Approaching hypercalcemia in monoclonal gammopathy of undetermined significance: insights from the iStopMM screening study

Abstract

Hypercalcemia in monoclonal gammopathy of undetermined significance (MGUS) presents a clinical challenge because 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 Iceland Screens, Treats, or Prevents Multiple Myeloma screening study. Of the 75 422 Icelanders aged 40 years and above who underwent screening for MGUS, we included 2546 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.

Introduction

Multiple myeloma (MM) is defined by the presence of monoclonal immunoglobulins (M-proteins) or free light chains in the serum and associated clinical hallmarks of hypercalcemia, renal impairment, anemia, and bone lesions (CRAB) or MM-defining biomarkers.¹ MM is preceded by monoclonal gammopathy of undetermined significance (MGUS), an asymptomatic premalignant state.² MGUS is common, with a prevalence of 4.2% in individuals above the age of 50 years. MGUS carries a 1% to 1.5% risk per year of progression to MM or related lymphoproliferative disorders.^3,4 No treatment is recommended for MGUS, but indefinite follow-up is recommended with the aim of detecting MGUS progression.⁵ To identify progression in individuals with MGUS, regular blood testing is performed to detect changes in M protein concentrations and signs of MM-related end-organ damage, including hypercalcemia.⁵

Hypercalcemia is present in ~15% to 21% of newly diagnosed patients with MM, and virtually all patients with MM with hypercalcemia also have concurrent bone disease.^6-8 However, hypercalcemia is relatively common in the general population, with a prevalence of ~1% to 4%, and is caused by hyperparathyroidism or various malignancies in >90% of the cases.^9-11

Hypercalcemia in individuals with MGUS presents a clinical challenge as it may indicate progression to malignancy that requires prompt therapy, although, at the same time, it is not clear to what extent hypercalcemia in MGUS indicates progression. Current diagnostic criteria for MM recommend ruling out other causes of hypercalcemia in the absence of other diagnostic criteria.¹ However, these recommendations are based on expert opinion, and we are unaware of any studies providing evidence on approaching this clinical challenge. Therefore, we were motivated to evaluate the underlying causes of hypercalcemia in a prospectively followed MGUS cohort.

Study design

This study is based on the Iceland Screens, Treats, or Prevents Multiple Myeloma (iStopMM) study, a population-based screening study of MGUS, and a randomized controlled trial of follow-up strategies to evaluate population-based MGUS screening. In total, 75 422 Icelanders ≥40 years of age (51% of the eligible population) were screened for MGUS. Two-thirds of those with MGUS were invited for regular follow-up appointments that included serum calcium measurements. The methodology of iStopMM has been described in detail elsewhere and has been approved by the Icelandic Committee of Science Ethics (Number 16-022, date: 26 April 2016).¹²

This study included people who attended follow-up visits in iStopMM between April 2017 and February 2022. Serum calcium and albumin measurements were collected from a central Icelandic laboratory database, where virtually all these measurements in Iceland are stored. When possible, albumin-adjusted calcium was calculated.¹³ Hypercalcemia was defined as total serum calcium ≥2.55 mmol/L or ionized calcium levels ≥1.40 mmol/L (≥10.20 mg/dL and ≥5.61 mg/dL, respectively). When hypercalcemia was detected in iStopMM participants, ionized calcium and parathyroid hormone (PTH) were measured. Medical records of individuals with hypercalcemia were thoroughly evaluated in collaboration with a senior endocrinologist at Landspítali–The National University Hospital of Iceland to establish the persistence of hypercalcemia and to ascertain the underlying diagnosis made during subsequent clinical care. Information about MGUS-related factors was obtained from iStopMM. Descriptive statistics were used, and groups were compared using the Student t test and Fisher exact test.

Results and discussion

On the basis of a nationwide screening study that included 75 422 persons, we systematically studied 2546 individuals with MGUS to detect hypercalcemia. Of the 2546 persons with MGUS enrolled in the active follow-up, 191 (7.5%) had hypercalcemia detected at least once. Of those, 98 (51%) had hypercalcemia that either subsided without treatment or was found to be artifactual (eg, by subsequent measurement of ionized calcium). Thus, the hypercalcemia was transient in half of the cases (Figure 1). The findings highlight the importance of confirming hypercalcemia when detected by repeat measures and measures of ionized calcium.

Figure 1. The distribution of persistent hypercalcemia and its underlying cause in individuals with MGUS identified by active follow-up of cases in the iStopMM study.

LP, lymphoproliferative disorders other than MM.

The remaining 93 participants (49%) with persistent hypercalcemia had a median albumin-adjusted calcium and ionized calcium levels of 2.62 (range, 2.55-3.37) mmol/L and 1.46 (range, 1.33-1.87) mmol/L, respectively. As in the general population,^11,14 they were more likely to be female (68% vs 45%; P < .001) and older than other participants (median age 73 vs 70 years; P < .001). When compared with persons without hypercalcemia, there was no difference in the MGUS-related factors, except for the M protein isotype, with those with hypercalcemia more frequently having immunoglobulin A and immunoglobulin M MGUS (Table 1).

Table 1. Demographic and clinical characteristics of individuals with MGUS enrolled in clinical follow-up in the iStopMM study, according to whether they had persistent hypercalcemia or not.

	Hypercalcemia (n = 93)	No hypercalcemia (n = 2453)	P value
Median age (range), y	73 (41-92)	70 (42-100)	<.001
Female (%)	68%	45%	<.001
Median M protein (range), g/L	0.26 (0.06-3.3)	0.23 (0.02-2.6)	.23
M protein type			.04
IgA	13 (14%)	247 (10%)
IgG	45 (48%)	1250 (51%)
IgM	22 (24%)	468 (19%)
Light chain	11 (12%)	272 (11%)
Biclonal	2 (2%)	216 (9%)
Abnormal FLC ratio	36 (39%)	896 (37%)	.66
Percent BMPC			.42
0%-5%	15 (16%)	478 (20%)
6%-10%	13 (14%)	467 (19%)
11%-60%	9 (10%)	192 (8%)
≥60%	0 (0%)	1 (0%)
Missing	56 (60%)	1315 (54%)
SMM	7 (8%)	200 (8%)	.98

Data are presented as numbers and percentages or ranges.

BMPC, bone marrow plasma cells; FLC, free light chain; SMM, smoldering multiple myeloma.

The cause of hypercalcemia was identified in 75 participants (81%). No definitive cause could be determined in 15 participants (16%), and 3 participants (3%) died from causes unrelated to the underlying plasma cell disorder before a diagnostic evaluation could be carried out. Hypercalcemia was caused by progression to MM in 3 cases (3%) (Figure 1). Bone disease and other concurrent CRAB features were present at diagnosis in all these cases (supplemental Table; available on the Blood website). One participant had hypercalcemia due to the progression to diffuse large B-cell lymphoma. Multiple other clinical signs and symptoms, including lymphadenopathy and B-symptoms, prompted the workup that led to the diagnosis. Hence, hypercalcemia rarely signified MGUS progression, and similar to previous studies,^6,7 no cases of hypercalcemia indicating MGUS progression were observed without other clinical hallmarks of MM, including bone disease. All observed cases of MM-related hypercalcemia were characterized by serum total calcium levels below the 2.75 mmol/L cutoff defined in current guidelines.¹ These findings suggest that hypercalcemia is not a reliable marker of MGUS progression and that current definitions poorly capture MM-related hypercalcemia.

Overall, the causes of persistent hypercalcemia were similar to those in the general population.^11,14 Primary hyperparathyroidism was the most common cause of hypercalcemia (56.0%) and malignancies other than MM were the second most common cause (16.0%). Drug-induced hypercalcemia was caused by D-vitamin supplements in 5 cases and tacrolimus in 1 case. Sjögren syndrome was among other causes (Figure 2). These results reveal that hypercalcemia in individuals with MGUS is usually no different from hypercalcemia in those without MGUS. On the basis of these findings, we conclude that in the absence of other signs or symptoms of MGUS progression, hypercalcemia in those with MGUS should be approached in the same manner as in those without MGUS.

Figure 2. Identified causes of hypercalcemia in individuals with MGUS according to sex.

LP, lymphoproliferative disorders other than MM; PHPT, primary hyperparathyroidism; THPT, tertiary hyperparathyroidism.

This study has several strengths. First, the cohort is based on a large screening study including more than 75 000 people. Serum calcium levels were systematically obtained, so the cohort has, in effect, also been screened for hypercalcemia. Second, the participants with MGUS were actively monitored for progression to MM or other lymphoproliferative disorders, thus providing robust data on hypercalcemia occurring in this setting. Finally, medical records and laboratory test results are stored centrally, yielding a virtually complete data set, including clinical information and serum calcium measurements.

This study also has important limitations. The underlying causes of hypercalcemia were determined by a review of medical records, relying on adequate diagnostic evaluation and accurate clinical documentation, and in some cases, this was insufficient to establish the underlying cause. In particular, subclinical causes such as dietary factors could have gone unnoticed. However, as the participants were enrolled in follow-up for MGUS progression, including the development of hypercalcemia, MGUS progression is unlikely to have gone unnoticed. It is also important to keep in mind that although MM was ruled out as a cause of hypercalcemia at the time, it does not rule out future progression. Second, albumin-adjusted serum calcium levels have been criticized for being inaccurate, particularly in the setting of hypercalcemia,¹⁵ which potentially explains the high rate of transient hypercalcemia observed in this study. However, only those with persistent hypercalcemia underwent additional evaluation, and this limitation is unlikely to have significantly affected the overall interpretation of the findings. Finally, this study is based on the ethnically and genetically homogenous Icelandic population, and thus, the rate and underlying causes of hypercalcemia may not be representative for other populations.

In conclusion, this first comprehensive study on hypercalcemia in MGUS revealed comparable causes of hypercalcemia in individuals with and without MGUS and that hypercalcemia is not a strong indicator of MGUS progression. Furthermore, hypercalcemia is often transient in individuals with MGUS. Thus, in the absence of other CRAB features, we suggest that hypercalcemia in individuals with MGUS would be approached in the same way as in those without MGUS. As a general approach to incident hypercalcemia, we recommend repeating serum calcium measurement, preferably by measuring serum ionized calcium, followed by measuring PTH if elevated calcium level is confirmed. If hypercalcemia is persistent and PTH level is below normal limits, indicating a normal physiologic response, further workup should be performed to rule out underlying malignancy, including progression to MM or related lymphoproliferative disorders.¹ These findings contribute to an evidence-based approach to the care of individuals with MGUS.

KEY POINTS.

• Hypercalcemia in MGUS rarely indicates progression to MM; 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.