Priya introduces the topic of discussion: Myeloma: To Transplant or Not?
Currently, autologous SCT is the standard of care in myeloma because of its high response rate and relatively low morbidity and mortality. However, it is neither curative nor applicable to all patients. Growing understanding of cellular mechanisms, proteins, and key signal transduction factors has led to a tremendous opportunity in the context of new drug development in Multiple Myeloma. With new drugs continuing to improve response rates in patients, the role of stem cell transplants is set to change. And today, we are discussing whether and when to Transplant or Not.
I will try to provide you with a summary of the key points in Dr. Richardson's excellent discussion, and should you want a more detailed understanding, please listen to the entire broadcast.
One Size does not Fit All!
Doctor Richardson started by noting that Dana Farber works very hard to provide a patient centered program for multiple myeloma patients. His answer to the central question as whether and when to transplant or not is that, "One Size Does Not Fit All". Transplant can be very beneficial in the younger patients for which it is intended, however, there is a number of patients where benefits are not observed. And fortunately with the new novel drugs, we are able to obtain the same quality and depth of response that previously we could only obtain with transplant. A key question going forward is who benefits from transplant and when should the transplant be conducted, early or late. Data from various clinical trials shows that progression free survival (PFS) is better, but transplant itself does not provide a meaningful benefit in overall survival (OS). New Clinical Trials are ongoing to provide critical answers as to how the new novel treatments should be used in conjunction with transplant.
Clinical Trials are Ongoing
What researchers have found is that when you use a proteasome inhibitor, immunomodulator, and steroid, such as in this case RVd (Revlimid, Velcade, and dexamethasone), the response rates are remarkably high. In the Dana Farber led Phase 1/2 multi-center study published in 2010 in Blood, a response rate of 100% with 50% of patients obtaining a complete remission was shown. For those patients in this study that went on to transplant, no advantage in progression free survival at 18 months was observed compared to those who did not undergo transplant . This gave Dana Farber and their partners the impetus to conduct a larger Phase 3 trial, in collaboration with their colleagues in the Intergroupe Francophone du Myelome (IFM), knowing that with such an active regimen of RVd they needed to investigate further what role transplant should take in myeloma treatment. In this current Phase 3 trial they are looking at using the RVd regimen either before stem cell mobilization with chemotherapy with a long period of maintenance until progression and then transplant versus the same treatment, but with transplant administered early, followed by maintenance until progression. So patients have the same treatment regimen with the difference being the timing of the transplant. This is important, because one size does not fit all, and in the context of this clinical trial they are not saying some patients will get a transplant and others do not. Far from it, in this trial there is real equipoise (an equal distribution of weight; even balance; equilibrium), wherein all patients get a transplant, but it is a question of timing, either early or late. What they hope is that it will provide answers for patients in the future by characterizing patients, not just by their clinical features, but also by the genetics of their cancer as to which types of myeloma will benefit from transplant and for which may not, and for whom transplant can be left in reserve.
Several other subsequent trials have confirmed the efficacy of the RVd regimen, both adding more drugs to the RVd mix, or exciting recent data with Kypolis as KVd , and finding the results were encouragingly similar in all of these trials. Therefore, this concept makes the Phase 3 RVd trial all the more significant, with RVd becoming something of a new standard of care for younger newly diagnosed patients.
Dr. Richardson noted that there is a difference between RVd and so called VRd, which utilizes dex as a once a week schedule. Specifically, RVd partners the dexamethasone with the Velcade infusions both on the day of and the day after, which provide better outcome, and significantly reduces neuropathy Subcutaneous administration of Velcade also helps reduce neuropathy further.
Dr. Richardson then discussed the important and encouraging role of Kyprolis and Pomalyst, in the relapse and refractory setting, and the potential for the monoclonal antibodies Daratumumab and Elotuzumab for future use in both the up front and refractory setting, as well as other new agents in development.
Nick Van Dyke - Just published this week, a Chinese retrospective study compared single transplant plus novel agents versus novel agents alone, and found materially better progression free survival AND overall survival in the transplant group. While the study was retrospective and not a statistically perfect analysis, at some point isn’t there enough logic and anecdotal evidence to suggest that if novel agents alone aren’t curing people, and Melphalan is effective, then Melphalan plus novel agents would be better than novel agents alone? Not necessarily in elderly patients or those for whom 5-7 years is an acceptable prognosis, but at least for younger patients that are otherwise in good health and want 10, 15 or even more years?
Dr. Richardson - This is the central issue, and the original study in the late 90's by the French group in the pre novel agent era showed that early or late transplant had no overall survival advantage. Recently there have been several retrospective studies that showed no difference from early vs. later transplant in the context of novel therapy use. For example, the Mayo group using lenalidomide and dexamethasone as initial therapy, followed by early and late transplant, and showed a result opposite to the Chinese study, with no outcome difference, and more recent data has come from two studies by Antonio Polumbo of Turin, Italy utilizing lenalidomide and dex, followed later by either novel agents and low dose melphalan, vs. transplant, followed by maintenance, resulted in the following observations. The toxicities were less in the non transplant patients, the response rates were the same, the progression free survival was better in the transplant patients, and finally that maintenance to progression for either group had a survival advantage. One thing missing in these studies was the lack of the use of a proteasome inhibitor like Velcade in either of the Italian studies, which is belieived to be key to improved survival.
Nick Van Dyke - Trials are being done between no transplant and single transplants which may or may not have maintenance. Nobody believes that a single transplant cures patients, but there are doctors and centers that believe aggressive induction, tandem transplants and maintenance do offer curative potential for some and long remission for others. Understanding that these centers who believe they have superior outcomes don't want to randomize patients away from a protocol they believe could cure them, are there any efforts to compare novel agents only against an aggressive tandem protocol with maintenance, and if not, why not?
Dr. Richardson - The current CTN trial which is completing enrollment is designed to answer this question. This trial consists of three arms, one of which is single transplant, followed by RVd consolidation, and Revlimid maintenance. The second is two transplants followed by Revlimid maintenance, and the third is a single transplant followed by Revlimid maintenance. In a Dutch German study they did find some advantage with two vs. one transplant, but the CTN study will answer more definitively this question, but one of the issues with dual transplants is toxicities that limit the ability to use additional treatments with novel agents in the future.
Jack Aiello - I know that Maintenance studies after transplants have shown approximately a 2-yr improvement in Progression-Free Survival (4 yrs vs. 2 yrs). I’ve heard that Maintenance trials have also shown OS benefit. Can you quantify that benefit?
Dr. Richardson - The CALGB (now known as the Alliance) Trial where patients had treatment with novel agents and then transplant, which was followed by maintenance with lenalidomide until progression, vs. no maintenance showed convincingly that the maintenance arm had a significant progression free survival advantage( approximately double the control arm). More importantly it showed a overall survival benefit. We believe the aggregate data thus support the use of maintenance for a period greater than two years or up to progression.
Jack Aiello - With ASH just over a month away, what does your crystal ball indicate will be the 1 or 2 most exciting announcements for Myeloma patients?
Dr. Richardson - We will see important updates of existing trials, updates for treatments for older patients who are not transplant eligible, and on new drugs that we are finding work well with both bortezomib and lenalidomide. We will also see nice data with regard to the combination of Carfilzomib, and Pomalidomide, and the new monoclonal antibodies targeting CD38.
Pat Killingsworth - Can transplant be improved so that it becomes indispensable to myeloma treatment rather than eliminated as a treatment option?
Dr. Richardson - Transplant has improved significantly not least as a result of improvements in supportive care. New forms of melphalan are under development which are intended to be less damaging to stem cells. We are also trying to improve induction treatment for transplant, and finally the emerging role of consolidation with novel agents may be a real substitute for a second transplant. The improvements in transplant are thus arguably a result of the treatments we build around transplant, such as induction, consolidation and maintenance.
For the final twenty minutes Dr. Richardson was kind enough to take the time to answer numerous questions from the audience. Priya Menon is working with Dr. Richardson to provide answers for all of the submitted questions, and when they are available I will provide a link and/or another blog post. We all very much appreciate Dr. Richardson's broadcast, and his efforts with his colleagues to improve myeloma treatment.
For more information on multiple myeloma survival rates and life expectancy go to the web site www.myelomasurvival.com or you can follow me on my twitter account at: https://twitter.com/grpetersen1 A bio for Dr. Richardson follows:
Additionally, Dr. Richardson holds leadership positions in several professional bodies and serves on the editorial board of the Journal of Clinical Oncology, Journal of Oncology, American Journal of Hematology/Oncology, The Oncologist, Clinical Cancer Research, and the British Journal of Hematology He also previously served as chairman of the Multiple Myeloma Research Consortium, awarded the MMRC center of the year in 2009, and assumed the Chairmanship of the Alliance Multiple Myeloma Committee in 2011.
Dr. Richardson has published more than 200 original articles, and more than 100 reviews, chapters and editorials in top peer-reviewed journals, including the New England Journal of Medicine, Blood, Journal of Clinical Oncology, Leukemia, Clinical Cancer Research and British Journal of Hematology. His honors are exceptional and extensive, including the Warren Alpert Prize for his contribution to the development of the first-in-class proteasome inhibitor, bortezomib.