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Levels Of Uninvolved Immunoglobulins Linked To Prognosis In Newly Diagnosed Multiple Myeloma

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Published: Mar 24, 2014 4:39 pm

Results of a recent Greek study indicate that levels of a multiple myeloma patient’s “un­in­volved” im­mu­no­glob­u­lins at the time of diag­nosis may have an impact on the patient’s prognosis.

The human body produces a variety of different im­mu­no­glob­u­lins, which are proteins used by the body to fight infections.  In healthy people, the blood levels of the different im­mu­no­glob­u­lins fall within certain known ranges.

Multiple myeloma patients, however, typically overproduce one type of im­mu­no­glob­u­lin, also called the monoclonal (M)-protein, which is found at higher-than-normal levels in a myeloma patients’ blood.

The im­mu­no­glob­u­lins that are not overproduced in a myeloma patient are known as the patient’s “un­in­volved” im­mu­no­glob­u­lins.

In their recent study, the Greek investigators found that myeloma patients who had all un­in­volved im­mu­no­glob­u­lins at normal levels at the time of their myeloma diag­nosis had longer median over­all sur­viv­al (55 months) than patients who did not (42 months).

In addition, patients who had “preserved” (within normal range) un­in­volved im­mu­no­glob­u­lin levels at diag­nosis often did not have risk factors typically linked to a poorer prognosis at diag­nosis — factors such as having advanced-stage myeloma, very high M-protein levels, or kidney failure.

Yet, when the researchers statistically controlled for a range of factors that could affect a patient’s prognosis at diag­nosis, they still found that having normal levels of un­in­volved im­mu­no­glob­u­lins had an independent, favorable impact on patient prognosis.

The researchers note, however, that it is not yet clear why the sup­pres­sion of un­in­volved im­mu­no­glob­u­lins has such an independent impact on the prognosis of multiple myeloma patients.

Background

Multiple myeloma is a cancer of the plasma cells, which produce various types of antibodies that fight infection. These antibodies, also known as im­mu­no­glob­u­lins, are each comprised of two identical heavy chains and two identical light chains. There are five types of heavy chains, abbreviated as IgG, IgA, IgM, IgD, and IgE. There are also two types of light chains, called kappa lambda.

Each plasma cell will produce one type of im­mu­no­glob­u­lin. Normally, people have many types of plasma cells and therefore a variety of im­mu­no­glob­u­lins.  However, multiple myeloma patients typically overproduce a single type of plasma cell.  When this happens, it leads to the overproduction of one im­mu­no­glob­u­lin, also called the M-protein, which accumulates in the blood.

Different types of myeloma are classified according to the type of M-protein that accumulates in the blood.

IgG myeloma is the most common form of the disease. IgA myeloma is the next most common form, followed by IgM myeloma. IgD and IgE myeloma are rare (see related Beacon Weekly Poll).

According to the Greek researchers, sup­pres­sion of un­in­volved im­mu­no­glob­u­lins – a condition also known as immunoparesis – is common in multiple myeloma.

However, the researchers point out that the prognostic significance of this phenomenon has not been extensively studied yet.

They therefore sought to assess how the sup­pres­sion of un­in­volved im­mu­no­glob­u­lins affects prognosis in newly diagnosed multiple myeloma patients. In addition, they also investigated the association between the sup­pres­sion of un­in­volved im­mu­no­glob­u­lins and other disease characteristics.

Study Design

The Greek researchers retrospectively analyzed the data for 1,755 newly diagnosed multiple myeloma patients in the database of the Greek Myeloma Study Group.  Patients were included in the study if they were diagnosed between January 1990 and December 2012 and if information about their pre-therapy im­mu­no­glob­u­lin levels was available.

The median patient age was 67 years.

The majority of patients included in the analysis (57 percent) had IgG myeloma, followed by IgA myeloma (25 percent), light chain myeloma (17 percent), and IgD myeloma (2 percent).

Overall, 38 percent of the patients received treatment with novel agents, such as thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide), as their primary therapy.

The study authors classified a patient’s uninvolved immunoglobulin as suppressed if its level was below the lower limit of the immunoglobulin’s normal range.  The lower limits used were as follows: IgG, 700 mg/dL; IgA, 70 mg/dL;  and IgM, 40 mg/dL.

Study Results

The results show that at least one un­in­volved im­mu­no­glob­u­lin was sup­pressed in 87 percent of patients, and at least two un­in­volved im­mu­no­glob­u­lins were sup­pressed in 65 percent of patients. According to the Greek researchers, these rates are similar to those observed in previous studies.

Immunoglobulin Levels And Other Characteristics At Diagnosis

Suppression of at least one un­in­volved im­mu­no­glob­u­lin was most common in patients with IgA myeloma (92 percent), followed by patients with light chain myeloma (89 percent) and patients with IgG myeloma (84 percent).

It also was more common in patients with advanced-stage myeloma.

Anemia, low platelet counts, and kidney impairment were more common in patients with sup­pressed im­mu­no­glob­u­lins, compared to those with preserved im­mu­no­glob­u­lin levels.

Patients with chromosomal abnormalities also had a higher rate of sup­pressed im­mu­no­glob­u­lins; however, the number of patients for whom information about chromosomal abnormalities was available was comparatively small (16 percent of the over­all sample).

Immunoglobulin Levels And Overall Survival

The researchers found that patients with preserved un­in­volved im­mu­no­glob­u­lins had a better median over­all sur­viv­al (55 months) than patients with sup­pressed un­in­volved im­mu­no­glob­u­lins (42 months).

Among patients who received conventional chemotherapy as their initial therapy, the three-year over­all sur­viv­al was higher in patients with preserved un­in­volved im­mu­no­glob­u­lins (62 percent), compared to those with one or more sup­pressed un­in­volved im­mu­no­glob­u­lins (51 percent).

The same result was seen in patients whose initial treatment included novel agents; in these patients, there was a 79 percent three-year over­all sur­viv­al rate for those with preserved un­in­volved im­mu­no­glob­u­lins, versus 65 percent of patients with sup­pressed un­in­volved im­mu­no­glob­u­lins.

Other factors that were associated with lower over­all sur­viv­al included age at diag­nosis above 65 years, poor kidney function, poor over­all health, treatment that did not include a novel agent, and advanced-stage myeloma.

Even after the researchers controlled for these factors, however, preservation of un­in­volved im­mu­no­glob­u­lins had an independent favorable effect on over­all sur­viv­al.

Immunoglobulin Levels And Progression-Free Survival

To see if patients with preserved im­mu­no­glob­u­lin levels at diag­nosis also had better progression-free sur­viv­al after their initial treatment, the researchers analyzed data from a subset of 500 patients who were treated at a single institution and who were followed for disease progression according to a strict protocol.

Most of these patients had received treatment with novel agents; 12 percent had preserved un­in­volved im­mu­no­glob­u­lins.

The median progression-free sur­viv­al was 25 months for all patients. Patients with preserved un­in­volved im­mu­no­glob­u­lins had significantly longer progression-free sur­viv­al (60 months) than patients with at least one un­in­volved im­mu­no­glob­u­lin (24 months).

Other factors that were associated with shorter progression-free sur­viv­al included age over 65 years, low hemoglobin levels, and advanced disease stage.

For more information, please see the study by Kastritis, E. et al., “Preserved levels of un­in­volved im­mu­no­glob­u­lins are independently associated with favorable outcome in patients with symptomatic multiple myeloma,” Leukemia, March 18, 2014 (preview online) (doi: 10.1038/leu.2014.110) (abstract).

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17 Comments »

  • Multibilly said:

    Thanks for another interesting article Beacon staff!

    In this paper, what actually constitutes “suppression”? Is suppression defined as being below a normal level or instead being in some given lower percentile of a normal range?

    I am IgG type SMM and I have an IgM of 45 (normal range = 40-230 mg/dL)and an IgA of 110(normal = 70-400 mg/dL), respectively. That puts me in the the lower 3% and 12% of the normal ranges for IgM and IgA, respectively. Are these levels considered to be “suppressed”?

  • Myeloma Beacon Staff said:

    That’s a great question, Multibilly. Sorry we forgot to address it directly in the initial version of the article (we’ve since updated the article to include the relevant information). In any case, here’s the answer to your question — straight from the paper:

    “Suppression of the immunoglobulins was defined as a reduction of an uninvolved immunoglobulin below the lower limit of normal, which for IgG was <700 mg/dl, for IgA <70 mg/dl and for IgM was <40 mg/dl)."

    So, based on these definition, your IgM and IgA levels would not have been considered suppressed.

  • Steve said:

    Hmmmm….admittedly I’ve only read the summary description above once, and rather quickly at that….nevertheless it would seem to me that the further along a patient has progressed with their particular disease the more we would expect to see increasing suppression of other immunoglobulin…yes?

    So perhaps what we’ve seen described in this study is that those patients diagonosed earlier in their disease, and thus by definition a certain greater level of uninvolved immunoglobulin, tend to have a better prognosis, i.e., a longer overall survival from the date of diagnosis, than those patients who are diagnosed later in the development of thier disease…yes?

    Am I missing something here regarding the significance of such a conclusion, or, does this study just have a firm grasp of the obvious?

    Thanks…

  • Myeloma Beacon Staff said:

    Hi Steve – Thanks for the questions and discussion of the study’s results.

    The authors make a point in their paper of showing that, as you suggest, suppression of uninvolved immunoglobulins is associated with other signs of more advanced disease. Patients were more likely to have suppressed immunoglobulins, for example, if they were at a more advanced disease stage at diagnosis. And patients who had kidney issues, anemia, or reduced platelet counts, also were more likely to have suppressed uninvolved immunoglobulins.

    So, at one level, the point you’re making is correct. Suppressed uninvolved immunoglobulins at diagnosis are yet another sign of more advanced disease.

    However, a key finding of the study is that, even when you throw all of these measures of advanced disease state into the mix, suppression of uninvolved immunoglobulins still has an independent negative impact on a patient’s prognosis.

    Let’s put it another way. According to the study, if you take two patients with exactly the same signs of advanced disease at diagnosis, but one has suppressed uninvolved immunoglobulins and the other doesn’t, then the one who doesn’t have suppressed uninvolved immunoglobulins will tend to have a better prognosis.

  • Dianem said:

    Hi – interesting article. After reading about the suppression immunglobins I checked out the abnormal ranges from my last blood test. I was diagnosed with MGUS 2.5 years ago (FISH found trisomic 7) and am currently out of range with IgG (1630 mg/dL) and the IgM stated less than 20mg/dL! What are the implications of a suppressed immunglobin M related to MGUS? Do not have any CRAB features and current spike is .9. My oncologist always makes the same comments – keep exercising, eat a healthy diet, and if any symptoms arise to notify her. Thanks, Diane

  • Myeloma Beacon Staff said:

    Hi Diane,

    There is research similar to the article above related to MGUS and the risk of progression to symptomatic myeloma. In fact, two articles last year looked at the issue, although they did so in ways that are slightly different from what the Greek researchers did.

    If you’d like more information, here are the references:

    “Suppression of uninvolved immunoglobulins defined by heavy/light chain pair suppression is a risk factor for progression of MGUS”
    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3691011/ (full text)

    “Involved/uninvolved immunoglobulin ratio identifies monoclonal gammopathy of undetermined significance patients at high risk of progression to multiple myeloma”
    http://onlinelibrary.wiley.com/doi/10.1111/bjh.12679/abstract (abstract)

    Also, as you may know, suppression of one or more uninvolved immunoglobulins (immunoparesis) is one of the factors in the Spanish (PETHEMA) system for categorizing smoldering myeloma patients based on their risk of progression to symptomatic myeloma.

    This article from the 2013 ASH Education Book has more information on the latest research related to MGUS and factors affecting the risk of progression to myeloma:

    “Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies”
    http://asheducationbook.hematologylibrary.org/content/2013/1/478.full (full text)
    (see, especially, the section on “Clinical predictors of progression”)

  • Dianem said:

    Thank you Myeloma Beacon staff. I read the articles and based on my limited understanding, I’m assuming due to the M spike of 0.9, IgG MGUS, a trisomic, no CRAB, and suppressed IgM, it appears I’m in an intermediate risk group for progression. I was initially assessed (bone marrow aspiration) here in AZ by the Scottsdale Mayo 2.5 years ago, and then referred to a general hematologist-oncologist for only blood screenings. Diane

  • Steve said:

    Thank you for the article. However, please assure your readers that one result does not a diagnosis make. I have kappa light chain disease and my lambda levels have bounced around from below normal to well within normal, depending on a host of factors. I am a 7 year survivor – so the lesson is don’t rely on single result.

  • Myeloma Beacon Staff said:

    Thanks for your comment, Steve. Your point about lab values varying is well taken. The issue is mentioned regularly in discussions in the Beacon’s forum. Patients and physicians should be confident in the lab results they have before making any important decisions based on them.

  • Alice said:

    Hi Myeloma Beacon

    What about those cases where the uninvolved immunoglobulins recover to normal range after treatment? Does this improve prognosis?

    I was diagnosed with IgA myeloma with reduced IgG. IgM was and still is normal. Since achieving complete response nearly 3 years ago, my IgG level has slowly increased and is now in normal range, albeit at the lower end. However, I also have kidney amyloidosis and had nephrotic syndrome on diagnosis. My proteinuria has steadily improved too. I’m sure I read somewhere that nephrotic syndrome can cause reduced IgG. So, I’m not sure if my reduced IgG is due to the myeloma per se, or a result of the amyloidosis causing nephrotic syndrome. Confused……

  • Myeloma Beacon Staff said:

    Thanks for your question, Alice.

    In this study, the researchers only looked at the level of uninvolved immunoglobulins at the time of diagnosis. They did not do any analyses to see whether the degree to which suppressed immunoglobulins recover has an impact on prognosis.

    Unfortunately, we’re also unaware if there are any studies that look into that question.

    It does not appear that patients who had amyloidosis in addition to myeloma were excluded from the study.

    (Or, to put it another way, the study seems to have included myeloma patients regardless of whether or not they also had amyloidosis.)

    All that having been said, it’s always a good sign when you have responded well to treatment thus far. We hope that continues to be the case for you!

  • Indrani Dutta said:

    Dear Sir,

    I have been diagnosed as an autoimmune hepatitis patient by doctor of Fortis Anandapur, Kolkata India after having a endoscopic test. A lot of investigations done, but the disease could not be ascertained. However at last doctor have come to conclusion of the aforesaid disease. My IgG have been shown as 26+. Please let me know is it on better side or bad side. Please also suggest how to recover from this disease sooner as I am in the hospital for 1 month 8 days and the high cost is not affordable now for my husband.

    Regards,
    Indrani Dutta

  • Myeloma Beacon Staff said:

    Hello Indrani,

    We’re sorry to hear about your current situation.

    We are not physicians and, in addition, have little experience regarding hepatitis. Thus, you really should seek advice from your physicians in regard to your questions.

    That said, you should know that IgG levels apparently are elevated in many people with autoimmune hepatitis, and, from what we have read, they typically drop back down to normal levels as the hepatitis is treated.

    If the IgG level you provided is from a serum (blood) test, and if the units are g/L (grams/liter), then your value of 26 is, in fact, above the normal range, which is listed as being between 7.23 – 16.85 g/L.

    Best of luck to you.

  • JBH said:

    Hello,

    Thank you for this article and all the links in this thread. I have read them all and while admittedly there are several things that are too complex for me to completely comprehend, it appears as though even with these numerous studies on prognostic indicators and likely hood to progression, the FLC ratio remains the one indicator that qualifies “high risk SMM” and the ability to participate in clinical trials?

    I found it interesting that back in 2003, they considered osteopenia, infection, hyperviscosity and amyloidosis in addition to CRAB as qualifiers for treatable disease and the don’t any longer – with the exception of amyloid. I experience frequent infections, averaging one ever 2 months, in the last year.

    I am IgG Kappa, IgG Lambda (biclonal) and here are my last immunoglobulin results from July 2013.
    Component Results
    Component Value Flag Range & Units Status
    IgG 1500 751 – 1560 mg/dl Final
    IgA 71 (L) 82 – 453 mg/dl Final
    IgM 34 (L) 46 – 304 mg/dl Final

    My current follow up consists of blood work every six months, is this sufficient given the suppressed unaffected immunoglobulins and the results of this study?

    Thank you so much for accepting my comment and questions.

    Best Regards,

    JBH

  • Myeloma Beacon Staff said:

    Hello JBH,

    Thanks for your comment and your feedback regarding the article.

    The question you’ve asked is probably best addressed in the Beacon’s discussion forum given that it focuses heavily on your specific situation.

    Our suggestion would be that you post your question there and, when you do, that you also include additional information (such as your diagnosis history and additional lab results) to help fellow forum participants better understand your current situation.

    Note that it is not necessary to be a registered forum member to post or otherwise participate in the forum.

    Best of luck to you.

  • Paula said:

    I am IgG Kappa and have been smoldering for exactly 6 years. My IgA has been steadily decreasing more than the IgG increase. My IgA was below normal at diagnosis and continues to fall. This really concerned me at the time of my diagnosis but my hematologist at the time (no longer) just blew it off as an incidental finding. I hadn’t thought much more about it but I am going to bring it up to my current hematologist in a couple of weeks at my visit.

  • Myeloma Beacon Staff said:

    Glad you found the article and the comments here helpful, Paula. We appreciate the feedback.