Sunday, December 7, 2014

Everything you Wanted to know about Transplants (new and improved!)

Hello folks.

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.
Then there are two classes of drugs that have come to be called "novel agents":
  • 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.  
Lastly, there are steroids.  Steroids suppress the immune system and kill plasma cells.  There's predinose, and Dexamethasone (trade name Decadron), aka "demon dex" which is it's 5X-stronger-brother.  If you are killing plasma cells, you are killing MM cells (which are aberrant plasma cells).  The immune system suppression helps with the side effects that would be caused by some immune reaction to other drugs (for example, the rashes that are commonly experienced with Thalidomide and Revlimid) as well as keeping the immune system from producing too much immunoglobulin, which is where the MM sits.  You don't want those cells trying to reproduce even more aggressively while we are trying to kill them off, after all.

It goes without saying that none of this is healthy.  The purpose of all this medicine, obviously, is to kill cells.  Killing cells through disrupting DNA is nastier and more chaotic than killing cells through other means.  Consequently, there are more side effects -- both near-term and long-term -- from chemotherapy that messes with DNA.  Patients must judge for themselves whether or not the additional side effects are worth the additional killing power.

Do transplants work as well as other types of therapy?  Do other types of therapy work just as well as transplants?

The answer is: we don't know yet.  We do know they work differently, and that different cells are susceptible to different things, depending on the individual characteristics of one's disease.

Consider the above diagram.  Group A, above, represents types of cells that are only sensitive to alkylators like Melphalan.  Dr. Roger Tiedemann at Princess Margaret Hospital in Toronto has shown that in vitro (that is, in a lab outside the human body) the precursor cells of Myeloma do not exhibit the cell structure required to be susceptible to novel therapies.  Dr. Tiedemann's research shows that alkylators are essential to kill these precursor cells -- they can't be touched by Velcade or Revlimid or their cousins.  Velcade and Revlimid are the equivalent of mowing a lawn full of weeds: you are getting rid of the parts of the dandelions that you can see, but the roots are still there and no amount of lawn-mowing will stop the weeds from eventually growing back.  Not everybody agrees with this research...but it is an idea to consider.

In group C, on the other hand, are cells that are sensitive to Velcade or Revlimid but are not sensitive to Melphalan.  By definition, "high risk" MM exists either in this group, or completely outside any of these circles -- and if one has a flavor of the disease that isn't sensitive to any of the weapons we use, one is said to have refractory disease and one is then reliant upon new therapies in order to extend one's life.  Back to those in group C, though: there is concern that for patients with disease that is not killed by Melphalan, that result of screwing around with that DNA can cause mutations in the MM cell that can make it more aggressive.  This explains why Total Therapy with Melphalan doesn't have long-term success for high-risk patients, and explains why UAMS has moved away from transplants for those patients.  Dr. Sagar Lonial at Emory believes this, also, to be the case -- and does not treat these "high risk" patients with transplants.

There there are those in group B -- people with disease that could be killed by multiple means.  Here, does one just use novel agents?  Or does one use novel agents plus Melphalan?  Or does one use the kitchen sink?  This requires a perspective on the concept of combination therapy, which I attempt to explain below.

The concept of combination therapy

The last piece of the puzzle we need to put this all together is the idea of combination therapy, which is a pretty simple notion: multiple medicines with different mechanisms of action work better together than they do individually, whether because they are synergistic (medicine A kills 1,000 cells, medicine B kills 1,000 cells, but the two together kill 3,000 cells because they make each other more effective) or whether because inclusion of an additional agent helps make a medicine that has become ineffective once again effective.  This second idea is an important one, because it relates to whether or not one believes in transplanting early or late, if at all.

Here's a tortured metaphor that will nonetheless suffice to illustrate the point.

Imagine the Myeloma cells are sitting around in a room that has a single door.  The medicine is a helpful monster (I'm envisioning Sully from Monsters Inc).

So the cells are sitting in the room and the monster walks in, causing a physiological reaction represented with startling verisimilitude in the above illustration.  The monster starts eating the MM cells.  The MM cells -- notwithstanding their look of slack-jawed terror in the above photo (which may have been captured by electron microscope) -- are smart.  They see the door is blocked by the monster and they start looking for another way to get out of the room.  Some of the cells will start cutting a new door in the side of the room and leave through that new door.  The idea behind using multiple agents in combination is that every potential door the MM is likely to try to cut in the walls of the room will have another type of medicine standing behind it, and ultimately one or more of those helpful monsters will eat the cell before it can figure out how to get out of the room.

The concept of so-called "triplets" (e.g., VRD, CyBorD) and "doublets" (e.g., RevDex) working better than single agents is established and pretty much universally accepted at this point.  This also explains why transplants done before the era of novel agents didn't perform as well as transplants now do when novel agents are included in the regimen.  The enhanced efficacy of drugs achieved in combination therapy creates more durable response: deeper remissions and, in some cases, even cure.

It stands to reason that clobbering MM with VDT-PACE plus Melphalan plus more VDT-PACE in combination -- all in rapid succession, no 9 months of waiting while the MM gets smart -- and then following this with three years of VRD in maintenance is just a very aggressive version of this same combination philosophy. 

The question is whether or not there are a lot of patients in group B -- the center circle in the diagram above -- who don't need all of that medicine, whether because their disease biology is particularly susceptible to novel agents alone, or whether because the newest novel agents (Kyprolis and Pomalidomide) are so powerful that they can accomplish all this on their own.  These patients need some of what Total Therapy offers. but not the whole kitchen sink.

How do we know when enough is enough?

We have imprecise measures for that at the moment.  

Since this is an individual disease, ultimately it requires an individualized approach.  Even assuming everybody was the same age, had the same overall health, had the same opinion on side-effects impacting quality of life, etc., there would still be almost as many precise flavors of myeloma as there are individuals with the disease.  

An idea that is gaining currency is the notion of treating until such time as the patient has achieved what is called "MRD negativity" -- with MRD standing for "minimum residual disease."  If you eliminate all traces of Myeloma with one course of Velcade, per this line of thinking, why bother continuing.  And that theory would be great if we could test at a sufficiently sensitive level and with consistent and comprehensive measurement.  

The problem is we can't at this time.

MRD tests come in different stripes.  Generally speaking, the most sensitive was developed originally through the "Salamanca group" (doctors in Spain) and has been adopted at several centers in the US, for example at UAMS.  This uses a highly sensitive type of test ("multi-color flow cytometry") to identify myeloma cells and can detect one myeloma cell in one million.  Is that sensitive enough?  Well, it might be.  Maybe.  Except that it looks for 6 or 7 proteins that we know MM cells express.  But what if some cells don't express those proteins?

Then there's the problem of consistency.  I've written before that MM cells sit in bone marrow in patches and that one's bone marrow is like the coat of a dalmatian.  You could pull bone marrow from one spot and looking at that one spot only, deduce that the dog was all black or all white.  

Until such time as MRD can be tested in the blood, where MM cells circulate evenly, we won't be able to definitively say someone has no trace of the disease whatsoever.    Right now, people are telling me to be confident because over a period of 18 months I have tested negative for MRD four different times.  But even that is only four spots in my marrow.

Then there's the issue of the time it takes to do an MRD test relative to when the medication is administered.  Delivering the combination therapy in rapid succession before the MM can figure out how to cut another hole in the wall, so to speak, is part of what Total Therapy seeks to do.  You're done with the second transplant long before you see the result of the first transplant, which conventional wisdom believes takes 100 days to show up.  Heck, by the time 100 days have passed from your first transplant in Total Therapy, you've had your second transplant and at least one cycle of VDT-PACE consolidation therapy, if not two.

So we aren't there yet, unfortunately, for a number of reasons.

When should one transplant?

Given what we have discussed, the decision on when to transplant can actually be framed up more simply than one might expect.

If you have disease that is not likely to respond to (or worse, be complicated by) Melphalan, then do not transplant.  If your bone marrow studies indicate that the abnormalities exhibited by your MM cells are consistent with those of other patients that have not responded to transplants, then you are in group C of that three-circle diagram.  No transplant for you.

If you have disease that is likely to respond to Melphalan, then the question becomes one of how extensive you (and your doctor) believe the combination impact and synergy between medicines is:
  • 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.

Should there be one transplant or two?

In the context outlined above, the notion of a "tandem transplant" is easily considered and assessed.  There's no mystery to it: a tandem is simply twice the Melphalan at a time when the disease has not yet learned how to outwit the medicine.  You might have disease that isn't responsive to Melphalan in the first place, in which case a tandem won't do any good.  You might have disease that is responsive to Melphalan but needs more than the usual dose, in which case it will make a difference and potentially a big one -- but again, it depends on the types of medicine and how much is done after the tandems.  I know people that have done a tandem but without the VDT-PACE before and after, and they have lost remission.  So the Melphalan alone -- even in a tandem -- is not enough to cure the disease with any consistency.

How long will remission last after a transplant?

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.  :)