A role for ionizing radiation in myelomagenesis?

Using data from the monoclonal-protein screening study on Nagasaki atomic bomb survivors, Iwanaga and colleagues report in this issue of Blood that ionizing radiation is associated with an elevated risk of MGUS, particularly for individuals exposed at younger ages.

Beyond age, sex, race, and a positive family history of multiple myeloma, no consistent extrinsic risk factors have been clearly linked to multiple myeloma.¹  Previous studies evaluating the risk for multiple myeloma among individuals exposed to radiotherapy have generally not found evidence of excess risk, and the same has been true in prior studies of atomic bomb survivors.^2-4 

A few studies have evaluated the relationship between monoclonal gammopathy of undetermined significance (MGUS) and ionizing radiation. For example, in a small retrospective study including 285 MGUS cases and 570 hospital-based controls, ionizing radiation was found to be associated with an increased risk of MGUS.⁵  In a prior study based on 6737 atomic bomb survivors, 112 developed MGUS reflected in a crude incidence rate of 164 per 100 000 person-years, and with a sharp increase in incidence after age 60.⁶  The MGUS incidence was not significantly associated with radiation dose, and the authors found that transformation from MGUS to multiple myeloma occurred at a insignificantly higher rate among radiation exposed (vs nonexposed) persons.⁶ 

In the largest investigation to date, Iwanaga et al assess the relationship between MGUS and radiation exposure in Nagasaki atomic bomb survivors.⁷  Based on more than 50 000 study participants, a total of 1082 MGUS cases were identified (yielding an overall prevalence of 2.1%; 95% CI 1.9%-2.2%). Importantly, the authors found that individuals exposed to radiation at age 20 years or younger had a higher prevalence of MGUS comparing those exposed at a distance within 1.5 km (vs > 3.0 km). Very similarly, among individuals exposed at age 20 years or younger, the prevalence of MGUS was higher in individuals exposed to more than 0.1 Gy (vs < 0.01 Gy). However, in contrast, among those exposed at age 20 years or older, the exposure distance and the dose intensity yielded no statistical association with regard to MGUS. Thus, individuals exposed at younger ages had a higher risk for MGUS when exposed to higher radiation doses. Finally, when evaluating the risk of developing multiple myeloma among MGUS cases, there was no statistical association with regard to radiation exposure.

The findings of the study by Iwanaga et al are important for several reasons. Their results indicate that ionizing radiation exposure might play a role in the causation of plasma cell disorders. Given that we currently lack insight into mechanisms underlying the development of plasma cell disorders, this is an intriguing observation that potentially could facilitate the discovery of biological mechanisms involved in myelomagenesis. For example, ionizing radiation induces chromosomal and genomic instabilities⁸  and chromosomal abnormalities are indeed commonly found in MGUS and multiple myeloma.⁹  Furthermore, as pointed out by the authors, beyond the observed association between radiation and MGUS risk, there are emerging data from other studies to support a role for genetic susceptibility,¹⁰  and immune-related and inflammatory conditions¹¹  in the development of myelomagenesis. Interestingly, there has been recent evidence to suggest that radiation-induced inflammatory reactions and radiation-induced genomic instability may be interrelated with a predisposition to radiation carcinogenesis.⁸  Taken together, more research is needed to clarify underlying mechanisms of the observed excess of MGUS among persons exposed to ionizing radiation.

From a general clinical perspective, the study by Iwanaga et al addresses an important question related to the rapidly growing use of computed tomography (CT) in clinical practice during recent years. Indeed, increasing attention has been focused on the potential for radiation exposure from CT to induce cancers. This is a particular concern for children since they have increased organ radiosensitivity and a long lifetime to potentially develop radiation-related cancer.¹²  Along the same lines, it would be interesting to assess the prevalence of MGUS among individuals exposed to CT and other types of medical ionizing radiation at younger ages.