Tuesday, November 25, 2014

Songs for Life

I was asked to be -- and agreed to be -- a judge in a project called "Songs for Life" which is an innovative effort to raise awareness of Multiple Myeloma and fund MM research, as well as research for other cancers.   The project was started by Jenny Ahlstrom who has poured a lot of time and energy into this and I'm happy to play a small part.

Contributors submit songs that are voted on by the general public, before they are narrowed down to those reviewed by the panel of judges for inclusion on a CD that will be released in the next few months (February 2015 is the target date).

When the album is produced, all proceeds will go the CrowdCare Foundation, a non-profit patient-driven organization that funds cancer research.

Jenny asked me to post the following -- there's still time to vote so if you want to listen to a bit of music in your spare time and support the fight against this disease, give the site a visit!
Which songs are your favorite? Vote for the songs you think should be included on the final Songs For Life album to help cancer patients and fund #cancer research. Last day to vote is November 30 at midnight! http://songsforlife.org/vote-2015-submissions-fb/
Happy Thanksgiving to you all!  I am once again thankful for my therapy, my doctor and his team, my supportive family and my friends, including all of you!!

Thursday, November 20, 2014

Remembering Pete Dalis

This disease stinks.  Putting it mildly.

Peter Dalis was UCLA's athletic director for almost 20 years.  I became friends with Pete when I joined Bel-Air Country Club a few years ago.  He was on the membership committee.  I learned at that time that he had just been diagnosed with smoldering myeloma.  I thought "well, there's at least one vote in my favor in the admissions process!"  :)

Pete was very loyal to UCLA, preferring to be treated there rather than going to see a world-leading MM specialist.  I'm not sure whether the diagnosis wasn't as accurate or if he simply had challenging MM from a cytogenetic perspective, but whatever the reason, his health deteriorated rapidly over the past few months.  He went from looking great to looking very frail.  He wasn't able to join me at a reception I held with the MMRF at Bel-Air as he was in the hospital; I saw him after that and he looked like a shadow of his former self.  The disease was obviously taking its toll.  He said that he had tried Revlimid and there were too many complications or it wasn't effective; he said he had similar issues with Velcade.

I had hoped that I would be able to get him in to see somebody with real insight into how to treat his particular disease -- but to my shock and sadness, I learned that Pete died this past Saturday.

I didn't know him as well as I'd have liked, but in my interactions he was a true gentleman.  A person of sincerity, warmth, and profound integrity.

His obituary from the LA Times mentions MM as the culprit.  A very sad story.  My thoughts are with his lovely wife and his family.  I had hoped we would celebrate our collective victory over this disease; instead, I am left with a tragic reminder of how important it is to be seen by a true specialist and to get in front of the disease before it gets on top of you.

I'll miss you, Pete.

Tuesday, November 11, 2014

I'm good on paper, at least!

Just got the call back from my doctor.

No MM under SPEP, IFE is normal, light chains normal, IgG and IgA are in normal range, IgM still recovering from transplant (as expected), B2M normal, liver numbers on the cusp of high but that's where they always are (if I need a new liver in 30 years, it'll be a high class problem).

So the question remains: why is this flank pain, which I noticed during my workout this morning, still there?

I will be getting imaging in Arkansas in January, but it the pain doesn't abate in two weeks, I may jump the gun and get some done here.

Meanwhile, keep calm and carry on, eh?  :)

Friday, November 7, 2014

Kidney pain. Nothing? Or...

So after being cold-free for, I dunno, two years or something, the combination of kids running through on Halloween, everybody in my family being sick, a 36-hour cross country golf trip with little sleep and the germ exposure of four airplanes, and being lackadaisical with the hand sanitizer caught up with me.  I'm in the closing stages (hopefully) of a week-long bug that Tamiflu and Levaquin helped minimize.

One of the things I noticed was a pain in my right flank.  It hasn't gotten worse, but it hasn't cleared up, either.  Could it be a pulled muscle from golf?  Maybe, I suppose.  It's a dull pain, doesn't show up often, and when I notice it, it's not particularly painful and certainly isn't sharp, but it feels like a bruise and it feels deep.  Ribs?  Could be -- and that would likely mean a tumor.  Kidney stone?  Could be.  Ache from the random virus that is getting me down?  Could be.  Kidneys being impacted by light chains from recurrent disease?  Could be.

I recall I had this once before, although searching the blog is fruitless so either the search function here doesn't work as advertised, or I didn't write about it.  I had a pain in that area.  It was, if memory serves, a little worse than it is now, because I remember being prescribed Norco for it (Vicodin, essentially).  I went to the hospital, had X-rays and an MRI because I thought it might be a kidney stone, and imaging was negative.  Bloodwork was fine.  No cancer.  I went home with the Norco and a few days later it was gone.

That's hopefully what this is.  Random pain, maybe from the virus, maybe not.

So I went in to the doctor yesterday.  I've not been as religious about seeing him (versus simple labs and weekly visits) as I should be, because while GD is fine for carrying out BB's instructions, he's not a leader in the field and is unlikely to unroot problems that aren't commonplace.  And I figure I see BB 3X a year, and while I'm in complete remission (if not cured, more on that in a future post) that frequency seems fine.

Anyhow, he poked and prodded and slapped me on the back in a few strategic places and from that highly nuanced procedure we determined that it's not a kidney stone because I'd evidently have been shrieking in pain were it one.  (Note to self: check the bottle of Dilaudid and make sure it's not expired if I ever get a kidney stone.)

His answer: if it doesn't clear up in two weeks, I need imaging.

I'll get the full gamut of cancer markers back next week; if it light chain disease or secretory MM returning, we'll know then.

This does segue to the "am I cured" post I just mentioned would be coming up.  It occurs to me that the last time I had this pain, I wondered if it was a kidney stone, but it didn't occur to me that it could be recurrent disease.  I never had a fear that it might come back.

Those graphs under Eli Wallach's face in the post from a few months ago call that into question.

I also asked GD about reimmunization as I'd like to be able to travel with the family at some point and our efforts in having a "nice relaxing family vacation" over the holidays proved to be rather challenging given that I couldn't confidently travel to half the places that we were considering (e.g., resorts in Mexico).  GD's response was that he needed to check the protocol with City of Hope; this is what I meant when I pointed out that he's a good doctor but not necessarily a thought leader here.  I hesitate to schlep out to City of Hope for reimmunization advice, especially since I don't think they'll let you in the building until they've drawn blood and God help me I'm sick of that even though I still do it all the time.

Lastly, I'm giving thought to other tests that I might use to help me restore my shaken confidence in the curative protocol of the TT4 "Lite" Arm (the Standard arm is doing just fine; if I were in that arm, I'd be breathing easy right now).  These include deep sequencing and the HevyLite Assay, which my good friend SR tells me can be ordered by a doctor through LabCorp.  As she put it, the value of this is as follows:

HevyLite helps determine if your immune system has reconstituted itself. So, it tells you if your uninvolved immunoglobulins are being suppressed. And it indicates clonal tides when the involved Ig is out of normal range..in other words it detects the new clone long before relapse shows on IFE or SPEP and it tells you about the heavy chain intact immunogloblin long before SPEP as well.
If deep sequencing comes back negative, AND HevyLite comes back negative, AND the damn pits in my spine have gone away when I get imaging on them in January, AND BB shows me updated information on the TT4 Lite Arm that suggests a plateau exists versus the cliff in the data reported here earlier...then maybe I can close this chapter and get on with it.  :)

Until then, we enjoy every day, right?  Which means I ignore that pain and keep on golfing.

Have a good weekend, everyone!

Friday, October 31, 2014

Hello all!

A Happy Halloween to you.

I have been BURIED at my new job at Activision, the world's largest video game company.  It has been great so far -- I'm extremely busy and it can be stressful but I feel the stress in my head, as in a desire to perform, rather than in my gut, which is where it resided for the last few years at my previous employer.  It got to the point where I found the situation had sufficiently deteriorated that I feared it was creating an environment that could give my disease an excuse to return.  I'm in a much better place right now.

I have been interacting elsewhere with Myeloma patients and there is enough misinformation out there where I'd like to have some upcoming posts on the role of transplants, where Total Therapy stands today (hint: newly diagnosed patients should look into it) and the importance of advanced imaging.

I also want to finish what I started a couple of posts ago.  The upshot of it is: I wish I'd have had the full blown Total Therapy instead of the "lite arm" of it -- although my own personal biology is doing well.  I'll have to see what the most recent studies show when I return to Arkansas in January for more follow-up.  BB alluded to the fact that an update of the curves posted below exists, and hopefully those curves do show a plateau.

For the moment, it proves that alkylators work on newly diagnosed standard risk patients -- and it proves that they work better than novel agents without them.  After all, the only difference between Total Therapy 4 standard and lite is that the lite arm got less of the alkylators.  They use the same amount of novel drugs.  And look at the difference in progression-free survival?

It's getting harder and harder to argue that, for newly diagnosed patients younger than 70 years old and with standard risk characteristics, Total Therapy isn't the best therapeutic route.

I shall pick this thread up when time permits.  For the moment, I wanted you to know that I'm still doing well -- and I certainly hope the same for you and yours!

Thursday, September 25, 2014

Breaking the silence here!

Hello friends.

I apologize for keeping things so quiet here but I've been in a career transition and part of doing that given my medical condition is securing long term disability insurance, life insurance and other things of that nature.  While I remain in stringent complete remission and continue to hope that I have been cured, part of what I wanted to comment on in the wake of those published statistics would involve sharing my unease about the "lite" version of the protocol.  And I didn't want to be commenting on any lack of total confidence at a time that I was attempting to secure certain kinds of insurance during my employment negotiations.

Having now accepted the new position (I am leaving Disney to join the video game company Activision) and secured the insurance, I am free to comment here again, which I will do next week, starting with a recap of the outstanding call with Dr. Tricot that happened last week.

Thanks for your patience and for the emails of concern over the past few weeks as I sorted this out!

Friday, September 5, 2014

A non-update!

Hello friends.  Still alive and kicking here.  I will post an update on September 17th, most likely, after the Curetalk call with Dr. Guido Tricot, formerly a colleague of BB's and continuing with a similar approach to the disease where he practices in Iowa.   I will then explain my mysterious absence on September 23rd, at which time the timing of that particular date and the reason for my absence will be made clear.  Everything is fine, though!

Friday, July 25, 2014

A quick and meaningless update...

I'm waiting for BB to get back to me with more specifics.  For a couple of reasons, I'm not going to post about this for the next few weeks.  As of now, though, I'm fine.  Complete remission as of last week's very sensitive tests.  Onward!

Monday, July 21, 2014

Good, bad and ugly

I'm pretty sure I've used that reference before here.  In fact now that I think about it, I remember feeling sorry for Eli Wallach.  I can picture his agent calling him.  "Eli, baby, have I got a part for you!  There's this movie, see, called The Good, The Bag and The Ugly.  The parts of The Good and The Bad have already been cast…"

The Good

What a handsome devil, eh?

So the good news is that my tests last week came back negative for MRD (clean bone marrow) and my numbers look really, really good.

The Bad

A tough customer indeed, is Mr. Van Cleef.   As another "Van", by the way, I have no idea what a "Cleef" is.  A Dutch pronunciation of Cliff?  Hmm.

The bad news is that the MRI is unchanged.  Stable, faint, sub 1cm focal lesions (not currently active for cancer) are still seen at T2, T3, T4, T10 and T12.  I like the faint part, I suppose.  I sure wish they would go away, though, for reasons which will shortly become apparent to readers that see this post through to its conclusion.  As was published by Arkansas just last week (more on this below) these lesions can be issues because "MRD…only evaluates a random marrow aspirate and does not assess any dormant consecratory myelomatous cells, which can be present in focal lesions on magnetic resonance imaging (MRI), and can provide a disease reservoir for relapse."

In other words, as I have reported from time to time in this blog, I want those bloody things gone.

The Ugly

Yes…well…forgive me if I feel more sorry for myself than Eli after all.   Get a load of these graphs, from this article just published by UAMS about how stem cell transplants are curing people.:

Recall I was in the "TT4 Lite" arm of the study.  This can be most readily identified as the lines as the bottom were people are relapsing left and right without any indication of a plateau.

Specifically, TT4 patients with deletion 13 and hypo diploid disease (that's too few chromosomes versus too many -- and it's odd because too many chromosomes is generally a better prognosis) have done well and reached a plateau after two years.  However the other cohorts in TT4 Lite have no fared well at all.  For this with no cytogenetic abnormalities, if this graph is right (and there may be an error in it since there appears to be a cliff at the 5.5 year mark and it suggests something's wrong with the graph selection) there's no plateau and the relapse rate is high with only 30% of people still in CR at the 5.5 year point.  Looking at it objectively, I think there must be a mistake in the graph…so maybe I feel a *little* better if that's the case (I've asked my friends at UAMS to clarify) but still, it looks like the Lite arm isn't faring nearly as well as the Standard arm.   Did I sell my therapy short?  Should I have gone through something more rigorous?  Should I go through something more rigorous right now?

We'll see what they have to say.

I do feel like the goalposts keep being moved farther and farther back.  Can I make it another five years in complete remission and breathe easy?  That's a lot of waiting…

It's ugly.

Tuesday, July 8, 2014

A gold mine of information today!

It was a very productive panel discussion today with Dr. Tiedemann.   There were a lot of important insights, some of which may be controversial but what the heck, let's have fun.  My notes, unfortunately, were eaten by my computer here so this is from memory.  I encourage you to listen back to the broadcast.

* Myeloma progenitor cells are immature cells that are more evolved than stem cells (which can form any type of blood) and are "on their way" to becoming plasma cells, but have not yet become plasma cells

* These immature cells do not express a particular protein which is associated with immunoglobulin expression.  Implication #1: non-secretors probably have these cells moreso than mature plasma cells.

* We don't know whether or not these immature cells start out with cytogenetic abnormalities, or the plasma cells that they become later develop those abnormalities

* Because these cells do not express a particular protein, he believes that proteasome inhibitors are not able to kill them.  Implication #2: a regimen based solely on Velcade or Carfilzomib will not cure the disease, full stop.

* He notes that cells which are resistant to treatment by IMIDs (Revlimid, Pomalidomide, Thalidomide) also fail to express a different protein.  It is unclear whether or not these drugs are killing progenitor cells or merely suppressing their ability to spawn more cells.   Implication #3 and it's a biggie…we don't know for sure, but if these drugs are not killing progenitor cells, then a regimen based solely on novel agents will not cure the disease, full stop.  This is a big deal for doctors that espouse the "well, novel agents might work just as well as transplant."

* When asked what types of medicines DO kill the progenitor cells, he said that there was a belief that high dose melphalan (transplants) do, and that anthracyclines (like adriamycin) might but we don't know.

* He volunteered (I didn't even say the word "cure", promise) that some patients were being cured, and that those who experienced the best results likely used both novel agents (to kill the more mature plasma cells which are capable of self-replicating and after all do need to get killed!) and high dose melphalan (to kill the progenitor cells).  Implication #4: sounds a lot like Total Therapy.

* I asked him whether or not that cytogenetic abnormalities that reflect disease that doesn't respond that well to transplants were observed in progenitor cells or only in the more mature cells -- he said they were researching this now, but did not know.  He also said it was a really good question.  I felt like I did my job today!  ;)

* Importantly (I was going to ask this but someone else did, thankfully), the topic of MRD tests came up and he affirmed that multi flow cytometry tests for MRD likely WOULD show progenitor cells because even though they don't express the one kind of protein required for a protease inhibitor to latch on to them, they do express other proteins that trigger identification under sensitive MRD testing in the marrow.  He did say that there was (only a) theory that some types of cells wouldn't show up, however the progenitor cells turn into plasma cells in "a matter of a couple of weeks" and therefore an MRD test done a couple of weeks after treatment should show the presence of progenitor cells if there are any kicking around.  

I am puzzled by this last phenomenon because of the recurrence of the disease in high risk patients under Total Therapy.  Evidently per other information shared by Dr. Usmani (formerly of Arkansas), at least some of these HRMM patients test MRD negative at some point -- yet they experience relapse.  If that's the case, what is MRD missing?  Is it simply that bone marrow is spotty and it could be clean in one place and not clean in another?  Or is MRD not sensitive enough?   I have something to ask Bart when I see him next week.

I also have to say -- and I don't like politicizing this blog but it's too topical not to -- that people who pine for Canada's health system aren't MM sufferers.  Revlimid still is not available to the newly diagnosed.  There isn't nearly the investment in clinical trials or the ability to enroll in one in Canada.   "It's not like the US," as the good doctor said.  Look, there are no easy answers to the healthcare crisis -- but when it comes to treatment for this disease, I for one am glad that we have the big horrible system that we have here.  :)

And that, my friends, constitutes one very informative session.  And I got a doctor to -- without me soliciting it -- say that patients are being cured.  :)    "Just not nearly as many as we would like."  That's the God's honest truth right there.

Let's keep the research coming, folks!

Another CureTalk Panel today -- interesting stuff!

And no, for once, I won't be asking expressly about whether or not the disease is curable!  :)

The guest today is Dr. Rodger Tiedemann from Princess Margaret Hospital in Toronto.  Dr. Tiedemann published papers last fall in which he discussed why Velcade and other proteasome inhibitors cannot cure Myeloma.  The mechanism that they impact (the proteasome mechanism) doesn't exist in the immature progenitor cells that cause Myeloma.   He likened the use of these drugs to having a goat eat the weeds in your garden, but not getting rid of the roots.

This prompts a number of lines of inquiry -- if it were me interviewing him, I'd get to all of the answers.  I hope the format permits it!

- How does MM originate, and what is the lifecycle of a MM cell?  What are the differences between a progenitor or precursor cell, and later MM cells?   Do progenitor cells carry the chromosomal abnormalities, or does that happen as MM cells proliferate and develop more "genetic chaos"?

- If proteasome inhibitors do not work on the progenitor cells, what kids of therapies do?  IMIDs (Revlimid, Pomalidomide, Thalidomide)?  Alkalytors (Melphalan?)  Anthracyclines (Adriamycin)?  Or do we have nothing that works on them?  Does this vary by disease biology (for example, del17 progenitor cells are more resistant to therapy than other kinds)?  Where does immunotherapy enter into the mix?

- If we have something that works on them, could treating with multiple agents get both the progenitor and the more mature cells?  If this isn't the case, how does he explain people that appear to be cured?

We'll see how much of this we get to -- hopefully a lot, because it has a lot of ramifications (among them: if IMIDs don't get the progenitors either, then we know definitively that the existing novel agents alone are not capable of curing anybody -- this would put an end to one existing controversy and theory).

It should be an interesting conversation -- hope some of you can join us!

The Cure Panel Talk Show on
Multiple Myeloma
e Myeloma on 8 JULY 2014 @ 6:00 pm ET .
To access the teleconference :
Dial -in   (718) 664-6574    approximately 5 minutes prior to the scheduled start time.
Listen to the LIVE Broadcast here:

Monday, June 30, 2014

Why I am a pain about this whole "cure" thing

Hello folks.   I am returned from a weekend in Vegas.  As I remarked to me friend and fellow MM warrior SuzieRose, I figure that whatever cells eight types of drugs didn't kill, a weekend in Vegas ought to finish off.

Our friendship is an ironic one, since it started out in a rocky way via an argument online about doctors and curative protocols and what not.  I've learned a great deal more about the disease and how to consider the cure issue since that time, and I think she has also developed a more nuanced perspective.  It's tempting when one is dealing with this disease to focus on one's own biology and experience and generalize the specific.  We all do it -- I certainly have done so from time to time.  It's very difficult and takes practice not to do it -- or to extrapolate from anecdotal experiences and assume patterns are observed based on that.  The most capable and valuable online Myeloma bloggers all do this from time to time -- it's human nature.

In my own case, as I have said time and time again here, I recognize that my progress to date has been fortuitous (with a few little bumps along the way) and that even if my success is typical for the UAMS Total Therapy protocol, it's not typical for Myeloma.  I have qualified my enthusiastic support for UAMS/MIRT/Total Therapy (which remains enthusiastic indeed) by noting that depending on individual disease biology, age, health and other factors, it's not for everybody.

But it IS for a large subset of people.  Because cure is out there.  And in a moment I'll explain why it matters and why I am persistent in talking about it, both informally here and quasi-formally on panels in which I participate, such as in last Friday's conversation with Dr. Kumar of Mayo, MN, who is a true expert among a group of true experts.

It wasn't long ago that this group of true experts said, unqualifiedly, that this is an incurable disease.  Yet now, as can be heard here on a replay of the panel conversation, Dr. Kumar notes that the disease is curable in some cases -- it's a question of how many.  It's not surprising to me that Mayo will move incrementally on this issue: five years ago, nobody was saying it's curable, but now there is just too much data to ignore.  An immediate flip-flop is neither called for, nor practical for an institution that is conservative and managing its own reputation as well as prudently observing a graduate accumulation of research data.  It would be irresponsible to announce the disease is curable in any event, because even if TT worked for all low risk patients (and it doesn't), there is a meaningful subset of MM patients with disease biology that doesn't respond to it.

Unless and until everybody can be cured, we can't, and shouldn't say the disease is curable.   However, it's equally inaccurate to say that it is universally incurable, or that cures are as rare as "black swans" (no offense to my friends working on that project).  The disease is curable in some cases, through aggressive treatment, for those who are prepared to go through the disruption of that treatment.

Why do I harp on this continually?   Why does nearly every doctor with whom I engage on a panel get some variant of the question that I have been pressing with increasing statistics to back me up?  It's not, as some have accused me of, because I'm defending my doctor.  His legacy in treating this disease is secure.  It's not to make me feel better about my own treatment decision -- I'm secure in that, whatever the outcome.  I will admit I'll feel more relieved if it's acknowledged widely that I'm cured at some point, but that's neither here or there right now.

The reason I am pressing for this is that newly-diagnosed patients deserve to know, and because it influences research, treatment, and patient life post-therapy.

In ONE comment thread, in ONE online support community, in a response to a question simply about "where are you from and where are you being treated" (in other words, as innocuous a question as could possibly be raised, here are some responses.

From a 51 year old diagnosed five months ago: "[I am] so scared and sad.  I'm crying right now.  It's so hard."
From a 48 year old diagnosed four months ago:  "I fired [my] oncologist.  It's hard."
From a 59 year old diagnosed one month ago:  "I am scared too."
Another: "It can be VERY depressing very quickly.  It is a difficult road with a LOT of wrong turns...It takes a lot of tears."
 A caregiver adds:  "I can only imagine how [frightened] you must feel." 
One who was diagnosed ten years ago while smoldering at 53 and who now is beginning treatment:  "[I'm] scared as hell…overwhelmed right now and scared to death with what I am reading."
"How is it that you were diagnosed in 2001 and still in remission?"
I can go on and on.

How much better -- more hopeful -- could patients be if instead of being told "you have incurable cancer" they are told "you have a cancer that may be curable in some cases, and you have a number of options for treatment depending on your preferences?"  How much clearer could their decisions be, if they weren't understandably torn apart emotionally by a diagnosis that can seem like a death sentence?  How much better would they feel if they were able to look at a number of choices and, with their doctor or doctors, make the one that seems best for them -- versus being scared into following whatever protocol their doctor happens to prefer without explaining the context for that decision?

If the disease is curable, it directs research and therapy to better outcomes.  Five years ago, papers were published saying that compete remission wasn't a meaningful marker.  This is FLAT.  OUT.  WRONG.  People have backtracked on it now and are continuing to do so.  But if CR isn't a meaningful marker, it's not a goal of treatment.  If it *IS* a meaningful marker (as a precursor to a cure that could be out there) then research is focused on getting to CR, treatment is focused on getting to CR, etc.   If the disease is curable for low-risk patients, then more research is directed towards those with biology that doesn't respond to existing treatment -- which of course benefits all patients.  These are meaningful and important influences on the direction of research and therapy.

If the disease is curable, those of us carrying on with the realities of daily life think and are thought of differently.  This disease, if incurable, crushes careers, wipes out insurability, destroys relationships.  If curable, careers are interrupted but not destroyed -- insurers (life, medical, disability) will insure patients after a period of remission, just as they do with other cancers -- and just maybe there will be less stress placed on interpersonal relationships.   I have a friend whose scientific experience and advice I have referenced in this blog in the past, and he married a woman whom he knew to have terminal cancer, with only a short time left to life.  This was an incredibly compassionate and loving act.  Not all people have that much integrity -- it takes a very special person and the stories I hear about patients being abandoned by spouses and loved ones after a diagnosis are devastatingly sad.  If the disease is curable, it can't help but be thought about differently.

This is why it's important to keep pounding this drum.

I've gotten two members of the Mayo Dream Team (I don't say that sarcastically -- they are among the best) to say in a public forum that the disease is curable, and over time they'll admit it more readily, as will others.  It may even be enough for me to let up on them and ask a different question next time.  :)

That said, this issue remains of vital (literally) importance.  And ignoring it does patients and caregivers a disservice.  So I will pound the drum as needed from time to time.




Tuesday, June 24, 2014

Gum update, and Cure Talk panel this Friday, 6/27

So I met yesterday with two doctors and a dental hygienist.  One doctor had nothing to do with anything, other than he noted that I didn't have any bruising or nosebleeds (he's an ENT).  The second doctor is a neuro-oncologist who knows what happens to people after transplants.  He said that my bleeding was "more profound that he would like to see" but also thought it might resolve on its own.  He says that post-transplant, platelets -- even if they are in sufficient number -- sometimes don't behave the way platelets do before transplant.  In any case, he didn't see a reason to be alarmed.

I will get clotting factors run in Arkansas, and possibly a platelet smear.  I need to talk with the PA there to make sure these tests are added to the usual battery I will receive upon showing up.

This neuro-oncologist also told me that the dentist was unlikely to want to touch me.  But the hygienist was unafraid.  She consented to not going all-in on the tooth scraping, but she cleaned them up.  It wasn't a bloody as I was afraid it would be.  And this morning I even made it through a tooth-brushing without much incident.

In other news less related to gum care, I am participating in another Cure Talk panel on this Friday, June 27th, at 5PM ET.   In addition to our usual group of patient panelists, we are having MM expert Dr. Shaji Kumar of Mayo to discuss some interesting topics.   Among them the newest treatments and trials being discussed at ASCO, the Mayo Measles experience, and of course my usual question about whether or not aggressive treatment is curing some patients.   It may seem like I am beating a MM-afflicted horse* with this but there are reasons for my question, which range from newly-diagnosed patients are given an accurate portrayal of their options, to influencing the way insurance companies (medical, life, disability, etc.) view those with this condition.

You can register for the call here:


The dial-in for the call is 718-664-6574.

Hope some of you can join us!

*Get the hilarious metaphor?  Not a dead horse, because he might be curable.  Brilliant, right?  ;)

Friday, June 20, 2014

A recent and odd little issue...

Fans of the early seasons of The Simpsons will likely recognize the tertiary character pictured above.  He was a jazz musician held in high regard by Lisa Simpson for his saxophone playing -- and his name was Bleeding Gums Murphy.

It seems I am enrolled in his musical academy these days.

About three weeks ago I started noticing blood after brushing my teeth.  About two weeks ago I started noticing during the day that my gums were on the "warm side" which gave me some concerns.  Even with a soft-bristled brush and carefully brushing, my gums bleed every time I brush them.

This gave me two concerns: (1) do I have some kind of osteonecrosis of the jaw issue related to the bone-strengthening agents I was on, and (2) do I have an issue with platelets that could be indicative of myeloma or leukemia or something else wrong with the blood.

I did a little research on osteonecrosis and it doesn't manifest itself in bleeding gums, thankfully.

In my visit to the doctor this week, my labs showed platelets at normal levels (a little on the low side of the normal range, but 175K against a range of 130-400K being normal, so it wouldn't explain this).  I did note that I bled more than usual from the site of the port access when they stuck me with the IV.  So something funky is going on.  But it's not platelets.   Importantly, the most recent cancer numbers are clean as a whistle.  My immune system continues to recover from the transplants and now my IgG and IgA are both squarely in the normal range.  IgM continues to be very low -- 18 mg/dL versus a normal range of 48-271.   By the way, who decides what normal rangers are?  Are they simply standard deviations away from the mean?  Why is it 48, for example, and not 50?  Modestly interesting questions but not so interesting that I'm going to research answers.

Argh.  Intellectual curiosity got the better of me.  Couldn't help myself.  Yes, "normal" is determined by two standard deviations on either side of the mean.  Meaning 95% of the population falls in the range.

Okay, back to the primary point of the post.

I will be getting some analysis of some other things in my blood -- "clotting factors" -- when I return to Arkansas in a couple of weeks.  Unfortunately, a little Googling can be dangerous.  I had always assumed that if platelets are okay, then clotting factors are okay -- but they are unrelated.  It turns out that you can have messed up clotting factors and have normal platelets.  And it turns out that if you have this…it can be hemophilia.   It can also be something called von Willebrand disease.

Now do I think I have these things?  No.  My clotting factors have been normal in the past.  And everything I know about hemophilia came from watching the movie Nicholas and Alexandra when I was a pre-teen.  I learned from this and my helpful parents that somebody in the Csar's family (or multiple members thereof) died from hemophilia, which meant they couldn't stop bleeding.  Years later I probably picked up the inference that all those inbreeding Hapsburgs passed this genetic problem along to their kids.

I may have my shortcomings, and some of them could be laid at the feet of my parents from both nature and nuture, but I can't say there was a lot of inbreeding going on in my family.  They got that part right, anyhow!

Nonetheless, something is going on.  I shouldn't feel a warm sense of blood when I run my teeth over my gums.  Even if they aren't bleeding, it feels odd.  Something is amiss.

I'm going to the dentist next week.  I will confess I didn't always take the best care of my teeth, but I am certainly not an extreme outlier.  I think in the quiet darkness, many of us admit to ourselves that we are not diligent flossers.  That said, while my gum health hasn't been in the top decile, it's never been worse than average and I'm a good and frequent brusher.  So I don't think it's just lackadaisical oral care that is contributing to all this.

The bottom line is: I dunno what's happening.  And this falls in the category of slightly embarrassing things that I wouldn't put out on the Internet for the world to see, but there could be others with this issue and if nothing else, I hope this blog reports side effects so that others experiencing them can be aware of them.

Secondary cancer in finger?  Check.  GI issues?  Check.  Hair loss from Velcade?  Check.  Weird rash on fingers and hands?  Check.  None of these are particularly dignified, but this isn't a dignified disease.  And if talking about these embarrassing little topics can help a few people, then I'm prepared to endure some public indignity.  :)

I am participating in another CureTalk panel next Friday, so I will update about that soon.   Have a good weekend, all!

Friday, May 16, 2014

Immunotherapy update

If you're like me…well, I pity you because you're living with a Myeloma diagnosis.  :)

But seriously, folks, if you're like me, you may have seen a lot of conversation about various drugs in development that end in -mab.  Thisamab and thatamab and the otherthingamab.

While I continue to hope that Total Therapy will be curative for me and I won't need to worry about a relapse, I certainly do think from time to time about how to plan for next steps in therapy should I need them.  The Arkansas protocol would be to continue the carpet bombing.  It may surprise some of you to hear that I'm not sure I'd necessarily sign up for that.

With any luck, this will be entirely an academic exercise.  But were the disease to return tomorrow, I might try to resume treatment with next-generation Velcade (Carfilzomib, or Kyprolis as it is now known) or next-generation Revlimid (Pomalidomide, or Pomalyst as it is now known).  I might try to buy some time with these drugs, because while these have been important breakthroughs, they are in existing families of drugs (Kyprolis is, like Velcade, a protease inhibitor; Pomalyst is, like Revlimid, an immunomodulatory drug).   These drugs have been demonstrated to help overcome disease that has become resistant to their older cousins, and that's an important development indeed for all Myeloma patients.

However, they aren't "game changers" the way their older cousins were.  When Velcade came out, it was the first proteasome inhibitor, and was a game changer.  It represented a new way to target and kill Myeloma.  When Thalidomide was used for Myeloma, it was the first immunomodulatory drug in the armamentarium against MM and it was also a game changer.   But subsequent drugs in these families -- while helpful and prolonging overall survival and putting patients into deeper remissions -- have been tweaks to a successful formula rather than a new way to fight.

Immunotherapy -- already used in other cancers like lymphoma -- is a potentially new way to fight MM and could be another game-changer in a few years' time.

There are two drugs in this class that I've heard a lot about: daratumimab and elotuzimab.  I had a vague idea about them but I had the opportunity to sit in yesterday on a conference call hosted by the MMRF on the topic of immunotherapy, and it was IMMENSELY valuable to an understanding of how researchers are thinking about fighting this disease with this class of drugs.   I thought I would try to synthesize the key findings and try to present them in a (relatively) easy-to-understand way.

First, we can group the types of there are two different types of immunotherapy that people are working on for Myeloma: antibody treatment, immune regulation, and vaccines.   Antibody treatment seeks to target MM cells for the immune system to kill; vaccines seek to help build an immune system capable of wiping out the MM cells.  They are similar, and yet distinct approaches.

Antibody Treatment

The idea behind antibody-based treatment is to identify MM cells and kill them.  It sounds easy when expressed that way, but the idea behind chemotherapy, for example, is that it kills everything in its path that is rapidly dividing.  The goal of antibody therapy is to do a better job of targeting the MM cells.  Once this is done, there are two different ways to kill the cell: (1) deliver a poison to the targeted cell, or (2) help the immune system kill it through its own natural means.

Identifying the Cells

Myeloma cells express proteins on the surface of the cell.  These proteins are generally identified as "clusters of differentiation" with a number associated with them, for example CD38.  Some proteins have different names, such as CS-1.   I don't know what the CS stands for and my Google-fu is inadequate to the task, even when I have found articles discussing the topic.

Proteins commonly expressed by Myeloma cells include CD38, CD138, CD45, etc.   These are the same proteins that Arkansas' highly-sensitive test for Minimal Residual Disease looks for -- they look at millions of proteins on the surfaces of cells in the bone marrow and look for CD138, CD38, CD45, CD56, CD81, CD20, CD20 and CD19.  If they can't find any, then that test is negative for MRD.

Antibody Development for Poison Delivery

Antibodies in this instance are manufactured agents that identify and attach to these specific proteins.  They are called monoclonal antibodies, because there are many of the same kind, designed to attach specifically to certain protein targets.

There are a number of them in clinical trials.  For example:

* Elotuzumab targets the CS-1 protein

* Datatumimab targets the CD38 protein

* Lucatuzumab targets the CD40 protein

* Several agents in earlier trials target the CD138 protein (these are currently called B-B4, nBT062 and DL101)

The idea in this treatment is to attach a "backpack" of poison to the antibody so that it binds to the protein on the MM cell and delivers this poison to the cell.  Since it is good at binding to those specific proteins that are generally expressed on cancer cells and not on healthy cells in the body, it's effective without causing a lot of side effects.

Sounds great, right?

Well, the problem is that MM cells are smart.   I'm not sure exactly why, but they find ways around this.  And researchers are also trying to determine how much of these drugs is enough to target the maximum number of cells -- too much of the drug in current trials reduces effectiveness, so there is an optimal dose that people are trying to triangulate.   At the same time, though, there must be other issues that have led my doctor to tell me that these therapies are not (yet, at least) ready for primetime in MM, and aren't (yet, at least) the game changers that they are in Lymphoma.

Immune Regulation

Another way that immunotherapy can be used to fight MM is by strengthening the immune system's response.

The human immune system is extremely complex.  One key part of it as T-cells (a type of lymphocyte, which is itself a type of white blood cell).  T-cells are called T cells because they express something called a "T cell receptor" on their surface, and this is responsible for recognizing certain antigens, or hostile cells in the body.   T cells float through the body and "interrogate" the cells they find.  When they find something that expresses the particular protein that they are looking for, they bind to that cell and look for a secondary signal.   This is basically a "failsafe" mechanism so T cells don't kill cells that they aren't supposed to kill.   They notice something wrong, and zoom in for closer inspection, essentially.  This is called a "checkpoint."

Now, Myeloma cells are smart.  Normally, when a cell is abnormal (like a Myelomic cell would be) and the T cell locks on to it, the conversation goes like this:

T Cell:  Hello.  We've had reports of disturbances in the neighborhood.  Is everything okay?

Abnormal cell:  Hey, uh, no.  There's three burglars in here.  Blow up the house.

T Cell:  Okay.  I will blow up the house.

Instead, the smart Myeloma cell conversation is like this:

T Cell:  Hello.  We've had reports of disturbances in the neighborhood.  Is everything okay?

Abnormal cell:  Oh sure, officer, everything's fine.  I heard shots down the street, you should check that out instead.  I so appreciate you coming by, though. 

T Cell:  Okay.  Sorry for the inconvenience.

There are two ways to prevent this from happening.   The first is preventing the occupant of the house from answering the officer's question, which causes the officer to blow up the house.  The second would be preventing the officer from understanding the abnormal cell's response, which again would cause the officer to blow up the house.

In both these cases, the "checkpoint" process is being disrupted.  Hence, this class of drugs is called a "checkpoint inhibitor."

The answer from the Myelomic cell (the "nothing to see here, officer" response above) is a protein on the Myelomic cell called PD-L1.  There is a trial now of a checkpoint inhibitor called BMS-936559 (really rolls off the tongue, eh?) that blocks expression of this protein.

The ability to HEAR the answer from the tumor relates to a protein on the T cell called PD-1.  There are two drugs being developed that target this -- nivolumab and lambrolizumab.

Vaccine Development

Vaccines for Myeloma would notionally work the same way that other vaccines work -- these vaccines essentially train T cells in our bodies to recognize and kill tumor cells, in the same way that they are trained to recognize and kill measles.

While there are several different sub-approaches within this category, the basic idea is that T cells are infused with the "memory" to identify and kill Myeloma.  Generally, these cells are removed from the body, sent to school to learn to identify and kill Myeloma, grown so that there are a lot of educated T cells, and put back in the body.   There is some interesting work being done in this area in Chronic Lymphoid Leukemia and it looks to be quit promising.

We aren't there yet in Myeloma, but people are working on it.  It again relates to finding the best targets that can be used to help teach the T cells what to kill.

Where this goes from here?

In the future, the hope is that immunotherapy will yield a number of targeted treatment options that will induce remission, and that a combination of vaccines, engineered T cells and immune checkpoint inhibitors can stimulate strong and durable anti-myeloma immunity to eliminate any minimal residual disease.  

This might be introduced in a post- transplant setting where there is very little disease left, and we could then see if the immunotherapy was enough to kill the small amount remaining.   With more sensitive testing for minimal residual disease, we could then track the effectiveness of these immunotherapies.

The doctors on the presentation both thought it would be 5-10 years before we saw the full import of this research, and both were resistant to admit that the treatment could be curative.  But they both expressed some qualified hope that they might be in some cases, and they both were very optimistic that immunotherapy could represent an important new arrow in the quiver of Myeloma treatment.

I'm off to a small event that I'm co-hosting with the MMRF this evening, and look forward to reporting back on anything interesting that I hear.   Have a good weekend, friends!

Tuesday, May 6, 2014

So what exactly is an Autologous Stem Cell Transplant?

I have been counseling a number of folks lately -- seemingly an increasing amount -- about their treatment options in this disease.  And in the case of newly diagnosed patients with standard risk characteristics who are young enough to benefit from being cured versus not being cured, I urge them to consider transplants in general, and tandem transplants in particular as part of a Total Therapy regimen.

In the midst of this, my good and extremely learned friend SR was kind enough to educate me a bit on the specific way that certain types of chemotherapy work (alkalyting agents, such as those used in stem cell transplants).   So I thought it might be useful for me to explain a bit about what an autologous stem cell transplant procedure really is (hint: it's not a transplant) and why it is effective in many cases of standard risk myeloma.

So with your permission, a quick chemistry lesson as pertains transplants.

A true transplant -- such as an allogeneic transplant where the patient receives the immune system of a donor -- is just that: a transplantation of the donor's immune system into the patient's immune system.  You're taking something from somebody else and installing it.  Like a heart and lung transplant, or a liver transplant, or a kidney transplant.

In contrast, an autologous stem cell transplant takes one's own cells.  There is no transplantation.  An autologous stem cell transplant is simply administration of a type of chemotherapy in high-dose to kill myeloma cells, followed by a "rescue procedure" that involves putting one's own cell back into one's body in order to rebuild blood and…uh…not die, essentially.

Generally speaking, the chemotherapy administered with an auto transplant is called an alkalyting agent.  The most common one is called Melphalan, and the second most common one is called Bendamustine.  Cyclophosphomide, which is the C of VDT-PACE that is used for induction in Total Therapy, is another alkalytor.

Alkalytors work like this:

* An alkyl is a portion of a molecule.  There are many different kinds of alkyls.

* An alkalyting agent like the above-mentioned chemotherapies (which all derive from mustard gas, by the way…fun stuff) transmits a synthetic alkyl into the DNA of a cell.  It joins with the DNA in the cell, and since the alkyl the agent transmits is inherently unstable, this screws up (highly medical term there) the DNA of the cell.

* Once the DNA of a cell gets screwed up, the cell takes inventory of itself, dutifully raises its hand and says "umm, I'm screwed up, time for me to cash in the chips here, guys."  In more technical terms, the cell is activated for programmed (i.e. intentional) death.   This is the normal response for a cell with damaged DNA to be removed from the body, and this process is called apoptosis.

* For a reason I do not know at this time at the biochemical level, this occurs with fast-dividing cells.  Cancer, hair, and digestive tract (hence hair loss and GI issues from transplant meds).  The DNA that gets mangled is concentrated in your cancer cells, but it's there in plenty of normal cells, too.

So what, exactly, is an auto-transplant and what does it have to do with this?

An auto-transplant is the administration of a high-dose of an alkalyting agent, followed by steps to help the patient recover from the damage the medicine does.  Simple as that.

The medicine is administrated in a "mega-dose" (100X a "normal dose" of these agents) and it murders the hell out of Myeloma, while also causing a lot of collateral damage.  It does such an effective job of killing that it temporarily destroys the body's ability to make blood -- no more red blood cells, no more white blood cells, no more platelets.  Hopefully no more (or very little, to be more accurate) myeloma, either.

If no steps were taken to help the patient, the patient would die in a matter of days.  After all, you need red blood cells to live, white blood cells to keep an infection from killing you, platelets to keep from bleeding out from a cut (or suffering internal bleeding that kills you).   Turns out all those blood cells are important!   So in an auto transplant, after chemo is given, the patient is given their own immature blood cells that restore the patient's marrow and help to manufacture new blood.  This is not a transplant of another's immune system -- it is a rescue procedure.  Not too different from giving somebody low in potassium some potassium, or giving somebody low in red blood a unit or two of blood.  Just a bit higher stakes, is all.

So when people (doctors or laymen) say they believe in a transplant -- whether a single transplant to deepen remission, or tandem transplants to hopefully cure the disease -- all they are really saying is that they believe that in most cases, melphalan kills myeloma cells.  A lot of them.  Maybe almost all of them, even.

In Total Therapy, or a tandem transplant setting, all that is happening is the patient is getting twice as much Melphalan.  There's no magic to it beyond that -- you're simply giving the patient more of a medicine that is believed to be effective against standard risk disease.

In summary auto transplants are just that: a type of medicine, highly effective in most cases, from which help is required to recover.

Interestingly, SR went on to explain one particular type of disease biology that is not as responsive to current transplant protocols.   Some of you may have come across the concept of "deletion 17p" as a means of defining disease biology.   There is a genetic component of DNA called TP53 (for tumor protein 53) and it is part of the long arm of chromosome 17 (17p).   TP53 is the part of the DNA that says "okay, the cell raised its hand and is ready to bow out gracefully" (more accurately: TP53 allows the body to assess DNA damage to a cell and either repair it or target it for apoptosis -- programmed cell death).    If a patient does not have this genetic characteristic, the alkalyting agents do their part by screwing up the DNA, but the body does not recognize that for what it is, and fail to kill the cell.  Consequently, patients who have del17p don't respond as well to transplants as those who don't have that particular genetic abnormality.

One last note: Revlimid has been associated with the risk of secondary cancers -- I had a squamous cell carcinoma in my finger that was likely related to ongoing Revlimid use.  But Revlimid is only associated with increased risk of secondary cancers if the patient has received alkalyting chemotherapy. Something to keep in mind.   If you do a transplant followed by Revlimid maintenance, make sure you understand the reason behind it (i.e., is the doctor pursuing cure) and you are informed about the trade-offs.  In my own case, the risk of getting a secondary cancer that might kill me was lower than dying from the Myeloma -- that was the calculation I made and I'm happy with it, even in hindsight.

Okay, that's enough for today.  :)    But hopefully, this entry can be useful to those who are considering a transplant and want to understand a bit more about what it is, and why it works.

Tuesday, April 22, 2014

A changing of the guard...

My beloved doctor Bart Barlogie has led MIRT and UAMS since its inception, managing not just the clinical and research aspects but all of the administration of the center.  I've seen first-hand how hard the guy works -- 12 hour days 7 days a week are just the start of it.  He's never not thinking about his patients and this disease.

I'd been led to believe that he would be passing the torch -- partially at least -- as he confided in me some time ago that he's been looking for his successor.

Today, he has announced who it will be.  Bart will stay on in a clinical and research capacity, but the administrative "general manager" function will be handed off to Dr. Gareth Morgan, formerly head of the Myeloma unit at the Royal Marsden NHS Foundation Trust in the UK, and professor of hematology (or heamatology to those who speak The Queen's!) at the Institute of Cancer Research there.

Here's a link to the story as reported by the Myeloma Beacon.

I have mixed feelings about this, of course.  I'm glad to see my friend be able to slow down, and I'm heartened by the fact that he will continue his clinical practice and research activities.  However I also want to make sure he remains directing my care.  It's funny -- when I first got there, I learned of his passion for motorcycles and in giving him a book on the history of Ducati, I wrote in it that he's not allowed to get in a crash until he's cured me.  :)   No crashes that I know of, but he's also not allowed to retire until he's cured me, either!  : )

I looked up Dr. Morgan and he seems like a very sound choice -- although my first search simply included the words "myeloma" and "curable" beside his name and the results were not as direct as I'd have ideally liked.  After all, there's no point in continuing my care under a physician who doesn't fully subscribe to the whole philosophy of Total Therapy.   At least not at this time -- if it (God forbid) fails me in the future, then I can consider a wider net.  But for now, I want to remain in the hands of somebody that entertains the possibility -- if not the likelihood -- that standard risk Myeloma can be cured using Total Therapy in the majority of newly diagnosed cases.

All that said, I know Bart is a perfectionist and I know he's been working on wooing Dr. Morgan for at least a year.  Consequently, he must be the right person for the job.  There's no way Bart would put his legacy in the hands of anybody in whom he did not have total confidence.

Perhaps I will have the opportunity to meet with Dr. Morgan in my upcoming July visit…which reminds me, I need to schedule that soon...

Tuesday, April 8, 2014

And yet more evidence of plateau (cure) from another unrelated source...

A friend a fellow MM patient DH alerted me to an interesting article just published in an alternative means of testing for Minimal Residual Disease called Deep Gene Sequencing.  Evidently it is more sensitive than MFC tests for MRD.  The MFC test reports that I have "<.01%" (which means it cannot detect MRD with greater accuracy than 1 in 10,000 cells).  Evidently Deep Gene Sequencing is accurate to 1 in 1,000,000.   Not sure how I sign up for this!

It's not perfect, though, for the same reasons other MRD tests that rely on bone marrow are not.  MM cells are not evenly distributed throughout the bone marrow -- one could have negative bone marrow in one spot and find residual disease elsewhere.  A test needs to rely on circulating cells (i.e., in the blood).  This is still being worked on.

Since the test is imperfect, there were relapses among patients who were MRD negative -- though not among all of them.  And here is where it gets interesting:

No matter whether patients were MRD negative or not, after approximately 80 months, NOBODY EXPERIENCED RECURRENCE.   That's right, another plateau.

The full article, from the Myeloma Beacon, is here.

So in the last week, we've seen two studies -- one in Italy and this one in Spain -- demonstrate that after 8-10 years, the disease rarely if ever comes back.

Monday, April 7, 2014

More on that NIH article -- cure is out there!

A kindly if mysterious email from an address ending in .fi (Finland?) attached the NIH article for me, which I reproduce here minus the tables.

There are a few big points here.   The first is that a plateau was observed after 10 years of continuous complete remission.   The second is that MEDIAN progression free survival for someone who reached complete remission through a simply induction of VAD and one or two transplants without no novel agents was over ten years.  That means more than half of the people that reached complete remission were still in remission 10 years later -- and in that group NOT ONE relapse after 10 years.

The issue is that with VAD and Melphalan (the transplant chemo) only, the CR rate was only 19%.  That's clearly not good enough.  But in Total Therapy, the CR rate of standard risk patients is 60% -- higher if one considers trace levels of M protein to be a return to a "cure with MGUS" state (although it must be said that the study I'm about to quote did not group such persons into the CR group, and so they did not have this same outcome -- albeit they also didn't have the novel agents that Total Therapy uses).

At any rate, a plateau exists in this study.  That's great news, and certainly corroborates the claim that Arkansas has made about the disease being curable.

The study itself, with apologies for ugly formatting but I do have a day job after all.  :)

Long-Term Results in Multiple Myeloma After High-Dose Melphalan and Autologous Transplantation According to Response Categories in the Era of Old Drugs
Massimo Martino,1 Maurizio Postorino,2 Giuseppe Alberto Gallo,1 Giuseppe Messina,1 Santo Neri,6 Eugenio Piro,4 Massimo Gentile,7 Tiziana Moscato,1 Renza Monteleone,1 Roberta Fedele,1 Carla Mazzone,7 Giuseppe Console,1 Giuseppa Penna,5 Caterina Alati,3 Iolanda Donatella Vincelli,3 Giuseppe Irrera,1 Caterina Musolino,5 Francesca Ronco,3 Stefano Molica,4 Fortunato Morabito7


We investigate the prognosis of multiple myeloma in 173 patients treated with high-dose melphalan and autologous transplantation in the era of old drugs. The relapse rate is low for patients in complete remission after 10 years of follow-up with a PFS and OS values of 58% and 70%. The achievement of depth response represents the most important prognostic factor.

Background: The aim of this study was to investigate the correlation between the long-term prognosis of multiple myeloma (MM) and the quality of response to therapy in a cohort of 173 patients treated with high-dose melphalan (HDM) and autologous transplantation in the era of old drugs. 

Patients and Methods: A total of 173 patients with de novo MM who received a transplant between 1994 and 2010 were analyzed. VAD (vincristine, doxorubicin [Adria- mycin], dexamethasone) was used as front-line regimen before auto-HPCT. The conditioning was HDM 200 mg/m2. Patients were evaluated for clinical response using the criteria from the European Group for Blood and Marrow Transplantation, modified to include near complete remission (nCR) and very good partial remission (VGPR). 

Results: The response distribution after transplantation in our series was complete remission (CR) in 33 cases (19%), nearly complete remission (nCR) in 38 cases (22%), VGPR in 30 cases (17%), partial remission (PR) in 65 cases (38%), and stable disease (SD) in 7 cases (4%). Patients were followed for 48 ` 36 months. Median overall survival (OS) was not reached for the CR group. Progression-free survival (PFS) was 122 months for CR, 55 months for nCR, 56 months for VGPR, 32 months for PR, and 22 months for SD. Significant differences in PFS and OS were found between the CR and nCR groups (P 1⁄4 .003 and P 1⁄4 .001, respectively), between the CR and VGPR groups (P 1⁄4 .002 and P 1⁄4 .001, respectively), and between the CR and PR groups (P 1⁄4 .000 and P 1⁄4 .001, respectively). Responses were clustered in 3 main categories, ie, CR, nCR þ VGPR þ PR, and SD. The respective 10-year PFS and OS values were 58% and 70% for CR, 15% and 18% for nCR þ VGPR þ PR, and 0% and 0% for SD. 

Conclusion: The achievement of depth and prolonged response represents the most important prognostic factor. The relapse rate is low for patients in CR after 10 years of follow-up, possibly signifying a cure. [emphasis mine]


The treatment of multiple myeloma (MM) is in continuous and rapid evolution. Drugs currently used for the treatment of this disease include alkylating agents, corticosteroids, proteasome in- hibitors, immunomodulatory drugs, and anthracyclines.1 Patients who are considered potential candidates for autologous hemato- poietic progenitor cell transplantation (AHPCT) receive 2 to 4 cycles of a nonmelphalan-containing regimen and then proceed to stem cell harvest.2 For many years, VAD or pulsed high-dose dexamethasone (HDD)3 were used as frontline induction therapy, but now the strategy has changed with new agents such as immu- nomodulatory drugs and proteasome inhibitors, bortezomib in particular. Before the advent of new drugs, the complete remission (CR) rate after induction therapy was < 10%, and several trials have shown an association between depth of response to therapy and long-term outcome.4 New induction regimens offer high overall response rates, approaching levels previously noted only with AHPCT.5 Combined treatment based on novel-agent induction regimens and high-dose chemotherapy (HDC) provide further improvement in the depth of response,6,7 and for this reason, MM remains the leading indication for AHPCT worldwide,8,9 and the International Myeloma Working Group recommends that AHPCT be offered at some point during the course of treatment to a medically fit patient.10

As a contribution to the field of HDC and AHPCT in MM, we report the results of this therapeutic approach in patients coming from a regional network and treated during the era of the old drugs. We analyzed correlations between prognosis and different response categories after long-term follow-up.

Patients and Methods

A total of 173 patients with de novo MM who received AHPCT between 1994 and 2010 were analyzed. Main patient characteristics at diagnosis are summarized in Table 1. The induction chemo- therapy was performed in 6 different institutions in southern Italy. One hundred forty-six patients underwent a single transplantation and 46 patients had a tandem transplantation.
Table 1 Main Patient Characteristics at Diagnosis
VAD was used as a frontline regimen before AHPCT. The source of stem cells was peripheral blood stem cells in all cases. Stem cells were collected after cyclophosphamide mobilization at doses ranging from 3 to 4 g/m2 in association with granulocyte colony-stimulating factor 5 mg/kg. The conditioning HDC was high-dose melphalan (HDM) 200 mg/m2.

Information about response status after transplantation, evaluated simultaneously by electrophoresis (EP) and immunofixation (IF) for serum and urinary M-protein, was available for all cases. Patients were evaluated for clinical response using the criteria from the European Group for Blood and Marrow Transplantation,11 which was modified to include nearly complete remission (nCR) and very good partial remission (VGPR). Patients were divided into different groups: CR, defined as absence of a detectable M-component in serum and urine by IF in 2 measurements over 6 weeks and < 5% plasma cells in the bone marrow; nCR, defined by a negative EP result but positive detection of an M-component by IF; VGPR, defined by detection of an M-component at EP e/o IF and reduc- tion in M-component levels between 90% and 99%; partial remission (PR), defined by an M-component reduced to between 50% and 90%. The remaining patients were considered non- responders, both with progressive disease (PD) or stable disease (SD). Patients with progressive disease were excluded from analysis.

Patients were followed until death or the end of the study, and all participants were monitored by both EP and IF in serum and urine throughout follow-up. In this period, a relapse was considered a major event and it was defined as follows: in patients with CR, by recurrence of a detectable M-component on IF, even with negative EP results; in those with nCR, by a positive EP; in those with VGPR, PR, or SD by an increase of > 25% compared with the lowest M-component level previously achieved.

The evaluation of response was performed after a median time of 3.6 months (range, 3.0-6.7 months) from transplantation, and the follow-up was started at the time of response assessment and included all patients.12 Progression-free survival (PFS) was measured from the start of follow-up to the date of progression, relapse, or death; patients alive and event free were censored at the date of the last clinical control. OS was calculated from the start of follow-up to date of death or last follow-up visit.

The statistical analysis according to the different response categories was performed using SPSS software (SPSS Inc, Chicago, IL). Data are expressed as mean ` SD, survival curves were calculated according to the Kaplan-Meier method, and differences between curves were evaluated with the log-rank test. P values < .05 were considered to reflect statistical significance. Death and event rate were calculated as number of deaths (or events) per 100 patients per year.


The response distribution after AHPCT in the series was 33 cases of CR (19%), 38 cases of nCR (22%), 30 cases of VGPR (17%), 65 cases of PR (38%), and 7 cases of SD (4%) (Table 2).

Patients were followed for 48 +/- 36 months. Median survival was not reached for the CR group [emphasis mine]; PFS and OS curves are reported in Figures 1 and 2, respectively. The median PFS was 122 months for patients who achieved CR [emphasis mine], 55 months for patients who achieved nCR, 56 months for patients who achieved VGPR, 32 months for patients who achieved PR,and 22 months for patients who achieved SD. The median OS decreased in parallel with PFS in the 5 response categories: 166 months (with 9% of patients deceased) for CR, 72 months (34% deceased) for nCR, 69 months (47% deceased) for VGPR, 49 months (71% deceased) for PR, and 29 months for SD.

Significant differences in PFS and OS were found between the CR and nCR groups (P 1⁄4 .003 and P 1⁄4 .001, respectively), between the CR and VGPR groups (P 1⁄4 .002 and P 1⁄4 .001, respectively), between the CR and PR groups (P 1⁄4 .000 and P 1⁄4 .001, respectively), between the CR and SD groups (P 1⁄4 .000 and P 1⁄4 .001, respectively), between the nCR and PR groups (P 1⁄4 .009 and P 1⁄4 .012, respectively), and between the VGPR and PR groups (P 1⁄4 .002 and P 1⁄4 .001, respectively). A statistically significant difference in OS was found between the nCR and VGPR groups (P 1⁄4 .04), whereas no difference was demonstrated in terms
of PFS. The median survival of both PFS (Fig. 1) and OS (Fig. 2) in patients with SD was significantly shorter compared with the other response groups (Figs. 1 and 2).

Based on these results, the responses were regrouped into 3 categories (CR, nCR þ VGPR þ PR, and SD) and an additional survival analysis was performed. As expected, a statistically signifi- cant difference was found among the 3 groups in terms of both PFS and OS. We found a plateau phase in OS after 10 years [BIG emphasis mine!]; the 10-year probability of PFS and OS values were, respectively, 58% and 70% forCR,15%and18%fornCRþVGPRþPR,and0%and0% for SD (Fig. 3).

Because a different median follow-up was revealed among groups, we normalized data calculating the event and death rate, ie, the number of events or deaths per 100 patients per year. Notably, both event (5.5% cases per year) and death (1.5% cases per year) rates of patients with CR were lower compared with patients achieving less profound responses up to roughly 1 log increase in patients with SD (Table 3); however, a 3-fold increase was demonstrated in patients with nCR or VGPR, and a one-third increase was seen in patients with PR. In particular, the death rate was 1.5% for CR cases and increased up to 10-fold in patients with nCR and in those with VGPR, up to 21% and 39% in the PR and SD groups, respectively.

The HDM approach was effective in shifting in CR 23 of 163 patients (14.1%) for whom conventional chemotherapy (CC) failed to produce CR obtained this clinical result after HDM. The clinical outcome for those patients achieving CR before or after HDM did not differ significantly.


We report in this study the long-term results in 173 patients with MM who were treated with an induction regimen containing the older drugs and HDM with AHPCT. We found a plateau phase in OS after 10 years, with 70% in the CR group alive at 10 years. The relapse rate is low for patients in CR with > 10 years of follow-up, possibly signifying a cure [again, BIG emphasis mine]. Because this is a retrospective study, many parameters are lacking and making conclusions is difficult, and the favorable results after HDM in patients who achieved CR should be considered with caution considering the potential inclusion criteria biases of a retrospective study. Despite these limitations, our data are useful for providing insight into the selection of patients who might derive maximum benefit from intensive chemotherapy.

Unfortunately, we do not have information available on the posttransplantation therapy after relapse or disease progression, which clearly has a substantial impact on OS; however, most of these patients likely received new drugs. This information would be helpful in understanding the extent to which newer agents contributed to prolonged survival. This is a limitation of the study, but it also has to be considered that at the time HDM was proposed, the new drugs were not available for induction therapy.

The rationale to proceed to HDC with AHPCT was to increase the depth of response,13 and over the past decade this approach has been considered the standard of care for younger patients with newly diagnosed MM14-16 based on an increased rate of CR, prolonged disease-free survival,17-22 and OS17,19 compared with CC in several randomized studies. However, not all the published studies have demonstrated the superiority of AHPCT,20-22 and a systematic review and meta-analysis has shown a significant benefit with single AHPCT in terms of prolonged PFS but not of OS23 In the following years, different studies evaluated the efficacy of additional therapies after AHPCT based on a second autograft with the rationale of reducing residual disease.24-26 The tandem AHPCT approach achieved improvement in OS [ANOTHER BIG EMPHASIS mine],25 even though a survival benefit was seen mainly in those patients in whom at least a VGPR was not achieved after the first transplantation.26 Recently, a Cochrane Review compared tandem AHPCT with single AHPCT as first-line treatment in patients with symptomatic MM with respect to OS, PFS, quality of life, and treatment- or transplantation-related mortality.27 They did not consider any study to be sufficiently informative for contemporary treatment decisions concerning the question of single versus tandem AHPCT in view of inherent biases. In addition, none of the trials integrated the so-called novel agents that are now considered standard treatment for MM.28 Interest in optimizing initial therapy and conditioning regimens before AHPCT remains strong. Numerous new doublet, triplet, quadruplet, and multidrug combinations are available for initial therapy in MM,1 and it is probable that incorporation of novel agents into transplantation programs results in increased rates of immunophenotypic or molecular remissions, or both,10 compared with those reported in the recent past. Moreover, we do not have data about switching induction regimens in patients who achieve only a nCR or PR before transplantation. An appropriate HDC conditioning regimen contributes to the efficacy of AHPCT mainly through the cytoreduction effect, and the development of a more effective approach may help in improving the outcome.29

However, attainment of CR after both induction therapy and AHPCT is 1 of the strongest predictors of long-term outcomes30,31 and represents a major end point of current treatment strategies.32 Moreover, sustained CR is predictive of favorable long-term out- comes,33 and continuous efforts are being made to improve the sensitivity of methods used for CR assessment, including molecular techniques34 and immunophenotyping assays.35,36 In our series HDM was effective at producing a CR in 14.1% of patients for whom CC failed to produce a CR; these patients had an outcome similar to that of patients who underwent transplantation and achieved CR.

The results from our study demonstrate a correlation between depth of posttransplantation response and outcome in the era of the old drugs, confirming previous reports. Moreover, our analysis clearly differentiated patients achieving CR (negative on IF) from those achieving nCR (positive on IF). These data are in line with a Spanish study32 in which results from a large series of uniformly treated patients demonstrated an association between quality of response after transplantation and both event-free survival (EFS) and OS. Patients achieving CR had significantly longer EFS (median, 61 vs. 40 months) and OS (medians not reached) versus patients achieving nCR, who likewise had somewhat better outcomes compared with patients achieving PR (median EFS, 34 months vs. nCR; median OS, 61 months).

In a recent study, Martinez-Lopez et al showed that achieving CR after HDC and AHPCT is the most important prognostic factor in MM, even after long-term follow-up.37 The relapse rate was low in patients who maintained a CR after > 11 years of follow-up. [My emphasis -- another corroborating study!] In this study, the median OS for the CR category was 7.6 years.

A recent meta-analysis, including 10 prospective trials38 in MM, showed that the depth of the response to treatment in this disease, particularly CR defined by an absence of the M-component and absence of plasma cells in the bone marrow, is clearly related to a better OS and PFS, but in some trials CR and nCR and VGPR were analyzed together,17,25,39 whereas our and other authorsdata33 indicate that these posttransplantation response categories are different regarding their impact on long-term disease outcome.

The prevailing opinion is still that myeloma is an incurable disease. Nevertheless, in our cohorts, none of the patients main- taining a CR 10 years after HDC and AHPCT experienced a relapse of disease, thus suggesting that a small fraction of patients with a long-term CR can be cured. [HUGE EMPHASIS MINE].  This emphasizes the importance of response stability over time in MM33,40,41 and reinforces the idea of using maintenance treatments to avoid recurrence of the disease and to increase the response rate. However, this does not mean that additional treatment that drives more patients into CR also gives them a better prognosis. Neither is the correlation of CR-longer survival an argument for maintenance therapy. The benefit of these additional approaches has to be proved by randomized trials.
Another concern is that IF, used to assess response status after transplantation, has well-known limitations, and it is a subjective and sometimes difficult to interpret method. The introduction of more objective and sensitive methods,34,36 including imaging techniques42 to assay response, will not replace IF but could lead to a deeper evaluation of the response to treatment.

In conclusion, the achievement of depth and prolonged response after AHPCT represents the most important prognostic factor, supporting the concept that a small cure rate could also be achieved in patients treated with old drug combinations as induction and consolidated with an AHPCT. 

Author Contributions
Study concepts: MM, MP, and FM
Study design: MM, MP, and FM
Data acquisition: MM, MP, GAG, GM, SN, EP, TM, RF, GC,
GI, CA, IDV, CM, FR, SM, and FM
Quality control of data and algorithms: MM, MP, GAG,
and FM
Data analysis and interpretation: MM, MP, and FM Statistical analysis: MM and MP
Manuscript preparation: MM, MP, and FM Manuscript editing: MM, MP, and FM
Manuscript review: MM, MP, GAG, and FM

We wish to thank all the centers in southern Italy that gathered all relevant information to locate eligible patients and performed data management: Hematology and Bone Marrow Transplant Unit, Reggio Calabria (Pasquale Iacopino, Elisabetta Massara); Hema- tology Unit, Reggio Calabria (Francesco Nobile, Vincenzo Callea, Caterina Stelitano); Hematology Unit, Caserta (Antonio Abba- dessa); Hematology Unit, Papardo, Messina (Maura Brugiatelli); Hematology and Oncology Unit, Catanzaro (Maria Grazia Kropp, Rosanna Mirabelli); Hematology Unit, Catanzaro University (Francesco Tassone, Marco Rossi); Hematology Unit, Cosenza (Ernesto Vigna); and Oncology Unit, Rossano Calabro (Francesco Iuliano).

The authors have stated that they have no conflicts of interest. 

  1. Rajkumar SV. Doublets, triplets, or quadruplets of novel agents in newly diagnosed myeloma? Hematol Am Soc Hematol Educ Program 2012; 2012:354-61.
  2. Gertz MA, Ansell SM, Dingli D, et al. Autologous stem cell transplant in 716 patients with multiple myeloma: low treatment related mortality, feasibility of outpatient transplant, and effect of a multidisciplinary quality initiative. Mayo Clin Proc 2008; 83:1131-8.
  3. Alexanian R, Barlogie B, Tucker S. VAD-based regimens as primary treatment for multiple myeloma. Am J Hematol 1990; 33:86-9.
  4. Harousseau JL, Attal M, Avet-Loiseau H. The role of complete response in multiple myeloma. Blood 2009; 114:3139-46.
  5. Harousseau JL, Moreau P. Autologous hematopoietic stem cell transplantation for multiple myeloma. N Engl J Med 2009; 360:2645-54.
  6. Palumbo A, Rajkumar SV. Multiple myeloma: chemotherapy or transplantation in the era of new drugs. Eur J Haematol 2010; 84:379-90.
  7. Bladé J, Rosinol L, Cibeira MT, et al. Hematopoietic stem cell transplantation for multiple myeloma beyond 2010. Blood 2010; 115:3655-63.
  8. Passweg JR, Baldomero H, Gratwohl A, et al. The EBMT activity survey: 1990-2010. Bone Marrow Transplant 2012; 47:906-23.
  9. Reece DE, Bredeson C, Pérez WS, et al. Autologous stem cell transplantation in multiple myeloma patients < 60 vs > 60 years of age. Bone Marrow Transplant 2003; 32:1135-43.
  10. Cavo M, Rajkumar SV, Palumbo A, et al. International Myeloma Working Group consensus approach to the treatment of multiple myeloma patients who are can- didates for autologous stem cell transplantation. Blood 2011; 117:6063-73.

    11. Bladé J, Samson D, Reece D, et al. Criteria for evaluating disease response and pro- gression in patients with multiple myeloma treated by high-dose therapy and hae- mopoietic stem cell transplantation. Myeloma Subcommittee of the EBMT. European Group for Blood and Marrow Transplant. Br J Haematol 1998; 102:1115-23.
    12. AndersonJR,CainKC,GelberRD.Analysisofsurvivalbytumorresponseandother comparisons of time-to-event by outcome variables. J Clin Oncol 2008; 26:3913-5. 13. Giralt S. Stem cell transplantation for multiple myeloma: current and future status.
    Hematology 2012; 17(suppl 1):S117-20.
    Hahn T, Wingard JR, Anderson KC, et al. The role of cytotoxic therapy with
    hematopoietic stem cell transplantation in the therapy of multiple myeloma: an
    evidence-based review. Biol Blood Marrow Transplant 2003; 9:4-37.
    Barosi G, Boccadoro M, Cavo M, et al. Management of multiple myeloma and related-disorders: guidelines from the Italian Society of Hematology (SIE), Italian Society of Experimental Hematology (SIES) and Italian Group for Bone Marrow
    Transplantation (GITMO). Haematologica 2004; 89:717-41.
    Smith A, Wisloff F, Samson D. Guidelines on the diagnosis and management of
    multiple myeloma 2005. Br J Haematol 2006; 132:410-51.
    Attal M, Harousseau JL, Stoppa AM, et al. A prospective randomized trial of
    Autologous bone marrow transplantation and chemotherapy in multiple myeloma.
    N Engl J Med 1996; 335:91-7.
    Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous pe-
    ripheral blood stem cell transplantation in multiple myeloma: up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood 1998; 92:3131-6.
    19. Child JA, Morgan GJ, Davies FE, et al. High-dose chemotherapy with hemato- poietic stem-cell rescue for multiple myeloma. N Engl J Med 2003; 348:1875-83. 20. Bladé J, Rosiñol L, Sureda A, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial
    from the Spanish cooperative group PETHEMA. Blood 2005; 106:3755-9.
    Fermand JP, Katsahian S, Divine M, et al. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from
    the Group Myelome-Autogreffe. J Clin Oncol 2005; 23:9227-33.
    Barlogie B, Kyle RA, Anderson KC, et al. Standard chemotherapy compared with high-dose chemoradiotherapy for multiple myeloma: final results of phase III US
    Intergroup Trial S9321. J Clin Oncol 2006; 24:929-36.
    Koreth J, Cutler CS, Djulbegovic B, et al. High-dose therapy with single autol-
    ogous transplantation versus chemotherapy for newly diagnosed multiple myeloma: a systematic review and meta-analysis of randomized controlled trials. Biol Blood Marrow Transplant 2007; 13:183-96.
    24. Barlogie B, Jagannath S, Vesole DH, et al. Superiority of tandem autologous transplantation over standard therapy for previously untreated multiple myeloma. Blood 1997; 89:789-93.
    25. Attal M, Harousseau JL, Facon T, et al. Single versus double autologous stem-cell transplantation for multiple myeloma. N Engl J Med 2003; 349:2495-502.
    26. Cavo M, Tosi P, Zamagni E, et al. Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: bologna 96 clinical study. J Clin Oncol 2007; 25:2434-41.
    27. Naumann-Winter F, Greb A, Borchmann P, et al. First-line tandem high-dose chemotherapy and autologous stem cell transplantation versus single high-dose chemotherapy and autologous stem cell transplantation in multiple myeloma, a systematic review of controlled studies. Cochrane Database Syst Rev 2012; 10: CD004626.
    28. Chanan-Khan Giralt S. Importance of achieving a complete response in multiple myeloma, and the impact of novel agents. J Clin Oncol 2010; 28:2612-24.
    29. Martino M, Olivieri A, Offidani M, et al. Addressing the questions of tomorrow: melphalan and new combinations as conditioning regimens before autologous hematopoietic progenitor cell transplantation in multiple myeloma. Expert Opin Investig Drugs 2013; 22:619-34.
    30. Alexanian R, Weber D, Giralt S, et al. Impact of complete remission with intensive therapy in patients with responsive multiple myeloma. Bone Marrow Transplant 2001; 27:1037-43.
    31. Bladé J, Esteve J, Rives S, et al. High-dose therapy autotransplantation/intensifi- cation vs continued standard chemotherapy in multiple myeloma in first remission. Results of a non-randomized study from a single institution. Bone Marrow Transplant 2000; 26:845-9.
    32. Lahuerta JJ, Mateos MV, Martínez-López J, et al. Influence of pre- and post- transplantation responses on outcome of patients with multiple myeloma: sequential improvement of response and achievement of complete response are associated with longer survival. J Clin Oncol 2008; 26:5775-82.
    33. Barlogie B, Anaissie E, Haessler J, et al. Complete remission sustained 3 years from treatment initiation is a powerful surrogate for extended survival in multiple myeloma. Cancer 2008; 113:355-9.
    34. Martínez-Sánchez P, Montejano L, Sarasquete ME, et al. Evaluation of minimal residual disease in multiple myeloma patients by fluorescent-polymerase chain reaction: the prognostic impact of achieving molecular response. Br J Haematol 2008; 142:766-74.
    35. Paiva B, Vidriales MB, Cerveró J, et al. Multi parameter flow cytometric remission is the most relevant prognostic factor for multiple myeloma patients who undergo autologous stem cell transplantation. Blood 2008; 112:4017-23.
    36. Lahuerta JJ, Martinez-Lopez J, Serna JD, et al. Remission status defined by immunofixation vs. electrophoresis after autologous transplantation has a major impact on the outcome of multiple myeloma patients. Br J Haematol 2000; 109: 438-46. 

    1. Martinez-Lopez J, Blade J, Mateos MV, et al. Long-term prognostic significance of response in multiple myeloma after stem cell transplantation. Blood 2011; 118: 529-34.
    2. van de Velde H, Liu X, Chen G, et al. Complete response correlates with long- term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica 2007; 92:1399-406.
    3. Lonial S, Gertz MA. Eliminating the complete response penalty from myeloma response assessment. Blood 2008; 111:3297-8.
    40. Barlogie B, Zangari M, Bolejack V, et al. Superior 12-year survival after at least 4-year continuous remission with tandem transplantations for multiple myeloma. Clin Lymphoma Myeloma 2006; 6:469-74.
    41. Gay F, Larocca A, Wijermans P, et al. Complete response correlates with long-term progression free and overall survivals in elderly myeloma treated with novel agents: analysis of 1175 patients. Blood 2011; 117:3025-31.
    42. Zamagni E, Cavo M. The role of imaging techniques in the management of multiple myeloma. Br J Haematol 2012; 159:499-513