The White House crusade against … MGUS?

From the White House, the First Lady is leading a well-publicized campaign against childhood obesity that has the potential to impact not only the health of children, but also one of the most frequent hematologic disorders of the elderly, MGUS. In this issue of Blood, Landgren and colleagues suggest that in addition to race and age, obesity also appears to be associated with a significantly increased risk for the development of MGUS.¹ 

It is well known that the incidence of myeloma and monoclonal gammopathy of undetermined significance (MGUS) are 2- to 3-fold higher among blacks, and that prevalence of MGUS can be as high as 3% among those older than age 70,²  but does the risk of MGUS and subsequent myeloma now represent yet another reason to say no to dessert?

The presence of a paraprotein with less than 10% plasma cells and the absence of end-organ damage characterize MGUS, carrying with it an aggregate risk of progression to myeloma or other B-cell disorders of 1% per year.²  The preexisting diagnosis of MGUS is associated with a higher risk of thrombosis,^3,4  osteoporosis, hip fracture,⁵  and neurologic disorders⁶  compared with age-matched non-MGUS controls. But are all MGUS patients the same? Is the risk of progression to malignancy equal among all patients, or are there “benign” and “malignant” MGUS patients? Studies from Kyle and others have identified a stratification model for MGUS that identifies groups of patients with high risk of transformation versus patients with low risk of transformation to a malignant B-cell disorder.⁷  This can be identified predominately by the magnitude of the m-protein, type of heavy chain (immunoglobulin G versus others), and the presence of an abnormal free light chain ratio. Based upon these criteria, there are high-risk MGUS patients whose risk of progression is on the order of 58% at 5 years, and low-risk MGUS patients whose risk of progression is 5% at more than 20 years. Although there are recent studies that suggest that MGUS almost always precedes the diagnosis of myeloma,^8,9  they are based on patients who have myeloma retrospectively demonstrating the presence of a preexisting monoclonal protein. But is the reverse true? Closely evaluating the 2 papers that suggest that MGUS and myeloma are linked, it is notable that they used banked serum samples, such that all that can easily be determined is the presence or absence of a monoclonal protein. One cannot tell whether these patients had preexisting indolent myeloma or MGUS from these samples, and while one may accept that all myeloma patients have preceding MGUS, do all MGUS patients develop myeloma?

It is clear that MGUS can occur for many different reasons, and not all of them guarantee a future myeloma diagnosis. Patients with low-risk MGUS can also have concomitant autoimmune or chronic viral illnesses that result in the production of a small clonal protein that has little or no chance of clinical sequelae, and among the group with the highest incidence, those older than age 80, it is also likely that many patients will die of other causes. So does a higher risk of MGUS mean a higher risk of myeloma? Although the higher relative risk for developing MGUS is associated with obesity in the current article, other papers evaluating the risk for developing myeloma with obesity are much less clear with only weak or no significant correlations.^10-12  In the discussion, Landgren et al seem to imply that MGUS-ogenesis is synonymous with myelomagenesis as they suggest that factors known to sustain growth of the malignant plasma cell clone such as interleukin 6 (IL6) and insulin-like growth factor-1 (IGF-1) are overexpressed in obese patients and thus may be related to the pathology of MGUS, yet the role of these cytokines in tumor cell initiation is much less established. We know IL6 and IGF-1 are local cytokines that are secreted by either the marrow microenvironment or by plasma cells themselves, used to sustain the viability of a malignant clone. In vitro work suggests that myeloma plasma cells can be induced to proliferation and enhanced to survive when these cytokines are present,¹³  but do we know that IL6 and IGF-1 can have an impact before establishment of the malignant clone? Do these cytokines play a role in the initial development of MGUS that is destined to become myeloma, or are they most important in sustaining a malignant clone once established?

Much of the data evaluating the risk factors for developing MGUS focus on a heterogeneous condition, and treat it as homogeneous. This equates developing MGUS with myelomagenesis, and therefore developing MGUS is considered a harbinger of doom. However, not all patients with MGUS will develop myeloma. The correct association is not between obesity and myelomagenesis, but rather between obesity and the development of MGUS, of whom those with low-risk disease are less likely to develop cancer in their lifetime. This observation is quite different from race and age, where we clearly know that the risk of developing MGUS and myeloma is higher among blacks and those with more advanced age. What we know for now is that not all clonal plasma cell disorders are created equally, and that while obesity is linked with MGUS development, pathophysiologically the link between MGUS, myeloma, and obesity is less clear. Until we have more molecular tools to stratify and identify groups of MGUS and myeloma patients to better identify risk of progression and outcomes, clinical and basic laboratory criteria will have to suffice. Although there are clearly other reasons to be healthy and active, increased risk of myeloma as a consequence of obesity has yet to be definitively proven.