Myeloma Determination Study | Paul Richardson, MD | IMS 2022

Hello, my name is Dr. Paul Richardson and I'm the Director of Clinical Research at the Jerome Lipler Multiple Myeloma Center at Dana-Farber Cancer Institute in Boston. And I also serve as the clinical program leader there, as well as the R.J. Corman Professor of Medicine at Harvard Medical School. It's really my privilege to have been part of a phenomenal International Myeloma Society meeting here in Los Angeles. Not only is it wonderful to be together with everyone, but also the quality of the work presented in the discussions has been simply superb. It's truly an international meeting, so we've had an enormously varied number of presentations, not just based on American work, but very importantly on partners in Europe and across the world. And so that's been a very important focus of the meeting. In terms of the work, it's been my privilege to present here on behalf of my co-investigators. Probably the most impactful has been results from our determination study. Just to remind everyone, this was a very large national trial run across 56 centers. We started the design for this trial back in 2008, so that's almost 14 years ago. Started the actual French study that we were partnered with in 2009 and our own study in 2010. In that context, we ran two parallel studies to try and best understand the role of autologous stem cell transplant in newly diagnosed transplant eligible patients under the age of 65. And to understand whether early transplant was in fact the gold standard or in fact could there be delayed transplant in selected patients based upon the results of the study. What we were looking to do was explore not only the impact of RVD therapy as induction but as consolidation. And then above all, the role of maintenance until progression, which back at that time was a serious area of concern because maintenance clearly mattered. The question was how long? Could it be until progression or should it be shorter? So our French partners ran their trial with maintenance for just one year and we ran our study with maintenance until progression based on our own data from the CLGB 111 study where we'd shown not only a two and a half year progression free survival gain to maintenance until progression, but most importantly we also showed a two and a half year survival gain with this approach. So this was really an important trial in the United States. Now the good news is it's taken us since we started 12 years to report the results, which tells you how well folks have done. Because obviously when we report on a study, we have to have maturity of follow up but above all events that allow us to interpret the results. And what I'm very pleased to report is that we showed a dramatic progression free survival advantage to early transplant and in particular advantage to maintenance in both arms with some of the best results ever seen with either approach. But what we also show, which is so important to understand, is that if you kept transplant in reserve and used it or other strategies later, there was identical survival overall. So this was really important to understand because when you have a big progression free survival gain, yet overall survival is actually the same, it begs the question is there an interaction here that may be both helpful and perhaps in some respects less helpful. So what was very important in our trial was to demonstrate at this meeting or analyze at this meeting how different risk groups of patients behaved with the treatment that they were assigned to. So on the one hand, with RVD alone we were able to show excellent tolerability, maintenance and progression got some of the best results in that regard. Response rates were actually very similar between both arms of the trial. We did show MRD negativity however was higher if you had early transplant versus delayed. What was important to note there, it was around 40% for the RVD alone group versus around 54% for those who had transplant early. And that difference trended to significance. Interestingly that also translated into progression free survival equivalence. In other words, if you achieved MRD negativity you had identical progression free survival whether or not you had transplant or not. But what was really impressive was the progression free survival advantage of early transplant compared to keeping it in reserve. It actually was a gain of around 20 months. But what's so important to note is that in those who had a delayed transplant or could use it later, in fact 28% of these patients did, although 72% of patients chose other approaches the survival was actually very very similar between the two arms with long term follow up now exceeding around 76 months, almost 80 months in fact. So very important information. Now at this meeting what we showed was that in the high risk patients transplant early did appear to make an important difference. This certainly was true in terms of progression free survival and it was also a trend towards And what we mean by that is that whilst it didn't achieve significance there was a clue that in particular high risk patients the use of early transplant may impact on survival. So very important finding. The question is who were these high risk patients? Well what we ascertained was they weren't necessarily patients with 17P deletion for example but they may have had other cytogenetic abnormalities and other particular cytogenetic abnormalities associated with higher risk. So not all cytogenetic abnormalities behave the same. So in the conclusion of our talk was that number one different risk profiles did differently. High risk disease clearly seemed to benefit from early transplant in terms of progression free survival by a large margin and a trend in overall survival and at the same time however those with standard risk features or above all those who achieved MRD negativity even if they had a transplant or didn't did very well. So lots of food for thought going forward recognising that in the modern era now we don't use RVD alone we use RVD plus an antibody and so this has really changed the playing field yet again for the better and obviously there are other quadruplets like KRD, Dara that is widely used and others under study such as combining isotuximab with those same platforms and all of these are showing great promise with very high rates of MRD so I think the future for patients looks really very rosy and if you need a transplant it clearly is an appropriate thing to do if you're eligible and if you're of the right age and have the right fitness but if for whatever reason a transplant is perhaps better to be kept in reserve for whatever other issues there may be clearly these data support the role of it being reasonable to do that on the understanding that if you collect stem cells and use them later that may be a very reasonable strategy to use. Now an important point of discussion at the meeting was that in certain healthcare systems this may not be the case. In the US we're obviously blessed with many new drugs, in other countries the healthcare systems may not allow that and so for that reason at the meeting there was a consensus that transplant clearly for eligible patients was the right thing to do early if one was thinking in a global sense. Thinking to the future and especially to US patients the ability to sort of say one size does not fit all I think was clearly supported by the data and the discussion that we had.