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4537 Hypercalcemia in Individuals with Monoclonal Gammopathy of Undetermined Significance: Results from the Istopmm Study

Program: Oral and Poster Abstracts
Session: 652. Multiple Myeloma and Plasma Cell Dyscrasias: Clinical and Epidemiological: Poster III
Hematology Disease Topics & Pathways:
Research, adult, Clinical Practice (Health Services and Quality), elderly, Plasma Cell Disorders, Diseases, Lymphoid Malignancies, Study Population, Human
Monday, December 12, 2022, 6:00 PM-8:00 PM

Ástrún Helga Jónsdóttir1*, Sæmundur Rögnvaldsson, MD1,2*, Helga Ágústa Sigurjónsdóttir2,3*, Sigrún Thorsteinsdóttir, MD, PhD3,4, Brynjar Vidarsson, MD2, Páll Torfi Onundarson, MD2,3, Bjarni Agnarsson, MD2,3*, Margrét Sigurdardóttir, MD2*, Ingunn Thorsteinsdóttir, MD, PhD2*, Ísleifur Ólafsson, MD, PhD2*, Signy Vala Sveinsdottir, MD2*, Robert Palmason2,5*, Ásdis Rósa Thórdardottir3*, Elias Eythorsson, MD, PhD2*, Asbjorn Jonsson, MD2,6*, Runolfur Palsson, MD2,3*, Olafur Skuli Indridason, MD, MHS2,3*, Gauti Kjartan Gislason, MSc3*, Andri Olafsson3*, Jon Kristinn Sigurdsson3*, Ingigerdur S Sverrisdottir, MD2,3,7*, Thorir Einarsson Long, MD, PhD3,5*, Thor Aspelund, PhD3*, Malin Hultcrantz, MD, PhD8, Brian G.M. Durie, MD9, Stephen Harding, PhD10, Ola Landgren, MD11, Thorvardur Jon Love, MD, PhD2,3* and Sigurdur Y Kristinsson, MD, PhD2,3

1Faculty of Medicine, University of Iceland, Reykjavík, Iceland
2Landspitali - The National University Hospital of Iceland, Reykjavik, Iceland
3Faculty of Medicine, University of Iceland, Reykjavik, Iceland
4Department of Hematology, Rigshospitalet, Copenhagen, Copenhagen, Denmark
5Skåne University Hospital, Lund, Sweden
6Akureyri Hospital, Akureyri, Iceland
7Sahlgrenska University Hospital, Gothenburg, Sweden
8Myeloma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, Sloan Kettering Cancer Center, New York, NY
9Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Outpatient Cancer Center, Los Angeles, CA
10The Binding Site Inc., Birmingham, United Kingdom
11Myeloma Division, Department of Medicine, Sylvester Comprehensive Cancer Center, University of Miami, Miami, FL


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.


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.


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.


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.

Disclosures: 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: Janssen: Consultancy, Other: Independent Data Monitoring Committee (IDMC) member for clinical trials, Research Funding; Amgen: Research Funding; Merck: Consultancy, Other: Independent Data Monitoring Committee (IDMC) member for clinical trials; Pfizer: Consultancy. Kristinsson: Celgene: Research Funding; Amgen: Research Funding.

*signifies non-member of ASH