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What’s in a number? I’m a t(11;14) not t(4;14)

Posted on July 14 2014 by Pat Killingsworth | 1,596 views

When I was first diagnosed back in April, 2007, I was told by my Mayo Clinic specialist that I had no concerning genetic prognostic indicators.  In other words, I was a low risk multiple myeloma patient.  But this spring I learned that had changed.

Sometime between 2007 and 2011, my myeloma showed a significant shift.  No one told me about it; I noticed the change while glancing at a post transplant report in my file prior to meeting with Dr. Melissa Alsina, my specialist at Moffitt Cancer Center in Tampa, Florida.

Honestly, I didn’t give it much thought.  Regular readers know I don’t put as much stock in genetic indicators as some.  My view: low risk, high risk; we’re likely to use most all available myeloma therapies before we’re gone.  Sometimes the drugs that are supposed to work don’t, and those that aren’t supposed to work do.  I may be living proof of my theory.

I mistakenly believed that I had developed a t(4;14) chromosomal translocation following my autologous stem cell transplant in July of 2011.  Organizing my office in our new Fernandina Beach, Florida home Sunday, I discovered a copy of the report that I had noticed in May.  It turns out I was wrong on both counts.

I’m not a t(4;14).  I’m a t(11;14).  And the genetic change didn’t occur post transplant; it happened sometime prior to that.

What are the implications?  I think it’s unclear.  Overall survival numbers are 20% or so worse for patients with a t(11;14), the most common myeloma translocation.

But I’ve already outlived the median OS number for t(11;14) by almost three years.

My understanding is that proteasome inhibitors–like Velcade and Kyprolis–whould work better than IMiDs (Thalomid, Revlimid, Pomalyst) for those of us with t(11;14).  Yet Velcade barely worked for me.  Conversely, Rev has worked so well over the years that my new specialist, Dr. Roy at Mayo Clinic, Jacksonville, has started me on a doublet of Pomalyst (pomalidomide) and dex following my third relapse.

Blowing by the life expectancy median, and a positive response to IMiDs; two anecdotal arguments supporting my point that cytogenetics may be overrated–at least until researchers can do a better job connecting the dots.

I’m not trying to intentionally rile-up tech savvy advocates.  Just sharing how little difference any of it has seemed to make in my myeloma therapy.

True, a t(11;14) doesn’t mean I’m high risk.  But I do think my story could be inspirational for those of you with higher risk genetic indicators.  Drugs that aren’t likely to work sometimes do.  And we can outlive projections; I’m living proof of that!

Feel good and keep smiling!  Pat

21 Comments For This Post

  1. Holt Says:

    Remember Pat that the drug ABT-199 which is currently in clinical trials specifically targets t(11:14) as you discussed in your May 13 post concerning Chuck’s treatment. So this may actually be good news.

  2. suzierose Says:

    Hi Pat,

    As you said, t (11:14) is considered standard-risk with a median survival in excess of 5 years.

    “Most studies have suggested that the presence alone of t(11;14) may confer a favorable outcome (Table 1), but this effect is not strong enough to be statistically significant (probably because of small magnitude of this translocation) [22–24]. Moreover, due to heterogeneity within patients with t(11;14) there exists a difficulty in establishing a favorable outcome for patients with this genetic aberration. For instance, the presence of K-RAS mutations in patients with t(11;14) is also more prevalent (50%) than in patients with other primary IgH translocations (10%) [25]. In addition, the presence of t(11;14) is associated with an aggressive phenotype such as plasma cell leukemia [23]. A recent study with a larger series of patient with t(4;14) has suggested that the effect of t(11;14) on prognosis remains neutral [24] (Table 1).”

    What is high-risk myeloma?
    Martha Lacy tells us:
    http://www.managingmyeloma.com/knowledge-center/faq-library/744-what-is-high-risk-myeloma

    Not sure how your story gives hope to those of us who are high-risk. :)

  3. Marilyn Smith Says:

    Pat— this information is very good but scary. I assumed that when Steve was tested at diagnoses and found to be low risk that we never had to think about it again. I (we) were not aware that things could change. Maybe it is best to not go back and look what a persons risk is now and just trust your Doctor is doing what is best for her patient. If you know than you would worry. By the end of this week or beginning of next you should know how you re doing on the Pom. I can’t imagine that it won’t be a great improvement, It is Doctor Lacy’s favorite drug. Please let us know when you know as we are all praying for you. Mikie

  4. jc Says:

    Interesting. I am also 11:14. My doctor is leaning toward velcade upon relapse. Not really encouraging Revlimid right now. Starts to make some sense…especially the risk for leukemia and the questions of Revlimid increasing leukemia chances. Oh my, which poison is the least bad:) But encouraging to know velcade is suppose to work on 11:14…and my doctor knows my MM to the nth.

    My last labs dropped down some, down from all the numbers that were creeping up. Some dropped as much as 50%. I am taking no drugs. Is that normal for people relapsing? Or just the normal nature of the beast.

  5. Pat Killingsworth Says:

    I did read up on ABT-199 again, Holt. Interesting how none of these therapies ever comes up with any of my specialists. I’m not sure if its because they’re too busy or know I don’t qualify.

    Hope? I’ve already outlived t(11;14) OS median; at least what I read. I know dozens of high risk patients. All have outlived OS median for high risk patients. You’re going to outlive the OS median, too, suzierose. I find that hopeful!

  6. Pat Killingsworth Says:

    Marilyn, I look at it as watching myeloma develop drug resistance before our eyes. No surprise; we all know its going to happen. Sorry!

    JC, Rev is thought to be the inferior choice for ll;14s. But like I wrote, it worked well for me (hopefully POM, too) and you’re going to end up trying it at some point. That’s what bugs me about all of this. What, our docs should refuse to prescribe an 11;14 Rev or POM because of tendencies? May really help, especially in combination. Transplants the same way. Some say they won’t work as well. Others that it doesn’t matter. If the time is right, an SCT is still a good option for many. Hate to see them taken off the table based on probability. Not sure what to say about your numbers. First question would be, which numbers? Blood counts or myeloma indicators?

  7. jc Says:

    The kappa light chains and the Plasma cells in the blood dropped. Creat. improved also. It could just be the difference in doing a mail in lab to Mayo verses doing one right at Mayo. Just happy the bad numbers took a little break this month.

  8. Pat Killingsworth Says:

    Sometimes we shouldn’t look a lab gift horse in the mouth!

  9. Holt Says:

    suzierose — what was the source of the material you quoted?

  10. Nick Says:

    In the interest of furthering the dialog, I’d like to make some observations that could be helpful to some readers.

    First, let’s consider what high risk and low risk are. They are not “independent variables.” High risk disease means nothing more or less than “disease which shares characteristics with the disease of patients that have been shown to not respond well to the way we treat the disease here at center X.” Places that don’t use Velcade probably still think del 13 is high risk — and for them and their patients, it is. Low risk disease means nothing more or less than “disease which shares characteristics with the disease of patients that HAVE been shown to respond well to the way we treat the disease here at center X.”

    With respect to your biology, Pat, according to MAYO research, 11;14 is not a meaningful factor in time-to-progression or overall survival for people that received high dose Melphalan. Meaning: 11;14 responds to Mel. But 4;14 was a high risk factor in these regimens — meaning Mel doesn’t work for patients with 4;14. Perhaps 50% percent of transplants “don’t work” but I would posit most of the “not working” cases are due to patient biology rather than a random roll of the dice.

    UAMS research confirms both of these assessments. Their trials show that 4;14 doesn’t respond to Mel — in its regimens that didn’t include Velcade (TT1, TT2, TT2a which had Thalidomide) it was considered high risk. But in TT3, patients responded. The difference is TT3 had Velcade. So it follows that 4;14 responds to proteasome inhibitors. Of course there could also be a synergistic impact so Velcade alone may not be enough, but without Velcade, 4;14 doesn’t respond. (For what it’s worth, your 11;14 is considered a favorable element per UAMS).

    Every patient — you, me, our allo friends, Suzierose, all of us here — are individuals and none of us are bound by an iron law of median OS. It is an “output” of our individual experiences, not the driver of them — just like disease definition is the output of therapy, not a driver. But there is irrefutable value in statistics. Suzierose’s knowledge of her disease biology is unmatched by any patient I’ve encountered, and that is what has allowed her and her doctor to develop a plan for her specific treatment that is tailored to her cytogenetics. This is how we will get to individualized medicine.

    But back to what I said before, none of us are bound by an iron law of outcomes. May we all push that median farther out by beating our disease!

  11. suzierose Says:

    Hi Holt!

    Here you go:
    http://www.hindawi.com/journals/gri/2011/798089/

  12. suzierose Says:

    Well said Nick!

    ICAM.

    suzierose.

  13. Holt Says:

    Thanks suzierose!

  14. J Says:

    Hi Pat,
    I am reaching out to see if you have seen something like this in a patient with t(11,14) in your research…
    My mom’s bone biopsy came back normal cytogenetics at diagnosis, however it said insufficient speciman to test for t:(11,14). My mom has a lot of bone damage, her light chains were over 7000, and M spike over 8 at diagnosis. After one cycle of RVD she has no m spike, normal kappa/lambda ratio, and normal kappa lights…basically everything is normal. Does this sound like normal reaction to chemo with this abnormality?

  15. nil desperandum Says:

    Since this is a discussion of genetic markers, risk stratification and center-specific therapies, there is additional information for HRMM patients in the Emory group’s paper referenced on a previous thread, (Leukemia, 2014 28(3) p690-693) that is pertinent.

    Namely, in addition to reporting very encouraging results for HRMM using a regime of RVD induction/HDT/RVR maintenance (93% OS at 3 years), the authors also propose possible reasons why this regime appears to be superior to TT3 results for HRMM:

    1) The study cohorts may be somewhat different since UAMS uses broad gene expression profiling while the Emory group follwed these markers only: Del-17p, Del-1p, T(4:14), T(14:16), or PCL.

    2) But more important they thought, was minimal exposure to alkylators (aside from the one HDT) ‘which may contribute to the selection and evolution of more aggressive and resistant clones.’

    HRMM patients are probably wise to avoid heavy exposure to alkylating agents pending confirming studies.

  16. Pat Killingsworth Says:

    Of course you’re right, Nick. Median PFS or OS means one half are above the median number, and one half below. Interesting that I’m not 4;14, yet I did not respond to melphalan. Like you implied, these are only indicators. But I would argue–as I often do–that it makes my case; the technology is not ready for prime time! Wrong too often to be reliable–yet. I’ve read conflicting reports about 11;14 OS. I can reference one study that shows a big difference, and another I just read that says that there is no difference. But if I listen to my own argument it doesn’t really matter. You and suzierose can knock yourself out with the numbers. I’m more interested in the psychological angle. For example, why won’t patients (including yourself) acknowledge that half of patients do worse than median OS. One half. But the assumption is always that we’ll be the ones that do better. To me, if someone is going to play by the numbers they can’t have it both ways. I’m just saying…

  17. nil desperandum Says:

    Pat, it is an uncomfortable observation, but the same can be said of our doctors. 50% would in the bottom half of an objective ranking of myeloma expertise, but not ours. Still I don’t know how I could believe otherwise.

  18. Pat Killingsworth Says:

    Well said, nil!

  19. Pat Killingsworth Says:

    Could be, J. Rejoice! Awesome response bodes well for her overall survival–if you believe the stats. Good for her!

  20. Nick Says:

    Pat –

    I would never suggest that half of patients don’t do worse than Median OS. It’s certainly true — by definition, that’s precisely what it means. :) If you’ve seen me ever suggest that this isn’t the case, it’s because I’m cheerleading and encouraging people.

    In any given protocol, in any given study, half of the people are going to die earlier than median OS, and half of them are going to live longer than median OS.

    The key is, of course, not all cytogenetics or protocols are the same. Comparing median OS of MM across all risk factors or all protocols isn’t much more more accurate than comparing median OS of all cancers.

    To have the best possible outcome, I’m suggesting that patients understand their biology and with their doctors choose a protocol that has been demonstrated to be effective in treating their particular disease. For example, based on what I cited above, if you have 4;14 you better have treatment that includes proteasome inhibitors. As another example, based on what nil desperandum (a great use of Latin!) notes and what Suzierose has long argued, there’s a limit to the effectiveness of alkylating agents with HRMM. Which, going back to what I said, makes sense: we call the disease HRMM if it doesn’t respond to what is typically done — if alkylators worked great with HRMM, it wouldn’t be called HRMM. It’s so tautological as to be meaningless, really. Now, if somebody says Del 17 doesn’t respond to alkylators (which both Suzierose and UAMS point out) then we’re getting somewhere.

    As for ND’s point on doctor quality, of course that’s true as well — which is why you have objective means of determining doctor quality, starting with resources like Gary’s page that provides survival statistics by center, the number of patients they see, whether they are both researchers and clinicians, etc. Once you get to a certain quality level (I have argued for the somewhat arbitrary 20 doctors, you have said there are more, but I think we both know the number isn’t in the hundreds) it’s as much about philosophy as it is quality. If you believe in conservative treatment, Dr. Rajkumar is better than Dr. Barlogie. If you believe in aggressive treatment, Dr. Tricot is better than Dr. Chanan Khan. But I don’t think any of those doctors would suggest that the others in that group were not well above the median in terms of the capabilities of hem/oncs to treat this disease.

    To close with some humor, ND’s point about doctors also reminds me of a wonderful George Carlin joke. Paraphrasing: “somewhere in the world…is the world’s worst doctor. By process of elimination, there has to be somebody practicing medicine who is worse than anybody else in the world. And somebody has an appointment with him tomorrow!” :)

    Be well, everyone.

  21. Pat Killingsworth Says:

    Thanks, Nick! Of course my point wasn’t directed at you specifically; human nature dictates we all think thta we’ll be “in the upper half.” It’s all good. Researching probabilities helps. It lays the groundwork for what’s coming down the line. But your example of high risk patients not responding well to alkylators–and patients like me projected to respond well–makes my point that researchers aren’t quite there yet. You must know high risk patients that have responded well following a stem cell transplant; our friend, Danny Parker, is an example. And patients that don’t–even when they should–like me. And if a doctor is running out of therapy options for a high risk patient, you can bet they’ll try Cytoxan or melphalan. And sometimes one or both work. My fault; I’ve got us spinning in circles, chasing our tales. We’re both right! I’m just disappointed that our docs still can’t accurately project which therapy combination will work best for which patient. If you argue otherwise, just reference my real world examples above. I know, I know: we’re talking about tendencies. Playing the odds. Guess I expect it all to be tighter and more accurate in 2014. It will come. Not there yet.

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