Hypercalcemia in MGUS: keep the differential diagnosis broad

In this issue of Blood, Jónsdóttir et al use the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study to shed light on a common clinical challenge: distinguishing whether hypercalcemia in monoclonal gammopathy of clinical significance (MGUS) signals progression to multiple myeloma (MM) or is more likely due to other unrelated conditions.¹ This is particularly important because hypercalcemia is a hallmark of MM, but it can also arise from a variety of other causes, such as hyperparathyroidism, malignancies other than MM, or medications.

The iStopMM study, a population-based cohort study of nearly 75 000 individuals in Iceland, remains a visionary and key resource in advancing our understanding of MGUS and its associations with a wide range of diseases.² The findings from the iStopMM study have already led to several practice-changing studies, including those identifying that individuals with MGUS have a higher rate of baseline comorbidities, which resulted in an overestimation of the risk of MGUS in those with other reported conditions such as autoimmune diseases, and redefining the free light chain reference ranges among patients with renal failure.^3,4 The unique strength of the iStopMM study lies in its large, consecutive, population-based cohort with rigorous ongoing longitudinal data collection—it is truly a hallmark study for advancing our clinical and biological understanding of precursor plasma cell states.

In their analysis, Jónsdóttir and colleagues demonstrate that hypercalcemia in MGUS, in the absence of other “CRAB” end-organ damage (anemia, renal failure, osteolytic bone lesions), is rarely directly due to MM progression, warranting broadening of the differential diagnosis and further workup. They show that, most of the time, isolated hypercalcemia in MGUS is more like a false alarm---transient or caused by something unrelated, such as primary hyperparathyroidism or non-MM cancers. This finding is not necessarily surprising---in patients with MM, non–parathyroid-hormone–mediated hypercalcemia most often occurs due to osteoclast-mediated bone resorption, and retrospective studies have shown the vast majority of patients with hypercalcemia present with concomitant bone disease.^5,6 However, the clinical relevance of hypercalcemia in patients with MGUS, who are otherwise asymptomatic, has not been shown previously. The International Myeloma Working Group guidelines on the management of patients with MGUS suggest that patients with unexplained hypercalcemia should always undergo bone marrow evaluations.⁷ However, the study challenges the assumption that isolated hypercalcemia in MGUS is a strong indicator of progression to MM. In fact, only 3% of patients with persistent hypercalcemia in this cohort developed MM, and all of them had osteolytic bone lesions.

Jónsdóttir et al offer clinicians an evidence-based approach to managing and working up hypercalcemia in patients with MGUS. Their work provides reassurance that, in the absence of other MM-related features, isolated hypercalcemia in MGUS should be evaluated and treated like hypercalcemia in the general population. Although MGUS is most often incidentally diagnosed, and patients are asymptomatic, the diagnosis of a precancerous disorder can be associated with significant patient-reported anxiety.⁸ The study will allow providers to counsel patients presenting with hypercalcemia and MGUS appropriately and will reduce unnecessary anxiety, unnecessary investigations, or premature treatment interventions for MGUS patients. However, although these findings are significant, they also have limitations. The study was conducted in a genetically homogeneous population in Iceland, which may limit broader applicability of the results. Further cohort studies may be needed to validate the findings.

In conclusion, the iStopMM study adds another clinically significant and relevant finding for clinicians and patients highlighting that isolated persistent hypercalcemia in MGUS is rarely indicative of progression to MM.

Conflict-of-interest disclosure: The authors declare no competing financial interests.