A monoclonal gammopathy in search of clinical significance: 57 years later

To the editor:

The articles by Landgren et al and Weiss et al published in a recent issue of Blood provided incontrovertible evidence that all multiple myelomas are preceded by monoclonal gammopathy of undetermined significance (MGUS).^1,2  While this association is expected, the findings are important and further strengthen the biologic significance of MGUS. What remains unclear and perhaps the most important question at the moment is the clinical significance of MGUS when there is yet no treatment that can prevent its progression to myeloma. Several clinical questions urgently beg answers.

First, do myeloma patients with a preceding diagnosis of MGUS have a better outcome in terms of survival and major complications (fractures and dialysis-dependent renal failure) compared with those who don't? This needs to be addressed due to the high prevalence of MGUS (5.3% among age ≥ 50 years) and its low likelihood of progression (0.4%/year).^3,4  There are potential harms or disadvantages of indefinitely following MGUS. While comprehensive quality-of-life studies in MGUS are not available, the psychological burden of cancer anticipation can be disturbing. A preliminary study from our group showed that patients seen at our hematology clinic had similar degrees of psychological distress during follow-up visits regardless of whether the hematologic condition was benign or malignant. The distress level was the same among patients with MGUS and myeloma.⁵  Moreover, the health care costs of following MGUS can be considerable. Based on the US Census Bureau, we calculated the number of patients harboring MGUS to be at least 3.6 million.⁶  Assuming that only 25% are diagnosed, there would still be almost a million patients to follow annually. This is confounded by the fact that there is a projected shortage of 2550-4080 hematologists-oncologists by 2020.⁷ 

Second, assuming there is clinical benefit, what is the optimal way of following MGUS? Experts recommend annual follow-up with monitoring of monoclonal protein (M-protein).^8,9  However, we do not know if subsequent development of myeloma is generally detected at the time of scheduled follow-ups or in-between these appointments when patients present with symptoms. If the latter were true, this would argue against routine follow-up. In both studies by Landgren et al and Weiss et al, half of the patients who developed myeloma had relatively stable M-protein and none were high risk according to the Mayo Clinic model.^1,2  Therefore, monitoring of M-protein may be less important than once thought. Perhaps surveillance for CRAB signs (hypercalcemia, renal failure, anemia, and bone lesions) may be more useful. After all, treatment is not indicated in smoldering myeloma.

Finally, should clinicians use a higher threshold when ordering tests to look for monoclonal gammopathy? MGUS is by definition and clinical intention almost always an incidental finding. One could argue that every MGUS diagnosed is a failed clinical diagnosis of multiple myeloma and related disorders. Routine screening for MGUS is not indicated.

Since its first description by the Swedish hematologist Jan Gosta Waldenström in 1952, the clinical significance of MGUS remains to be determined.¹⁰