Approaching Hypercalcemia in Monoclonal Gammopathy of Undetermined Significance: Insights from the iStopMM study

• Hypercalcemia in MGUS rarely indicates progression to multiple myeloma; no isolated hypercalcemia indicating progression was observed.

• Hypercalcemia cases in MGUS had similar causes to those in the general population. The approach to isolated hypercalcemia should be general.

Hypercalcemia in monoclonal gammopathy of undetermined significance (MGUS) presents a clinical challenge since it may indicate progression to multiple myeloma (MM) but could also be due to a multitude of unrelated disorders. To inform the approach to this clinical challenge, we conducted a nested cohort study within the iStopMM screening study. Of the 75,422 Icelanders aged 40 years and above who underwent screening for MGUS, we included 2,546 with MGUS who were in active follow-up, including regular serum calcium measurements. In total, 191 individuals (7.5%) had hypercalcemia detected at least once, of whom 93 had persistent hypercalcemia (48.7%). MM was found in 3 participants with persistent hypercalcemia (3.2%); all had concurrent bone disease and other end-organ damage. The most common causes of hypercalcemia were primary hyperparathyroidism (56.0%) and malignancies other than MM (16.0%). In this first comprehensive study on hypercalcemia in MGUS, we observed that hypercalcemia rarely indicated MGUS progression and never in the absence of other symptoms of MM. More than half of hypercalcemia cases were transient and the underlying causes were similar to those in the general population. We conclude that hypercalcemia in MGUS should be approached in the same way as in those without MGUS.