[Cheryl G]

Re: Suppression of uninvolved immunoglobulins / HLC pairs?

by Cheryl G on Sat Apr 25, 2015 3:35 pm

Hi Helen,

I am glad to see that you're getting a lot of really helpful feedback.

I just noticed that, in one of your first postings, you mentioned that your M-spike reports always come back with the notation " Polyclonal immunoglobulins are suppressed."

As Terry mentioned, polyclonal immunoglobulins are your healthy immunoglobulins. So, as it turns out, your M-spike reports have been telling you for a while what you just confirmed by calculating and listing out the estimates of your "healthy" IgG levels -- they're suppressed below the normal range.

Apparently, this is not uncommon in people with MGUS. Having one or more immunoglobulins that is below normal is called "immuno­paresis." In one study of MGUS patients, it occurred in half of the patients. Another study that looked at a general sample of people over the age of 65, and identified people with MGUS within that sample, found that 70 percent of the people with MGUS had immunoparesis.

There's a short thread about immunoparesis here in the forum, which was started by someone with MGUS. In it, Dr. Libby has some feedback which may be helpful for you:

"It is quite common for myeloma patients to have reduced serum immunoglobulins. In general there are no consequences but there can be. This is termed "immuno­paresis". Patients with low serum immunoglobulins are at in­creased risk for in­fec­tions (pneu­monia etc). Usually we do not treat the low immuno­globulin level (with monthly in­fusions of immuno­globulins) unless a patient has repeated bacterial in­fec­tions like pneu­monia, sinusitis or bronchitis."

(From the forum discussion "Immunoparesis", started Nov 16, 2012)

Hope this helps a bit. Basically, I think the suppressed "healthy" IgG is something for you to be aware of, but it's probably not something you have to worry about unless you find yourself getting sick very frequently.

Good luck!

References:

M Pizzuti et al, "Association Between Immunoparesis and a Skewed Free Light Chain (FLC) Ratio: A New Prognostic Factor Of Progression from MGUS To Multiple Myeloma?" Blood, Nov 2013 (ASH abstract)

BM Cherry et al, "Immunoparesis and monoclonal gammopathy of undetermined significance are disassociated in advanced age," American Journal of Hematology, Feb 2013 (full text of article)

[Helen L]

Re: Suppression of uninvolved immunoglobulins / HLC pairs?

by Helen L on Sat Apr 25, 2015 6:12 pm

Thanks Cheryl and Toni for those informative articles.

It is good to know that immunoparesis is so common. I could not find any studies that said having a reduced "involved" immunoglobulin is a risk factor for progression. I did, however, find articles that say having a reduced "non-involved" immunoglobulin is a significant risk factor for progression to multiple myeloma or lymphoid disorder. (Although another study found it wasn't).

"Three factors were significantly associated with progression: abnormal free light-chain (FLC) ratio (<0.26 or >1.65), M-protein concentration (≥1.5 g/dL), and reduction of 1 or 2 noninvolved immunoglobulin isotype levels (immunoparesis)."

Source: I Turesson et al, "Monoclonal gammopathy of undetermined significance and risk of lymphoid and myeloid malignancies: 728 cases followed up to 30 years in Sweden," Blood, Jan 2014 (full text of article)

"Extensive bone marrow (BM) infiltration, abnormal free light chain (FLC) ratio and serum monoclonal (M)-protein 3 gr/dl were the most significant factors for progression, whereas the type of heavy (IgG vs IgA) or light chain or immunoparesis of the uninvolved immunoglobulins were not. "

Source:E Kastritis et al, "Extensive bone marrow infiltration and abnormal free light chain ratio identifies patients with asymptomatic myeloma at high risk for progression to symptomatic disease. Leukemia, Nov 2012 (abstract)

I really appreciate knowing that I have immunoparesis, as I can keep an eye on any infections and talk to the doctor if I get sick frequently. I'll also do a bit more digging about through some academic journals.

Thanks again!

[Carol of Eden]

Re: Suppression of uninvolved immunoglobulins / HLC pairs?

by Carol of Eden on Sat May 02, 2015 12:54 pm

Hi Helen,

Apropos to your situation, I have IgG kappa smoldering multiple myeloma (after 4.5 years MGUS) and I, too, seem to have a reduced polyclonal IgG. I discussed this with the "transplant doctor" whom I've seen once (I do not need treatment at this time). He said that the M-protein and the immunoglobulins (IgG,etc.) are determined by different tests, and the results do not completely mesh. My takeaway is that the concept is correct (total Ig = polyclonal Ig + M-spike), however some incompatibility between the tests means that this calc of polyconal Ig is only roughly accurate.

At times my m-spike tested HIGHER than my total IgG, which I think proves that the tests are not entirely compatible. (My M-spike is around 2.40 g/dl, and IgG around 2650.) I must have very little polyclonal IgG, but can't know how much (maybe the HevyLite test would tell?). My on­col­o­gist made sure I got all the pneumonia vaccines. I am being more careful to avoid in­fec­tions, and whenever I get a respiratory infection I take antibiotics, as I seem to get secondary in­fec­tions readily. These measures have improved my quality of life and energy level, despite being mildly anemic.

I recently saw a study that found immune-compromised individuals roughly doubled their re­sponse to the flu vaccine by being vaccinated twice, and I may discuss this with my doctor.

[Helen L]

Re: Suppression of uninvolved immunoglobulins / HLC pairs?

by Helen L on Sun May 03, 2015 12:45 pm

Hi Carol,

I am sorry to hear your MGUS moved to smoldering. I hope it will remain there and not progress further.

Your transplant doctor did a good job of explaining the issue around using this calculation. Also, if your total IgG is sometimes < than your M-Spike, then that clinches it! Perhaps when the doctors on this forum have used that calculation, then the tests they were specifically referring to were performed at the same lab using the same testing method.

I wonder if you have any auto-immune problems with your low polyclonal IgG? I am worried about having vaccinations because of this very issue.

I keep having 'attacks' whenever I battle any type of cold or even if I am just worn down. These are always attacks of sudden and painful inflammation. I have just dealt with three weeks of Blepharitis (inflammation of the eyelids) and the bottom of my right foot has been inflamed now for over a month. I worry that a vaccination will cause something (I just never know what unpleasant thing will happen to me next).

The next time I see my rheumatologist, I will ask her about vaccinations. For some strange reason, I have not had any infections that I know of - although maybe all these inflammation problems are being caused by an unresolved infection.

Thanks for sharing, Carol.

[Carol of Eden]

Re: Suppression of uninvolved immunoglobulins / HLC pairs?

by Carol of Eden on Tue May 05, 2015 1:25 am

And I hope you never find yourself in SMM-land, Helen. Still, one adjusts and comes to terms, and having the companionship of fellow travelers here is a great comfort. In fact, I find this journey fascinating.

My tests were all from the same lab. I have no actual knowledge of why the results differ and seem to not make sense (if M-spike can be higher than total Ig), but have accepted it as simply beyond my present technical level. I theorize, but not worth sharing.

I do not have any serious known autoimmune issues, though some food intolerances, a long-ago case of iritis, and other things have made me wonder. I do not have problems like rheu­ma­toid arthritis, thankfully (sister does).

I used to avoid vaccinations as I wondered if they introduced some un-natural materials into the body and might cause more harm than good. But now that I know my immune system is so compromised, and have suffered the quality-of-life problems of having a respiratory infection last 2 months and set back my overall health, I decided that it makes more sense to get the vaccinations. I am not at all sure they are very effective, as my ability to produce antibodies is apparently limited. My health care provider does not offer tests that would confirm how effective the vaccinations are (titer tests for flu / pneumonia vaccines), so I just get them anyway.

People with myeloma seems to have a vulnerability to pneumonia, which is life-threatening, but in your case you may not have such a serious risk. In my case, the "transplant doctor" rec­om­mended I get the pneumonia vaccines, hematologist followed up on it but had not come up with that recommendation previously. I pointed out to my hematologist how little functional IgG I must have – not sure she had figured that out. I don't know if the vaccine rec's were just because I am SMM, or because of the low antibody numbers.

I am sorry you get those attacks of inflammation with colds and being run down. I don't have that and have not thought out the implications, but hopefully your rheumatologist can do so. Do your immunoglobulins get used up fighting your own body? Or is it other immune factors such as T-cells that are involved with autoimmunity?

No vaccine against a cold, but flu and pneumonia: perhaps the question in your case is "do I face greater risk or discomfort by being exposed to an infection, or from the vaccine that would prevent that infection?".

Does the stimulation of your immune system against a virus cause an unintended effect of stimulating an auto-immune reaction?

I understand I am at greater risk for shingles (NOT fun!!), but I cannot get the vaccine as it is a live vaccine. I wish I could have gotten it before I was diagnosed as immune compromised. I think normally it is give only over 60 years old (and I am 56, so never would have qualified). This might be something to discuss with your doctors – to get that now, in case you cannot get it later.

I suspect that my below-normal IgA antibodies might be the reason for many of my in­fec­tions – sinus, bladder, intestinal – as they involve mucous membranes, and I have read that IgA anti­bodies defend against infections of the mucous membranes. If I read your tests correctly, you do not have low IgA.

There are also other components of the immune system such as T-cells and other white cells, so it is not just our antibodies. So complex.

I think we learn a lot from observation of ourselves, over time. Best of luck!

[Dr. Jason Valent]

Re: Suppression of uninvolved immunoglobulins / HLC pairs?

by Dr. Jason Valent on Tue May 05, 2015 9:03 am

The earlier posts are quite correct on the calculation for healthy / normal versus "unhealthy" IgG levels.

The healthy IgG can be calculated as follows:

Total IgG level - M spike = Healthy IgG.

With results from our lab, it takes moving a decimal point in either the total IgG or the M-spike to use the above equation correctly, but that is not an "apples to oranges" difference.

Example:

Suppose a patient has a total IgG level of 2500 mg/dL and an M-spike of 1.5 g/dL. In mg/dL, the M-spike of 1.5 g/dL is 1500 mg/dL, so

Total IgG 2500 mg/dL - M-spike 1500 mg/dL = Healthy IgG of 1000 mg/dL

In g/L, the same equation looks like this:

Total IgG 25 g/L - 15 g/L M-spike = Healthy IgG 10 g/L

because 1 g/dL = 10 g/L.

These calculations are important particularly if patients are subject to frequent or severe in­fections. Sup­ple­mental IgG can be given (IVIG infusions) to help patients who experience frequent or life threatening infection. I tend to use a healthy IgG cutoff of 500 mg/dL (5 g/L) to consider sup­ple­menting IVIG for patients with infection complications.

As pointed out in Dr. Hofmeister's posting mentioned above, this does not work as well for IgA myeloma, as the M-spike may overestimate or underestimate the "unhealthy" IgA due to lim­i­ta­tions of the protein electrophoresis test. In these cases, following the total IgA levels may be a more accurate representation of the disease response. Using the immunofixation electro­phoresis will determine when a evaluation for a complete response is necessary.

I hope this helped and does not add more confusion.

[Helen L]

Re: Suppression of uninvolved immunoglobulins / HLC pairs?

by Helen L on Wed May 06, 2015 12:05 pm

Thanks so much for the replies!

Dr. Valent - Thanks for providing the cut-off value that you use when deciding whether to give sup­plemental IgG. You mention that you would give supplemental IgG if a person is ex­peri­encing frequent or life-threatening infections and a total IgG under 5 g/L. Since I have not had frequent infections (that I know of), but I do have healthy IgG < 5g/L, I suppose I don't need to follow up on this ...

My next appointment with the hematologist / oncologist is one year away.

My "healthy" IgG results for the past year are (achieved from subtracting my M-Spike from my total IgG):

4.5 g/L (April 2015)
2.7 g/L
2.9 g/L
2.6 g/L
1.2 g/L
3.9 g/L (Jan 2014)

The reference range is 6.7 - 15.2 g/L.

I am really confused about whether I should be doing something about this - or just have a wait-and-see approach.

[Cheryl G]

Re: Suppression of uninvolved immunoglobulins / HLC pairs?

by Cheryl G on Tue Jun 16, 2015 10:42 am

Hi Helen,

I've been wanting to get back to you about your last question for a while. I'm so sorry I didn't do so until now.

As far as I know, there really isn't much that can be done about low levels of "healthy" IgG except for intravenous infusions of immunoglobulin (IVIG). Those infusions are not cheap, however, so I'm not sure how easy it will be for you to get approval to receive it. Also, given how your doctor has been so far, I'm not sure if she will even think it's necessary for you to receive the infusions.

I suspect that all you can really do is be more cautious than usual about avoiding infections, since the low level of the healthy IgG probably makes you more susceptible to infections.

Good luck!