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