BB's phone message, KA's advice and sub-Q velcade

Some quick and sundry updates here.

First, although I had pried the information from his team last Friday, BB himself called me on Monday (I don't know why but I didn't see the phone "ringing" or vibrating).   I was hoping to actually embed the audio here but I can't do it at this time (will do my best since the cadence is what makes this humorous).   Anyhow, the voicemail is:

"Hey Nick, this is Bart.  All studies are good and negative.  Okay?  Great news.  Calm down.  Thanks, bye."

I feel like saying, in full Walter Sobchek mode, "I'm perfectly calm, dude...calmer than you are."   And I am, in fact, pretty calm these days.

So the plan at present is to continue on single agent Velcade in a ~20% higher dose (1.5mg/m2) until those damn pits in my spine heal up, with a check-up (including bone marrow, PET, MRI, etc.) in six months' time and cancer markers run every two weeks from blood.

I spoke with KA yesterday on a phone consult to validate this approach.  It was a very pleasant conversation, the highlights of which were:

• He agrees that I should remain on something to ensure the full adherence to BB's approach with its hope for cure

• He agrees that Revlimid should be discontinued since I've had a ton of alkalyting agents (e.g., platinum, adriamycin, cytoxan, etoposide, melphalan in high dose) that alter DNA and it is in combination with these alkalyting agents that Revlimid use is most likely to lead to myelodysplasia and, potentially, Leukemia

• He thinks Interferon wouldn't do anything other than make me feel like I have the flu constantly

• He thinks a proteasome inhibitor (like Velcade) could be a long-term option for me (as in potentially forever) and that in a couple of years there is likely to be an oral version (i.e., a pill) that would make it easier to take.  I think he doesn't full subscribe to Bart's confidence in a cure provided the MRI is clean.  We'll see -- this stuff remains poison and I don't want to be on it forever.

• He "wouldn't sell the house simply because of the MYC gene."  While it is no longer over-expressed, I still wanted KA's thoughts on it.  He said that "with respect, [BB] is probably guessing about its responsibility for the remission loss" and I'm sure BB might agree, but I don't know how extensive the regression studies are so it might be a very educated guess -- or it could be statistically proven.  At any rate, the fact that it is normally expressed gives me some comfort -- particularly when combined with BB's voicemail.  I asked KA what maintenance drugs target MYC and he said "a few years ago, I'd have said none...but it turns out they all do.  Revlimid is particularly effective."  So perhaps Revlimid is what caused the MYC to normalize over the last three years of therapy.

• He noted that over time, the bones should resolve and the heterogenous marrow should probably even become homogenous but that he wouldn't use the latter as a requirement of remission (he wouldn't say cure, obviously).  He said that PET scans were extremely sensitive and the marrow funkiness could be caused by many things (e.g., an inflammation).  I didn't bother to mince words and point out that we were talking MRI since clearly Arkansas and Dana Farber diverge on treatment long before this point.

I thought it was good that one of the world's foremost experts on novel drugs (versus transplants) essentially concurred with BB at this point.  I'm going to continue with a couple more opinions because one other common point of commentary between BB and KA was that "we're in uncharted water here" insofar as there are no studies to point to.  So it can't hurt to get a couple more viewpoints to corroborate the approach.  Next up is BD.

PHEW!!!!!! Good news from Arkansas!

First of all, thank you all SO much for your prayers, emails, voicemails, texts, comments, intentions, positive vibes and well wishes.  They do make a difference, both in how challenging news is handled and, perhaps, in the outcome of events.   I deeply appreciate them!

So, let me share the good news.  My gene array came back about as good as it possibly could have, which means:

1.  Negative for myeloma (and this was in the heterogenous marrow of a former lesion, so if it was gonna show up anyplace, that is where it would show up)

2.  "No cytogenetic evidence of myelodysplasia" which means, most likely, that there were some funky looking white cells but they are made to look funky by the Revlimid, rather than my body manufacturing them.  We're off Revlimid so hopefully that will all resolve by next time but meanwhile, my marrow doesn't appear to be pre-leukemic.  Phew!!!

3.  The MYC gene which was over-expressed (the numbers being 18,390 and 13,928 in the two gene arrays I did before I started treatment, 17,000 after one day of Velcade and 19,602 after one week of treatment) came back at 3,200.  This puts it clearly in the second quartile (meaning somewhere between 50 and 75% of patients have more of this gene than me).  I need to speak with Bart to find out what this means, exactly, but it's no longer over-expressed.  So that MAY mean that I don't need to worry about spontaneous remission loss.

Triple phew!

One lingering question I have is whether or not my friend BB (the patient, not the doctor) who unfortunately lost remission due to this MYC gene had experienced a similar "normalization" through therapy -- in which case I'm not out of the woods -- or if his MYC gene had never been "normalized."  If the latter is the case, than it likely means that I won't face a high chance of remission loss -- and it means that BB (the patient) can look to his own MYC marker going forward in treatment as something that could indicate the efficacy of his therapy.   If the former is the case, then I still need to worry -- because he lost remission and if his MYC gene was normalized, then even though mine is not being over-expressed, I'm still at risk.

At least until those lesions resolve and the bone marrow becomes homogenous.  I had thought we only needed to look for the first but based on BB's (the doctor, now) concerns last week I might need to wait for the heterogenous marrow to give way to homogenous marrow.  Although I'd also been told in the past that this may never happen given the destruction of the marrow during transplants.  So I'm not sure.

Another conversation with BB (the doctor) is in order and I'm setting that up.

We still need to figure out what maintenance drugs to use since I'm now off Revlimid -- we want those stupid pits in my spine to heal up so we can breathe easier and get back to the "you're cured" track!   How I long for those words...

For the moment, though, the concerns of last week have abated.  Good lord, it's hard to explain how much stress that puts somebody through -- I'm not sure I fully realized it myself until the burden of that anxiety was lifted with this news.  I'm really emotionally spent.

Time to celebrate this evening with a great bottle of champagne!!!

Thank you all -- I will continue to update frequently as I learn more, including in numerous consults over the next couple of weeks.

The second opinion derby, redux

Howdy folks.

After getting knocked about a bit, I think I have found my sea-legs a bit and am going about the process of speaking to people that have specifically studied this MYC gene and may have thoughts on how to target it with specific maintenance drugs.  Of course my hope and expectation is to still handle all of this through UAMS but it can't hurt to be informed and I feel like BB is operating from the gut versus from a pool of data so it also can't hurt for me to understand how other's guts would lead them.

It may be challenging to do so.  Consider the fact, for example, that I remain in complete remission.  I can't send anybody slides of bone marrow because it won't show any myeloma cells.  I can't send anybody blood because it will be normal.  Nobody else really uses MRIs the way UAMS does; if I sent them an MRI it would show a few small inactive lesions and some heterogenous marrow which is to be expected from myeloablative therapy.

I think there are probably a limited number of doctors who would even consider ANY kind of maintenance for somebody in my condition, having concluded three years of VRD and retained remission that whole time.

Nonetheless, I've begun looking at which doctors have looked at the MYC gene -- either with respect to Myeloma or even with respect to other blood cancers.  The people whom I'm hoping to speak with include:

- KA at Dana Farber.  He's done work on MYC and he's a leader with novel agents.  Ironically, friend and fellow blogger GP was incredibly kind and sent a brief summary of my situation to KA's partner, PR.  He responded immediately by saying I should be speaking to somebody else outside Dana Farber. : \   Oh well, I'm still intending to do my phone consult with KA next Tuesday.   But this leads us to...

- RF at Mayo Scottsdale.  He evidently has done extensive research on MYC and is considered the leading expert on this gene (or at least one of them).  He's done presentations with BB on treatment of high risk MM before so they at least know each other.  I've sent an email to him asking to set up a consult, but haven't heard anything as yet.

- BD at Cedars Sinai.  A luminary researcher, he's done work on MYC and probably understands this disease as well as just about anybody.  I have a call into him to schedule a phone consult, although I could also drop by since he's local.

- SF at City of Hope.  He's got a tremendous amount of experience across different types of blood cancers and has done work on MYC.  He also understands BB's protcol.  And he's a great person.  And close to home.  So that checks a lot of boxes.

We'll see if I can speak with at least two of these people -- I'm particularly keen on speaking with RF.  Then we'll have some idea of what to throw into the mix along with Velcade if the gene array indicates that I still have this MYC gene running amok.

If I don't, then this is all much ado about no--  well, much ado about very little.  I'll still need to stay on Velcade until the lesions resolve even if I don't have the gene problems.   But that will be a bump in the road versus a majorly disconcert event.

Fingers crossed for good results on Friday.  BJ sent me a little text, since we had trouble getting cells from one of the bone marrow sites, that the results are "going to be good...or it wouldn't be this hard" (to collect the cels, I hope).   I presume that at least means that if I had myeloma cells the marrow would be more substantive.  This is part of what we hope for, but really we want:

* No myeloma cells
* No myelodysplasia
* No over-expression of MYC

If we're good on all those fronts, then we return to our maintenance program with Velcade alone, most likely, and watch and wait for those little spine pits to resolve.

I shall keep you posted.

I must also say I am particularly touched, as always, by the emails, calls, texts and posts offering support, prayers, positive thoughts and intentions, and even humorous and insightful historical commentary on the evolution of certain conventions in grammar!  :)

A more thoughtful recap of my current status

Hello friends.

I've had a couple of days to think through what the current situation is and so I'm going to try to recap it here.

I've finished three years of maintenance therapy.  This is supposed to be the "woo-hoo!" moment at UAMS when BB tells me "the Myeloma is gone and will not be coming back" and I can drop all meds except Acyclovir (the anti-viral that keeps Shingles away, which I need to stay on while my immune system recovers, which it would finally be allowed to do since I would be off the meds that suppress it).

Quoting the now 70+ year old BB directly from last week's appointment, "my usual approach is to continue to treat until such time as all the sh*t is outta there, so to speak."   This means traditional evidence of complete remission (no M-spike under the most stringent blood tests, normal urine, normal marrow) but also what BB called "Arkansas complete remission" (or MRI complete remission) which also means that all formerly-active lesions in the bones are fully resolved (i.e. replaced / refilled) with new bone, as confirmed under MRI.  His hypothesis is that these lesions are microenvironments in which myeloma cells can restart.  If the lesions are replaced with bone, it means they won't be able to do so.

We have been watching my 19 formerly active lesions resolve over the last three years of maintenance therapy, and all have gone (so I thought) except for five small ones in my spine, which have shrunk from 2.5cm at baseline (i.e., when I showed up to be treated) to 4 mm as of a 18 months ago.  But they have remained stable over these past 18 months.  I was hoping to see them gone since in addition to the normal maintenance protocol of Velcade, Revlimid and Dex, I was on the bone-strengthening bisphosphonate agent Zometa, the frequency of which was increased to one infusion per month over the last six months (I think I got four of them, actually -- same difference since this aspect of treatment is far from an exact science).

Last week, the MRI revealed that the five spinal lesions had still not resolved.  They were termed "small" and were not sized, but in the summary of results they were considered "stable" relative to the last scan six months ago.  This was problem number one.  BB wants to continue to treat until such time as...uh...well until such time as these are fully resolved, to use more polite phraseology than was employed in the actual consult.  In and of itself, this wouldn't be a huge deal...but this prompts questions about what medicine(s) to continue to take while waiting for resolution, and how effective they will be.

I've been on Velcade, Revlimid and Dexamethasone for three years of maintenance, but readers will know that I've had concerns about continuing on Revlimid.  It has been a key agent in maintenance therapy since Total Therapy 3 was begun in around 2003 and is widely used now.  About a year ago, it was noticed (by numerous entities, including the company that produces it) that Revlimid was associated with secondary malignancies -- solid cell tumors and leukemia, to be precise.  I had a squamous cell carcinoma in my finger, so we can check that box.  I had pre-leukemic cells in my marrow six months ago...so before we check that box, BB wants me off this stuff.  I agree.  For a while, the value of Revlimid (inclusive of these risks) is a no-brainer.  But after three years, has it done everything that it should do?  Is it now at the point where the risk of continued use is greater than the risk of remission loss?  Perhaps.  In fact, normally I would be pretty easy to convince except for certain aspects of my current situation.

Then there is the matter of -- for someone looking to continue maintenance with some urgency -- what it can be replaced by.  I want to keep up the attack on whatever rogue cells aren't yet with the program and make my body as inhospitable as possible for Myeloma cells while my bones continue to heal.  I suggested Pomalidomide, which as many readers know, is the next generation Revlimid.  BB said "yeah, good idea, but we can't get it."  I believe this is because Pomalidomide is still only available -- even to Arkansas -- as a single agent except perhaps in refractory cases, and I'm thankfully not yet a refractory case.  And if we are to use just one agent, BB wants to keep me on Velcade since he believes this is the most effective anti-Myeloma agent there is.  He asked me if I can tolerate it without the Dex and I said "sure!" -- mostly because I want off the Dex.  So that does seem to indicate that Dex in maintenance is not used for its plasmacytolitic (i.e. killing plasma cells) properties but because it helps counterract the effects of Velcade (flu-like symptoms, GI issues, etc.)    I will be increasing the dosage of Velcade from the already high 1.3mg/m2 to 1.5mg/m2 (normal is 1mg, and that's for people with raging disease, not the complete remission which I currently enjoy).   And Velcade has caused a lot of GI pain that requires Vicodin to keep at bay...so I'm not looking forward to increasing it.  However, Dex is responsible for a lot of ills so I'll be glad to be rid of it.

So all this would be fine, if a little unnerving...I'm done with maintenance, I'm still in complete remission, I've got some small lesions that haven't resolved yet, and I'm staying on Velcade until they fully resolve.

Except it's not that easy.

UAMS is very advanced in its genetic assessment of the disease.  In an era where most centers still rely on something called FISH (fluorescence in situ hybridization), a test that was developed 25+ years ago to look for out-of-place chromosomes, UAMS uses an assessment of 80 genes which, given its massive database of tissue samples, can indicate the risk profile of a given patient with accuracy.  The test is called a "gene array" or "gene expression profile" and involves a large core sample of bone marrow.  I had four of these done over about a four week period beginning a little before my therapy started in February of 2009 and going a couple of weeks into it.  These tests indicated that I had low-risk disease with some high-risk characteristics, and based on those high-risk characteristics I was given the additional Velcade (1.3mg/m2 versus 1.0mg/m2) in maintenance.  I have not had a gene array done since then because (a) they are painful, and (b) they did not have further clinical significance other than assigning this low- or high-risk categorization.

Until now.  Now they are still painful, but they do have some further clinical significance.

One of the genes they profile is called MYC.  This gene was originally linked to a type of Lymphoma.  Is essentially acts as a "utility infielder" with respect to genetic screwups that cause cancer.  Myeloma cells are abnormal either because chromosomes have been deleted (chromosome 13 is a common deletion that used to be considered a high risk factor, as an example) or added, or because there are chromosomes that have been translocated within a given cell (meaning parts of the cell's genetic code have been swapped).  A common if not typical translocation is 4;14 -- meaning the 4th something-or-other is where the 14th-something-or-other should be and vice versa.  And the commonality of some types of translocations means that there are certain genetic components that are prone to swapping with other parts.

The MYC gene acts as a utility infielder because it can essentially cause any part of the genetic locus on which it appears to swap with any other part.  Having this gene over-expressed is therefore a bad thing.  In the not-quite-four years since I started therapy, they have learned enough to know that it is, in fact, a VERY bad thing.   When I was originally diagnosed and BB was going through the genes with the chief genetic dude in his group, they were puzzled by something.  I had some important low-risk factors, but a puzzling backdrop.  They didn't understand its significance at the time.  Now they do.

This MYC gene, along with the others, is measured in some kind of units.  I don't know the scale, but it looks like, from a review of my data, everything is in the 300 to 1500 unit range.

My MYC genes were between 13,000 and 20,000.

And the significance is this MYC gene can cause a sudden and unexpected loss of remission in low-risk patients that have done well in therapy and are seemingly on their way to being cured.

To wit, me.

And my friend BB (a patient, not the doctor), who unfortunately lost remission about six months ago and has been undergoing absolutely hellish treatment trying to get the disease back under control.  He has been told by BB (this time the doctor), who originally told him he was likely to be able to cure him, that "we are not talking about cure any more...we are talking about control."  And BB (both of them) know the prognosis is dire.  Essentially BB (both of them, but especially the patient) is relying on new agents to be developed so that as current ones fail -- including both Carfilzomib and Pomalidomide in BB's case -- new ones can take their place and keep the Myeloma at bay.

Since my MYC gene is "sky high" to quote BB (back to the doctor now, unless otherwise noted) I am at particular risk for losing remission, and to be frank, losing my battle here.

In short, if the disease comes back, I move from the green line to the blue line.   The Y-axis is remission but might as well be a proxy for survival.

You will see that the green line (hell, I think it's green, I'm colorblind and on a graph of this size I can't distinguish it well...it could also be red, but I know it's not the blue one) is almost flat after three years.   Let's say that 95% of people don't lose remission, among those 148.   But it might be that 10 of those 148 have this MYC gene and 7 of them lose remission.

Unfortunately, that is the sub group in which I may now find myself...

UNLESS the three years of therapy I underwent have caused my genetic profile to change and this MYC is no longer expressed abnormally.

So I underwent several Fine Needle Aspirations of former lesion sites to see what the genetic material in there looks like, and a gene array, and a regular bone marrow.  I will be looking for the results of the marrow (to confirm continued remission and hopefully not to reflect any pre-leukemic cells) in the next couple of days.  It should have been done last week but the sample was damaged somehow -- this has no clinical significance.   They may just have dropped it or it may have been done in a former site where there wasn't enough marrow left to do anything with.   So they are going to use one of the FNA aspirations for this analysis instead.

I will be looking for the result of the FNA to additionally confirm that there are no myelomic cells.  The pits in my spine are not large enough to take a sample from, but they can go to a former site in my hip (which is where they went) for it, so they took a number of samples there.

This brings up ANOTHER problem.  I was told the lesion in my hip (the ilium, for you bone fans) was fully resolved.  But evidently BB and RVH (the guy who does the FNA work and reads MRIs) aren't fully satisfied because there is heterogenous marrow there.  So I may not even be able to be as confident about the lesions I *THOUGHT* were resolved...let alone about the ones that haven't resolved yet.

Anyhow, if the marrow and FNAs are normal, then I will be waiting only on the gene array analysis which will not be ready until Friday.  This will be an important one because it will reveal how extensively the MYC gene is expressed.

If everything is normal, then I breathe easier, stay on Velcade and wait for the lesions in the spine to heal.

If the current marrow is normal but the gene is still expressed, then I have to consider more aggressive therapy -- even though I am still in complete remission.  And I will be scared to death.

If the current marrow is abnormal, then it's even worse.

All this makes the selection of the ongoing drugs that much more important.  If I'm only on Velcade, will that be enough?  After I suggested Pomalidomide, BB said "I'm also thinking possibly Interferon" which was a component of earlier Total Therapy trials but which wasn't demonstrated to have any increase in overall survival -- just progression-free survival.  So it was removed from the protocol in favor of VRD maintenance some time ago...I don't know precisely when but it's out there on the interwebs (sic) for anybody who is really interested.   This makes me nervous...BB normally has an answer for everything and now he is operating on intuition and gut instead of data and protocol, and that scares the crap outta me.

I then said "do I need to do something more drastic, like another round of VTD-PACE."  Long-term readers, as well as other informed Myeloma folks, may recognize this as a cocktail of potent chemotherapy including Cisplatin, Adriamycin, Cytoxin and Etoposide, as well as the comparatively trivial velcade, thalidomide and dex.  BB smiled wryly and said "this was going through my mind as well...this is the problem with you, you know too damn much."  :)    He then suggested that I consider going on anti-depressants as he wanted to be completely honest with me about what he is giving me and why, and that the conversations were likely to lead to a lot of anxiety.  I certainly understand the anxiety part...and I have NOTHING WHATSOEVER against anti-depressants or those who take them.  However, I'd resisted them in the past because I knew I was going to be putting chemicals into every other organ in the body and taxing the heart (Adriamycin), the ears (Cisplatin), the liver (EVERYTHING), the kidneys (likewise, everything), etc.  I wanted to keep the brain as one organ that wasn't targeted for chemical change.  I have also "lost a bit off my fastball" in terms of mental acuity, which is VRD-related and should improve as these meds are reduced or wound down...but I don't want to do anything else to the ol' bean if possible.

Nonetheless, I can't deny that facing the renewed prospect of the sleeping dragon here -- after I thought we'd been going about the process of slaying it rather effectively over the past 3.5 years of aggressive therapy -- is a very disconcerting and stressful thing.  Depending upon the outcome of these marrow tests, I may or may not need to add Cymbalta to the drug cocktail that I will be on.  In the meantime, I shall medicate with mild doses of fermented juniper, grapes and wheat as circumstances merit (usually determined by time of day!)

So my friends, triumph is momentarily replaced by trepidation.  Confidence by anxiety.  Relief by stress.

What remains constant are the love and support of my family, my friends, the readers of this blog, and the team at UAMS -- for all of which I am grateful.

(Addendum: apropos of my recent Churchill reference, he is reputed to have said "ending a sentence in a preposition is something up with which I shall not put."   How does one properly conjugate the preceding paragraph?  I could see "for which I am grateful" except I really want to convey the point that I'm grateful for all the components of support!  Got any suggestions?   This is the type of crap that I think about to keep my mind off my physiology at 5:13AM!)

It's been a sh*t day...so I close with a bit of inspiration

Pardon my borrowing the greatest man of the 20th century, but it's the right expression for now.

This is for you, Jill, whom I love with all my heart.

I am in charge here.  Cancer can kiss my butt.

Disconcerting update from Little Rock...

With my next post, I had hoped to simply catch up on some interesting things that I am late to report -- like the CureTalk conversation, etc.

But this has been preempted.

I remain in complete remission, but the MRI has not changed.  This was, at first, just frustrating...because I know I don't want to stop medicine until those remaining pits have resolved.

Unfortunately, there's more to it.  BB was concerned that they haven't gone away.  Not only out of principle, but also because they have learned more about genes in the last four years and one of the genes that was expressed in my myeloma is something called MIC and that can cause "sudden and unexpected loss of remission."   This is what happened to my friend BB (not the doctor, but with whom I had dinner the other night here) and that BB was low-risk, and suddenly lost remission, and now has high risk disease and a pretty grim diagnosis, though he is fighting and there is always hope.

My disease has the same propensity to do that.

Now the MRI didn't change -- there are still five residual "small" lesions in the spine.   They are too small to be aspirated.  But the former region in my hip -- which was fully resolved but which Bart says indicates some potentially undesirable marrow characteristics -- is large enough for them to stick a needle in.

So I agreed, provided they are knocking me out.  I discussed with BB (the patient, not the doctor ) that FNA doesn't stand for "fine needle aspiration" but rather for "keep that F*@#ing Needle Away from me!"  :)    

Regardless of outcome, I will continue on Velcade at a higher dose than before.  He is okay with me dropping Revlimid because he is concerned about secondary cancers at this point, particularly given my squamous cell carcinoma and the preliminary myelodysplastic cells in my marrow from last time.  He is okay with me dropping dex so long as I can tolerate the Velcade.  But the Velcade continues.  I can get it subcutaneously, so that's something, I suppose.

If the FNA shows something, then I may be looking at another round of the original chemo -- VTD-PACE.  Not something I'm looking forward to, but if it's necessary, I'll do it, I guess.

He said he is now taking me off protocol and "going out on a limb" but "we're in this together."

That's not what I wanted to hear.  I wanted to hear "the myeloma is gone and will not be coming back."

I have so many concerns, I don't know where to begin, really...among them, will I ever be confident that this is really gone forever?  I suppose if all those lesions resolve and the marrow returns to normal, I can be confident.

I'll need to come back here for more testing, almost certainly, at some point in the next few weeks.

My thoughts are scattered...apologies for the incoherent post.  Pretty shaken right now.