Findings from a recent study indicate that a history of certain in­fec­tions is as­so­ci­ated with an increased risk of a person eventually developing multiple myeloma.

The study is based on data for more than 15,000 U.S. myeloma patients and 200,000 people from the general U.S. population.  It did not include in its analy­sis in­fec­tions that myeloma patients had less than a year prior to their di­ag­no­sis.

The in­ves­ti­ga­tors found that people in the study who were eventually di­ag­nosed with multiple myeloma were more likely to have had respiratory tract in­fec­tions or shingles one year or more prior to their di­ag­no­sis than individuals of a similar age and gender from the general population.

In addition, a history of in­fec­tions was as­so­ci­ated with a higher risk of being di­ag­nosed with myeloma even when the researchers looked only at in­fec­tions that occurred several years prior to a patient being di­ag­nosed with myeloma.

These findings – particularly the significance of in­fec­tions several years prior to a myeloma di­ag­no­sis – suggest that in­fec­tion may play a role in the development multiple myeloma, the in­ves­ti­ga­tors explain. Bac­ter­ia or viruses that cause in­fec­tions may play a direct role in bringing about the onset of myeloma, or their impact may be indirect, perhaps through the in­flam­ma­tions they cause.

The authors also note, however, that their findings may also be a reflection of myeloma, even in its earliest stages, compromising a patient's immune system, making the patient more likely to develop in­fec­tions.  The in­fec­tions "may instead be a manifestation of an underlying immune disturbance present several years be­fore multiple myeloma di­ag­no­sis and thereby part of the natural history of disease progression."

Background

It is well known that patients with multiple myeloma are more susceptible to in­fec­tions due to their weak­ened immune systems. Cancerous myeloma cells accumulate in a patient's bone marrow, where they limit production of healthy red and white blood cells.  Since white blood cells are responsible for the pro­duc­tion of antibodies, the body’s ability to fight pathogens is limited.

It is less clear whether a long-term history of certain in­fec­tions is as­so­ci­ated with a person having an in­creased risk of developing multiple myeloma.

On the one hand, there have been a number of studies that show that a history of pneumonia is as­so­ci­ated with a higher risk of developing both multiple myeloma and its precursor disease monoclonal gammopathy of undetermined significance (MGUS).

On the other hand, results for a number of other types of in­fec­tions, and their potential association with developing myeloma, are less consistent -- in part because previous studies have been limited by small sample sizes.

Thus, the authors of the current study decided to analyze records for very large samples of multiple myeloma patients and healthy individuals to determine if there was an association between a history of in­fec­tions and the development of multiple myeloma.

Study Design

For their study, the in­ves­ti­ga­tors from Queens University in Belfast, Northern Ireland and the U.S. National Cancer Institute (NCI) drew on data from two different sources.

The first was the NCI's SEER-Medicare database.  The NCI created the SEER-Medicare dataset by linking patient records from the Surveillance, Epidemiology, and End Results (SEER) database, which is a key source of U.S. cancer statistics, with beneficiary claims records from the U.S. Medicare program -- the federally funded health insurance system for U.S. citizens 65 years of age and older.

The SEER-Medicare database provided information on 15,318 multiple myeloma patients who were di­ag­nosed between 1992 and 2005, and who were 66 years of age or older at the time of their di­ag­no­sis. Ap­prox­i­mate­ly two-thirds of the myeloma patients (64 percent) were di­ag­nosed between 1999 and 2005.

The Medicare data in the SEER-Medicare database enabled the researchers to determine how often each patient in the database visited a hospital or physician's office due to an in­fec­tion in the years prior to the patient being di­ag­nosed with myeloma.

The second source of data the researchers drew upon was a companion database of Medicare beneficiary claims that the NCI developed specifically to enable comparisons with the SEER-Medicare database. This companion Medicare database includes records for a randomly selected sample of 5 percent of all Medicare beneficiaries over the relevant period.

From the comparison Medicare database, the researchers selected claims for 200,000 people matched to the myeloma patients in the SEER-Medicare database based on age and gender.

The median ages of the patients in the SEER-Medicare dataset and the matched Medicare dataset were both between 75 to 79 years old.  The in­ves­ti­ga­tors recognize in their article that the older age of the patients in their study may limit the degree to which their results can be generalized to all myeloma patients.  In the U.S., the median age of a myeloma patient at di­ag­no­sis is 69.

The study's analysis was restricted to in­fec­tions that occurred more than 13 months before a myeloma patient's di­ag­no­sis. The researchers looked at both the entire available history of a patient's in­fec­tions 13 or more months prior to di­ag­no­sis, as well as in­fec­tions recorded during four defined periods of time prior to di­ag­no­sis: 13 to 30 months, 31 to 48 months, 49 to 72 months, and more than 72 months (six years).

The in­fec­tions analyzed by the researchers included respiratory tract in­fec­tions, gastrointestinal in­fec­tions, urinary tract in­fec­tions, and skin in­fec­tions.

Results

Overall, myeloma patients were more likely than the general population to have a history of respiratory tract in­fec­tions (such as bronchitis, influenza, pneumonia, and sinus in­fec­tions), shingles (herpes zoster in­fec­tion), and cystitis (lower urinary tract in­fec­tion).

The researchers observed the strongest association between a history of shingles and the development of multiple myeloma.  People di­ag­nosed with myeloma were 39 percent more likely to have a history of shingles than age- and gender-matched members of the general population.

Likewise, a history of pneumonia was 27 percent more likely among myeloma patients compared to the general population, and cases of the flu (influenza) were 18 percent more likely among myeloma patients.

On the other hand, a history of the common cold, kidney in­fec­tions, or gastrointestinal in­fec­tions was not significantly more likely in myeloma patients compared to the general population.

The researchers also found that a history of shingles, pneumonia, bronchitis, and sinus in­fec­tions was consistently more likely among myeloma patients, compared to the general population, across all the specific time periods prior to di­ag­no­sis that they analyzed -- even six years and longer before di­ag­no­sis.

Indeed, the researchers found that myeloma patients were particularly more likely than the general pop­u­la­tion to have shingles (a 48 percent greater likelihood), pneumonia (41 percent), bronchitis (29 percent), and sinus in­fec­tions (28 percent) in the period 31 to 48 months prior to di­ag­no­sis.

The authors note that the latter findings may indicate that a myeloma patient's immune system is weakest during the 31 to 48-month period prior to di­ag­no­sis.

Or it may indicate that certain in­fec­tions during this period are particularly likely to initiate processes that eventually lead to the development of multiple myeloma.

Infections As A Risk Factor For Myeloma?

The study authors are clear in their article that their findings do not prove that in­fec­tions lead to a greater risk of myeloma.  It is possible, they admit, that causality may run in the other direction -- that is, that undi­ag­nosed, still-developing multiple myeloma may increase a person's risk of in­fec­tions prior to a myeloma di­ag­no­sis.

Nevertheless, the in­ves­ti­ga­tors lean toward interpreting their results as indicating that in­fec­tion may, in fact, increase the risk of multiple myeloma.

One key finding of their study in favor of this view, they argue, is the fact that myeloma patients are more likely to have a history of in­fec­tions far in advance of their eventual di­ag­no­sis.  It seems "unlikely," the researchers argue, that un­di­ag­nosed myeloma could lead to a higher risk of in­fec­tions so long before the disease be­comes symptomatic.

In addition, the in­ves­ti­ga­tors note that shingles -- which in their study was found to be particularly as­so­ci­ated with the later development of myeloma -- also has been linked to other blood cancers, including cer­tain forms of lymphoma and leukemia.

Likewise, in­flam­ma­tion, which is one of the body's reactions to in­fec­tion, is well-established as a promoter of several types of cancer, the authors note.  In this regard, the researchers point to their finding that a number of different in­fec­tions are as­so­ci­ated with an increased risk of myeloma, and most of those in­fec­tions are not due to a single virus or bacteria.

This, the in­ves­ti­ga­tors write, suggests "that in­flam­ma­tion rather than exposure to a particular antigen may be as­so­ci­ated with the malignant transformation to multiple myeloma."

For more information, please refer to the study in the International Journal of Cancer ^[1] (abstract).