My wife was diagnosed with multiple myeloma about 7 months ago. Her initial BM biopsy included FISH cytogenetics and the report said that she was "positive" for del(p17) and for t(4;14). However, the detailed comments reveal that the corresponding signals were seen in only 6.2% and 8.1-12%, respectively, of about 250 plasma cells examined. If these abnormalities are really present then she should be considered "high risk." Most papers discussing studies of these abnormalities do not specify a threshold for deciding whether an abnormality is present or not, but I found a few that do and they tend to set it around 10%. One paper implied that these anomalies are seen in a small percentage of the plasma cells of healthy people, but that this percentage varies by laboratory.
We have asked my wife's doctors to tell us how important this result is, but they don't seem to know. There appears to be disagreement within her team about whether she should be considered high risk or not. Yet it's very important to know. Can anyone help?
Here's a related theoretical question: I understand that the myeloma plasma cells are "clonal", being all copies of a single abnormal cell that started the disease process. In that case, I would expect to find a given genetic abnormality in either all or none of the myeloma cells. What am I missing here?
For reference, here is the important text from the FISH report:
"... the panel revealed THREE signals for the ATM gene in 18 of 259 cells analyzed (6.9%), ONE signal for the p53 gene in 16 of 259 cells analyzed (6.2%), an FGFR3/IGH fusion signal pattern in 30 of 250 cells (12%) in which 12 of these cells showed the gain of an additional IGH signal, and the gain of 1 to 2 copies of the IGH locus using the IGH/MAF probes which represents the derivative chromosomes produced by the translocation t(4;1) in 20 of 246 cells analyzed (8.1%). These findings are positive for the gain of the ATM locus on the long arm of chromosome 11, the 17p13.1(p53) deletion on the short arm of chromosome 17, and the translocatoin t(4;14)."
Thanks for any help.
Larry
Pasadena, CA
Forums
9 posts
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LarryD - Name: Larry D'Addario
- Who do you know with myeloma?: wife
- When were you/they diagnosed?: September 2012
- Age at diagnosis: 65
Re: FISH: how to tell whether result is significant?
Hi Larry,
You wrote "Here's a related theoretical question: I understand that the myeloma plasma cells are "clonal", being all copies of a single abnormal cell that started the disease process. In that case, I would expect to find a given genetic abnormality in either all or none of the myeloma cells. What am I missing here?"
Unfortunately people with multiple myeloma can have multiple mutations. I have included some references below. For example if 20% of my plasma cells were myeloma and I had 5 different mutations (that are present in different cells) then on average you would expect ~4% of the total for each mutation (clone).
The Mayo clinic guidelines (link below) have set out a Risk Stratification of Active Multiple Myeloma with the currently known genetic mutations.
All the best for you and your wife,
Libby
Risk Stratification (an excerpt from the Mayo clinic guidelines)
It is apparent that multiple myeloma is a very heterogeneous disease, and treating all patients in the same way is too simplistic. Similar to other lymphoproliferative diseases, such as lymphoma, a stratified approach is appropriate to ensure that patients are given therapy that is likely to optimize outcomes and minimize toxic effects.
http://www.mayoclinicproceedings.org/article/S0025-6196(13)00077-3/fulltext#sec1
Research Provides Insight Into Genetic Changes Responsible For Multiple Myeloma (EHA 2012)
By Virginia Li
Published: Jul 2, 2012 10:02 am
Overall, 97 percent of patients had at least two sets of myeloma cells with different genetic mutations at diagnosis. These results suggest that myeloma is not only a heterogeneous disease across patients, but that each patient has heterogeneous disease.
Of the patients who provided multiple DNA samples available, 80 percent demonstrated shifts over time in the amount of myeloma cells with certain genetic mutations. Additionally, 60 percent of patients acquired more chromosomal additions or deletions."
You wrote "Here's a related theoretical question: I understand that the myeloma plasma cells are "clonal", being all copies of a single abnormal cell that started the disease process. In that case, I would expect to find a given genetic abnormality in either all or none of the myeloma cells. What am I missing here?"
Unfortunately people with multiple myeloma can have multiple mutations. I have included some references below. For example if 20% of my plasma cells were myeloma and I had 5 different mutations (that are present in different cells) then on average you would expect ~4% of the total for each mutation (clone).
The Mayo clinic guidelines (link below) have set out a Risk Stratification of Active Multiple Myeloma with the currently known genetic mutations.
All the best for you and your wife,
Libby
Risk Stratification (an excerpt from the Mayo clinic guidelines)
It is apparent that multiple myeloma is a very heterogeneous disease, and treating all patients in the same way is too simplistic. Similar to other lymphoproliferative diseases, such as lymphoma, a stratified approach is appropriate to ensure that patients are given therapy that is likely to optimize outcomes and minimize toxic effects.
http://www.mayoclinicproceedings.org/article/S0025-6196(13)00077-3/fulltext#sec1
Research Provides Insight Into Genetic Changes Responsible For Multiple Myeloma (EHA 2012)
By Virginia Li
Published: Jul 2, 2012 10:02 am
Overall, 97 percent of patients had at least two sets of myeloma cells with different genetic mutations at diagnosis. These results suggest that myeloma is not only a heterogeneous disease across patients, but that each patient has heterogeneous disease.
Of the patients who provided multiple DNA samples available, 80 percent demonstrated shifts over time in the amount of myeloma cells with certain genetic mutations. Additionally, 60 percent of patients acquired more chromosomal additions or deletions."
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LibbyC - Name: LibbyC
- Who do you know with myeloma?: myself
- When were you/they diagnosed?: 2009
- Age at diagnosis: 43
Re: FISH: how to tell whether result is significant?
Libby,
Thanks very much for responding.
LibbyC wrote:
> Unfortunately people with multiple myeloma can have multiple mutations. I
> have included some references below. For example if 20% of my plasma cells
> were myeloma and I had 5 different mutations (that are present in different
> cells) then on average you would expect ~4% of the total for each mutation
> (clone).
Yes, but I think this example is not realistic. FISH is done on bone marrow aspirate from a biopsy. Normally there are zero plasma cells in the bone marrow, so if any are found there then essentially 100% are myeloma cells. Then if there are 5 different types of myeloma involved (due to different mutations), then perhaps 20% of the cells would be of each type.
Besides, I've read that when labs do "control" FISH studies on healthy people, they find ~5% of their plasma cells have the high-risk anomalies of myeloma. But I think this is done using blood rather than bone marrow, otherwise it would be hard to find enough plasma cells to test.
> The Mayo clinic guidelines (link below) have set out a Risk Stratification
> of Active Multiple Myeloma with the currently known genetic mutations.
I've read the Mayo clinic guidelines, but they don't answer my question. They classify risk according to whether the abnormalities are present or not, as if it were a yes-or-no thing. They don't discuss how to define the boundary between "yes" and "no".
Again, thanks for writing.
Best wishes,
Larry
Thanks very much for responding.
LibbyC wrote:
> Unfortunately people with multiple myeloma can have multiple mutations. I
> have included some references below. For example if 20% of my plasma cells
> were myeloma and I had 5 different mutations (that are present in different
> cells) then on average you would expect ~4% of the total for each mutation
> (clone).
Yes, but I think this example is not realistic. FISH is done on bone marrow aspirate from a biopsy. Normally there are zero plasma cells in the bone marrow, so if any are found there then essentially 100% are myeloma cells. Then if there are 5 different types of myeloma involved (due to different mutations), then perhaps 20% of the cells would be of each type.
Besides, I've read that when labs do "control" FISH studies on healthy people, they find ~5% of their plasma cells have the high-risk anomalies of myeloma. But I think this is done using blood rather than bone marrow, otherwise it would be hard to find enough plasma cells to test.
> The Mayo clinic guidelines (link below) have set out a Risk Stratification
> of Active Multiple Myeloma with the currently known genetic mutations.
I've read the Mayo clinic guidelines, but they don't answer my question. They classify risk according to whether the abnormalities are present or not, as if it were a yes-or-no thing. They don't discuss how to define the boundary between "yes" and "no".
Again, thanks for writing.
Best wishes,
Larry
-
LarryD - Name: Larry D'Addario
- Who do you know with myeloma?: wife
- When were you/they diagnosed?: September 2012
- Age at diagnosis: 65
Re: FISH: how to tell whether result is significant?
LarryD wrote:
> Libby,
>
> Thanks very much for responding.
>
> LibbyC wrote:
> > Unfortunately people with multiple myeloma can have multiple mutations. I
> > have included some references below. For example if 20% of my plasma cells
> > were myeloma and I had 5 different mutations (that are present in different
> > cells) then on average you would expect ~4% of the total for each mutation
> > (clone).
>
> Yes, but I think this example is not realistic. FISH is done on bone marrow aspirate
> from a biopsy. Normally there are zero plasma cells in the bone marrow, so if any
> are found there then essentially 100% are myeloma cells. Then if there are 5
> different types of myeloma involved (due to different mutations), then perhaps 20% of
> the cells would be of each type.
>
I'm with Libby on her math in this thread. I would also underscore that she says "on average". In reality, the percentage distribution of the 5 mutations could be quite different, with one or two mutations dominating the mutated population scene. Normal, healthy plasma cells all originate and develop in the bone marrow and coexist with the the mutated myeloma cells, so her description is correct. Upon leaving the marrow as B cells, these plasma cells then develop into fully differentiated plasma cells.
http://www.myeloma.org.au/myeloma/whatismyeloma.aspx
> Libby,
>
> Thanks very much for responding.
>
> LibbyC wrote:
> > Unfortunately people with multiple myeloma can have multiple mutations. I
> > have included some references below. For example if 20% of my plasma cells
> > were myeloma and I had 5 different mutations (that are present in different
> > cells) then on average you would expect ~4% of the total for each mutation
> > (clone).
>
> Yes, but I think this example is not realistic. FISH is done on bone marrow aspirate
> from a biopsy. Normally there are zero plasma cells in the bone marrow, so if any
> are found there then essentially 100% are myeloma cells. Then if there are 5
> different types of myeloma involved (due to different mutations), then perhaps 20% of
> the cells would be of each type.
>
I'm with Libby on her math in this thread. I would also underscore that she says "on average". In reality, the percentage distribution of the 5 mutations could be quite different, with one or two mutations dominating the mutated population scene. Normal, healthy plasma cells all originate and develop in the bone marrow and coexist with the the mutated myeloma cells, so her description is correct. Upon leaving the marrow as B cells, these plasma cells then develop into fully differentiated plasma cells.
http://www.myeloma.org.au/myeloma/whatismyeloma.aspx
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Multibilly - Name: Multibilly
- Who do you know with myeloma?: Me
- When were you/they diagnosed?: Smoldering, Nov, 2012
Re: FISH: how to tell whether result is significant?
The genetic anomalies in Myeloma can be seen throughout the progression- In MGUS, SMM (smoldering) and active multiple myeloma.
The existence of FISH (or cytogenetic) anomalies (high or standard) in MGUS or smoldering does not have bearing on the risk of progression. To date, the predictive tools to estimate the risk of progression is determined by the extent of bone marrow plasma cell, M spike, and SFLC.
The existence of FISH (or cytogenetic) anomalies (high or standard) in MGUS or smoldering does not have bearing on the risk of progression. To date, the predictive tools to estimate the risk of progression is determined by the extent of bone marrow plasma cell, M spike, and SFLC.
-
Dr. Ken Shain - Name: Ken Shain, M.D., Ph.D.
Beacon Medical Advisor
Re: FISH: how to tell whether result is significant?
I probably should clarify a bit my previous statement. Cytogenetic abnormalities are not currently included in the best known approaches to classifying (Mayo and PETHEMA), for example, smoldering myeloma in terms of progression risk. However, it is true that there is recent research suggesting that some abnormalities may be linked to a higher risk of progression. However, these are not, as of yet, included in risk models. If a patient has those abnormalities, I would recommend that he/she be monitored more closely to watch for signs of disease progression.
High risk of progression in the smoldering population is still determined by the Mayo staging (or PETHEMA). But even these two current smoldering staging systems are imperfect and even lack congruity- are not always in agreement. Therefore, it remains critical that we continue to learn more and identify new ways to predict progression, so to better afford our patients the best information about their disease. Hopefully this will continue to have new risk stratification tool to be incorporated in the future.
Along these lines, there is emerging data looking at the treatment of Mayo high risk smoldering myeloma patients (not cytogenetic high risk). The data looks quite promising in terms of PFS (progression free survival) and OS (overall survival) with Revlimid and Dex. Very early data with Carfilzomib, Revlimid, and Dex in the smoldering look very interesting based on response only. However, this too remains to be confirmed and has not been adopted in myeloma care management strategies. We will continue to keep a close eye on these and like clinical trials.
High risk of progression in the smoldering population is still determined by the Mayo staging (or PETHEMA). But even these two current smoldering staging systems are imperfect and even lack congruity- are not always in agreement. Therefore, it remains critical that we continue to learn more and identify new ways to predict progression, so to better afford our patients the best information about their disease. Hopefully this will continue to have new risk stratification tool to be incorporated in the future.
Along these lines, there is emerging data looking at the treatment of Mayo high risk smoldering myeloma patients (not cytogenetic high risk). The data looks quite promising in terms of PFS (progression free survival) and OS (overall survival) with Revlimid and Dex. Very early data with Carfilzomib, Revlimid, and Dex in the smoldering look very interesting based on response only. However, this too remains to be confirmed and has not been adopted in myeloma care management strategies. We will continue to keep a close eye on these and like clinical trials.
-
Dr. Ken Shain - Name: Ken Shain, M.D., Ph.D.
Beacon Medical Advisor
Re: FISH: how to tell whether result is significant?
Dr. Ken Shain wrote:
> The genetic anomalies in Myeloma can be seen throughout the progression- In
> MGUS, SMM (smoldering) and active multiple myeloma.
> The existence of FISH (or cytogenetic) anomalies (high or standard) in MGUS
> or smoldering does not have bearing on the risk of progression.
Dr. Shain,
Thanks for responding.
My question was not about progression from MGUS, since my wife was diagnosed with active multiple myeloma 8 months ago. Ever since her initial BMB, we have been unable to get a good explanation of her FISH results (report quoted in my original post). The question is whether these results imply that she has high-risk disease, justifying more aggressive treatment. In summary:
1. del(17p) detected in 7% of 259 cells
But various authors use higher thresholds:
Drach 1998 (Blood 92:802) used cutoff of 8.6% based on count+3sigma from healthy controls
Dewald 2003 (Br J H 121:287) "upper limit of normal" is 8.5% at 95%CI.
Reece 2009 (Blood 114:522) used cutoff of 10% (>200 scorable required)
Avet-Loiseau 2010 (JCO 28:4630) found no effect on prognosis for del(17p) in <60% of cells, but significant for >60%
Neben 2012 (Blood 119:940) used cutoff of 10%
Chen 2012 (Am J Clin Path 137:208) used cutoff of 10%.
2. t(4:14) detected in 8.1% of 246 cells.
However:
Guitierrez 2007 used cutoff of 8% for various anomalies including t(4;14) based
on healthy controls
Neben 2012 used cutoff of 10% for various anomalies incl t(4;14)
Also, Richardson 2010 (Blood 116:679) suggests that the "normal" range for detection of the MM-important anomalies may be different for each laboratory.
The lab report said that my wife is "positive" for these anomalies, but the literature seems to suggest that her results are actually in the normal range. How can we decide whether she is high risk or not?
Thanks,
Larry
> The genetic anomalies in Myeloma can be seen throughout the progression- In
> MGUS, SMM (smoldering) and active multiple myeloma.
> The existence of FISH (or cytogenetic) anomalies (high or standard) in MGUS
> or smoldering does not have bearing on the risk of progression.
Dr. Shain,
Thanks for responding.
My question was not about progression from MGUS, since my wife was diagnosed with active multiple myeloma 8 months ago. Ever since her initial BMB, we have been unable to get a good explanation of her FISH results (report quoted in my original post). The question is whether these results imply that she has high-risk disease, justifying more aggressive treatment. In summary:
1. del(17p) detected in 7% of 259 cells
But various authors use higher thresholds:
Drach 1998 (Blood 92:802) used cutoff of 8.6% based on count+3sigma from healthy controls
Dewald 2003 (Br J H 121:287) "upper limit of normal" is 8.5% at 95%CI.
Reece 2009 (Blood 114:522) used cutoff of 10% (>200 scorable required)
Avet-Loiseau 2010 (JCO 28:4630) found no effect on prognosis for del(17p) in <60% of cells, but significant for >60%
Neben 2012 (Blood 119:940) used cutoff of 10%
Chen 2012 (Am J Clin Path 137:208) used cutoff of 10%.
2. t(4:14) detected in 8.1% of 246 cells.
However:
Guitierrez 2007 used cutoff of 8% for various anomalies including t(4;14) based
on healthy controls
Neben 2012 used cutoff of 10% for various anomalies incl t(4;14)
Also, Richardson 2010 (Blood 116:679) suggests that the "normal" range for detection of the MM-important anomalies may be different for each laboratory.
The lab report said that my wife is "positive" for these anomalies, but the literature seems to suggest that her results are actually in the normal range. How can we decide whether she is high risk or not?
Thanks,
Larry
-
LarryD - Name: Larry D'Addario
- Who do you know with myeloma?: wife
- When were you/they diagnosed?: September 2012
- Age at diagnosis: 65
Re: FISH: how to tell whether result is significant?
Each lab that runs FISH has a specific threshold that the deem to be positive. If the report indicates it is a positive result, I would consider it positive. Is she truly high risk with low, but positive results? And should she be treated with aggressive therapy?
In my clinic you/she is high risk. I would not want to err on the side of standard in this case. With all the literature you presented it does bring in to question that validity. The lower ranges are more commentary on threshholds/testing. Avet Louseau et al comment on and risk stratification of 60%. It is very appealing data and suggests that those with <60% are not in the same high risk group. I would suggest my clinical experience is different. But all of these risk stratification tools are tools and imperfect. The true answer will be time and treatment. I have patients who are standard risk an do poorly despite these "positive" results.
Aggressive therapy? I would recommend that she be treated with a Bortezomib (Velcade) based therapy. More specifically, Bortezomib, Lenalidomide, Dex. Depending on your wife's age and perfomance status the dosing can be modified to maximize tolerance. It is a bit more aggressive, but generally quite well tolerated. Transplant if she is a candidate, and maintenance with Bortezomib (if she continues to tolerate the medication (or altenatively Lenalidomide (Revlimid)) and not Thalidomide.
Our hope is that your wife's disease course does not take the path of the t(4;14) del17p patient. However, I would consider her high risk and treat her as such.
In my clinic you/she is high risk. I would not want to err on the side of standard in this case. With all the literature you presented it does bring in to question that validity. The lower ranges are more commentary on threshholds/testing. Avet Louseau et al comment on and risk stratification of 60%. It is very appealing data and suggests that those with <60% are not in the same high risk group. I would suggest my clinical experience is different. But all of these risk stratification tools are tools and imperfect. The true answer will be time and treatment. I have patients who are standard risk an do poorly despite these "positive" results.
Aggressive therapy? I would recommend that she be treated with a Bortezomib (Velcade) based therapy. More specifically, Bortezomib, Lenalidomide, Dex. Depending on your wife's age and perfomance status the dosing can be modified to maximize tolerance. It is a bit more aggressive, but generally quite well tolerated. Transplant if she is a candidate, and maintenance with Bortezomib (if she continues to tolerate the medication (or altenatively Lenalidomide (Revlimid)) and not Thalidomide.
Our hope is that your wife's disease course does not take the path of the t(4;14) del17p patient. However, I would consider her high risk and treat her as such.
-
Dr. Ken Shain - Name: Ken Shain, M.D., Ph.D.
Beacon Medical Advisor
Re: FISH: how to tell whether result is significant?
Dr Shain,
Thanks for your very useful reply.
--Larry
Thanks for your very useful reply.
--Larry
-
LarryD - Name: Larry D'Addario
- Who do you know with myeloma?: wife
- When were you/they diagnosed?: September 2012
- Age at diagnosis: 65
9 posts
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