Hypercalcemia in Individuals with Monoclonal Gammopathy of Undetermined Significance: Results from the Istopmm Study

Introduction Multiple myeloma (MM) is a malignancy of bone marrow plasma cells, characterized by monoclonal immunoglobulins in the blood or urine and associated organ dysfunction encapsulated in the CRAB criteria (hypercalcemia, renal impairment, anemia, and bone lesions). MM is always preceded by monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant stage. MGUS is relatively common in the general population, with an age-adjusted prevalence of 3-6%, dependent on gender and race. No treatment is recommended for MGUS, but a regular follow-up to detect progression to MM is advised. This includes regular measurements of serum calcium to capture MM-associated hypercalcemia. Hypercalcemia in the general population is most commonly caused by hyperparathyroidism or non-MM malignancy. We are unaware of any systemic study designed to guide physicians on how to react to hypercalcemia in individuals with MGUS.

The aim of this study was to examine the underlying causes of hypercalcemia in individuals with MGUS and which diagnostic factors along with hypercalcemia are indicative of MM in order to guide the approach to hypercalcemia in individuals with MGUS in the clinic.

Methods The ongoing Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study is a population-based screening study for MGUS and a randomized trial of follow-up strategies. In total, 80,759 Icelanders aged 40 years and above enrolled in the study, and 75,422 were screened for MGUS using serum protein electrophoresis (SPEP) and a free light chain assay. Two-thirds of those who screened positive for MGUS were randomized to active follow-up at the study´s clinical research center. Participants who were in active follow-up in the study between April 1. 2017, and March 1. 2022, and had albumin-corrected serum calcium levels ≥ 2.55 mmol/L or serum ionized calcium levels ≥ 1.40 mmol/L were identified. The medical records of the participants were reviewed in collaboration with a senior endocrinologist to establish the persistence of hypercalcemia and underlying diagnosis. If MM was found as the cause of the hypercalcemia, then other CRAB features present at diagnosis were also recorded. In addition, the characteristics of the study cohort were compared with individuals without hypercalcemia who were in active follow-up in iStopMM using Student's t-test and Fisher exact test.

Results Of the 2,546 individuals with MGUS in active follow-up, 191 (7.5%) had at least one elevated serum calcium measurement, of whom 93 had persistent hypercalcemia (48.7%) (Figure 1A). Thus, more than half had transient hypercalcemia. Individuals with hypercalcemia were more likely to be female (68% vs. 45%; p < 0.001) and were older than those without hypercalcemia (median age 73 vs. 70 years; p < 0.001). Primary hyperparathyroidism was found to be the most common cause of persistent hypercalcemia (56%), with malignancies other than MM following as the second most common cause (16%). In 18 cases (19%), the cause of hypercalcemia was not identified (Figure 1B). However, MM was ruled out in every case according to iStopMM protocols. MM was found in 3 participants with persistent hypercalcemia (3%); all had bone lesions and other concurrent CRAB features.

Conclusion In this nationwide screening study, based on 75,422 individuals, we examined hypercalcemia in 2,546 individuals with MGUS and found that it was rarely associated with MM. Additionally, we found no cases of isolated hypercalcemia in MM. Importantly, more than half of hypercalcemia cases were transient, and when persistent, the underlying causes among individuals with MGUS were similar to those in the general population.

Based on these results, we conclude that hypercalcemia, particularly isolated hypercalcemia, is not a strong indicator of MGUS progression and is most often caused by other underlying diseases. Thus, in the absence of other CRAB features, hypercalcemia in MGUS should be approached in the same way as in patients without MGUS. Measurements of serum calcium should be repeated, and hyperparathyroidism should be ruled out before undertaking further assessments for possible malignancy, including MM. These findings contribute to a more evidence- and value-based approach to the care of individuals with MGUS.

Onundarson:Fiix prothrombin time.: Patents & Royalties. Hultcrantz:Amgen, Daichii Sankyo, Cosette, GSK: Research Funding; Intellisphere LLC: Consultancy; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Curio Science LLC: Consultancy; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Durie:Celgene/BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Harding:The Binding Site: Current Employment, Membership on an entity's Board of Directors or advisory committees. Landgren:Merck & Co., Inc.: Other: Independent Data Monitoring Committee (IDMC) member for clinical trials; Rising Tide Foundation: Research Funding; Janssen: Honoraria, Other: Independent Data Monitoring Committee (IDMC) member for clinical trials, Research Funding; Leukemia & Lymphoma Society: Research Funding; MMRF: Honoraria; Aptitude Health: Honoraria; Tow Foundation: Research Funding; Riney Foundation: Research Funding; NCI/NIH: Research Funding; Theradex: Other: Independent Data Monitoring Committee (IDMC) member for clinical trials; Pfizer Inc: Consultancy; Amgen: Honoraria, Research Funding. Kristinsson:Celgene: Research Funding; Amgen: Research Funding.