Immediately after writing my last post I contacted a good friend, Nick van Dyk, who is currently a patient at Arkansas. You remember Nick, right? I posted his story here a few weeks ago. A tandem transplant recipient, Nick was more than happy to share his thoughts about the discrepancies in data I seem to be finding. Here is Part One of his three part rebuttal:
It seems to me there are three major discussion points here. The first is the nature of the Arkansas data, and how it stands up to contradictory claims. The second is the nature of the Arkansas treatment, and how broadly it applies. The third is what type of Myeloma patient benefits disproportionately from the Arkansas approach versus other approaches. Let me address these one by one, understanding that I’m trying to both think and speak more broadly than about my own experience, yet my observations are obviously informed first and foremost by having investigated the data and gone through the treatment protocol personally.
First, the nature of the data. To my knowledge, Arkansas has more data than any other Myeloma center in the world, and it certainly has the largest amount of “longitudinal data” — meaning they have tracked the progress of their patients over 20 years. The validity of the Arkansas data is, in my estimation, beyond reproach. Some have accused Arkansas of selection bias — meaning they choose patients that will do well on their protocol. I don’t think this is true — Barlogie tracks patients of all types and has many different protocols dealing with both low-risk and high-risk disease, both newly-diagnosed and refractory, and across all age groups. The most striking claims of cures are for newly-diagnosed patients in the low-risk category — about 85% of newly-diagnosed patients altogether. I know that about 40% of the patients Arkansas sees are newly-diagnosed. They are also viewed as a place of last resort, where very sick patients are sent after other hematologists have tried and given up. Barlogie tracks most if not all of the patients he sees across all these categories.
As for the claim that the tandem transplants don’t make a difference, I think it is important to understand how Arkansas uses tandem transplants versus other places, and which types of tandem transplants are being considered. Mainline therapy, as you know, uses drugs during induction (typically thalidomide and dex, or revlimid and dex, with some centers adding Velcade up front). Once the cancer is suppressed as much as can be expected from this induction therapy (and my understanding is that partial response is all that is required, but obviously many patients do better, achieving very good partial response, near complete remission or even complete remission). After the treating physician has determine the induction has gone as well as it can go, many will choose to follow this up with a transplant to “lock in the gains.” This generally leaves the patient with a low level of residual disease, which make take several years to return to an active state. In some cases, this remission could last ten years or longer, though these cases are quite rare, as we know. Sometimes, a second transplant is performed several months after the first transplant, whether because the first transplant didn’t do as well as was hoped, or because the second transplant is used to mop-up whatever disease was left.
In Arkansas, the transplants are used differently. There is an induction period, consisting of several more powerful drugs (strong chemos) in addition to the VTD that is used in many other places. The transplants occur as an active part of therapy, not to “lock in gains” but to play a part in the overall assault on Myeloma. The first transplant is done at a time where the disease has had very little time to build up drug resistance (induction is typically 1-2 months instead of anywhere from 6-12 months elsewhere). Thalidomide and dex are continued after the transplant, and the patient usually has 4-6 weeks to recover from the first transplant only. Most other centers will not even do another bone marrow for 100 days post transplant so they can see the full effect of it. In Arkansas, by this time, the second transplant is generally already done! The theory remains consistent: stay on top of the disease with every available therapy, do not let up, do not allow it to develop drug resistance. The second transplant is not done to “mop up leftovers” and it is done before there is enough data to judge the full efficacy of the first transplant. These two transplants are just both efforts to wipe out every last Myeloma cell. This overall treatment generally leaves the patient with very, very low levels of residual disease. In about 60% of the cases, complete remission is achieved. And near complete remission is achieved in most of the other cases.
So to compare the efficacy of tandem transplants versus single transplants, you would really need to be looking at tandem transplants the way Arkansas uses them. I think it would be very difficult to do so, because you would need long-term studies and you would need to consider the different approaches to maintenance. Some doctors, such as my original hematologist, don’t believe in maintenance. Some, such as City of Hope, didn’t used to but are beginning to. MAYO, I believe, falls into this camp. Then there are doctors like Vescio who keep people on Revlimid for the rest of their lives (or as long as they can continue to tolerate it) so that’s a longer maintenance regime than Arkansas proposes. In short, it’s very difficult to isolate one part of the protocol and test that for efficacy. This is part of the reason that it hasn’t been done.
Arkansas probably publishes and presents its work more actively than most, if not all, Myeloma centers. Their results and research are published frequently in Blood, the big hematology magazine for doctors, and they present regularly at ASCO (the American Society of Clinical Oncologists), ASH (the American Society of Hematologists), IMF (International Myeloma Foundation) and other events. Far from being hidden, it is out there. I would encourage everyone to learn as much as they can about it by visiting the UAMS webpage. In particular, I recommend the 2007 ASCO presentation entitled “The Myth of Incurability” which can be found here: http://myeloma.uams.edu/powerpoint/The-Myth-Of-Incurability-Barlogie-PPT.pdf. A followup presentation of interest, presented to ASH in 2008 and demonstrating 90% sustained complete remission in low risk Myeloma over a period of nearly five years can be found here: http://myeloma.uams.edu/powerpoint/4years.pdf. This is meaningful because at four and a half years, the patient is finished with maintenance, and the disease is not returning. At six years, the patient is most likely cured, based on the rate of recurrence observed over a long period of time in previous trials conducted by Arkansas. Some other presentations, for those interested, can be found here: http://myeloma.uams.edu/presentations.asp.
I have heard several claims against the Arkansas data, and in my opinion they are largely irrelevant to those for whom the Arkansas protocol is of interest (and I’ll get to them later). The first claim is that the data has selection bias — meaning the people entered into these trials might do just as well with less therapy. As I noted before, Arkansas tracks data on all patients, and can cut the data by disease type and a hundred other variables. Arkansas makes no secret about those for whom its therapies are most effective: low-risk, newly-diagnosed patients. Low-risk covers about 85% of all patients, so in theory, if everybody who was newly diagnosed opted for this type of treatment, this protocol would be effective for 85% of Myeloma sufferers. The remaining patients do achieve complete remission (more readily, in fact, than those with low-risk disease) but the recurrence of the disease is much higher. Arkansas is developing protocols for these diseases as well.
For the patient that will do well in the Total Therapy 4 protocol (the current low-risk protocol that randomizes between four courses of chemo versus two courses of chemo) I don’t think selection bias is relevant at all. They’re in the group already! But for these people, the question might still be asked: would these patients have done as well without the tandem transplant and all the stronger chemo agents? Could they have been treated with Velcade, Thalidomide or Revlmid and Dex and had one transplant and still done just as well, possibly with maintenance therapy and possibly without it? The answer is we don’t know, probably not, but maybe. Velcade is certainly a game changer, as can be seen from how well the people in Arkansas’ Total Therapy 3 (with Velcade) have done versus Total Therapy 2 (without Velcade). However, I don’t believe any hematologist believes Velcade will cure the disease. It may simply prolong remission. And the development of Carfilzomib (next-generation Velcade) is a sign that people believe a drug must be in the arsenal for when the disease becomes resistant to Velcade. So there’s your answer, in part. This conundrum does lead, though, to the other big question about Arkansas’ data: it has not been subjected to a double-blind trial, which is the gold standard of medical research, in which neither the patient nor the doctor knows what protocol a patient is in, and results are compared over time. I asked Barlogie directly about this, and his answer, while potentially self-serving, also strikes me as supremely ethical in both the general and medical sense. He said “I have something that cures people. I am not going to take 200 people that I can cure, and subject 100 of them to something that probably won’t cure them just so I can prove a point. If somebody else wants to randomize, they can do it until they are blue in the face.” That was good enough for me!
Thanks, Nick! Part two tomorrow.
Feel good, keep smiling and happy Thanksgiving, everyone! Pat