Hello,
I just finished my third cycle of Velcade, Revlimid, and dexamethasone and received my myeloma panel test results from the last cycle. While they show a reduction in my M-spike, the IgA and IgM are still very low.
Is it possible with immunoparesis at diagnosis to see an improvement in uninvolved immunoglobulin levels from induction therapy? If so, is it something that can be expected, or is it very unusual?
Also, is an improvement only possible with a stem cell transplant?
I want to go off IVIG therapy when induction therapy is completed, but I'm nervous considering these numbers have not changed. My normal IgG has improved from 350 to 650, but I was chronically sick from the immunoparesis before my IgG went so low and I started IVIG.
Thank you!
J
Forums
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jhorner - Name: Magpie
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: 2013
- Age at diagnosis: 49
Re: Immunoparesis - does it go away after treatment?
Hi J,
I have immunoparesis, too. All of my uninvolved immunoglobulins remain at extremely low levels, despite the fact that my kappa free light chains have decreased to almost the level of a complete response after five months of treatment with Kyprolis and Darzalex (I have kappa light chain myeloma).
My oncologist tells me that this is not unusual, and that my immunoglobulins may or may not eventually recover to normal levels; it is in fact quite common for them to never recover, and in many (if not most) cases this does not result in any significant increased susceptibility to infection. But, just in case, I do get monthly IVIG infusions.
As far as I know, having an autologous stem cell transplant does not cure immunoparesis.
All of the above is based on my own experience and conversations with two oncologists. I have no medical training of any kind myself.
I suggest you talk to your own oncologist -- preferably one who has had heavy experience treating multiple myeloma -- for more definitive and extensive information.
Congratulations on the reduction in your M-spike, and continued good luck!
I have immunoparesis, too. All of my uninvolved immunoglobulins remain at extremely low levels, despite the fact that my kappa free light chains have decreased to almost the level of a complete response after five months of treatment with Kyprolis and Darzalex (I have kappa light chain myeloma).
My oncologist tells me that this is not unusual, and that my immunoglobulins may or may not eventually recover to normal levels; it is in fact quite common for them to never recover, and in many (if not most) cases this does not result in any significant increased susceptibility to infection. But, just in case, I do get monthly IVIG infusions.
As far as I know, having an autologous stem cell transplant does not cure immunoparesis.
All of the above is based on my own experience and conversations with two oncologists. I have no medical training of any kind myself.
I suggest you talk to your own oncologist -- preferably one who has had heavy experience treating multiple myeloma -- for more definitive and extensive information.
Congratulations on the reduction in your M-spike, and continued good luck!
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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: Immunoparesis - does it go away after treatment?
Hi Mr. Potatohead,
You wrote:
It does not happen in every case, but one of the benefits of transplantation is the potential for full recovery of immune function.
"Most multiple myeloma patients (85-90%) exhibit immunoparesis at the time of diagnosis. (9) This condition is defined as a reduction in the levels of polyclonal or uninvolved immunoglobulins (Igs). (10) Several mechanisms are thought to be involved in immunoparesis, such as impaired B-cell differentiation related to humoral and cellular immune dysfunction, and the reduction of the quantity of B-lymphocytes due to cytokines produced by myeloma cells (TGF-β). (11) Moreover, it seems that this B-cell suppression is reversible and inversely correlated with disease stage. (12) In fact, the presence of immunoparesis in smoldering myeloma is considered to be a prognostic marker of progression to symptomatic myeloma, (13) and is also associated with adverse outcome in newly diagnosed symptomatic myeloma patients. (9) In the ASCT setting, after high doses of melphalan and the infusion of stem cells, an immune reconstitution is expected, including the reappearance of functional B-lymphocytes and, thereby, the recovery of polyclonal Igs. (14) On this basis, we hypothesized that persistence of immunoparesis after ASCT may predict worse progression or survival in patients with multiple myeloma, similarly to the other, aforementioned markers of immune dysfunction."
Source:
González-Calle, V, et al, "Recovery Of Polyclonal Immunoglobulins One Year After Autologous Stem Cell Transplantation As A Long-Term Predictor Marker Of Progression And Survival In Multiple Myeloma," Haematologica, January 2017 (abstract & full text of article)
In that study 52% had full IgG recovery one year after.
Mark
You wrote:
"As far as I know, having an autologous stem cell transplant does not cure immunoparesis."
It does not happen in every case, but one of the benefits of transplantation is the potential for full recovery of immune function.
"Most multiple myeloma patients (85-90%) exhibit immunoparesis at the time of diagnosis. (9) This condition is defined as a reduction in the levels of polyclonal or uninvolved immunoglobulins (Igs). (10) Several mechanisms are thought to be involved in immunoparesis, such as impaired B-cell differentiation related to humoral and cellular immune dysfunction, and the reduction of the quantity of B-lymphocytes due to cytokines produced by myeloma cells (TGF-β). (11) Moreover, it seems that this B-cell suppression is reversible and inversely correlated with disease stage. (12) In fact, the presence of immunoparesis in smoldering myeloma is considered to be a prognostic marker of progression to symptomatic myeloma, (13) and is also associated with adverse outcome in newly diagnosed symptomatic myeloma patients. (9) In the ASCT setting, after high doses of melphalan and the infusion of stem cells, an immune reconstitution is expected, including the reappearance of functional B-lymphocytes and, thereby, the recovery of polyclonal Igs. (14) On this basis, we hypothesized that persistence of immunoparesis after ASCT may predict worse progression or survival in patients with multiple myeloma, similarly to the other, aforementioned markers of immune dysfunction."
Source:
González-Calle, V, et al, "Recovery Of Polyclonal Immunoglobulins One Year After Autologous Stem Cell Transplantation As A Long-Term Predictor Marker Of Progression And Survival In Multiple Myeloma," Haematologica, January 2017 (abstract & full text of article)
In that study 52% had full IgG recovery one year after.
Mark
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Mark11
Re: Immunoparesis - does it go away after treatment?
Thank you both! Great information. It looks as though the only way to recover your immune system is a stem cell transplant and I was planning on putting that off for salvage therapy.
Unfortunately, my immune dysfunction has been problematic and I have not only had serious infections but I also suffer from "post exertional malaise", which means I get sick from exercise. I really wanted treatment to mean that I could get back to doing the things I enjoy.
Not an easy decision.
Thanks so much again.
J
Unfortunately, my immune dysfunction has been problematic and I have not only had serious infections but I also suffer from "post exertional malaise", which means I get sick from exercise. I really wanted treatment to mean that I could get back to doing the things I enjoy.
Not an easy decision.
Thanks so much again.
J
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jhorner - Name: Magpie
- Who do you know with myeloma?: Myself
- When were you/they diagnosed?: 2013
- Age at diagnosis: 49
Re: Immunoparesis - does it go away after treatment?
Hi Mark,
First of all, I have no excuse for not responding much, much earlier to your post citing a study that showed that about half of a cohort undergoing ASCT recovered from immunoparesis and, in addition, enjoyed significantly superior Progression Free Survival (PFS) and Overal Survival (OS) rates.
However, since you cited the study you referenced in your post, I have read a much more detailed and more recent study based on a much larger sample size, consisting of basically the entire population of Denmark’s multiple myeloma patients (https://www.ncbi.nlm.nih.gov/pubmed/29216227) diagnosed between 2005-2013, and representing a full population cohort of 2,558 individuals. Compare this with the study you cited, which was based on 295 patients who had undergone ASCT.
The first thing that must be said is that these studies have different goals; the Danish study I cited is aimed at determining whether qualitative or quantitative immunoparesis is an independent prognostic factor for either PFS or OS or both, whereas the Spanish study (as I will refer to it) you cited aimed to determine whether those recovering from immunoparesis after ASCT enjoyed benefits in PFS and OS.
The second thing I need to state is that I have no background in statistics whatsoever, apart from what can be imparted by looking up Wikipedia articles on the kinds of tests cited by both studies.
However, and please correct me if you think I have gone astray in the following conclusions, I think:
1. The Danish study failed to find any evidence of the absence of immunoparesis as an independent prognosticator of improved OS, and only inconsistent evidence in its role as an independent prognosticator of improved PFS. The Danish study did not restrict itself to one form of therapy (eg., ASCT), but simply measured PFS and OS across the cohort of everyone in Denmark suffering with multiple myeloma between 2005 and 2013 and evaluated with respect to the presence or absence of immunoparesis at diagnosis.
2. The Spanish study restricts itself to a population of about 300 patients who have undergone ASCT and measures the outcome of their recovery (or lack thereof) from immunoparesis and the effect that recovery, if present, has on PFS and OS when compared to the ASCT patients who did not enjoy a recovery from immunoparesis.
3. There is no evidence from either study that an ASCT by itself is a prerequisite for recovery from immunoparesis. The Danish study appears to say nothing about the impact of various treatments on recovery from immunoparesis, or on rates of PFS and OS among its full population cohort, except to contrast its cohort against that of a Greek study that, because it evaluated patients who had been diagnosed and treated earlier, failed to include many patients who may have had the benefit of treatment with more newly available novel agents.
4. It is unclear, according to both studies (and I believe this continues to be the conventional wisdom), what the mechanism is for immunoparesis, and precisely how immunoparesis does or does not contribute to an increased risk of bacterial infection. Current clinical practice does not call for the immediate initiation of IVIG therapy once immunoparesis has been diagnosed, but does call for it in cases where patients display a proclivity toward frequent, serious infections, whether or not immunoparesis is present (contrary to what an earlier post of mine in this thread suggested, which I now see is wrong).
5. It is also unclear, according to the Danish study, what the relationship is to current standard classifications of one’s response to available multiple myeloma therapies, and the degree of concomitant immunoparesis. Specifically, immunoparesis can exist among those who have exhibited a complete response or only a partial response to myeloma therapy; or, conversely, immunoparesis may be entirely absent in conjunction with only a partial response or complete response to therapy.
Granted the aforementioned handicaps I am suffering from in drawing any conclusions from these studies, it does nevertheless appear to me that the Danish researchers are correct when they say that there is no reliable basis for identifying immunoparesis (qualitative or quantitative) as an independent prognosticator of poorer OS among multiple myeloma, and that the evidence for it as an independent prognosticator of poorer PFS is flawed by contradictory results.
The Danish study also leads me to question the relevance of the Spanish study’s focus on those who underwent an ASCT. It is quite possible that the percentage of those who recovered from immunoparesis would have been the same or perhaps better under different therapy regimens, or that even if that were not the case, different regimens apart from ASCT might yield better criteria for improved PFS and OS because the presence or absence of immunoparesis is just not a good independent prognosticator of either.
First of all, I have no excuse for not responding much, much earlier to your post citing a study that showed that about half of a cohort undergoing ASCT recovered from immunoparesis and, in addition, enjoyed significantly superior Progression Free Survival (PFS) and Overal Survival (OS) rates.
However, since you cited the study you referenced in your post, I have read a much more detailed and more recent study based on a much larger sample size, consisting of basically the entire population of Denmark’s multiple myeloma patients (https://www.ncbi.nlm.nih.gov/pubmed/29216227) diagnosed between 2005-2013, and representing a full population cohort of 2,558 individuals. Compare this with the study you cited, which was based on 295 patients who had undergone ASCT.
The first thing that must be said is that these studies have different goals; the Danish study I cited is aimed at determining whether qualitative or quantitative immunoparesis is an independent prognostic factor for either PFS or OS or both, whereas the Spanish study (as I will refer to it) you cited aimed to determine whether those recovering from immunoparesis after ASCT enjoyed benefits in PFS and OS.
The second thing I need to state is that I have no background in statistics whatsoever, apart from what can be imparted by looking up Wikipedia articles on the kinds of tests cited by both studies.
However, and please correct me if you think I have gone astray in the following conclusions, I think:
1. The Danish study failed to find any evidence of the absence of immunoparesis as an independent prognosticator of improved OS, and only inconsistent evidence in its role as an independent prognosticator of improved PFS. The Danish study did not restrict itself to one form of therapy (eg., ASCT), but simply measured PFS and OS across the cohort of everyone in Denmark suffering with multiple myeloma between 2005 and 2013 and evaluated with respect to the presence or absence of immunoparesis at diagnosis.
2. The Spanish study restricts itself to a population of about 300 patients who have undergone ASCT and measures the outcome of their recovery (or lack thereof) from immunoparesis and the effect that recovery, if present, has on PFS and OS when compared to the ASCT patients who did not enjoy a recovery from immunoparesis.
3. There is no evidence from either study that an ASCT by itself is a prerequisite for recovery from immunoparesis. The Danish study appears to say nothing about the impact of various treatments on recovery from immunoparesis, or on rates of PFS and OS among its full population cohort, except to contrast its cohort against that of a Greek study that, because it evaluated patients who had been diagnosed and treated earlier, failed to include many patients who may have had the benefit of treatment with more newly available novel agents.
4. It is unclear, according to both studies (and I believe this continues to be the conventional wisdom), what the mechanism is for immunoparesis, and precisely how immunoparesis does or does not contribute to an increased risk of bacterial infection. Current clinical practice does not call for the immediate initiation of IVIG therapy once immunoparesis has been diagnosed, but does call for it in cases where patients display a proclivity toward frequent, serious infections, whether or not immunoparesis is present (contrary to what an earlier post of mine in this thread suggested, which I now see is wrong).
5. It is also unclear, according to the Danish study, what the relationship is to current standard classifications of one’s response to available multiple myeloma therapies, and the degree of concomitant immunoparesis. Specifically, immunoparesis can exist among those who have exhibited a complete response or only a partial response to myeloma therapy; or, conversely, immunoparesis may be entirely absent in conjunction with only a partial response or complete response to therapy.
Granted the aforementioned handicaps I am suffering from in drawing any conclusions from these studies, it does nevertheless appear to me that the Danish researchers are correct when they say that there is no reliable basis for identifying immunoparesis (qualitative or quantitative) as an independent prognosticator of poorer OS among multiple myeloma, and that the evidence for it as an independent prognosticator of poorer PFS is flawed by contradictory results.
The Danish study also leads me to question the relevance of the Spanish study’s focus on those who underwent an ASCT. It is quite possible that the percentage of those who recovered from immunoparesis would have been the same or perhaps better under different therapy regimens, or that even if that were not the case, different regimens apart from ASCT might yield better criteria for improved PFS and OS because the presence or absence of immunoparesis is just not a good independent prognosticator of either.
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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: Immunoparesis - does it go away after treatment?
Mr. Potato Head,
Thanks for summarizing those studies. I, too, have immunoparesis despite (or because of) a stem cell transplant.
David
Thanks for summarizing those studies. I, too, have immunoparesis despite (or because of) a stem cell transplant.
David
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Arizonan - Name: Arizonan
- Who do you know with myeloma?: Self
- When were you/they diagnosed?: April 2010
- Age at diagnosis: 54
Re: Immunoparesis - does it go away after treatment?
Thank you, David.
In my case, my levels of uninvolved immunoglobulins were about 25% below normal levels when I was first diagnosed with IgG kappa light chain multiple myeloma in March, 2015.
Since then, they have trended downward, despite periodic rallies that did not seem correlated with improvements in my free light chain levels as measured by the serum test and urinalysis.
Last April I finally had an autologous stem cell transplant after successful, albeit short, remissions achieved with the help of combinations of Kyprolis (carfilzomib) and Cytoxan (cyclophosphamide), followed by Kyprolis and Darzalex (daratumumab).
After the stem cell transplant, my IgM levels improved slightly, but have since collapsed again, along with my IgA levels.
And yet all other indicators – electrophoresis, serum free light chain, and bone marrow biopsy – indicate a stringent complete response.
My metabolic panel is all normal, and my blood counts are as well, except for slight anemia and neutropenia that my oncologist believes are artifacts of my continuing Kyprolis maintenance.
I think there is a lot yet to learn about what myeloma does to the immune system, and the immunoparesis puzzle is certainly a case in point.
In my case, my levels of uninvolved immunoglobulins were about 25% below normal levels when I was first diagnosed with IgG kappa light chain multiple myeloma in March, 2015.
Since then, they have trended downward, despite periodic rallies that did not seem correlated with improvements in my free light chain levels as measured by the serum test and urinalysis.
Last April I finally had an autologous stem cell transplant after successful, albeit short, remissions achieved with the help of combinations of Kyprolis (carfilzomib) and Cytoxan (cyclophosphamide), followed by Kyprolis and Darzalex (daratumumab).
After the stem cell transplant, my IgM levels improved slightly, but have since collapsed again, along with my IgA levels.
And yet all other indicators – electrophoresis, serum free light chain, and bone marrow biopsy – indicate a stringent complete response.
My metabolic panel is all normal, and my blood counts are as well, except for slight anemia and neutropenia that my oncologist believes are artifacts of my continuing Kyprolis maintenance.
I think there is a lot yet to learn about what myeloma does to the immune system, and the immunoparesis puzzle is certainly a case in point.
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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: Immunoparesis - does it go away after treatment?
Nine months after my successful autologous stem cell transplant, my uninvolved immunoglobulins continue to be suppressed (my IgM began to rebound, but is now declining again).
What is now more worrisome is that my involved immunoglobulin, lgG, has joined the trend, and is now well below the normal range (see below).
My oncologist has resumed my IVIG infusions in response, but has no explanation.
All my other numbers are good, except for red blood cell markers – e.g., hemoglobin, after rebounding to 12.9 is now at 11.8 g/dL.
My serum free light chains have ticked up a bit, but are still below the lower bounds for the normal ranges, with the exception of the ratio, which my oncologist attributes to a very low lambda level.
I wonder if anyone has an explanation for these or similar patterns? I am on maintenance with Kyprolis and dex.
Total lgG, Standard Range 700 - 1,600 mg/dL
Sep 07 2017 - 1,130
Sep 25 2017 - 960
Oct 09 2017 - 764
Oct 23 2017 - 1,490
Nov 06 2017 - 1,100
Nov 20 2017 - 933
Dec 04 2017 - 766
Dec 18 2017 - 727
Jan 15 2018 - 497
Jan 29 2018 - 441
What is now more worrisome is that my involved immunoglobulin, lgG, has joined the trend, and is now well below the normal range (see below).
My oncologist has resumed my IVIG infusions in response, but has no explanation.
All my other numbers are good, except for red blood cell markers – e.g., hemoglobin, after rebounding to 12.9 is now at 11.8 g/dL.
My serum free light chains have ticked up a bit, but are still below the lower bounds for the normal ranges, with the exception of the ratio, which my oncologist attributes to a very low lambda level.
I wonder if anyone has an explanation for these or similar patterns? I am on maintenance with Kyprolis and dex.
Total lgG, Standard Range 700 - 1,600 mg/dL
Sep 07 2017 - 1,130
Sep 25 2017 - 960
Oct 09 2017 - 764
Oct 23 2017 - 1,490
Nov 06 2017 - 1,100
Nov 20 2017 - 933
Dec 04 2017 - 766
Dec 18 2017 - 727
Jan 15 2018 - 497
Jan 29 2018 - 441
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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: Immunoparesis - does it go away after treatment?
Mr. PH:
My wife was diagnosed in mid 2015 with lambda light chain multiple myeloma, started treatment in October of 2015. At diagnosis her numbers were IgA 17, IgG 138, and IgM 4. As of last week, her numbers were IgA 8, IgG 205, and IgM <10. Interestingly, she doesn't appear unusual with respect to getting sick. If anything, she's less prone to sickness than other family members are. Since diagnosis, she's had two colds.
With all that being said, I think ones immune system and functionality is very complicated, to say the least. Don't believe that low immunoglobulin levels are in and of themselves a huge deal. If, on the other hand, repeated sickness is common, then a deeper dive would be indicated.
My wife was diagnosed in mid 2015 with lambda light chain multiple myeloma, started treatment in October of 2015. At diagnosis her numbers were IgA 17, IgG 138, and IgM 4. As of last week, her numbers were IgA 8, IgG 205, and IgM <10. Interestingly, she doesn't appear unusual with respect to getting sick. If anything, she's less prone to sickness than other family members are. Since diagnosis, she's had two colds.
With all that being said, I think ones immune system and functionality is very complicated, to say the least. Don't believe that low immunoglobulin levels are in and of themselves a huge deal. If, on the other hand, repeated sickness is common, then a deeper dive would be indicated.
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Gcsi - Name: Brett
- Who do you know with myeloma?: Spouse
- When were you/they diagnosed?: Oct 2, 2015 (MGUS 2002)
- Age at diagnosis: 62
Re: Immunoparesis - does it go away after treatment?
Thank you, Gcsi.
It’s good to know that others are in the same boat.
Like your wife, I am not getting infections despite my low immunoglobulin levels. But I am on two prophylactics in pill form: Bactrim (sulfamethoxazole and trimethoprim) for bacteria, and acyclovir for viruses.
I agree that there is more to susceptibility to pathogens than immunoglobulin levels. In fact, my oncologist, who has a doctorate in immunology in addition to an MD, told me that our understanding of the immune system is still at a rudimentary level.
What sorts of treatment(s) has your wife had? Did she undergo a stem cell transplant – autologous or allogenic?
It’s good to know that others are in the same boat.
Like your wife, I am not getting infections despite my low immunoglobulin levels. But I am on two prophylactics in pill form: Bactrim (sulfamethoxazole and trimethoprim) for bacteria, and acyclovir for viruses.
I agree that there is more to susceptibility to pathogens than immunoglobulin levels. In fact, my oncologist, who has a doctorate in immunology in addition to an MD, told me that our understanding of the immune system is still at a rudimentary level.
What sorts of treatment(s) has your wife had? Did she undergo a stem cell transplant – autologous or allogenic?
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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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