# A Case of Multiple Myeloma Coexisting with Primary Hyperparathyroidism and Review of the Literature

Authors: Nasir Hussain; Moona Khan; Aparna Natarajan; Mubeenkhan Mohammedabdul; Usman Mustafa; Kalpana Yedulla; Aibek E. Mirrakhimov
Journal: Case Reports in Oncological Medicine
 (2013)

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## Abstract

Hypercalcemia is a common medical problem with an estimated prevalence of 15% among hospitalized patients. Multiple myeloma (MM) and primary hyperparathyroidism (PHPT) are among the most common causes of hypercalcemia but coexistence of both pathologic processes in a patient is an extremely rare phenomenon. In this paper we have discussed a patient presenting with this rare phenomenon. We have also provided a comprehensive review of the scientific literature published on codiagnosis of MM and PHPT.


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## Body

## 1. Introduction

Hypercalcemia is a common clinical problem with an estimated prevalence of 15% among hospitalized patients [31]. The etiology of hypercalcemia is complex with many factors playing a pathogenic role. From a clinical standpoint, it may present with changes in mental status, generalized weakness, polyuria, and constipation. Multiple myeloma (MM) and primary hyperparathyroidism (PHPT) are among the most common causes of hypercalcemia but coexistence of the two pathologic processes in one patient is an extremely rare phenomenon. In this paper, we have discussed a patient presenting with this rare phenomenon and have reviewed the relevant scientific literature.


## 2. Case Presentation

A 92-year-old Caucasian female with a past medical history of Alzheimer’s dementia, seizure disorder, osteoporosis, and osteoarthritis was admitted to the hospital for an evaluation of a new onset confusion and constipation. Review of symptoms during admission was significant for anorexia, weight loss, constipation for the last three weeks, and history of a fall one month prior to the presentation. Family history was significant for MM in a sister. At the time of presentation, the patient was using donepezil, memantine, vitamin D with calcium, calcium carbonate (calcium containing antacid), and levetiracetam. Vitals at the time of admission were blood pressure 140/58, pulse 68, respiratory rate 18, oxygen saturation 98% on room air, and temperature 97.4. On physical examination, the patient was alert and oriented in place and person but not in time. Other significant findings were diastolic murmur in right second intercostal space, petechiae over lower extremities, and back tenderness, which the patient attributed to a recent fall. Lumbar spine X-ray was done three weeks prior to the presentation that showed degenerative changes with no evidence of fracture. Basic blood workup including complete blood count and comprehensive metabolic panel was done, which revealed anemia, leucopenia, and hypercalcemia. Home medications were held for concerns of hypercalcemia and confusion.Endocrinology and neurology services were consulted. MRI of the brain was done, which showed lytic lesions as shown in Figure1. MM was suspected; serum protein electrophoresis (SPEP), urine protein electrophoresis (UPAP) and bone marrow biopsy were done which confirmed the diagnosis of MM (IgG kappa) (International Staging System stage II). Bone marrow biopsy showed mildly hypercellular bone marrow with plasmacytosis (30%) as shown in Figure 2. Skeletal survey showed diffuse lytic lesions throughout long bones, pelvis, and skull (Figure 3). Surprisingly, intact PTH came back high suggesting primary hyperparathyroidism (PHPT). The data on laboratory tests are presented in Table 1.Table 1
Result name
Results
Reference range
WBC
2.9 K/mm cu
4.2–11.0
Platelet
156 K/mm cu
140–400
Hemoglobin Hb
9.0 g/dL
12.0–15.0
Hematocrit
27.1%
36.0–47.0
Reticulocyte
0.7%
0.5–2.8
Blood urea nitrogen
22 mg/dL
5–20
Creatinine
1.11 mg/dL
0.0–1.00
Sodium
143 mmol/L
135–145
Potassium
4.0 mmol/L
3.4–5.1
Chloride
104 mmol/L
98–109
Bicarbonate
33 mmol/L
23–31
Calcium
13.3 mg/dL
8.4–10.5
Total protein
7.0 g/dL
6.4–8.3
Albumin
4.0 g/dL
3.4–5.2
Aspartate amino transferase
20 IU/L
0–32
Alanine amino transferase
10 IU/L
0–40
Alkaline phosphatase
67 IU/L
35–104
Bilirubin total
0.2 mg/dL
0–10.0
Haptoglobin
157 mg/dL
36–195
Vitamin B12
532 pg/mL
211–946
TSH
1.160 uIU/mL
0.400–5.400
Vitamin D25 OH
47.0 ng/mL
30.0–100.0
25 Hydroxy D3
26 pg/mL
25 hydroxy D2
<8
Vitamin D 1,25(OH)2
26
18–72
Folate
>20.0 ng/mL
3.1–17.5
Ferritin
64 ng/mL
13–150
Phosphorous
2.8 mg/dL
2.0–4.0
Lactate dehydrogenase
137 IU/L
135–214
Total iron
30 ug/dL
30–160
Unsaturated IBC
234.0 ug/dL
110.0–370.0
Total IBC
264.0
228.0–428.0
Percentage of  iron saturation
11%
20–55
PTH intact on day of presentation
70.5 pg/mL
15.0–65.0
PTH 7 months later
540.0 pg/mL
PTH-related protein
18 pg/mL
14–27
Beta-2 microglobulin
3.3 mg/L (5.8 mg/L four months later)
0.8–2.2
Serum viscosity
1.5 relative to H2O
1.5–1.9
PT/INR
10.6/1.0 sec
9.211.8/0.9–1.1
APTT
29 sec
24–33
Immunoglobulins
IGA
29 mg/dL
50–400
IGG
692 mg/dL (1200, 5 months later)
600–1500
IGM
6 mg/dL
50–300
Free kappa light chains
1510
3.3–19.4 mg/L
Free lambda light chains
2.4
5.7–26.3
Free Kappa/lambda
629.17
0.26–1.65
Urine protein electrophoresis
Urine volume 24 hours
1150 mL/24 hour
Urine-protein electrophoresis (UPE)
253 mg/24 hour
0–165
Albumin UPE
30.6%
Alpha1
16.1%
Alpha2
14.1%
Beta
17.1%
Gamma
22.1%
Immunofixation
Free kappa light chains
24-hour-urine protein
310.5 mg/24 hour
0–150
24-hours-urine creatinine
0.7 g/24 hour
0.74–1.57
24-hour-urine volume
1150 cc
24-hour-urine creatinine
0.5 g/24 hour
0.74–1.57
24-hour-urine volume
900 mL (repeat test)
24-hour-urine calcium
239 mg/24 hour
100–300
Serum protein electrophoresis
Albumin
3.3 g/dL
3.1–5.0
Alpha 1
0.3 g/dL
0.2–0.5
Alpha2
0.7 g/dL
0.5–1.1
Beta
0.6 g/dL
0.6–1.1
Gamma
1.5 g/dL
0.7–1.7
Albumin/globulin
1.0
M spike
1.09 g/dL
Total protein
6.5 g/dL
6.4–8.3
Immunofixation
Monoclonal paraprotein of class IgG kappa
CD56 NK cells
63%
3–35
CD 138 marker
26%
Lambda B-cell marker
1%
1–7
Kappa B-cell marker
73%
2–14%
CD45 LCA
98%
92–100
CD38 Marker
26%
1–17
Pathology. Normal female bone marrow karyotype. No clonal, structural, or numerical chromosome abnormalities identified. FISH analysis indicates normal hybridization signals with MM probe panel. This excludes majority of chromosome rearrangements known to be associated with MM.
Surgical Pathology. Mildly hyper cellular bone marrow with plasmacytosis consistent with MM.
Leukemia/lymphoma panel. Bone marrow aspirate shows 30–40% plasma cells with kappa light chain restrictions. (plasma cell dyscrasia).
Peripheral Smear. Lymphocytes with foamy cytoplasm, no rouleaux formation, adequate polys with occasional platelet clumps.Figure 1
MRI demonstrating lytic lesions.Figure 2
Mildly hypercellular bone marrow with plasmacytosis (30%), consistent with multiple myeloma.Figure 3
Skeletal survey showing lytic lesions in long bones and skulls.Hypercalcemia was managed with intravenous hydration, calcitonin, bisphosphonates, and furosemide. The patient was started on melphalan and prednisone, which were later switched to lenalidomide with a high dose of dexamethasone due to a poor treatment response. After one and a half year, the patient is still following in our outpatient oncology center being on a low dose of lenalidomide with a stable M protein.


## 3. Discussion

Hypercalcemia is common in patients with MM and occurs in 28% of myeloma cases [32]. MM may cause hypercalcemia through multiple mechanisms. First, plasma cells produce various cytokines, including TNF-β and IL-6, that activate osteoclasts and lead to calcium washout from bones to the bloodstream [33]. Second, some studies suggest that MM cells may secrete parathyroid hormone-related peptide similarly to other malignancies, such as squamous cell lung carcinoma [34, 35]. Third, serum calcium may be falsely elevated because of a binding to immunoglobulin [36, 37].Clubb et al. [38] described first-case linking PHPT and paraproteinemia in 1964. Drezner and Lebovitz were the first who described a case of concomitant MM and PHPT in 1979 [30]. Some researchers speculate that the association between MM and PHTP may not be coincidental [39, 40], although mechanisms explaining codiagnosis are not known. Arnulf et al. showed that the prevalence of monoclonal gammopathy is higher in patients with PHTP as compared to general population [40]. Pest et al. hypothesized that elevated PTH may mediate the induction of MM through the downstream biological effects of IL-6 [1]. This hypothesis was supported by the study performed by Pirih et al., who showed that PTH decreases apoptotic cell death of the hematopoietic stem cells via the IL-6 [41].PHPT leads to hypercalcemia via direct bone resorption [42] mediated by osteoclasts. Another important mechanism is through an increased calcium absorption in the duodenum and greater reabsorption in the kidneys.The above-mentioned pathogenic mechanism gives an insight to how PHPT and MM may be linked. Some studies have suggested that calcium may act as a mitogenic factor [43], whereas others suggest that myelomatous proteins may interfere with polypeptide hormone synthesis bind their circulating fractions, and/or block their peripheral effects that may secondarily stimulate parathyroid gland [29]. However, both of these diseases are common among elderly and may share similar risk factors, such as ionizing radiation [44, 45], and a simple coincidence may be the case.Summary of published cases [1–28] is presented in Table 2. Codiagnosis of PHPT and MM should be suspected in cases of difficult-to-control hypercalcemia. Most of the cases of coexistent MM and PHPT have been observed in females (23 out of 29 reported cases). The youngest patient with codiagnosis was a 45-year-old female and the oldest patient was a 92-year-old female. PHPT is more common in females, whereas the opposite is true for MM. Differences in incidence of the two diseases may explain female preponderance (MM less frequent than PHPT). Initial diagnosis was highly variable, eleven cases had primary diagnosis of hyperparathyroidism, ten had primary diagnosis of MM and seven had both diagnosis made at presentation. The type of immunoglobulin chains of MM observed in all the cases was variable as six patients had light chain MM, remaining patients had a combination of heavy and light chain MM, one patient had nonsecretory type of MM. All the patients had calcium ≥11 mg/dL at the time of presentation. Majority of patients had parathyroid adenoma as a cause of PHPT, few had chief cell hyperplasia, and none had parathyroid cancer. Parathyroidectomy, combination of radiotherapy, and chemotherapy had been used for treatment of this coexistent condition with variable success. Rao et al. [2] suggested that parathyroidectomy in patients with coexistent PHPT and MM serves three folds; first, it removes confusion about etiology of hypercalcemia; second, it alters prognosis of myeloma; third, calcium can be used as a tumor marker in cases if there is a recurrence of tumor. Considering age, our patient was not a candidate for surgery, in such patient population medical alternative to parathyroidectomy is needed. Ten out of 29-patients died within 5 years after codiagnosis, and out of those ten, eight died within one year.Table 2
n
Author
Age/ Gender
Type of MM
Ca (mg/dL)
Therapy for MM and PHPT
Parathyroid histology
Outcome
Initial diagnosis
1
Pest et al. [1]
76 F
IgA-?
13.2
Hydration, bisphosphonates, Lasix, melphalan, cyclophosphamide, and steroids
Adenoma
Survived
PHPT
2
Rao  et al. [2]
54 M
IgG-lambda
11.2
Adriamycin, melphalan, prednisone,  cyclophosphamide, and parathyroidectomy
Adenoma
Died after 12 years
Both
3
Jackson and Orland  [3]
45 F
IgG-lambda
17.1
Hydration, Lasix, prednisone, and melphalan
Adenoma
—
MM
4
Chisholm et al. [4]
80 M
Kappa
13.1
Parathyroidectomy, radiotherapy, melphalan, prednisone, vincristine, carmustine, cyclophosphamide, hydration, and Lasix
Adenoma (c-cells)
Died 2 years later
PHPT
5
Francis et al. [5]
70F
Lambda
11.6
Norethisterone, vincristine, melphalan, and prednisone
Adenoma
Died 3 weeks later
PHPT
6
Mundis and kyle [6]
76 F
IgG-kappa
11.0
Melphalan, prednisone, and parathyroidectomy
Adenoma (c-cells)
survived
MM
7
Stone et al. [7]
47 F
IgA-kappa
13.7
Melphalan, prednisone, radiotherapy, parathyroidectomy, hydration, and mithramycin
Adenoma
Died
MM
8
Hoelzer and Silverberg  [8]
51 F
IgA-lambda
11.9
Parathyroidectomy?
Adenoma (c-cells)
—
PHPT
9
Schneider and Thomas  [9]
74 F
IgG-kappa
12.0
Melphalan, prednisone, and parathyroidectomy
Adenoma
Survived
MM
10
Toussirot  et al. [10]
82 M
Kappa
15.2
Melphalan, prednisone, and parathyroidectomy
Hyperplasia
Died
PHPT
11
Goto et al. [11]
73 F
Kappa
13.2
Parathyroidectomy, melphalan
Adenoma
Died 1 year later
PHPT
12
Otsuka et al. [12]
77 F
IgG-lambda
Melphalan, prednisone, bisphosphonates, calcitonin, and parathyroidectomy
c-cells hyperplasia
Survived
—
13
Fery-Blanco et al. [13]
68  F
IgG-kappa
11.28
? chemotherapy and surgery refused
Adenoma
Died
Both
14
Sarfati et al. [14]
62 F
IgA-kappa
16.4
Mithramycin, lasix, plasmaphoresis, Adriamycin, vincristine, prednisone, and parathyroidectomy
Adenoma
Survived
MM
15
Rosen  et al. [15]
81 M
IgG-kappa
13.4
Hydration, bisphosphonates, melphalan, prednisone, radiotherapy, needle aspiration of  parathyroid gland, and refused surgery
Adenoma
Survived
MM
16
Tomon et al. [16]
60 F
IGA-kappa
—
—
—
—
MM
17
Fanari et al. [17]
59 F
lambda
12.7
Hydration, bisphosphonates, cinacalcet, bortezomib and dexamethasone
Possible Adenoma
Died 4 months later
Both
18
Bogas et al. [18]
72 F
IgG-kappa
13.66
Melphalan, prednisone, and Interferon?
Adenoma
Died 4 years later
Both
19
Katayama et al. [19]
50 F
PHPT
20
Romagnoli et al. [20]
70 F
—
—
Parathyroidectomy, steroids and chemotherapy
Adenoma
—
PHPT (MEN-1)
21
Toh and Winocour et al. [21]
71 M
12.0
Melphalan, prednisone, and bisphosphonates
Died 6 weeks later
MM
22
Sopen~a et al. [22]
77 F
Kappa (ns)
12.9
Bisphosphonates, refused surgery, or chemotherapy
Died 1 year later
Both
23
Khandwala  and Boctor [23]
72 F
—
11.7/ 16.6*
Parathyroidectomy, bisphosphonates, calcitonin, melphalan, and prednisone
Adenoma
—
PHPT
24
Patel et al. [24]
73 F
IgG- kappa
13.5
Bisphosphonates, steroids, thalidomide, plicamycin, and parathyroidectomy
Adenoma
—
MM
25
Avcioglu et al. [25]
52 F
IgG-kappa
12.6
Parathyroidectomy and steroids
Adenoma
—
Both
26
Chowdhury and Scarsbrook  et al. [26]
87 F
—
—
—
—
—
PHPT
27
Dalgleish and Gatenby [27]
59 F
IgG-lambda
11.68
Hydration, lasix, prednisone, mithramycin, cyclophosphamide, and parathyroidectomy
Adenoma
Survived
MM
28
Peters et al. [28]
73 M
IgA-lambda
16
Parathyroidectomy, chemotherapy, and radiotherapy
Hyperplasia
Died 1 week later
PHPT
29
Our case
92 F
IgG-kappa
13 .3
Bisphosphonates, Lasix, hydration, calcitonin, melphalan, prednisone, lenalidomide, and dexamethasone
—
Survived
Both
30
Johansson and Werner [29] mentioned 3 cases of MM and PHPT (no detail of the cases is given), one other such as has been described by
Drezner   and Lebovitz [30] without much detail.

*Calcium at time of diagnosis of MM.


## 4. Conclusions

A search for concomitant cause of hypercalcemia should be pursued in cases of difficult-to-control hypercalcemia and in elderly individuals, in whom the incidence of PTHP and MM is common.



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