I'm sure you have been waiting with bated breath for the update here...heh heh. :)
Seriously, though, particularly for a couple of family members I'm sorry I didn't post an update yet. Needed a little time to relax after four days of testing and long flights in both directions. It's more work than it sounds like to walk around a hospital, going from tube to tube (MRI, PET/CT, etc.) and getting poked and prodded.
Here are the key results:
* MRI shows the same damn pits in my spine plus 1 cm lesion in my pelvis which I had not noted on previous MRIs. Except this is the site from which the fine needle aspiration was done six months ago, so I suppose I should have recognized that much, at least. In any case, that FNA was negative for myeloma so it is BB's opinion that these pits are "shadows" of former activity. Nonetheless, he wants to see me continue on therapy until they have resolved.
* PET is negative (that's good) with essentially stable uptake of the sugary goop that I have to drink. We could call that FDG-avidity or SUV (something uptake value, not sports utility vehicle) but Uptake of Sugary Goop will do for now. In any case, this metric was 1.6 before in one area of my spine and was 1.5 on this test -- anything in this range is not considered an issue. My original PET had an uptake of 2.4, and after a week of therapy during which all active focal lesions were suppressed, it went down to 2.2. So anything under 2.0 is fine and dandy, I think, although these metrics are really more valuable in relation to each other, I think. These numbers refer to metabolic activity -- the degree to which sugar-starved cells go nuts for the sugar. So it's hard to directly relate them to cancer, per se, other than by noting areas which are abnormally active given baseline numbers. When I was originally diagnosed, BB's right-hand BJ told me that my cells were doing the tango but not yet doing the Watusi. This analogy is the qualitative equivalent of all these 2.4, 2.2, etc. numbers. In any case, the dance hall has been closed down for some time now and the continued stability of the PET is a good confirmatory sign.
* Standard bone marrow biopsy: negative for plasma cell myeloma (whooppee!!) and negative for myelodysplasia (whooppee again!). I don't have the results right in front of me but it also occurred to me that the MRI showed more homogenous marrow than before, which I think is good. That means the recovery is more widespread. I should add, though, that unlike previous BMBs, this one hurt like the dickens when I came out of my propofol-fog. They had to give me 25mg of Fentanyl (superstrong synthetic morphine) and that barely took the edge off it. Several days later, it's still sore. As this was unusual, I asked the nurse in the recovery room to summon the nurse who did the work (a rather...well, let's say densely-proportioned woman) so I could find out what the issue was. She told me that I had exceptionally strong bones and she had to use a particular amount of elbow grease to hammer the instrument into my hip. Ouch. I can thank the Zometa (the bone strengthening agent which I received several times via infusion) for that, I suppose. But I wish it had done an effective job of helping the stupid pits in my spine fell in instead of just making my hip bone resistant to the hammer and chisel that they used on me!
* Back to blood for moment, and keeping with the theme of recovery: blood work showed rising levels of IgA and IgM (these are immunoglobulins -- cells in the immune system -- that help fight off infection) as well as IgG. IgG was where my problems lay...the normal immunoglobulins were being buried beneath a tidal wave of monoclonal protein (malfunctioning IgG cells). The Revlimid that I was on intentionally suppressed these cells in order to ensure there was minimal opportunity for the cancer to multiply. Now that I'm off Revlimid, the immune system is beginning to return to normal operations. It's still suppressed, but it's coming back to normal levels and that's a good thing as well. At this rate, in another six months I can start thinking about getting reimmunized and also weaning myself off Acyclovir, the pill that keeps away the virus responsible for Shingles. I've heard it's also given out like candy to the casts of all these MTV reality shows since it also wards off other manifestations of that same virus (cough Herpes cough cough).
* Most intriguingly, a new test for Minimal Residual Disease was performed. This requires its own post with background information in order for it to make sense to y'all (have I been in Arkansas too long?) Rather than make you wait for me to explain it, though, I'll just say that the test is far more sensitive than any other tests they have done. One can be in complete remission according to convention tests (including Immunofixation and bone marrow) and still have 1 in 10,000 cancer cells. The new test is accurate to up to 1 in 6,000,000 cells. The bone marrow pull that was done for mine contained a hair under 1.5 mil cells. The lowest designation is "<.01% myeloma cells" (they don't do "zero" simply because the pathologist wants to cover his booty). Happily, I received this designation. That means out of the 1.5 mil cells, I had less than 150 (and probably 0) myeloma cells. This is enough, per BB's dictation, to qualify me for the "strictest definition of complete remission" which is great news!
* Now, to temper that...this is a new test and while they've been collecting data like mad over the last few months with it, BB told me that it's a nightmare to try to analyze it and they have to get things in order so that they can process it and determine exactly how significant it is. Do people that lose remission ever have MRD of 0? If they do, then it's a temporary metric. On the other hand, if those with an MRD of 0 have experienced no recurrence, then it could be a more significant marker. We wait and see, but for now, it's great.
The upshot: those pits in my spine are still a disturbing sign, and coupled with the lower-than-previously-thought cure fraction (recall a few posts ago) we need to keep up the assault so any remaining myeloma cells in those pits die off and those lesions fully resolve. However, BB felt good enough about the tests in general (as well as the normal expression of the MYC gene from six months ago) that he was comfortable reducing my weekly Velcade from 1.5mg/m2 to 1.0mg/m2, which is the "normal" dose. This should hopefully help with some of the GI pain, allopecia and other side effects.
On that topic, my fellow traveler JH happened to be in Little Rock and I had a great dinner with him and his father, who is a physician with an emphasis in hair loss (in addition to being a terrific guy). He was kind enough to take a peek at the crown of my head and we collectively concluded that (1) I'm never going band, (2) I'm likely experience a normal pattern of hair thinning, and (3) it's possible that the Velcade has accelerated this. Since the hair thickened when I elected to stop Velcade for a month, I think #3 is pretty likely. We'll see how well it responds to a reduction in dose.
One last random comment that may be of interest to other patients. The 80-gene test (or Gene Array) that is done on bone marrow at UAMS has many different characteristics that combine to form different "subtypes" of Myeloma. There are maybe two dozen of these that help define the particular manifestation of MM in a given patient. For example, two of my characteristics were hyperdiploid (this is a good sign...it means there are too many chromosomes instead of too few) and "Proliferation Subtype" (this is a bad sign, and means what we would surmise it does). The high MYC gene is or was probably one of the contributors to this.
Anyhow, when looking simply at the proliferation index (a metric of this proliferation factor) the cut off for high risk disease versus low risk is 10.0. Note this is not the sole factor contributing to high risk disease. At any rate, when I showed up, mine was close to 10 but below it (I forget the precise number but it was >1 and <10 6.5="" after="" class="goog-spellcheck-word" hours="" let="" nbsp="" s="" say="" so="" span="" style="background-attachment: initial; background-clip: initial; background-color: yellow; background-image: initial; background-origin: initial; background-position: initial initial; background-repeat: initial initial;">Velcade
administration, it crept up to 10.3 or so. Not good. But a week later after a test dose of Melphalan, it was -6.0, and it stayed low in subsequent tests. So Bart thought it was interesting that my own particular case showed an increase in this followed by big-time suppression and he asked his statistician to consider looking at this trend as a prognostic factor in other patients.
There's much more to report but I've gotta get to work here -- so I'll provide an additional update in the coming days.
Bottom line: yours truly is doing well, continuing therapy, and thankful for my clinical and therapeutic team as well as all of you!
Monday, March 25, 2013
Tuesday, March 19, 2013
Stupid lesions have not yet resolved. : (
I am currently awaiting my bone marrow procedures, which will include three pulls, I think -- the standard bone marrow, the gene array (which I may yet veto) and a new test for Minimal Residual Disease.
Since I make them knock me out for this with propofol (the Michael Jackson sleep drug) I was getting a pre-op consult with one of the physician assistants here. He was kind enough to pull up my MRI -- they have new software which allows you to scroll through your body bit by bit -- it was fascinating to see!
Less fascinating was the tech's write-up, that indicated "stable small lesions are observed in the thoracic spine and pelvis." I'd never seen one in the pelvis before -- that was troublesome. However since it's characterized as "stable" it must have been there before. Perhaps just not on the last MRI for some reason? I didn't recognize the name of the tech so it may have been somebody new...generally they like to have the same tech read the scan to ensure it's done consistently but it's now been five years of coming here, just about, and personnel change.
I saw BB at dinner last night and he noted that he has new talent coming in...he's lost some doctors who have moved on to private practice but he's retained his research specialist and one of his former doctors who moved on to work for doctor GT in Utah is coming back here, which is nice. I mused that he's a bit like a Head Coach for a top football team whose assistant coaches are constantly being poached or lured away by other jobs. Talent recruitment and retention is a big part of his job.
At any rate, there will be more to review and discuss about these persistent lesions tomorrow. It does mean there's probably no end in sight for the Velcade. And depending on what the MRD test shows, I'll either view it as an inconvenience or a critical necessity. Or perhaps I might even need to switch to new drugs if there is residual disease.
Since I make them knock me out for this with propofol (the Michael Jackson sleep drug) I was getting a pre-op consult with one of the physician assistants here. He was kind enough to pull up my MRI -- they have new software which allows you to scroll through your body bit by bit -- it was fascinating to see!
Less fascinating was the tech's write-up, that indicated "stable small lesions are observed in the thoracic spine and pelvis." I'd never seen one in the pelvis before -- that was troublesome. However since it's characterized as "stable" it must have been there before. Perhaps just not on the last MRI for some reason? I didn't recognize the name of the tech so it may have been somebody new...generally they like to have the same tech read the scan to ensure it's done consistently but it's now been five years of coming here, just about, and personnel change.
I saw BB at dinner last night and he noted that he has new talent coming in...he's lost some doctors who have moved on to private practice but he's retained his research specialist and one of his former doctors who moved on to work for doctor GT in Utah is coming back here, which is nice. I mused that he's a bit like a Head Coach for a top football team whose assistant coaches are constantly being poached or lured away by other jobs. Talent recruitment and retention is a big part of his job.
At any rate, there will be more to review and discuss about these persistent lesions tomorrow. It does mean there's probably no end in sight for the Velcade. And depending on what the MRD test shows, I'll either view it as an inconvenience or a critical necessity. Or perhaps I might even need to switch to new drugs if there is residual disease.
Monday, March 18, 2013
Greetings from Little Rock
Boy, is it cold here...and rainy. I'm currently hunkered down in the 8th floor of the cancer center, which is where the entire Myeloma team moved about six or eight months ago. They've got a couple of computers here so I thought I would avail myself of the Internet connection and update you folks.
There's not that much to report just yet, other than the blood draw went off without a hitch for once (this means they knew to expect me on the 4th floor at the infusion center rather than at the blood lab on the 1st floor). I had found the little topical freezing spray that my local oncology nurse had given me and a little spritz of that led to a painless port access. I came back an hour later for a lab printout and everything that's back fromt he labs looks good -- the cancer markers will take another day or so but I'm anticipating everything will be consistent with complete remission.
The PET machine was out of service so my 9:30AM PET scan has been rescheduled. They gave me the choice of 5:30PM today or 5AM tomorrow morning. Astute readers will likely guess that I chose the former option. Still being on West Coast time, even this morning's 7AM wakeup call seemed brutally early. 4AM is not in the cards.
I briefly visited with the irrepressible BJ, BB's right hand. The visit was enough to answer a couple of questions I had about a new test, the Minimal Residual Disease test which is being done in conjunction with a group in Salamanca, Spain.
The link below addresses a study wherein this test was used to identify those "high risk" myeloma patients that lost remission versus those who did not. I've not read this carefully enough to paraphrase it here but perhaps I'll do so at some point soon.
http://bloodjournal.hematologylibrary.org/content/119/3/687.long
The second link talks about which of the two tests is more accurate, and what a typical measurement is. The lowest measure was .001%, or 1 cancer cell in 100000. The median was 14 cancer cells in 100000 and the high was 1100 cancer cells in 100000. Notably, everybody in the study was in complete remission. So some of us with complete remission could still have 1 cancer cell in 1000 cells.
http://www.haematologica.org/content/90/10/1365.short
In this study, they also establish the threshold of "minimal residual disease" being 10 cancer cells in 100000 (.01% cancer cells). It seems like a subjective threshold, clearly, but it does serve a comparative purpose for test sensitivity.
I was told by BJ that the MRD test at MIRT is sensitive enough to detect one cancer cell in 6,000,000. It's a bone marrow test using some type of flow cytometry but I recall BB telling me something about an "8-way color array" (this is almost certainly wrong...consider it a placeholder, perhaps referring to the "multiparameter flow cytometry" that the first link above mentions). In any event, I shall be paying keen attention to the results of that test.
I'm off to the next appointment. More when events merit and time permits.
There's not that much to report just yet, other than the blood draw went off without a hitch for once (this means they knew to expect me on the 4th floor at the infusion center rather than at the blood lab on the 1st floor). I had found the little topical freezing spray that my local oncology nurse had given me and a little spritz of that led to a painless port access. I came back an hour later for a lab printout and everything that's back fromt he labs looks good -- the cancer markers will take another day or so but I'm anticipating everything will be consistent with complete remission.
The PET machine was out of service so my 9:30AM PET scan has been rescheduled. They gave me the choice of 5:30PM today or 5AM tomorrow morning. Astute readers will likely guess that I chose the former option. Still being on West Coast time, even this morning's 7AM wakeup call seemed brutally early. 4AM is not in the cards.
I briefly visited with the irrepressible BJ, BB's right hand. The visit was enough to answer a couple of questions I had about a new test, the Minimal Residual Disease test which is being done in conjunction with a group in Salamanca, Spain.
The link below addresses a study wherein this test was used to identify those "high risk" myeloma patients that lost remission versus those who did not. I've not read this carefully enough to paraphrase it here but perhaps I'll do so at some point soon.
http://bloodjournal.hematologylibrary.org/content/119/3/687.long
The second link talks about which of the two tests is more accurate, and what a typical measurement is. The lowest measure was .001%, or 1 cancer cell in 100000. The median was 14 cancer cells in 100000 and the high was 1100 cancer cells in 100000. Notably, everybody in the study was in complete remission. So some of us with complete remission could still have 1 cancer cell in 1000 cells.
http://www.haematologica.org/content/90/10/1365.short
In this study, they also establish the threshold of "minimal residual disease" being 10 cancer cells in 100000 (.01% cancer cells). It seems like a subjective threshold, clearly, but it does serve a comparative purpose for test sensitivity.
I was told by BJ that the MRD test at MIRT is sensitive enough to detect one cancer cell in 6,000,000. It's a bone marrow test using some type of flow cytometry but I recall BB telling me something about an "8-way color array" (this is almost certainly wrong...consider it a placeholder, perhaps referring to the "multiparameter flow cytometry" that the first link above mentions). In any event, I shall be paying keen attention to the results of that test.
I'm off to the next appointment. More when events merit and time permits.
Monday, March 11, 2013
Part 2 of the statistical update
I'm so sorry, folks, to be behind. I've received a number of terrific emails from the newly diagnosed to long-time fellow travelers and I want to thank all of you for writing to me. I'm particularly thankful, always, to hear from patients who have found this blog to be helpful to them as the lead their own fight against this disease. You inspire me and I'm thankful to play any part whatsoever in your battle.
So...where was I...
Ah yes, the lack of a plateau.
I sent BB a lengthy email explaining my concerns, and the basic math that I'd done on the back of an envelope to arrive at somewhere around 50-60% cure versus 87%. He commented quickly in an email that the 87% figure had been updated as a result of longer follow-up, and that this is expected, but that the Blood article (from which I presented figures below) indicated that "cure is still there."
It's a question of what percent.
He told me, in his playful way that has a serious undercurrent, that I was "doing a lot of arithmetic that was not really getting anywhere" and that I was a bit of a "pain in the ass." :) I know this is an endearing term from him so I relish it.
It is a huge testament to this doctor that, despite not having an appointment with me scheduled, he called me and spent 45 minutes not just discussing this data but also forwarding me articles, both published and unpublished, to help educate me.
He agrees that the final number will be somewhere better than TT2-Thal, but not the 87% that looked like could be the case. The numbers for TT4, which include more extensive maintenance than TT3 (the beginning of TT3 used only one year of Velcade, for example), are better than TT3, so the current cohort can be expected to do marginally better. BB has never in his career seen a decline in efficacy as therapies advance -- recall that in all the studies for pediatric leukemia as well as the TT regimens, the curves move up the Y axis towards the top of the graph as they advance.
The real answer is, we won't know until 10 years out where the final curve is. He also reminded me, as did a couple of blog followers, that these curves include mortality from other causes so you have to take those out -- doing so flattens the lines significantly, though they still don't reach a plateau yet.
I was casting about for something that would give me slightly better news on this, and BB was kind enough to tell me that they have compared PET scans after the commencement of treatment with treatment outcome. Before treatment begins, a PET scan is performed to identify the number and intensity of what are called "FDG-avid lesions" -- thriving cancer tumors. Then, after the first week of treatment, another PET scan is performed to see the impact of the treatment on patient biology. These same tests are done with MRIs, as well.
I've got some data to share, but presenting it is going to take some time, so I'll get back to that tomorrow. I will say that the news is slightly more optimistic than the 60% figure. Not 87%, but something. :)
So...where was I...
Ah yes, the lack of a plateau.
I sent BB a lengthy email explaining my concerns, and the basic math that I'd done on the back of an envelope to arrive at somewhere around 50-60% cure versus 87%. He commented quickly in an email that the 87% figure had been updated as a result of longer follow-up, and that this is expected, but that the Blood article (from which I presented figures below) indicated that "cure is still there."
It's a question of what percent.
He told me, in his playful way that has a serious undercurrent, that I was "doing a lot of arithmetic that was not really getting anywhere" and that I was a bit of a "pain in the ass." :) I know this is an endearing term from him so I relish it.
It is a huge testament to this doctor that, despite not having an appointment with me scheduled, he called me and spent 45 minutes not just discussing this data but also forwarding me articles, both published and unpublished, to help educate me.
He agrees that the final number will be somewhere better than TT2-Thal, but not the 87% that looked like could be the case. The numbers for TT4, which include more extensive maintenance than TT3 (the beginning of TT3 used only one year of Velcade, for example), are better than TT3, so the current cohort can be expected to do marginally better. BB has never in his career seen a decline in efficacy as therapies advance -- recall that in all the studies for pediatric leukemia as well as the TT regimens, the curves move up the Y axis towards the top of the graph as they advance.
The real answer is, we won't know until 10 years out where the final curve is. He also reminded me, as did a couple of blog followers, that these curves include mortality from other causes so you have to take those out -- doing so flattens the lines significantly, though they still don't reach a plateau yet.
I was casting about for something that would give me slightly better news on this, and BB was kind enough to tell me that they have compared PET scans after the commencement of treatment with treatment outcome. Before treatment begins, a PET scan is performed to identify the number and intensity of what are called "FDG-avid lesions" -- thriving cancer tumors. Then, after the first week of treatment, another PET scan is performed to see the impact of the treatment on patient biology. These same tests are done with MRIs, as well.
I've got some data to share, but presenting it is going to take some time, so I'll get back to that tomorrow. I will say that the news is slightly more optimistic than the 60% figure. Not 87%, but something. :)
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.
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.
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!
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.
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...
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
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
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.
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