I published the bulk of this in a post a couple of days ago. I didn't like the screwy way it was appearing here (I wrote the original in Word and pasted it in here and the formatting made it very difficult to read despite attempts to edit it) so I'm retyping it. At the same time, my post engendered a couple of follow-up questions which I am trying to address. Lastly, as ever, I'm never satisfied with my work so there are a couple of little improvements in language and phrasing, including one area where my friend Suzierose encouraged me to be a bit more precise.
I do a fair amount of outreach to Myeloma patients in both the online and the "real" world, and I've noticed that time and time again the same questions are being asked about transplants. These questions were prevalent five years ago, and they remain prevalent today. Should I have a transplant? Should I have it as part of initial therapy or save it for later? Should I have one or two transplants?
It also occurs to me that doctors -- even the most brilliant ones -- may or may not be excellent at making decision the way they are made in business, or even explaining concepts. Oftentimes research is at odds with simple, didactic explanations and clear, precise, strategic thinking.
So I'm going to try with this post to approach these transplant questions using the reasoning that I've learned and applied outside the medical field in order to provide a different perspective. I'm not a doctor -- so please take all this with the knowledge that I'm just trying to make sense of something from a layman's point of view. I'd like to acknowledge the help of my good friend and fellow MM warrior Suzierose, aka Myeloma Cinderella, who is no fan of transplants (for reasons that in the case of her biology are well-founded) but who has vetted the substance of what I write below. If it made it past her, you know it's gotta at least be even-handed! :)
I'm referring in this post to autologous transplants, not allogeneic transplants, for reasons which will be made clear.
What a Transplant Is, and What a Transplant is Not.
A transplant, first of all, is not a transplant.
It can be helpful to think of a transplant as high-dose Melphalan instead. I'm excluding from this the rare transplant done with a different type of chemo).
Melphalan is a type of chemotherapy that has been around for quite some time. And that's all there is, really, to a transplant: it's just a lot of chemo. After getting high-dose Melphalan, you get your own blood back to help you recover. That's it. There is no "transplantation" and getting the blood back serves no purpose in killing the myeloma. The purpose of an auto transplant is to kill Myeloma with Melphalan. This is in contrast to an allo transplant, the purpose of which is to kill Myeloma by introducing a donor's immune system to the patient. That is an entirely different ball of wax.
So the first concept to help you sort through this is that an auto transplant is not a transplant of anything. I suppose you could call it a replant. But it's best to think of it as high-dose Melphalan.
What a Tandem Transplant Is.
A tandem transplant, which is used in some aggressive protocols such as Total Therapy at UAMS/MIRT in Little Rock and at the University of Iowa under Dr. Guido Tricot, is nothing mystical or mysterious: it's just double the amount of Melphalan. If you are doing two transplants a year apart, that's not a tandem transplant. That would be two single transplants. The purpose -- and value -- of a tandem transplant is just to give you twice as much of the chemo at a time when the disease hasn't yet become resistant to it.
Do Transplants Work?
Often, but not always. It depends on what type of disease characteristics that one has. Very simply, if one has disease that is susceptible to Melphalan, a transplant will very likely be effective. Conversely, if one has disease that is not susceptible to Melphalan, a transplant will probably not be very effective.
Melphalan's "mechanism of action" (i.e. how it works) is changing the DNA of cells in the bone marrow and getting in the way of certain processes that cells need to survive. This mechanism is called alkylation, and Melphalan is in a class of drugs called alkylators or alkylating agents. Alkylation is the process of adding something disruptive to the DNA of cells in order to kill them. Very specifically in the case of Melphalan, the drug adds an alkyl group to the guanine base of DNA at the number 7 nitrogen atom of the imizadole ring. Aren't you glad that you don't need to know that for it to benefit you, or to understand what the role of a transplant is? Me too! :)
Melphalan is nasty stuff. In fact, it's very similar to mustard gas. So getting a high dose of Melphalan will kill a lot of cells. It may not kill all of them, because some cells can be corrupted by the cancer into lacking certain pieces of DNA that are needed for the Melphalan to work. And because it may not kill all the cells, it may not kill enough of them to cure the patient, or even to put the patient into a long-term remission. Additionally, if the cells are resistant to dying, but the Melphalan tries to monkey with the DNA anyway, cells could be pushed to mutate in other directions, creating what is called "genomic chaos" which ultimately means the Myeloma could become pissed off and quite nasty.
How do we determine if one's MM is of a type that is susceptible to Melphalan? You'll need a bone marrow biopsy for that. A more comprehensive test is the Gene Array test performed either at UAMS/MIRT or through Signal Genetics. This requires bone marrow. It also translates to a "risk score" that reflects the overall risk of the Myeloma. This can be used as a proxy for "will my MM respond to Melphalan" but it is really tailored for Total Therapy, so it's more like "will my MM respond to a combination of all the agents used in Total Therapy, including Melphalan."
Most patients (80-85%) have Myeloma of a type that will be sufficiently killed by Melphalan to have at least some response, and the response can be profound. Within this group, perhaps half of them require a LOT of Melphalan to kill all the cells (which is why tandems can be more effective than a single transplant). Melphalan used all by its lonesome used to get remission rates on the order of 30% (we're talking before the advent of combination therapy, discussed below). In combination therapy, it is more effective. Total Therapy throws the kitchen sink at the disease, with Melphalan being a centerpiece of that kitchen sink, and they achieve complete remission is about two-thirds of this 80-85% group, with almost all of the remainder returning to what is an "MGUS-like state" with very little disease (that might, in fact, not represent Myeloma but could be like the MGUS that is present in 2% of the general population).
From these observations, a couple of things can be explained. First, when people talk about "high risk disease" they have traditionally been talking about disease that has characteristics in common with other patients whose MM cells haven't been sufficiently killed by Melphalan (or other medicines). Second, this explains the philosophy of tandem transplants -- some people need more Melphalan than others to get the optimum effect from it in terms of killing as many MM cells as possible.
Do other types of therapy do the same thing?
Other types of therapy can also be effective, but with rare exception they don't necessarily do the same thing. This is important to the idea of combination therapy, which tries to kill MM by as many means as possible.
Here are a few alternatives based on therapy that I received in Total Therapy.
Traditional chemo used against newly-diagnosed Myeloma comes in several varieties:
- Cisplatin (the "P" of "PACE" therapy, which stands for platinum) works in a way similar to Melphalan. It also messes around with guanine DNA. It interferes with cell division, which is slightly different from the DNA disruption that Melphalan causes. When the cell finds out that it can't divide properly, it tries to repair itself. When repair proves futile, the cell politely dies (a process call "apoptosis" or "programmed cell death"). But cells have a way of learning to bypass platinum over time.
- Adriamycin, the trade name of Doxyrubicin, is the "A" in "PACE" (and Doxil is a modified version). These drugs also interfere with DNA through a process called intercalation. Intercalation disrupts DNA and the process through which cells replicate.
- Cytoxan (the trade name of cyclocphosphamide, the "C" of "PACE" and the Cy of the CyBorD treatment) works in a way very similar to Melphalan's mechanism of action.
- Etoposide is the "E" of "PACE" and works differently. This chemotherapy screws up a different part of the cell replication process by messing around with an enzyme that is needed by DNA strands during cell duplication, causing those strands to break. Cancer cells divide more rapidly than healthy cells and more reliant upon this enzyme than are healthy cells, so the cancer cells are disproportionately effected.
- IMIDs (the class of drugs to which Thalidomide, Revlimid and Pomalidomide all belong) work by inhibiting cells in the bone marrow that support the Myeloma cells, and by inhibiting the growth of blood vessels that Myeloma relies upon.
- Proteasome inhibitors (the class of drugs to which Velcade and Kyprolis belong) interfere with the process through which cells remove abnormal proteins. When a cell has abnormal protein, it tries to remove them in order to remain healthy. When this process is interfered with, the cell eventually realizes that it has too many abnormalities and gives up the ghost.
- If you believe that there are real synergies / combination benefits from using medicines at the same time, then transplant early, because you have naive disease that will be confronted by as many different types of medicines as possible. You'll kill off most of the MM that way.
- If you believe that combination benefits don't make that much difference, then transplant late. You'll kill off some of the MM with the first type of medicine, and when it returns, you'll kill off some of it with the second kind of medicine (Melphalan). Personally, I think this is a half-measure, both because I believe in the synergies and because I've seen too many friends have unsatisfactory results when they use Melphalan in this way (a "salvage" treatment after other forms of medicine have proven to be ineffective). But when all those studies talk about overall survival being the same regardless of progression-free survival being different in those that transplant early, it's because eventually, the myeloma cells figure out how to saw a new door in the room and get out. The early transplants block two doors up-front, while the late transplant simply waits until the MM cells have started to cut a second door before blocking it. In both cases, the Myeloma eventually cuts a third door. :(
- If you believe that synergies / combination benefits make a big difference, then consider Total Therapy and try to blow the MM out of the water. The idea here is to surround the room with a lot of different monsters so that as soon as the MM tries to cut a new exit hole in the wall, it will be confronted with one of them and then Sully the happy monster from Figure A and his friends will eat all the MM cells before they can get out of the room.
There's no way to know for sure. For some, transplants provide only a short period of remission. For others, it could be ten years. It depends on (1) the degree to which one's MM is sensitive to Melphalan, and (2) the other medicines used before and after transplant. We've collectively learned that maintenance certainly prolongs remission, if not survival. So it stands to reason that if you have a successful transplant, you will have a longer remission period if you follow it up with maintenance. Total Therapy adds "consolidation" chemotherapy after transplants as well. Another part of the kitchen sink.
But ultimately, the duration of remission depends on many factors. It is hard to cite statistics, in fact, both because everybody's disease is different and because a transplant in a given trial is not the same as a transplant in another trial. A single transplant given to somebody who has relapsed from many other medicines and done without maintenance cannot be compared against a transplant done at the onset of the disease with VRD administered at the same time -- much less compared against tandem transplants in a total therapy setting.
If you have disease that is resistant to Melphalan or not sensitive to it in the first place, remission from transplant will be hard if not impossible to achieve in the first place and it it unlikely that it would be nearly as long in duration as would be the case if you have disease that is not resistant to Melphalan and is sensitive to it. And if you believe in synergies and combination benefits, you will have a longer remission if you are treated with multiple agents before transplant plus maintenance afterwards than you will if you are treated with fewer agents. On the other hand, if you don't believe in synergy, you would say it doesn't matter -- but there are more and more studies that prove maintenance does make a difference, not just in PFS but in OS as well.
Where does this leave us?
If you are diagnosed when older, there's no need for a transplant as novel agents are good and getting better, and they can lead to control of the disease for quite some time -- unless you have high-risk disease, which by definition doesn't respond to a transplant either. In any case, being cured just means living long enough to die of something else, so if you have standard risk disease and are 75 (for sake of argument) at diagnosis, even if the medicine only gives you, say, 7 years, you are dying at 82 years old. Not bad. I'm 46 now. You can sign me up for that, I think.
If you are young and have disease that is unlikely to respond to Melphalan, then I would try the best novel agents you can, treating the disease aggressively in the hopes of suppressing it as long as possible. Immunotherapy is another option, and early theories indicate that the Myeloma might never learn to outsmart it -- if that is true, it's a good thing to try at any point in your therapy, ideally up-front. But at the time of this writing, that's all just a theory. We will need many, many years of data before we can be confident in it working in the long-term.
If you are young and have disease that responds to Melphalan, I would hit it hard, Total Therapy style.
As I have mentioned many times, this is an individual disease: everybody's biology is different. It is paramount that the newly diagnosed patient understand the characteristics of his or her Myeloma so that he or she can make informed decisions with his or her medical team -- and this team must include a Myeloma specialist. The average kindly corner hematologist / oncologist does not see enough of this disease to understand its twists and turns, is not involved in research, is not aware of the newest clinical trials and the best approaches, will not anticipate the range of response to therapy, etc. If your doctor can't read what I've written here and not only understand it but point out ten areas where I have oversimplified or don't have a full grasp of what is going on, then they shouldn't be treating you. :)