Friday, March 1, 2013

Lies, Damn Lies and Statistics.

A targeted Google search (perhaps one of this blog's contents would do the same, of course) reveals that I already used this header back in 2009, and yet that turn of phrase (whether from Benjamin Disraeli or Mark Twain) remains meaningful.

Before I jump in, though, let me say that if anybody missed yesterday's Curetalk broadcast and wants to listen to it, the link is right here.   It's four panelists with Myeloma, myself included, answering questions from patients about various aspects of treatment and side effects.

Now...to the matter at hand.

I've been contemplating for a few days how to address this.  It's fairly significant news and it's not good.   It's not about me, personally.  I remain in complete remission.  But it is sobering because of what it might mean for me down the road.

The upshot is this: we now have a longer follow-up period of data from UAMS on the survival curves of patients treated by the TT3 regimen.  And while the survival curves are still very impressive and while many patients are being cured, the cure rate is not what we thought it was.

Long time readers who are into these types of details will likely remember two curves that show the percent of low-risk patients who have achieved complete remission that have maintained this remission.  Or put another way, it shows the percent of patients that lose remission.

Figure 1

The blue line shows low risk patients in TT3 that have kept remission or near complete remission (this includes those patients who have a very low "MGUS" type residual level of the disease -- recall that MGUS exists in over 3% of the general population over 50 and is oftentimes meaningless).  The red line shows low risk patients in TT2, which used a different protocol and didn't have the advantage of Revlimid, Velcade or even Thalidomide in one of the arms.

You can see that after six years, the red line of TT2 has "flattened out" at around 45%.  This type of flattening out is the core principal of Total Therapy.  It was first observed in treating childhood leukemia (ALL) at St. Jude's over a period of several decades.

To explain the significant of this chart, I'm going to take a step back historically.

Figure 2


So you can see from Figure 2 here (which are the trials done at St. Jude) that a flat line exists -- that's cure.  If you get to the flat line in the curve, the disease does not return.  In the simplest terms, you can see from the yellow line (studies 1 to 4) in figure 2, after 15 years, nobody lost remission.  And really, after 5, very few people did.   Over time, the percentage cured increased and the therapies became more effective.  By the time of studies 11 and 12, about 70% of people were being cured.  By the time of study 15, the projection was that around 90% of people were being cured.  All good stuff for a disease that used to be considered incurable.

On the basis of this work, TT for Myeloma was pursued.  Over the years, it, too, has established curves that look similar to the progress of ALL.

Figure 3


So here, you can see the progress made from TT1 (which looks like a cure rate of about 17.5%) to TT2 with thalidomide and TT3.

Now, along the way UAMS developed a means of testing bone marrow to assess whether or not one has "high" or "low" risk.  About 85% of people have low risk, 15% have high risk.  The graphs in figure 3 include all patients.  But here in this next chart, we see the results of TT3 on those with high risk (red) versus low risk (blue) disease:

Figure 4



You can see the folks who are unfortunate enough to have high risk disease are not able to remain in remission very long.  While a large percentage of the people with low risk disease DO remain in remission for a long period of time.

All of this information was published in a document called The Myth of Incurability which was presented by Arkansas in late 2007 or early 2008, I believe, shortly before I was diagnosed.  At the time, they were about four years into the TT3 protocol.

I'm beginning to feel like this guy.



Bear with me, dear readers.

So far, so good, right?  I went and got tested, I'm in the blue group, I went through TT4 which was like TT3 but less toxic because TT3 was believed to be so effective that it couldn't be improved upon.

All's well.

A couple of years later (fall 2009, just as I was finishing my transplants) a new document was published and presented.  In this one, called Modeling for the Cure, we saw even better outcomes.

More information was available from the TT3 trial.  Figure 4, shown above, was updated.  And it was more fantastic news!

Figure 5

Notice here, the line in blue is FLAT at around 4 years.

The poor high risk folks continue to lose remission, while the low-risk cohort has plateaued.

This, my friends, is the chart that I have followed meticulously for the past three years.  I achieved complete remission in September 2009.  I'm approaching four years and all looks good (save for the lingering pits in the spine which I keep hoping will go away).  In fact, temporally speaking I have reached the plateau in this graph.  I'm cured.

Awesome.

On the basis of this data, UAMS used some standard statistical tools to forecast the "cure fraction" of these patients.

Figure 6


Here, the green line shows low-risk TT3 patients that have achieved CR or near-CR.  That's not the whole group.  But I made that group, and there looks like a plateau, again, at four years.  It hasn't been absolutely reached here, but it certainly looks pretty darn close and according to these common statistic tools, 87.6% of patients can expect to be cured.  The P statistic is a measure of "confidence" in the forecast -- a P of .0001 is very, very good.  In other words, this 87.6% is, statistically speaking, a number in which we can place a lot of confidence.

That is, if every curve behaves as they have in the past.

Meanwhile, more time goes by, and the numbers continue to look good, leading to the publication in a periodical called Leukemia in 2012 (love these periodical names: Leukemia, Blood, etc.).  In this publication, which can be found here, the numbers look great, still, but the goalposts have moved just a smidge.

Figure 7


Now I've got some color issues so I frankly couldn't even tell you what line to look at by color, but it's the one on the top.  That's TT3.  "Landmark" refers to four years after achieving CR -- that's the point where the plateau was observed in Figure 6, above.  Essentially the assumption is made that between treatment related mortality and disease recurrence, that stuff gets out of the way in the first four years according to previous work, so we can now measure from that point.

Some salient observations:

* It takes a long time to see where the TT1 plateau is reached.  It's not until around 11.5 years after the four year mark, or 15 years from the onset of CR.  That's pretty close to what we observed in Figure 3, above, so that makes sense.

* TT2 plus thal appears to have reached a plateau a bit earlier and much higher -- it appears to be leveling off at the 6 years post-landmark point.  It was a little early to see this on Figure 2 but Figure 2's data shows the beginning of it tapering off, so that comports well with this chart.

* TT3 looks very good...94% of people are still estimated.  So the 87.6% number from figure 6 isn't quite as good...it's 94% of that figure, or 82%.  In other words, 82% of low-risk patients achieving CR under TT3 are cured.  And since I've made it to the landmark, it's 94% chance that I'm cured.

According to this data.

Now the other shoe drops.   Here's where I would be tempted to end this post and make it a cliff-hanger, but I won't be doing that.  :)

A fellow patient, blogger and friend of mine, Gary Petersen (who was also on the Curetalk panel with me), was recently given new survival figures from UAMS.  And they are very good!  Take a look at this, for example:

Figure 8


So here, you can see that after 9 years of enrollment in TT3, including both high and low risk patients, and including both those and have achieved remission and not, about 70% of people are still alive, and about 55% or so have not seen their disease progress.  That means about 79% of people that are still alive have not relapsed.  Bear in mind, this includes death from ALL causes, not just Myeloma.  The National Cancer Institutes data is only 19.6% alive after 9 years -- so UAMS is more than 3X that good!   All great.

So I excitedly reached out to my friend Gary Petersen and said "I bet the numbers are even more impressive when you split out low risk from high risk."

Here's where things get not so great.

Figure 9


This shows overall survival with 9 years of data, now.  Again, this is all deaths, not just myeloma.  So both the curves fall off faster than would be the case if we just looked at Myeloma.   Nonetheless, you see a plateau for the high risk patients, but it's a straight line down for low-risk patients.  No plateau.

The next chart shows progression-free survival -- meaning no disease recurrence.  We expect this to be lower numbers than overall survival, obviously, since some people might have experienced a loss of remission but not have died yet.

Figure 10


Here, again, the red line of high risk patients plateaus.  But there is no plateau in the blue line.   I repeat...no plateau.  In the immortal words of Scooby Doo...


RUH ROH, RAGGY.

Or, in English...sh*t.

Which brings us to the next piece of data...for those who achieved complete remission, what percent have maintained that remission?   Recall (or simply use the "page up" or scroll bar here) in figure 1, for ALL patients (including high risk) this number looked to be in the high 80s and looked headed for plateau.  In figure 4 we hadn't seen a plateau yet but the number was in the high 80s.  In figure 5, we saw a plateau at four years that pointed to 90% of people not losing remission -- being cured.  This led to figure 6, which showed with a high degree of confidence that there was a plateau at 87.6% of people being cured.  And figure 7, with a couple more years of data, supported something close to this (82% maybe instead of 87.6%, but still 82%).

But now...

Figure 11


There's no plateau at all.   What looked like a plateau from about years 3-5 was a false plateau.  Remission losses resume again shortly thereafter.  In fact, six years after complete response shows only 76% of people are still in remission and it's ticking down at a steady rate.  You can see where it looks like it's going to flatten off...only to resume again.  I've never seen anything like it before in 20+ years of looking at data for a living.

Regardless, the medical import of this is fairly clear: we have moved beyond "Ruh Roh, Raggy" and directly into "ZOINKS!!!" territory.


ZOINKS!

(Interestinlgy enough, when I searched the web for this pic, it found it, ON MY OWN BLOG, haha...must've used it before somewhere).  Anyhow, it is fitting.

Zoinks, indeed.

Naturally, this updated statistical news went over a bit like a turd in the punchbowl at my prospective "victory over Myeloma" banquet.  

So, what can we assess from all this?

Well, we know that the outcome isn't gonna be any worse than TT2 with Thal was, and that stands at an overall cure rate of 45% for low-risk Myeloma.

While TT3 remission loss appears to be lower in the interim, we might end up at the same end state.

Which leads to the potentially REMARKABLE counter-intuitive conclusion that the new drugs in which everybody holds such promise -- Velcade and Revlimid -- might not be curing anybody whatsoever, and the cure could simply be coming from PACE and Melphalan, same as 10 years ago, and all the novel drugs do it keep remission longer.

Ugh.

Now, that's the worst case scenario.  Bear in mind, also, if somebody falls in a manhole or is stuck by a meteor (no offense to our Russian friends) they are included.  So the curve should be flatter.  Maybe the cure rate is 55%?

55%, for those playing the home version of the game, is not close to 82%.

Moreover, since the remission loss appears to kick in earnestly after about 5 years after CR (1 year from "benchmark") it's not as though I can say "well, I've made it this far, so I'm no longer at 55%, I'm at some higher number."

I'm thinking I'm looking at more like 60%.  That's not based on statistics.  That's based on my gut.  (Note: subsequent research will change this somewhat -- I'm reporting "real time" as it were from when I got this news).

Now, if I started treatment and somebody said "there's a 60% chance you will be cured" I'da been happy about it.

But I've gotten this far, and endured this much, and was anticipating a high number here...closer to 98% at this point than 60%.  The goalposts have moved.   Hawkeye Pierce was expected to leave Korea, and the mission county just went up on him.


I remember Hawkeye being more upset than this a lot of times but couldn't find a picture of him sobbing or screaming.  Trust me, I feel more frustrated than wistful.

So what does this mean?  What changes?

Nothing, really, other than I'll probably opt for continued Velcade even if it costs me my head of hair.

I'll fight.  I'll probably win.  I mean, what else am I gonna do at this point, give in to this sh*tty disease and die?

No, I will dig in and prevail.

But this sucks.

A preview of Part 2 to come early next week:  I've spoken with BB to get his thoughts on this and dug into some additional data about my own particular biology that augurs well.  It's not quite as bad an ending as the worst case from this blog entry.  It's still not 98%, though, which is where I started out last week.

Dammit.