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 ^[1] 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 ^[2] (Thalomid), Velcade ^[3] (bortezomib), and Revlimid ^[4] (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 ^[5]).