Lenalidomide, Bortezomib, and Dexamethasone With Autologous Stem Cell Transplantation
In this episode, Paul Richardson, MD, presents the primary results from the randomized phase 3 DETERMINATION trial, which was started in 2010. Dr Richardson speaks about the active combination of lenalidomide, bortezomib, and dexamethasone (RVd) and autologous stem cell transplantation and R maintenance to progression for patients with newly diagnosed multiple myeloma. Dr Richardson spoke on this topic at 2022 ASCO Annual Meeting in Chicago, Illinois.
- Richardson PG, Jacobus SJ, Weller EA, et al; DETERMINATION Investigators. Triplet therapy, transplantation, and maintenance until progression in myeloma. N Engl J Med. Published online June 5, 2022. doi:10.1056/NEJMoa2204925
For more coverage of the 2022 ASCO Annual Meeting, visit our Newsroom.
Paul Richardson, MD, is the Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute and the RJ Corman Professor of Medicine at Harvard Medical School (Boston, MA).
Jessica Bard: Hello everyone, and welcome to another installment of Podcasts366, your go-to resource for medical news and clinical updates. I’m your moderator, Jessica Bard, with Consultant360: A Multidisciplinary Medical Information Network.
Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone, according to the primary results from the randomized phase 3 DETERMINATION trial. Dr Paul Richardson presented these results at the 2022 ASCO Annual Meeting. Dr Richardson is the Clinical Program Leader and Director of Clinical Research at the Jerome Lipper Myeloma Center at Dana-Farber Cancer Institute and the RJ Corman Professor of Medicine at Harvard Medical School in Boston, Massachusetts. Thank you for joining us today. Please give us an overview of your session?
Dr Paul Richardson: Absolutely, Jessica. We presented the primary results from our randomized Phase III trial that we actually started in 2010, and it was remarkable that we were presenting results 12 years later for newly diagnosed myeloma. And that, in itself, says a lot because not so long ago, newly diagnosed myeloma clinical trials would be reporting within three to five years, primary evidence of progression-free survival and so on and our data would not mature until 12 years, which in itself says so much. What we looked at was the impact of novel therapy combinations and the evolving role of transplant in that setting, and our question was with the extremely active combination of lenalidomide dexamethasone, which we call RVD, which generates unprecedented response rates at the time we developed it over 10, 15 years ago, of 100% or so in Phase I, II trials in the upfront setting.
How then does transplant add to that? And what we showed was that when you combined RVD with autologous stem cell transplant, we saw very interestingly, a dramatic progression-free survival benefit for patients who had transplant early. For those patients who were assigned to transplant later, very interestingly, whilst they enjoyed excellent progression-free survival better than we'd seen to date, nonetheless, it was significantly less than those who had transplant early. The important point though, was that for the patients in whom delayed transplant was part of their treatment plan, only about 28% of them subsequently went on to transplant and survival with mature follow-up was identical for both.
So, it helped us understand that whilst there's progression-free survival benefit that's dramatic to the use of high dose mouthful and stem cell support the impact on overall survival ha has not appeared yet, which to us was quite surprising.
We were very pleased by the degree of progression-free survival benefit. So, what we were somewhat surprised about was that this big progression-free survival benefit didn't translate into an overall survival benefit. Now, obviously that's very good news for patients because it means if, for any reason, the patient chooses to keep transplant in reserve. It doesn't appear to result in a decrement in terms of overall survival. But, clearly auto autologous stem cell transplant used early resulted in significant clinical benefits. So, this was important.
So, with the three-drug combination, we showed excellent response rates in both arms of the study. We showed substantial progression-free survival benefit to early use of transplant, but no difference in terms of overall survival with relatively mature medium follow-up with 76 months. And importantly, we were able to dissect some side effect differences between early transplant and keeping it in reserve.
Now, perhaps much as expected. We saw hematologic toxicities with the use of early transplant acutely that were reversible. And, we also showed that quality of life underwent substantial drop using early transplant. But, this recovered over time. These were all expected. But, what we were also very struck by was that the overall rates of treatment related mortality were fortunately very low in both arms. Just 0.3% for those patients receiving RVD alone with transplant kept reserve versus 1.6% for those receiving early transplant. So, these were very gratifyingly low, but actually a little bit different, although not statistically significantly so.
What was striking to us was the issue of second primary malignancies. In our trial, we deliberately constructed the maintenance to be continuous until disease progression and/or intolerance. So, the use of lenalidomide maintenance until progression has remained a question because early studies had suggested it was the correct way to go. Studies in Europe had suggested that perhaps it could be curtailed at one or two years.
What we learned from our study was that, clearly, lenalidomide continuously until either progression or intolerance was absolutely the standard of care based upon a cross-trial comparison that was planned between our own study and a parallel French trial in which maintenance only continued for one year. And, we showed that in both arms, the continuous maintenance resulted in substantial clinical benefit.
So, this was very important. But, what was very important to us as well was, did this result in a higher incidence of second primary malignancies? Because this was a concern for lenalidomide use continuously. And, we're very pleased to see that in fact, lenalidomide use continuously was very similar in terms of overall second primary malignancy rate in both arms at around 10%. What was important though, was that we did see a difference in terms of secondary leukemia in particular AML, MDS.
And this, unfortunately, was very much against melphalan. Melphalan, on the early transplant arm, there were 10 cases of AML MDS versus none in the RVD alone arm. Now, these are fortunately very small numbers, remembering that we had over 720 patients in the trial, approximately 350 to 360 per arm. So, these were small numbers. But, nonetheless, important. So, understanding the differences and why they occurred is a critical sort of future direction.
But, the overall takeaway PFS benefits strikingly in favor of transplant, and overall survival, very similar. Salvage rate of transplants, is actually just 28%. So, 72% of patients received other novel therapies to get the same survival, recognizing we still have more maturity in survival to look forward to. And that, I think could be very informative. And then what we also showed was that response rates were identical, actually, between the two arms except for the highest quality responses. And most importantly, for what we called MRD.
If you tested Minimal Residual Disease assessment, which was looking to see if there was any disease by very sophisticated technologies left behind, and we were able to show that MRD negativity was significantly greater in those patients who received early transplant. But, very interestingly, no matter how you got to MRD, if you were in the transplant early arm or not, if you were MRD negative, your progression-free survival was the same.
So, this gave us an important clue that if you can help patients get to a certain junction point, get them to that MRD negative state, they can enjoy progression-free survival that's equivalent. So, this is a very important secondary endpoint in the trial, and it remains an exploratory one, but something that we are actively studying,
Jessica Bard: We covered a lot there, but could you break it down for us a little bit more? What adverse effects did RVD alone have then also combined with ASCT.
Dr Paul Richardson: Yes. I think there, we saw no unexpected side effects that were different or problematic. As I mentioned, the treatment-related mortality was very low in both arms, just 0.3% for RVD alone and, as I mentioned, 1.6% for the transplant early on. I think what is true is there were significantly more grade three or worse side effects in the transplant early arm. So, this is an important consideration for patients and providers alike. Quality of life, as I mentioned, took a substantial deficit if you underwent early transplant. But, the good news is it was transient. It occurred over about three to four months. And, as patients' quality of life recovered with maintenance, actually there was a rebound effect and they enjoyed excellent quality of life in the longer term. So, these are important pieces of information to share with patients because they're at the highest level of evidence.
This is from a randomized phase three comparison. The element of bias has been minimized by virtue of the study design. And so, because of that, I think clinicians and most importantly, patients and their families can make some important choices. What we were able to do in pre-specified analyses was look at different subgroups of patients and say, well does one size fit all? Does this progression-free survival uniformly benefit everyone? Or, are there certain subgroups by either virtue of disease, biology or other features such as race, does that influence outcome?
And, we were very pleased by the following. Number one, we were able to enroll the largest number of African American patients in our trial seen date in this setting, at approximately 20%. And interestingly, amongst our African American patients, the degree of progression-free survival benefit was actually quite modest compared to Caucasian counterparts.
That is very interesting. We're going to have to better understand why this is, but it helps patients think, "well will transplant really helped me?" Or can I keep something in reserve? We also have done this in other patient subgroups as well. But especially important were in the areas of what we call risk. So, those patients who have high-risk disease, we did see some very interesting trends. For example, if you had certain high-risk cytogenetics, transplant really helped you in terms of progression-free survival benefit. Interestingly, if you had others, actually the degree of benefit was less. So, we're making sense of all of this because what I think it is telling us is that in myeloma in particular, clearly, a tailored approach is appropriate to consider now, based on these data.
Jessica Bard: So, keeping some of those knowledge gaps in mind, what would you say is next for research here? Where do we go from here?
Dr Paul Richardson: Well, there's a super question, Jessica. I think that's exactly right, because remember, this trial was designed in 2008, 2009. We're now in 2022. Three drug platforms, then, were being established as a new standard of care using novel therapy backbones. Now, the excitement is we've got a fourth major class of drug in the upfront spec setting, namely the monoclonal antibodies and in particular, those monoclonal antibodies that target CD38. That's a ubiquitous marker on a malignant plasma cell. And, those antibodies have been real game changes in the setting of myeloma therapy. So for example, if you combine RVD with daratumumab or you combine carfilzomib, lenalidomide, and dexamethasone, so called KRd with daratumumab, we see not only incredibly high response rates, 100%, similar to what we see with RVD. But, the quality of responses dramatically go up and so do MRD rates. So for example, if you combine KRD with daratumumab, MRD negative rates of 70% have been reported without transplant.
So, this is a very important observation. It suggests to us that four-drug platforms upfront may take us to the next step where melphalan can clearly matter. But, it may be something that can be more judiciously used so we minimize the side effect profile and maximize the clinical benefit.
Jessica Bard: What would you say are the overall take-home messages from our conversation, today?
Dr Paul Richardson: Well, I think the key takeaways are that using high-dose alkylation with stem cell support and, in particular, melphalan, remains a standard of care. The degree of progression-free survival benefit that we saw is unprecedented. I think at the same time, one size clearly does not fit all. And, what we can say is that you can keep transplant legitimately in reserve for patients if they have an outstanding quality of response to initial induction therapy and continuous maintenance is the other critical takeaway. That that is a very important part of our new paradigm of care and should be considered a standard of care. And then, I think beyond that, the prospects for myeloma treatment in terms of newly diagnosed patients continue to evolve in a very favorable way.
Jessica Bard: Is there anything else that you'd like to add today?
Dr Paul Richardson: Well, I think a very important message from this trial was that it was an investigator-sponsored trial. It was a privilege to lead this study from Dana-Farber Cancer Institute, with the support of the Clinical Trials Network, the so-called CTN, and the endorsement of the intergroup, the so-called, Alliance. And very importantly, we were partnered with pharma in a very constructive way. We had superb support from Celgene BMS and Millennium, and in particular, that partnership allowed us to provide free medication to our patients, which was a huge plus from a patient perspective. And, at the same time, provide us with the resources to conduct the data analysis and study conduct at the highest possible level.
Give you a simple example. Our contract research organization conducted 28,000 monitored visits as part of the trial. So, the data quality was really of the best order and it was a remarkable multicenter collaborative effort across the United States, 56 centers. And, we were also partnered, in a parallel, fashion with our French colleagues in Europe to be able to compare and contrast critical questions, not least the continuous maintenance question.
So, altogether, a remarkable collaborative effort. And really to my mind, an example of how pharma, academia, investigators, groups can all partner together to do the best studies for our patients.
Jessica Bard: Well, thank you again for your time, today. It was a pleasure speaking with you and thank you for all the work that you're doing on this topic.
Dr Paul Richardson: Well, thank you, Jessica, and, greatly appreciate your interest