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 naïve 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.
