In my seemingly never ending decision process for determining whether or not to have an autologous stem cell transplant (ASCT), I have read about a tendency for the development of aggressive extramedullary disease post stem cell transplant.
I have read about this tendency on this forum and elsewhere, although I have not found any scientific studies concerning it.
From a theoretical point of view, the idea goes like this. The very powerful chemotherapeutic agent melphalan wipes out all but the most resilient myeloma strains (call them Alpha) during the stem cell transplant process. Some of the destroyed strains, while not as virulent against the body as Alpha, nevertheless can suppress Alpha.
When relapse occurs some time after the transplant, Alpha is frequently in ascendancy, free to wreak havoc on the body. One of its hallmarks is extramedullary disease, which has a poor prognosis.
So, while an autologous transplant can be effective in achieving a long remission, it will very often set the stage for multiple myeloma making an extraordinarily virulent comeback accompanied by extramedullary disease.
Now I know that sometimes extramedullary disease presents upon initial myeloma diagnosis, before stem cell transplantation, but in these cases it may be that Alpha is initially the dominant, active strain.
Has anyone encountered this theory in the context of studies concerning what happens after autologous stem cell transplantation?
Forums
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
Re: Aggressive myeloma post autologous stem cell transplant
Hi Mr. Potatohead,
I do not recall having read that a relapse after an autologous transplant is any more "virulent" than one for patients that did not use high-dose melphalan. It is known that patients that do an autologous transplant at some point in their treatment have a higher expected overall survival (OS) than those that do not, so I would not think the relapses are more difficult to treat. The normal course of myeloma with standard therapies like novel agents with or without autos is that successive relapses will be more difficult to treat with shorter periods of remission.
You wrote:
You could apply that same logic to novel agents. Why use novel agents if ultimately they will lead to a relapsed patient with difficult to treat disease?
Mark
I do not recall having read that a relapse after an autologous transplant is any more "virulent" than one for patients that did not use high-dose melphalan. It is known that patients that do an autologous transplant at some point in their treatment have a higher expected overall survival (OS) than those that do not, so I would not think the relapses are more difficult to treat. The normal course of myeloma with standard therapies like novel agents with or without autos is that successive relapses will be more difficult to treat with shorter periods of remission.
You wrote:
So, while an autologous transplant can be effective in achieving a long remission, it will very often set the stage for multiple myeloma making an extraordinarily virulent comeback accompanied by extramedullary disease.
You could apply that same logic to novel agents. Why use novel agents if ultimately they will lead to a relapsed patient with difficult to treat disease?
Mark
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Mark11
Re: Aggressive myeloma post autologous stem cell transplant
Hi Mr Potatohead
You've raised an interesting question. My wife's oncologist and multiple myeloma specialist have stated the reason her multiple myeloma is aggressive is because of her chromosome abnormalities. I always thought how aggressive the disease strain is (Alpha) or other, is because of the chromosome abnormalities.
I've only read abstracts and journals about various chromosomal abnormalities and how they seem to make the multiple myeloma clone aggressive or not. For instance, there is much written about del 1P32.3, (t4-14) translocation, del 17, gain 1Q. All of these abnormalities determine aggressive behavior of the clone and how quickly the multiple myeloma will cause relapse. Multiple abnormalities, greater than or equal to three, can be ultra high risk. No articles I've read indicate that chromosomal abnormalities can cause extramedullary disease after a stem cell transplant.
You've raised an interesting question. My wife's oncologist and multiple myeloma specialist have stated the reason her multiple myeloma is aggressive is because of her chromosome abnormalities. I always thought how aggressive the disease strain is (Alpha) or other, is because of the chromosome abnormalities.
I've only read abstracts and journals about various chromosomal abnormalities and how they seem to make the multiple myeloma clone aggressive or not. For instance, there is much written about del 1P32.3, (t4-14) translocation, del 17, gain 1Q. All of these abnormalities determine aggressive behavior of the clone and how quickly the multiple myeloma will cause relapse. Multiple abnormalities, greater than or equal to three, can be ultra high risk. No articles I've read indicate that chromosomal abnormalities can cause extramedullary disease after a stem cell transplant.
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wemery - Name: Wayne Emery
- Who do you know with myeloma?: Wife Nancy Emery
- When were you/they diagnosed?: March 2016
- Age at diagnosis: 66
Re: Aggressive myeloma post autologous stem cell transplant
Hi MrP,
I agree with Mark that your argument about high-dose melphalan 'releasing" virulent strains of myeloma cells could just as well be made for any myeloma therapy that achieves a deep response without being fully curative. The deep response theoretically could make it possible for the remaining myeloma clones to expand in the bone marrow with no competition from less aggressive clones.
There is one difference with melphalan, however, that might be relevant, although I suspect it's more relevant for newly diagnosed myeloma patients than late-stage patients. The difference is one of the reasons some myeloma specialists, such as Paul Richardson at Dana-Farber, feel that later transplantation may be better than early transplantation. In particular, it's the fact that melphalan can cause chromosomal abnormalities, and is considered "potentially mutagenic".
This is described in the FDA-approved prescribing information (label) for melphalan:
"Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans."
It's this aspect of melphalan which many people feel causes Revlimid to increase the risk of secondary cancers in patients who receive melphalan at the same time as Revlimid, or (possibly) in patients who receive Revlimid maintenance post transplant. The melphalan, it is hypothesized, makes the genetic structure of cells throughout the body less stable, and this makes it easier for Revlimid to cause secondary cancers.
This really isn't as important a consideration, however, in later-stage myeloma patients, where it's more important to make sure to use whatever myeloma therapies are still available. And, as Mark rightly suggests, melphalan certainly is an effective multiple myeloma therapy.
Overall, I wouldn't let the concern about a persistent "virulent" Alpha clone deter you from doing transplant.
I agree with Mark that your argument about high-dose melphalan 'releasing" virulent strains of myeloma cells could just as well be made for any myeloma therapy that achieves a deep response without being fully curative. The deep response theoretically could make it possible for the remaining myeloma clones to expand in the bone marrow with no competition from less aggressive clones.
There is one difference with melphalan, however, that might be relevant, although I suspect it's more relevant for newly diagnosed myeloma patients than late-stage patients. The difference is one of the reasons some myeloma specialists, such as Paul Richardson at Dana-Farber, feel that later transplantation may be better than early transplantation. In particular, it's the fact that melphalan can cause chromosomal abnormalities, and is considered "potentially mutagenic".
This is described in the FDA-approved prescribing information (label) for melphalan:
"Melphalan produces chromosomal aberrations in vitro and in vivo and, therefore, should be considered potentially mutagenic in humans."
It's this aspect of melphalan which many people feel causes Revlimid to increase the risk of secondary cancers in patients who receive melphalan at the same time as Revlimid, or (possibly) in patients who receive Revlimid maintenance post transplant. The melphalan, it is hypothesized, makes the genetic structure of cells throughout the body less stable, and this makes it easier for Revlimid to cause secondary cancers.
This really isn't as important a consideration, however, in later-stage myeloma patients, where it's more important to make sure to use whatever myeloma therapies are still available. And, as Mark rightly suggests, melphalan certainly is an effective multiple myeloma therapy.
Overall, I wouldn't let the concern about a persistent "virulent" Alpha clone deter you from doing transplant.
Re: Aggressive myeloma post autologous stem cell transplant
Good points, Mark. Overall survival is the ultimate benchmark. Just curious as to whether or not virulent disease hallmarked by extramedullary metastases is more likely with an aggressive agent like melphalan. Presumably there are multiple paths to shortened survival. The disease might be more unpleasant with an extramedullary course than one in which death comes through infection or kidney failure, depending on the pattern of tumor spread.
You make another excellent point, TerryH. I do remember reading the possibility you referenced in another thread some time ago: that melphalan's mutagenic properties may be behind the increase in secondary cancers that can accompany Revlimid maintenance.
wemery,
I don't personally believe that the aggressiveness of multiple myeloma is solely a product of certain chromosomal abnormalities. Certainly such abnormalities are factors, but are they the only factors? I think disease load, and host co-morbidities, are also important. Moreover, whatever chromosomal abnormalities are today implicated in rapid progression, there are likely to be other, yet-to-be-identified genetic or epigenetic influences as well.
Thanks, everyone, for your thought-provoking comments.
You make another excellent point, TerryH. I do remember reading the possibility you referenced in another thread some time ago: that melphalan's mutagenic properties may be behind the increase in secondary cancers that can accompany Revlimid maintenance.
wemery,
I don't personally believe that the aggressiveness of multiple myeloma is solely a product of certain chromosomal abnormalities. Certainly such abnormalities are factors, but are they the only factors? I think disease load, and host co-morbidities, are also important. Moreover, whatever chromosomal abnormalities are today implicated in rapid progression, there are likely to be other, yet-to-be-identified genetic or epigenetic influences as well.
Thanks, everyone, for your thought-provoking comments.
Last edited by MrPotatohead on Fri Jan 20, 2017 3:44 pm, edited 1 time in total.
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
Re: Aggressive myeloma post autologous stem cell transplant
I came across a study in the British Journal of Haematology that looked at the occurrence of extramedullary disease in patients receiving transplants. Here's the abstract:
"Extramedullary disease (EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty-three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy-proven EMD was identified, comprising 8·3% of the total study population. EMD was present at the time of diagnosis in 14·5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4·1 years (95% CI: 3·1, 5·1) and the median overall survival from time of EMD diagnosis was 1·3 years (95% CI: 0·8, 2·3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation."
Reference:
Weinstock, M, et al, "Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation," British Journal of Haematology, June 2015 (abstract)
As I read that, 76% of the patients who were diagnosed with extramedullary disease developed it after their transplant. That would be ~6.3%. So there is risk of the development of post-transplant extramedullary disease, but it doesn't seem like a terribly high risk. The statement that the incidence of EMD has not increased with the use of novel agents and transplants would seem to indicate that the transplant procedure itself does not promote its occurrence.
"Extramedullary disease (EMD), defined as an infiltrate of clonal plasma cells at an anatomic site distant from the bone marrow, is an uncommon manifestation of multiple myeloma. Six hundred and sixty-three consecutive patients with multiple myeloma who underwent stem cell transplantation between January 2005 and December 2011 were assessed for the presence of EMD. A cohort of 55 patients with biopsy-proven EMD was identified, comprising 8·3% of the total study population. EMD was present at the time of diagnosis in 14·5% of cases and at the time of relapse in 76% of patients. The most common EMD presentations at relapse were liver involvement and pleural effusions. EMD specimens had high expression of CD44 (92%) and moderate expression of CXCR4. The median overall survival from time of myeloma diagnosis was 4·1 years (95% CI: 3·1, 5·1) and the median overall survival from time of EMD diagnosis was 1·3 years (95% CI: 0·8, 2·3). This report demonstrates that the incidence of EMD has not increased with the introduction of novel agents and stem cell transplantation. The most common EMD presentations in the relapsed setting were liver and pleural fluid. The presence of CD44 and CXCR4 expression may represent new markers of EMD that warrant further investigation."
Reference:
Weinstock, M, et al, "Incidence and clinical features of extramedullary multiple myeloma in patients who underwent stem cell transplantation," British Journal of Haematology, June 2015 (abstract)
As I read that, 76% of the patients who were diagnosed with extramedullary disease developed it after their transplant. That would be ~6.3%. So there is risk of the development of post-transplant extramedullary disease, but it doesn't seem like a terribly high risk. The statement that the incidence of EMD has not increased with the use of novel agents and transplants would seem to indicate that the transplant procedure itself does not promote its occurrence.
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Mike F - Name: Mike F
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: May 18, 2012
- Age at diagnosis: 53
Re: Aggressive myeloma post autologous stem cell transplant
Thank you very much for this reference, Mike F. That is exactly the kind of information I was looking for.
I very much appreciate your post.
I very much appreciate your post.
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
Re: Aggressive myeloma post autologous stem cell transplant
Nice reference, Mike. Thanks.
MrP - Multibilly referenced a study similar to the one mentioned by Mike in this forum posting.
You may want to check it out. Also, if you haven't seen it already, the editorial that accompanies the study Mike referenced has some useful background information:
Blade, J, et al, "Extramedullary disease in multiple myeloma in the era of novel agents," British Journal of Haematology, 2015 (full text of article)
MrP - Multibilly referenced a study similar to the one mentioned by Mike in this forum posting.
You may want to check it out. Also, if you haven't seen it already, the editorial that accompanies the study Mike referenced has some useful background information:
Blade, J, et al, "Extramedullary disease in multiple myeloma in the era of novel agents," British Journal of Haematology, 2015 (full text of article)
Re: Aggressive myeloma post autologous stem cell transplant
You may want to review this article on extramedullary disease as it relates to allogeneic transplant patients.
Vincent, L, et al, "Factors influencing extramedullary relapse after allogeneic transplantation for multiple myeloma," Blood Cancer Journal, 2015 (full text of article)
Also note the articles in the reference section of the above article. It contains links to several interesting papers on the subject of extramedullary disease in allogeneic and autologous stem cell transplant patients.
Vincent, L, et al, "Factors influencing extramedullary relapse after allogeneic transplantation for multiple myeloma," Blood Cancer Journal, 2015 (full text of article)
Also note the articles in the reference section of the above article. It contains links to several interesting papers on the subject of extramedullary disease in allogeneic and autologous stem cell transplant patients.
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: Aggressive myeloma post autologous stem cell transplant
Many thanks, TerryH and Multibilly.
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MrPotatohead - Name: MrPotatohead
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: March, 2015
- Age at diagnosis: 65
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