There are two people who have posted recently reporting the development of mutations of myeloma plasma cells. In both cases these were post transplant.
Although we know that myeloma is a clonal disease subject to Darwinian principles of survival, it does seem that it can change into a different genetic type to survive. I think someone on the Beacon wondered whether the advent of novel agents had 'pushed' this development over time.
I wonder if any aggressive treatments or even maintenance might drive these mutations in some people. How many are picked up depends on the frequency with which genetic testings are carried out.
What this does not explain is those cases where someone has reported a 17p deletion which has 'disappeared' on treatment.
Any thoughts on this? If, as with antibiotic resistance, the aggressive treatments for myeloma with longer term exposure to novel agents is responsible for driving the development and growth of aggressive new mutations, not just expansion of existing small clones this seems of concern. These features may be the result of having an incurable disease that needs aggressive treatments to keep under control.
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Re: Development of multiple myeloma mutations
Hello Edna,
If you haven't seen it already, there is a separate thread here in the forum that focuses specifically on many of the issues you've raised in your post. It also has several useful references on the topic, including a link to a very good article that Dr. Gareth Morgan wrote for the Beacon on the evolution of myeloma mutations.
"Clonal heterogeneity & evolution in multiple myeloma" (started March 4, 2015)
I believe that, when tests show that mutations such as a 17p deletion are no longer present in a patient after they previously were present, this only demonstrates that no such mutation could be found with the sensitivity of common testing. It does not mean that there are literally no myeloma cells with the mutation in the patient's body any longer, although that could be the case.
Just as importantly, it does not mean that treatment has eliminated any aspects of the bone marrow microenvironment that could be favorable to the creation of those mutations in the future, even if all such clones have been eliminated.
As for myeloma therapies possibly creating or encouraging new mutations, I believe melphalan is believed to be one such treatment. This came up in discussions of the link between Revlimid and secondary cancers, where further research showed that the risk of such cancers was highest in patients who took Revlimid in combination with melphalan, and somewhat higher in patients who took Revlimid after having been treated with melphalan (e.g., during the stem cell transplant process).
I do think it appropriate to wonder, however, whether long-term therapy with just about any myeloma therapy could increase the risk of mutations developing in myeloma cells. Of course, if the long-term therapy is reducing the number of myeloma cells to minimal numbers, then the total opportunity for such mutations to develop is at the same time being drastically reduced.
If you haven't seen it already, there is a separate thread here in the forum that focuses specifically on many of the issues you've raised in your post. It also has several useful references on the topic, including a link to a very good article that Dr. Gareth Morgan wrote for the Beacon on the evolution of myeloma mutations.
"Clonal heterogeneity & evolution in multiple myeloma" (started March 4, 2015)
I believe that, when tests show that mutations such as a 17p deletion are no longer present in a patient after they previously were present, this only demonstrates that no such mutation could be found with the sensitivity of common testing. It does not mean that there are literally no myeloma cells with the mutation in the patient's body any longer, although that could be the case.
Just as importantly, it does not mean that treatment has eliminated any aspects of the bone marrow microenvironment that could be favorable to the creation of those mutations in the future, even if all such clones have been eliminated.
As for myeloma therapies possibly creating or encouraging new mutations, I believe melphalan is believed to be one such treatment. This came up in discussions of the link between Revlimid and secondary cancers, where further research showed that the risk of such cancers was highest in patients who took Revlimid in combination with melphalan, and somewhat higher in patients who took Revlimid after having been treated with melphalan (e.g., during the stem cell transplant process).
I do think it appropriate to wonder, however, whether long-term therapy with just about any myeloma therapy could increase the risk of mutations developing in myeloma cells. Of course, if the long-term therapy is reducing the number of myeloma cells to minimal numbers, then the total opportunity for such mutations to develop is at the same time being drastically reduced.
Re: Development of multiple myeloma mutations
Cheryl
Yes I read Gareth Morgan's article and am aware of the view some hold that myeloma may not be a single disease, that would explain heterogeneity in responses to treatments. But if the clones can further mutate under pressure from treatment to change, e.g. the usual para-protein used to track the disease changes then that is not what is normally seen when treating patients, except it appears some who were secretory become non secretory.
How important is this? If the newer myeloma targeting drugs are pushing forth new mutations in vivo, during treatment, not just knocking back dominant clones, then this could pose issues in treating the disease. The 'older' chemotherapy is not selective in targeting myeloma plasma cells, so one might not expect such mutations to arise with these, although disease progression / relapse would occur with.clones that survive the treatment.
Just a thought.
Yes I read Gareth Morgan's article and am aware of the view some hold that myeloma may not be a single disease, that would explain heterogeneity in responses to treatments. But if the clones can further mutate under pressure from treatment to change, e.g. the usual para-protein used to track the disease changes then that is not what is normally seen when treating patients, except it appears some who were secretory become non secretory.
How important is this? If the newer myeloma targeting drugs are pushing forth new mutations in vivo, during treatment, not just knocking back dominant clones, then this could pose issues in treating the disease. The 'older' chemotherapy is not selective in targeting myeloma plasma cells, so one might not expect such mutations to arise with these, although disease progression / relapse would occur with.clones that survive the treatment.
Just a thought.
Re: Development of multiple myeloma mutations
Very interesting question, Edna!
I've had discussions about this with a few people, including my myeloma specialist. From what I've read and been told, it does seem like it's possible for treatment to contribute to further mutations in the myeloma clone(s).
A few months ago I heard a talk by two myeloma specialists from the University of Iowa. If my notes are right, they said that patients who do not have del(17p) can acquire that mutation over time. But if you don't initially have t(14;16) or t(14;20), you won't ever acquire those mutations. And that's good news for patients who don't have those transpositions since those are resistant to Velcade, according to the specialists.
I don't understand the specifics of why some types of mutations can develop, but others can't. I wish I did.
I certainly am not an expert on any of this stuff, but I find it hugely interesting.
Mike
I've had discussions about this with a few people, including my myeloma specialist. From what I've read and been told, it does seem like it's possible for treatment to contribute to further mutations in the myeloma clone(s).
A few months ago I heard a talk by two myeloma specialists from the University of Iowa. If my notes are right, they said that patients who do not have del(17p) can acquire that mutation over time. But if you don't initially have t(14;16) or t(14;20), you won't ever acquire those mutations. And that's good news for patients who don't have those transpositions since those are resistant to Velcade, according to the specialists.
I don't understand the specifics of why some types of mutations can develop, but others can't. I wish I did.
I certainly am not an expert on any of this stuff, but I find it hugely interesting.
Mike
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mikeb - Name: mikeb
- Who do you know with myeloma?: self
- When were you/they diagnosed?: 2009 (MGUS at that time)
- Age at diagnosis: 55
Re: Development of multiple myeloma mutations
Hi Mike
I think that with deletions of genes, if you do not have the adverse deletion to begin with it is feasible that the deletion of part of the chromosome could arise later on in the disease pathway, e.g. due to selection pressure from treatment..
The .(14;16) and t(14;20) are translocations not additions or deletions of genetic material. The process by which these arise is during DNA replication and cell division with 'mismatching of chromosome parts' when DNA single strands come together to form a double strand. Once you have this mismatch further cell divisions or clonal expansion of these cells will always give rise to cells with this 'mismatch', so if you did not have it at the stage of diagnosis it is unlikely to develop later. That is how I might see the explanation if your notes are accurate.
.
I think that with deletions of genes, if you do not have the adverse deletion to begin with it is feasible that the deletion of part of the chromosome could arise later on in the disease pathway, e.g. due to selection pressure from treatment..
The .(14;16) and t(14;20) are translocations not additions or deletions of genetic material. The process by which these arise is during DNA replication and cell division with 'mismatching of chromosome parts' when DNA single strands come together to form a double strand. Once you have this mismatch further cell divisions or clonal expansion of these cells will always give rise to cells with this 'mismatch', so if you did not have it at the stage of diagnosis it is unlikely to develop later. That is how I might see the explanation if your notes are accurate.
.
Re: Development of multiple myeloma mutations
Hi Edna,
Thanks for the explanation. That helps me understand things a little better. I guess I'm still not completely sure why a transposition is unlikely to happen at some point after diagnosis, unless transpositions just naturally occur more rarely than deletions.
BTW, there is an opportunity to learn lots more about this topic. EdX is offering MIT's course on Molecular Biology: Transciption and Transposition (https://www.edx.org/course/molecular-biology-part-2-transcription-mitx-7-28-2x) beginning Oct. 27. I'm looking forward to giving it a try (in audit mode) and seeing if I can understand enough of it to keep my head above water.
Mike
Thanks for the explanation. That helps me understand things a little better. I guess I'm still not completely sure why a transposition is unlikely to happen at some point after diagnosis, unless transpositions just naturally occur more rarely than deletions.
BTW, there is an opportunity to learn lots more about this topic. EdX is offering MIT's course on Molecular Biology: Transciption and Transposition (https://www.edx.org/course/molecular-biology-part-2-transcription-mitx-7-28-2x) beginning Oct. 27. I'm looking forward to giving it a try (in audit mode) and seeing if I can understand enough of it to keep my head above water.
Mike
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mikeb - Name: mikeb
- Who do you know with myeloma?: self
- When were you/they diagnosed?: 2009 (MGUS at that time)
- Age at diagnosis: 55
Re: Development of multiple myeloma mutations
Hi Mike
I think it is not that translocations cannot occur later in the disease, but as possibly chance error events rather than selection pressure events it may be more often that in multiple myeloma they occur in that way. Again I am speculating from my scantily remembered knowledge (studied at university 40 years ago),
It is good you are trying to understand if that is helpful to you.
Edna
I think it is not that translocations cannot occur later in the disease, but as possibly chance error events rather than selection pressure events it may be more often that in multiple myeloma they occur in that way. Again I am speculating from my scantily remembered knowledge (studied at university 40 years ago),
It is good you are trying to understand if that is helpful to you.
Edna
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