Tuesday, December 2, 2014

The Grand Unified Theory of Transplants -- or "To Transplant or Not to Transplant"

Hello folks.

I do a fair amount of outreach in the online and real world, and I've noticed that time and time again the same questions are being asked about transplants that were asked five years ago.  Should they be done at all?  Should they be done up front or later?  Should there be one or two?  It also occurs to me that doctors -- even the most brilliant ones -- may or may not be excellent at making decisions the way they are made in business, or even explaining concepts.  So I'm going to approach this using the reasoning that I've learned and applied outside the medical field and outside research to try 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 a fellow MM warrior Suzierose, aka Myeloma Cinderella, who is no fan of transplants (for well-founded reasons) but who has vetted the substance of what I write below.

We're talking about auto transplants here, by the way, not allo transplants.

What a Transplant Is, and What a Transplant Is Not.

A transplant, first of all, is not really a transplant.

Think of a transplant as high dose Melphalan[1] instead.  Melphalan is a type of chemotherapy.  That’s it to a transplant, nothing more, nothing less: a transplant really is just a lot of chemo.  After this, you get your own blood back to help you recover.  That’s it.  There’s 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.  That is an entirely different ball of wax.

An auto transplant is not a transplant of anything.  I suppose you could call it a replant.  But it’s best thought of as high dose Melphalan.

What a Tandem Transplant is.

It follow from the above that a tandem transplant is nothing magical – it’s just double the amount of Melphalan.  If you’re doing it spaced a year apart, it’s not a tandem transplant -- it’s two single transplants.  The purpose – and value – of a tandem is simply 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 you have: very simply, if you have disease that is susceptible to Melphalan, a transplant will very likely be effective.  If you have disease that is not susceptible to Melphalan, a transplant will probably not be very effective.

Melphalan works by changing the DNA of cells in the bone marrow and getting in the way of certain processes that cells need to survive.  This process is called alkylation.  The Melphalan adds something to the DNA of cells that kills them.[2]

This kills a lot of cells.  It may not kill all of them; it may not kill enough of them; and it might also piss off the ones that survive.  It depends on whether or not the patient has myeloma that is susceptible to this precise type of treatment.  Most patients (80-85%) have cells that will be sufficiently killed by Melphalan to have some response.   Of that group, maybe half of them require a LOT of Melphalan to kill all the cells.

However…if the patient has cells that do not respond to Melphalan, not all the cells will be killed and the process of changing the DNA could result in an outcome where the remaining cells are resistant to this or other kinds of treatment, or whereby they mutate more rapidly and/or chaotically.

From this, 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 killed sufficiently by Melphalan (or by other medicines).  Second, this explains the role of tandem transplants – some people need more Melphalan than others to kill all the cells.  Which explains when Melphalan was used by itself got 30% remission rates, but tandems do much better than that.

Do other types of therapy do the same thing?

Other types of therapy can be very effective, but don’t necessarily do the same thing.

Here are a few alternatives based on therapy I’ve received.

Traditional chemo used against newly diagnosed Myeloma comes in several flavors:

  • Cisplatin (the “P” of “PACE” therapy, which stands for platinum) works in a similar way.  It also monkeys with the guanine DNA.  It interferes with cell division, which is slightly different than the interference from Melphalan.  When the cell finds out that it can’t divide, it tries to repair itself.  When repair proves futile, the cell politely dies.  But cells have a way of learning to bypass platinum over time.
  • Adriamycin, the trade name of Doxyrubicin, is the “A” in “PACE” therapy (and Doxil is a modified version).  These drugs also interfere with DNA through a process celled intercalation (which disrupts DNA and the process through which cells replicate).
  • Cytoxan (the trade name of Cyclophosphamide, the “C” of “PACE” and the Cy of the CyBorD treatment) works in a very similar way to Melphalan.
  • Etoposide is the “E” of “PACE” and works differently.  It 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, and causes those strands to break.  Cancer cells divide more rapidly than healthy cells and are more reliant upon this enzyme than healthy cells, so they are disproportionately effected.

Then there are two classes of drugs that have come to be called “novel agents.”

  • IMIDs (the class of drugs that includes Thalidomide, Revlimid and Pomalidomide) 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 (which include Velcade and Kyprolis) interfere with the process through which cells remove abnormal or misfolded proteins (and thus help the cell to survive).  When this process is interfered with, the cell eventually realizes it has too many abnormalities and politely dies.

Oh, and we can’t forget steroids.  Steroids suppress the immune system and kill plasma cells.  There’s prednisone, which is not as powerful or as effective as Dexamethasone.  If you’re killing plasma cells, you’re killing MM cells (they sit in the plasma).

It goes without saying that none of this is healthy.  The purpose, 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. 

Think of it this way.  The cells in group A, above, 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.  His research shows that alkyalytors are essential to kill these precursor cells.  In other words, these cells exist in group A and they can’t be touched by novel drugs like IMIDs and proteasome inhibitors.  Those other drugs are the equivalent of moving a lawn full of weeds -- you are getting rid of the parts of the dandelion that you see, but the roots are still there and no amount of lawn-mowing will stop the weeds from growing back.  Not everybody agrees with this research..but it’s an idea to consider.

In group C are cells that are sensitive to Velcade or Revlimid but are not sensitive to Melphalan.  By definition, “high risk” MM either exists in quadrant C here (since Melphalan doesn’t work for very long, if at all, on some disease biology) or it exists outside these circles completely and requires that new solutions be found.  There is concern that for patients with disease that is not killed by Melphalan, the results of screwing with that DNA can cause advanced mutations in the MM cell that can make it more aggressive.  This explains why Total Therapy with Melphalan doesn’t work long-term for high risk patients, and explains why UAMS has moved away from transplants for those patients, as has Dr. Lonial at Emory.

Then there are those in group B – people with disease that could be killed by multiple means.   Here, do you just use Melphalan?  Or do you just use novel agents?  Or do you use both?  This requires a perspective on the concept of synergy between medicines, which I attempt to explain below.

The concept of synergy

There’s one more piece of the puzzle before we can start putting this all together.   It’s a pretty simple notion: the idea that multiple medicines work better together than individually.  Myeloma is smart.  Permit me a crude analogy:

If the Myeloma cells are in a room with one door, think of the medicine as a helpful monster preventing the MM from leaving the room, and eating the MM cells in the room who are panicking, looking for a way out.  The cells will start looking around for other ways out of the room, and will essentially cut a new door in the side of the room and leave through that new door.  The idea behind using multiple agents is that every potential door the MM might cut in the room has another type of medicine standing behind it and ultimately one or more of those monsters eats the cell before it can get out of the room somehow.

The concept of so-called “triplets” (e.g., VRD) and “doublets” (e.g., Rev + Dex) 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 in the era of novel agents.  Synergy from using the drugs in combination created more durable response: deeper remissions and, in some cases, even cure.

It stands to reason that clobbering MM with VDT-PACE plus Melphalan plus VRD in maintenance is an aggressive version of this same philosophy – the question is whether or not there are a lot of patients in group B, above, who don’t need all of that – 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 they can do a great job all on their own.   They need some synergy, but not as much as VDT-PACE offers.

When should one transplant?

Given what is laid out above, the decision on when to transplant is actually a much simpler one.

First, if you have disease that is unlikely to respond (or worse) to Melphalan, do not transplant.  How do you find this out?  You’ll need advanced bone marrow studies – such as UAMS’ gene array – to tell you what chromosomal abnormalities you have and you’ll need to learn whether or not those chromosomal abnormalities are consistent with those of patients who have not responded well to transplants.  Because per the first part of this little essay, it’s not that they aren’t responding to the concept of a transplant – it’s that Melphalan doesn’t work on that type of myeloma.

If you do have disease that is responsive to Melphalan, then the question becomes one of how extensive you (and your doctor) believe the synergies between medicines are:

- If you believe that there are real synergies between medicines, then transplant early, because you have na├»ve 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 synergies don’t really make a 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 synergy 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 figures out how to saw a new door in the room and get out.  The early transplants block two doors up front, the late transplant simply waits until later to block the second door.  In both cases, the Myeloma eventually cuts a third door.  : (

- If you believe that synergies 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 medicine monsters so that as soon as the MM tries to cut a new exit hole in the wall, it will be confronted with something.

Should there be one transplant or two?

In the context outlined above, the notion of a “tandem transplant” is easily considered and assessed.  Again, there’s no mystery to it: it’s simply twice the Melphalan at a time when the disease has not learned how to outwit Melphalan yet.  You might have disease that isn’t responsive to Melphalan in the first place, in which case it won’t make a difference.  You might have disease that is responsive to Melphalan but needs more than then usual dose, in which case it will make a difference.  It is Arkansas’ contention that most people need more than the dose from a single transplant in order to kill the disease versus just control it.

How long does a remission from a transplant last?

It depends.  On a lot.

It’s very hard to cite statistics, both because everybody’s disease is different because a transplant is not a transplant is not a transplant.

One transplant given to somebody who has relapsed from a lot of other medicine 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, remission from transplant will be hard if not impossible to achieve in the first place, and won’t last as long as would be the case if you have disease that is NOT resistant to Melphalan.  And among those who have disease that IS responsive to Melphalan, if you believe in synergy, you will have a longer remission if you are treated with multiple agents at the same time plus maintenance than you will if you are treated with fewer agents.  If you don’t believe in synergy, then you would say that it doesn’t matter – but there are studies proving that maintenance does make a difference.

Where does this leave us?

If you are diagnosed when older, no need for a transplant as novel agents are good and getting better and they can lead to control of the disease for some time – remember, being cured just means living long enough to die of something else.  J

If you are young and do NOT have disease that responds 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.

If you are young and have disease that responds to Melphalan, I would hit it hard Total Therapy style.

Ultimately, 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…which MUST include an MM specialist.  If your doctor can’t read what I wrote here and not only understand it but point out ten areas where I drastically oversimplified, then they shouldn’t be treating you.   :)

[1]I am ignoring for the moment the rare transplant that uses Bendamustine or another agent.

[2] Very specifically, for those who have are playing along at home with the Johnny Neutron Nuclear Medicine Home game, Melphalan adds an an alkyl group to the guanine base of DNA at the number 7 nitrogen atom of the imidazole ring.