently CANDOUR. While all those trials were positive in terms of progression free survival, when you look at subset analysis, particularly for the trials in the newly diagnosed setting, it does not seem to be a significant advantage for patients with high risk chromosome abnormalities, here defined as deletion 17p, translocation [4;14] and translocation [14;16]. So that has raised some concern that perhaps, at least in the newly diagnosed setting, daratumumab may not add any to those regimens in patients with high risk chromosome abnormalities.
However, an alternative explanation that this may have to do with the low sample size, with the under-representation of high risk patients on those studies, or perhaps even a shorter follow-up, or perhaps even a real but yet diminished effect in high risk as compared to standard risk. So in order to try to address that question we performed a methodologically rigorous meta-analysis essentially looking at the entire literature, both published literature as well as abstract, presented in meetings for all trials that compared backbone myeloma regimen versus that backbone plus daratumumab. We came up with the six trials that we already cited.
Then we looked at the impact in PFS for both standard risk as well as high risk patients. In the newly diagnosed setting we looked for standard risk, the benefit of daratumumab was pretty obvious with a hazard ratio of 0.45 that was statistically significant. But when we looked at high risk for the first time we demonstrated that benefit was also significant with a hazard ratio of 0.67 with a confidence interval of 0.47 to 0.95, so statistically significant. In the relapsed refractory setting we saw a very similar picture with a significant hazard ratio of 0.38 in the relapsed refractory setting and 0.45 in the newly diagnosed setting.
So we think this study is very important because it reinforces here the notion that the reason why those individual trials didn’t show significant PFS improvement in the high risk setting has to do mostly with the smaller presentation of high risk patients in those trials and shorter follow-up and a somewhat slightly diminished biological impact that daratumumab has in high risk as compared to standard risk. Nevertheless, in the newly diagnosed setting daratumumab still reduced the risk of death or progression by a third with a hazard ratio of 0.67 which is really important for this very difficult to treat patient population.
While those trials were hetero-indifferent in terms of what that one regimen or even what population they included, we did formal testing for heterogeneity and there was no significant heterogeneity across these studies, suggesting here that the impact of daratumumab, the benefit of daratumumab, does not seem to be context specific or regimen specific. So this seems to have an impact really regardless of what the backbone regimen is.