My MGUS was identified in 2008 and has been developing. My bone marrow biopsies identified 5% plasma cells in 2008, 5-10% plasma cells in 2010, and 10-15% plasma cells in June this year, so I now have SMM. There is no indication of end organ damage.
Throughout this period my M spike has increased gradually from 2.2 in 2009 to 2.5 last month.
I do not meet CRAB criteria and no therapy is planned.
In a recent meeting with a blood cancer specialist, he indicated a concern about an upward trend in changes to FGFR3.
There were significant changes in FGFR3 between bone marrow biopsies in 8/2010 and 6/2011. Relevant excerpts from the lab reports are as follows:
August 2010 - One hundred interphase nuclei were examined and revealed a gain in chromosomes 3, 9, & 11, and FGFR3 DNA sequence in 8% to 14%.
June 2011 - One hundred interphase nuclei were examined and revealed gains of chromosome 3 (47%), chromosome 9 (33%), and chromosome 11 (45%). In addition, an extra signal for FGFR3 DNA sequence located at 4p was seen in 33%.
I am planning to get another bone marrow biopsy as a result of this change but I never had time to discuss with the specialist the signficance of this trend.
I did some research but could not find anything I could understand concerning FGFR3.
Does anyone know the significance of these changes in FGFR3?
Is it likely that additional changes in FGFR3 would indicate that therapy is a good idea?
Any information would be appreciated.
Forums
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chinook9 - Name: Brian
- Who do you know with myeloma?: Self
- When were you/they diagnosed?: MGUS 8/2008 SMM 6/2011
- Age at diagnosis: 65
Re: What is the Significance of Changes in FGFR3?
Bortezemib targets FGFR3.
According to this article the chromosomal translocations are prognostic(negative) factors independent of FGFR3 expression. This data may impact your decision to have another test performed.
Article you may find helpful:
"This study analyzed the frequency and clinical significance of t(4;14)(p16;q32) in multiple myeloma (multiple myeloma) among 208 patients with multiple myeloma and 52 patients with monoclonal gammopathy of undetermined significance (MGUS); diagnosed between 1994 and 2001....snip..
......These results indicate a significant clinical impact of the t(4;14) translocation in multiple myeloma that is independent of FGFR3 expression.....snip.... In a recent analysis no difference in survival was observed between FGFR3 expressors and nonexpressors......snip.....In summary, we have shown the frequency of t(4;14) to be 14.9% in our multiple myeloma cohort. The translocation predicts for poor survival and poor response to chemotherapy. The expression of FGFR3, the proposed target gene, is only detected in 74% of patients and does not appear to influence survival."
http://bloodjournal.hematologylibrary.org/content/101/4/1520.long
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IMHO
While I am not a clinician, the take away message seems to be that it is the t(4:14) translocation that is the defining event which results in changes in FGFR3. In that regard, if you are in what has been diagnosed as or they call MGUS or smoldering it would seem to suggest that you will advance quickly to multiple myeloma and when you do you will be diagnosed as having 'advanced' disease as a newly diagnosed multiple myeloma patient..based simply on the chromosomal changes that have transpired while you were progressing from MGUS to smoldering to multiple myeloma.
Current therapeutic guidelines will not recommend therapy however since, as you noted they are based on CRAB. If you have no CRAB, no therapy.
Have you had a PET scan? If not you may wish to do so as it is more sensitive than X-ray and may detect the presence of bone lesions not seen on X-ray, which would make you eligible for therapy. (not that therapy is a desired outcome/goal).
Based on how new tests are able to detect what is happening at the cellular level prior to the arbitrarily defined progression to multiple myeloma based on CRAB. We may see changes in therapeutic recommendations.
For instance, we know that the chromosomal changes that have already transpired are signs of disease progression and aggressive disease in the newly diagnosed multiple myeloma patient that is not consistently responsive to present chemotherapy..could that be because the cellular burden is too great before we start the chemotherapy?
It would be somewhat like how they changed the treatment for HIV from when the Tcell level is 200 and below, to when the Tcell level dropped under 1K. That made a significant difference in the outcome and survival for HIV patients. IOW's they were waiting too long to treat the disease and when they finally intervened therapeutically it was too late, thus many died of AIDS (dropped like flies) in the early 80s. A decade later, David HO changed all that.,,yep..took an entire decade!
The good news is that today HIV is treated as a chronic disease delaying progression to AIDS, MGUS in the future may be treated as a chronic disease delaying progression to multiple myeloma, when there are chromosomal changes seen at the MGUS stage.
Retrospectively, we may learn that MGUS with chromosomal changes should be treated independent of CRAB since it means 'advanced' disease. Based on the fact that we already know that chromosomal changes occur mainly as very late progression events when tumors are becoming more proliferative and less stromal cell dependent. Whereas, CRAB is not prognostic for the pathogenesis or aggressiveness of the disease, chromosomal changes are. CRAB is merely indicative of end organ damage as an outcome of disease pathogenesis, not the disease stage of the tumor and it's aggressiveness or progression stage.
According to this article the chromosomal translocations are prognostic(negative) factors independent of FGFR3 expression. This data may impact your decision to have another test performed.
Article you may find helpful:
"This study analyzed the frequency and clinical significance of t(4;14)(p16;q32) in multiple myeloma (multiple myeloma) among 208 patients with multiple myeloma and 52 patients with monoclonal gammopathy of undetermined significance (MGUS); diagnosed between 1994 and 2001....snip..
......These results indicate a significant clinical impact of the t(4;14) translocation in multiple myeloma that is independent of FGFR3 expression.....snip.... In a recent analysis no difference in survival was observed between FGFR3 expressors and nonexpressors......snip.....In summary, we have shown the frequency of t(4;14) to be 14.9% in our multiple myeloma cohort. The translocation predicts for poor survival and poor response to chemotherapy. The expression of FGFR3, the proposed target gene, is only detected in 74% of patients and does not appear to influence survival."
http://bloodjournal.hematologylibrary.org/content/101/4/1520.long
-----------------
IMHO
While I am not a clinician, the take away message seems to be that it is the t(4:14) translocation that is the defining event which results in changes in FGFR3. In that regard, if you are in what has been diagnosed as or they call MGUS or smoldering it would seem to suggest that you will advance quickly to multiple myeloma and when you do you will be diagnosed as having 'advanced' disease as a newly diagnosed multiple myeloma patient..based simply on the chromosomal changes that have transpired while you were progressing from MGUS to smoldering to multiple myeloma.
Current therapeutic guidelines will not recommend therapy however since, as you noted they are based on CRAB. If you have no CRAB, no therapy.
Have you had a PET scan? If not you may wish to do so as it is more sensitive than X-ray and may detect the presence of bone lesions not seen on X-ray, which would make you eligible for therapy. (not that therapy is a desired outcome/goal).
Based on how new tests are able to detect what is happening at the cellular level prior to the arbitrarily defined progression to multiple myeloma based on CRAB. We may see changes in therapeutic recommendations.
For instance, we know that the chromosomal changes that have already transpired are signs of disease progression and aggressive disease in the newly diagnosed multiple myeloma patient that is not consistently responsive to present chemotherapy..could that be because the cellular burden is too great before we start the chemotherapy?
It would be somewhat like how they changed the treatment for HIV from when the Tcell level is 200 and below, to when the Tcell level dropped under 1K. That made a significant difference in the outcome and survival for HIV patients. IOW's they were waiting too long to treat the disease and when they finally intervened therapeutically it was too late, thus many died of AIDS (dropped like flies) in the early 80s. A decade later, David HO changed all that.,,yep..took an entire decade!
The good news is that today HIV is treated as a chronic disease delaying progression to AIDS, MGUS in the future may be treated as a chronic disease delaying progression to multiple myeloma, when there are chromosomal changes seen at the MGUS stage.
Retrospectively, we may learn that MGUS with chromosomal changes should be treated independent of CRAB since it means 'advanced' disease. Based on the fact that we already know that chromosomal changes occur mainly as very late progression events when tumors are becoming more proliferative and less stromal cell dependent. Whereas, CRAB is not prognostic for the pathogenesis or aggressiveness of the disease, chromosomal changes are. CRAB is merely indicative of end organ damage as an outcome of disease pathogenesis, not the disease stage of the tumor and it's aggressiveness or progression stage.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: What is the Significance of Changes in FGFR3?
Suzierose,
First, I want you to know that you (along with MANY other members of this wonderful site) are quite an inspiration to me!! I have a chemistry background and have done quite a bit of multiple myeloma research since my precious little 71 year old, high energy, STUBBORN, SPUNKY mother was diagnosed at the end of October with multiple myeloma (IgG lambda with FISH detected 13 monosomy and t(4:14) translocation, BUT it PALES in comparison to all you've uncovered, shared, and discussed in such a short time!! Your attitude in facing this formidable enemy is so much like my mother's as well, and I want you to know that you are lifted in my prayers daily (as are all those & their loved ones who face this disease)!
Anyway, I read the fascinating article you linked in this subject, and, aside from the FGFR3 conclusions, does your research lead you to believe that t(4;14) is still indicative of poor prognosis? I've seen "more current" research that suggests newer treatments/drug combinations result in overall survival for t(4;14) patients similar to those who do not have this cytogenetic abnormality.
I am grateful for any input/thoughts!!!
God bless you and your indomitable spirit! =)
Lisa Byland
First, I want you to know that you (along with MANY other members of this wonderful site) are quite an inspiration to me!! I have a chemistry background and have done quite a bit of multiple myeloma research since my precious little 71 year old, high energy, STUBBORN, SPUNKY mother was diagnosed at the end of October with multiple myeloma (IgG lambda with FISH detected 13 monosomy and t(4:14) translocation, BUT it PALES in comparison to all you've uncovered, shared, and discussed in such a short time!! Your attitude in facing this formidable enemy is so much like my mother's as well, and I want you to know that you are lifted in my prayers daily (as are all those & their loved ones who face this disease)!
Anyway, I read the fascinating article you linked in this subject, and, aside from the FGFR3 conclusions, does your research lead you to believe that t(4;14) is still indicative of poor prognosis? I've seen "more current" research that suggests newer treatments/drug combinations result in overall survival for t(4;14) patients similar to those who do not have this cytogenetic abnormality.
I am grateful for any input/thoughts!!!
God bless you and your indomitable spirit! =)
Lisa Byland
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Lisa B. - Name: Lisa B.
- Who do you know with myeloma?: My mother, Barbara Henson
- When were you/they diagnosed?: 10-28-11
- Age at diagnosis: 71
Re: What is the Significance of Changes in FGFR3?
I was diagnosed with MGUS in 2004 by my primary doctor at that time. He sent me to my Oncologist for testing who had me come back every 6 months and then once a year because lab work was coming back good. I had to change to a different primary doctor because of different insurance and the new doctor never even heard of MGUS and what it could lead to and he laughed at me when i told him the full name and joked around about it. Well in Sept. 2009 i was diagnosed with PCL/Mulitple Myeloma. I now have a new primary doctor who fully understands my disease and monitors me very well. I didn't have a laptop back then and i didn't fully understand everything about MGUS. Luckily, at my work i took out a cancer policy in 2005 and now i get money reimbursed to me for different test, lab work, chemo, and having my transplant. The cancer policy was my very smart move before cancer diagnosis. Everyone, once you are diagnosed with MGUS take out a cancer policy because it sure does help in the future!
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texas-tea13 - Name: Steve
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: 09/19/2009
- Age at diagnosis: 59
Re: What is the Significance of Changes in FGFR3?
HI Lisa!
Thanks for the complimentary feedback. And I especially thank you for the much needed prayers.
I know it was easy to overlook, I did note in first sentence of post to Chinook9 that bortezomib was effective vs. FGFR3..here is more:
Bortezomib has been found to be active against the t4:14 chromosomal change which has been considered a negative prognostic factor.
"A few studies showed that patients with t(4;14) may benefit from the use of bortezomib as either induction therapy or long-term treatment.[43–45] In some of these studies, the long-term use of bortezomib totally overcame the poor prognosis associated with t(4;14).[43,44]"
http://www.medscape.org/viewarticle/750721_4
43 San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:906–917.
44. Pineda-Roman M, Zangari M, Haessler J, et al. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol 2008;140:625–634.
Thanks for the complimentary feedback. And I especially thank you for the much needed prayers.
I know it was easy to overlook, I did note in first sentence of post to Chinook9 that bortezomib was effective vs. FGFR3..here is more:
Bortezomib has been found to be active against the t4:14 chromosomal change which has been considered a negative prognostic factor.
"A few studies showed that patients with t(4;14) may benefit from the use of bortezomib as either induction therapy or long-term treatment.[43–45] In some of these studies, the long-term use of bortezomib totally overcame the poor prognosis associated with t(4;14).[43,44]"
http://www.medscape.org/viewarticle/750721_4
43 San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med 2008;359:906–917.
44. Pineda-Roman M, Zangari M, Haessler J, et al. Sustained complete remissions in multiple myeloma linked to bortezomib in total therapy 3: comparison with total therapy 2. Br J Haematol 2008;140:625–634.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: What is the Significance of Changes in FGFR3?
Thank you so much! I have much more reading to do! 
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Lisa B. - Name: Lisa B.
- Who do you know with myeloma?: My mother, Barbara Henson
- When were you/they diagnosed?: 10-28-11
- Age at diagnosis: 71
Re: What is the Significance of Changes in FGFR3?
Dear all,
The changes in FGFR3 in terms of chinook9's situation are not the same as the 4;14 translocation. Chinook9 has hyperdiploid plasma cells. What that means is that he has extra copies of several chromosomes in his myeloma cells, including the portion of chromosome that contains the FGFR3 gene (the short arm of chromosome 4). Extra copies of chromosomes are common in MGUS and smoldering myeloma. In symptomatic myeloma, patients with "hyperdipoid" disease have a better prognosis. There is nothing on chinook9's report below to suggest that a 4;14 translocation is present. The fact that the percentages of cells with extra copies of chromosomes has increased from 2010 to 2011 is a function of more plasma cells being present in the biopsy. I think this is what has grabbed the attention of his/her hematologist/oncologist.
As such, the presence of the FGFR3 finding in chinook9's case should have no bearing on the likelihood that this progresses, the prognosis, or the need for earlier treatment.. If anything, the cytogenetic features are favorable rather than unfavorable. The smoldering myeloma should be monitored closely, especially in light of the fact that the "M spike" has increased as have the numbers of plasma cells on the biopsy (as assessed by the increased proportion of cells with extra chromosomes and the higher levels of plasma cells on the biopsy as assessed by other means)..
I hope this helps. Good luck!
Pete V.
The changes in FGFR3 in terms of chinook9's situation are not the same as the 4;14 translocation. Chinook9 has hyperdiploid plasma cells. What that means is that he has extra copies of several chromosomes in his myeloma cells, including the portion of chromosome that contains the FGFR3 gene (the short arm of chromosome 4). Extra copies of chromosomes are common in MGUS and smoldering myeloma. In symptomatic myeloma, patients with "hyperdipoid" disease have a better prognosis. There is nothing on chinook9's report below to suggest that a 4;14 translocation is present. The fact that the percentages of cells with extra copies of chromosomes has increased from 2010 to 2011 is a function of more plasma cells being present in the biopsy. I think this is what has grabbed the attention of his/her hematologist/oncologist.
As such, the presence of the FGFR3 finding in chinook9's case should have no bearing on the likelihood that this progresses, the prognosis, or the need for earlier treatment.. If anything, the cytogenetic features are favorable rather than unfavorable. The smoldering myeloma should be monitored closely, especially in light of the fact that the "M spike" has increased as have the numbers of plasma cells on the biopsy (as assessed by the increased proportion of cells with extra chromosomes and the higher levels of plasma cells on the biopsy as assessed by other means)..
I hope this helps. Good luck!
Pete V.
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Dr. Peter Voorhees - Name: Peter Voorhees, M.D.
Beacon Medical Advisor
Re: What is the Significance of Changes in FGFR3?
Thanks for that distinction Dr. Voorhees.
You point out that MGUS patients can have changes in FGFR3 withOUT a t 4:14 translocation. The clue being an 'extra signal of FGFR " reported on FISH test vs. a report of deletion/gain on chromosome 14? I am still trying to sort out the FISH jargon..sometimes it says amplification and it is not good..but extra signal is positive or does it depend on what the extra signal/amplification is of?...details, details..
If you have a chance would you please give feedback on a few questions.
Is it common to see changes in FGFR3 without t4:14 translocation? i.e. what is frequency of occurence in MGUS/smoldering population.
Why was his oncologist concerned about the increases when hyperdiploidy is a good thing?
As, you have indicated this is an extra copy vs. a translocation and portends a favorable cytogentic change...what does that mean in terms of the rising M spike? Does the rise in FGFR3 indicate these copies are increasing to wage cellular battle vs the multiple myeloma cell and inhibiting progression to multiple myeloma?
Are there still extra or monoclonal proteins crowding out the albumin? Does the extra copy afford a protective effect, independent of the rise in the M spike?
Just curious.
You point out that MGUS patients can have changes in FGFR3 withOUT a t 4:14 translocation. The clue being an 'extra signal of FGFR " reported on FISH test vs. a report of deletion/gain on chromosome 14? I am still trying to sort out the FISH jargon..sometimes it says amplification and it is not good..but extra signal is positive or does it depend on what the extra signal/amplification is of?...details, details..
If you have a chance would you please give feedback on a few questions.
Is it common to see changes in FGFR3 without t4:14 translocation? i.e. what is frequency of occurence in MGUS/smoldering population.
Why was his oncologist concerned about the increases when hyperdiploidy is a good thing?
As, you have indicated this is an extra copy vs. a translocation and portends a favorable cytogentic change...what does that mean in terms of the rising M spike? Does the rise in FGFR3 indicate these copies are increasing to wage cellular battle vs the multiple myeloma cell and inhibiting progression to multiple myeloma?
Are there still extra or monoclonal proteins crowding out the albumin? Does the extra copy afford a protective effect, independent of the rise in the M spike?
Just curious.
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: What is the Significance of Changes in FGFR3?
OK, I was able to find this additional information, it is not specific to FGFR3 but does address the hyperdiploidy occurence for multiple myeloma:
"Overall, multiple myeloma is divided into two main genetic groups: (1) the hyperdidploid group (H-MM), which can be defined mainly by the gain of odd chromosomes 3, 5, 7, 9, 11, 15, 19, and 21 and (2) the nonhyperdiploid group (NH-MM), characterized by the presence of chromosomal translocations involving the immunoglobulin H (IgH) locus with several chromosomal partners (4, 8, 11, 16)".....snip.....H-MM is more common among males, has a higher incidence of multiple myeloma bone disease, and carries a more favorable outcome [6] (Table 1). Among patients with H-MM, 13 deletion and chromosome 1 abnormalities have not apparent prognostic significance but the presence of deletions of 17p13 in remains an important prognostic factor. In addition, a study showed that most of the prognostic value of H-MM was related to the gain of chromosome 5 "
http://www.hindawi.com/journals/gri/2011/798089/
Table ONE:
http://www.hindawi.com/journals/gri/2011/798089/tab1/
----------
It looks like Chinook9 had the GOOD gains of 3,9,11...
"Overall, multiple myeloma is divided into two main genetic groups: (1) the hyperdidploid group (H-MM), which can be defined mainly by the gain of odd chromosomes 3, 5, 7, 9, 11, 15, 19, and 21 and (2) the nonhyperdiploid group (NH-MM), characterized by the presence of chromosomal translocations involving the immunoglobulin H (IgH) locus with several chromosomal partners (4, 8, 11, 16)".....snip.....H-MM is more common among males, has a higher incidence of multiple myeloma bone disease, and carries a more favorable outcome [6] (Table 1). Among patients with H-MM, 13 deletion and chromosome 1 abnormalities have not apparent prognostic significance but the presence of deletions of 17p13 in remains an important prognostic factor. In addition, a study showed that most of the prognostic value of H-MM was related to the gain of chromosome 5 "
http://www.hindawi.com/journals/gri/2011/798089/
Table ONE:
http://www.hindawi.com/journals/gri/2011/798089/tab1/
----------
It looks like Chinook9 had the GOOD gains of 3,9,11...
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suzierose - Name: suzierose
- When were you/they diagnosed?: 2 sept 2011
Re: What is the Significance of Changes in FGFR3?
Dear Suzierose,
I am not sure that the exact frequency of extra FGFR3 signals by FISH testing is known. However, in this case, based on the numerous additional extra signals on other chromosomes, it is almost certainly a function of hyperdiploidy. The increased percentage of cells with hyperdiploidy in this patient's marrow is a function of an increased proportion of plasma cells in the marrow -- cytoplasmic Ig FISH or plasma cell purification was likely not done in this case if I had to bet. The FISH was probably done on the whole marrow population. The fact that the M spike is rising and the number of plasma cells increasing means that the smoldering myeloma is progressing and needs to be watched closely. There is a good chance that treatment will eventually be required. I just wanted to point out that this patient does not have a 4;14 translocation.
I hope this helps!
Pete V.
I am not sure that the exact frequency of extra FGFR3 signals by FISH testing is known. However, in this case, based on the numerous additional extra signals on other chromosomes, it is almost certainly a function of hyperdiploidy. The increased percentage of cells with hyperdiploidy in this patient's marrow is a function of an increased proportion of plasma cells in the marrow -- cytoplasmic Ig FISH or plasma cell purification was likely not done in this case if I had to bet. The FISH was probably done on the whole marrow population. The fact that the M spike is rising and the number of plasma cells increasing means that the smoldering myeloma is progressing and needs to be watched closely. There is a good chance that treatment will eventually be required. I just wanted to point out that this patient does not have a 4;14 translocation.
I hope this helps!
Pete V.
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Dr. Peter Voorhees - Name: Peter Voorhees, M.D.
Beacon Medical Advisor
12 posts
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