The Ongoing Role of Transplant for Multiple Myeloma Convention Connection: American Society of Hematology Meeting December 2010 Edward Stadtmauer, M.D. Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. Please have this discussion you re your own doctor, that s how you ll get care that s most appropriate for you. Dr. Stadtmauer, related to multiple myeloma what is the role of transplant today? Well, I really don't try to isolate transplant in the continuum of care for multiple myeloma. My feeling is our goal is to come up with the best combination of treatments in the year 2010, and soon to be 2011, that will lead to the longest productive lives of patients with myeloma. As you know, this last decade has just been a thrilling time for us who care for and for patients who have multiple myeloma in that we have had new agents, the proteasome inhibitors and the immunomodulatory agents, along with high doses of chemotherapy, particularly Melphalan, and autologous stem cell transplant. And these approaches have really led to a tremendously improved outcome. Our enthusiasm for doing high doses of Melphalan and stem cell transplant remains high mainly because there are number studies a couple of studies that are going to be presented at this ASH meeting that suggest that even with the new novel agents, Revlimid and Decadron, as demonstrated by the Eastern Cooperative Oncology Group, and Bortezomib and Thalidomide and Decadron, as demonstrated by the Italian group, that even with those initial therapies and the wonderful responses we're getting, if you add to that a course of high dose Melphalan and autologous stem cell transplant you can even further improve outcome. So how do you know who needs a transplant and who doesn't? Well, again, I don't think of it as who needs one and who doesn't, I think more in terms of who would most benefit by it? And, obviously, patients who have multiple other medical illnesses may have more difficulty with high dose chemotherapy. And we're learning that a aspect of a person called performance status, the ability to walk and move and not have infections and have kidney function that's working very well and have heart function, those things are very important. We would not be giving high doses of chemotherapy to patients who are very debilitated and have other medical illnesses. But in a patient who is well and who is up to the rigors of a course of high dose chemotherapy and stem cell transplant, at least up until a person in their 70s, it looks like there's the potential for improved outcome. 1
Doctor, so year after year I ask the same question and that is, is transplant dead, if you will, for multiple myeloma you are a transplanter but I know you want what's best for patients. What's your view at this point? Oh, definitely. Well, once again let me first say that, of course, we have to differentiate the donor bone marrow transplant, the allogeneic bone marrow transplant from the autologous stem cell transplant. And remember, in the autologous stem cell transplant the philosophy is simply to give a dose-intensive chemotherapy. To give more chemotherapy than you could otherwise give to see if you can try to overcome the resistance of a more aggressive myeloma with high doses of chemotherapy and the transplant is simply rescued from the high dose Melphalan. But it's really Melphalan a chemotherapy that is the treatment. And it seems like, at least as far as we know so far, that the best way of giving Melphalan is in that one hour high dose rather than low doses over a long period of time, though there are studies that are looking at that. In an allogeneic transplant, a donor bone marrow transplant, that's where you take you're primarily replacing the organ that is sick, the bone marrow, with someone else's bone marrow. And you replace it by infusing the hematopoietic stem cells from the donor. And, of course, that makes much more logical sense in a disease of the bone marrow, let's replace the sick disease. The problem is every time you infuse someone else's cells into a patient with that, those cells can also cause an immunologic reaction, graph versus host disease, which can lead to other organ dysfunction and is age limiting. So older patients, particularly patients over the age of 60 or so, have a substantially increased risk of an allogeneic transplant. So a lot of people can get confused or much more obviously we have much more concerns with the allogeneic transplant in terms of side effects versus benefit. One of the major reports that is going to be coming out at this meeting is actually a report that I'm involved in, where it's the largest report looking at patients who had newly diagnosed multiple myeloma and then patients who had a perfectly matched brother or sister went on to an autologous stem cell transplant, followed by a mini, or non-myeloablative or reduced-intensity allogeneic, or donor transplant. And the other proportion of patients who did not have a donor, a perfectly matched donor, had an autologous followed by a second autologous. And then we looked three years later and so far what that study is demonstrating is the toxicity of the allogeneic transplant, at least in this group of patients who are under the age of 70, the toxicity of graph versus host disease may not be worth the benefit relative to an autologous stem cell transplant. In other words, at three years both of those groups of patients were doing about the same, and so with allogeneic transplant, at least in that form, it may not be the optimal way of treating the patients. 2
Okay, so with medical therapies getting better and more coming and combinations, is it possible, though, that they could manage most myelomas as a chronic condition that you could live well with and not even approach the prospect of a cure through transplant? Well, I am the eternal optimist, and I definitely believe that with we're now third generation, fourth generation, proteasome inhibitors, third generation, and fourth generation immunomodulatory agents. The new chemotherapies, the new ways of targeting therapy, I'm confident that we will continue to improve therapy, the nontransplant therapies in this disease. And I'm confident that there will come a time when we will never use bone marrow transplant in any disease. But, again, the current with the current information we have, until we have data that with the newer agents the results, the ultimate outcomes, the long-term outcomes are the same or superior, which of course is what I hope, to incorporating a cycle or two of high dose Melphalan and stem cell transplant. I think we have to consider that the standard of care in the younger patient with this disease, and I think of it as under age 70, is to think of at least, assess a patient, for incorporation high dose Melphalan and stem cell transplant into that therapy. Doctor, questions that come up from the community, first is a consolidation transplant, what would that be and what would its use be? Well, so I think of the a cycle of high dose of Melphalan and an autologous transplant as consolidation of the remission that's induced by that initial therapy. There remains a question as to doing a second transplant, a second autologous transplant is superior to just doing one, and, in fact, there is a large multi-institution clinical trial sponsored by the National Institutes of Health in the United States that is looking at this question. Currently, they're accruing they're going to approve over 750 patients to a trial that will compare a single transplant to double transplant and hopefully answer that question. In fact, the most interesting arm of that trial, a third arm, is to say, "Well, why don't we do one transplant and then use go back to the Bortezomib and Lenalidomide and Decadron after the transplant and see if we can wipe up the last three cells of myeloma?" So using the newer agents after transplant as a consolidation. So I think that's a really interesting area and there's a lot of work looking at that. Doctor, anybody who's diagnosed with myeloma today wonders since transplant remains one of the options, how do we know whether in their journey it should be earlier or later? 3
There are a number of studies that have looked at one versus two auto-transplants in the past. About a decade ago, there were a number of studies that looked at this. And what the studies suggested overall for the entire group of patients, it did look like that two transplants to a superior outcome then a single transplant, of course, this was in the era before the new agents. However, if you did a subset analysis, what it suggested was the patients who after the first transplant still had measurable disease; those were the ones who benefitted the most from the second transplant rather than the ones who were in complete remission after the first transplant. So we're waiting for the new studies to come out to more completely guide us, but as of this moment off of a clinical trial I would say most of us who are considering two transplants would think twice about doing a second transplant in someone who is in a wonderful remission after the first transplant. Okay, and as far as, though, having a transplant to jump ahead of a long course of medical therapy? Oh, that's a really interesting question, the question of whether a transplant can be used instead of continuing chemotherapy. Up until recently that was one of the major blessings of doing a stem cell transplant that you would do it, a patient would be induced into a complete remission or the best remission they can get, and then you would have years of no therapy or perhaps a bisphosphonate for the bone lesions and it was a blessing to not have to be to not take those treatments. Over this last year there have been a number of studies now that do suggest that continued therapy may be better than not taking anything after a stem cell transplant, and the most compelling data comes from two studies; one in a cancer and leukemia comes from two studies; one of them is the CALGB-ECOG trial, which compared patients who had a stem cell transplant to Lenalidomide or placebo and suggested that the patients who took Lenalidomide maintenance therapy had over two years longer duration of remission then patients who didn't take that. There's a similar study from France that showed a very similar outcome, that the patients who took Lenalidomide after a transplant have longer duration of remissions than patients who don't. There will be a study that's presented here at this meeting that looks at a Bortezomib Velcade containing regimen that takes Velcade throughout the initial therapy, and then as a maintenance therapy, versus a non-velcade containing regimen showing significantly improved outcome for the arm that has the continued Velcade versus the one that doesn't. So there's more and more data to suggest that doing something after a stem cell transplant might be better than doing nothing. And so I think the argument that a stem cell transplant will mitigate and ameliorate the need for further therapy afterwards is probably becoming less of an issue. 4
For people diagnosed with myeloma today, are you hopeful? I am so hopeful. There is so much interest in this disease. There are so many new developments in multiple myeloma, we have the entire medical community geared up for the next generation of therapies from the physicians, the scientists, the pharmaceutical industry, the nurses, the supportive care, and most importantly, the patients themselves. There are tremendous support groups and resources for patients with multiple myeloma, so no one should go without the information they need and the hope that they need to get through. We've had data on the effectiveness of transplant for myeloma for many years and if you think about it, the novel therapies have been around just for four or five years and they're making a big difference. And there are others coming. So hopefully before long we'll be able to compare those therapies head-to-head with transplant and see if those therapies alone can do the job. Stay tuned. In Orlando, I'm Andrew Schorr. Please remember the opinions expressed on Patient Power are not necessarily the views of our sponsors, partners or Patient Power. Our discussions are not a substitute for seeking medical advice or care from your own doctor. Please have this discussion you re your own doctor, that s how you ll get care that s most appropriate for you. 5