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

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.


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.

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 Xray 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 Figure 1. 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 2 Case Reports in Oncological Medicine  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.
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, Case Reports in Oncological Medicine the patient is still following in our outpatient oncology center being on a low dose of lenalidomide with a stable M protein.

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-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  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.

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.