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.
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.
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.
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:
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.
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!
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.
On the basis of this data, UAMS used some standard statistical tools to forecast the “cure fraction” of these patients.
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.
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:
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.
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.
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…