Case Report

Denosumab for the Management of Hypercalcemia of Malignancy in Patients With Multiple Myeloma and Renal Dysfunction

Here, the International Myeloma Working Group (IMWG) updates its clinical practice recommendations for the management of multiple myeloma-related renal impairment on the basis of data published until Dec 31, 2022. All patients with multiple myeloma and renal impairment should have serum creatinine, estimated glomerular filtration rate, and free light chains (FLCs) measurements together with 24-h urine total protein, electrophoresis, and immunofixation. If non-selective proteinuria (mainly albuminuria) or involved serum FLCs value less than 500 mg/L is detected, then a renal biopsy is needed. The IMWG criteria for the definition of renal response should be used. Supportive care and high-dose dexamethasone are required for all patients with myeloma-induced renal impairment. Mechanical approaches do not increase overall survival. Bortezomib-based regimens are the cornerstone of the management of patients with multiple myeloma and renal impairment at diagnosis. New quadruplet and triplet combinations, including proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies, improve renal and survival outcomes in both newly diagnosed patients and those with relapsed or refractory disease. Conjugated antibodies, chimeric antigen receptor T-cells, and T-cell engagers are well tolerated and effective in patients with moderate renal impairment.

To report a rare case of ectopic parathyroid hormone (PTH) secretion from poorly-differentiated adenocarcinoma and the lessons learned in management.

A 54-year-old woman presented with fatigue, hip pain, and confusion. Workup revealed calcium of 16.9 mg/dl (N: 8.5–10.3 mg/dl), PTH of 981 pg/ml (N: 15–65 pg/ml), and parathyroid hormone-related peptide (PTHrP) of 20 pmol/L (N: 14–27 pmol/L). Parathyroid four-dimensional computed tomography was unrevealing. Magnetic resonance cholangiopancreatography demonstrated innumerable hepatic lesions. Biopsy of the liver and pubic ramus revealed poorly differentiated adenocarcinoma of unknown origin with acinar cell differentiation and focal PTH positivity.

Initial treatment with intravenous bisphosphonates and cinacalcet showed a poor response. Calcitonin had a short-lived response. Although chemotherapy significantly improved calcium levels, she was unable to tolerate chemotherapy. Despite a rise in PTH from 196 to 674 pg/ml, denosumab improved calcium levels from 13 to 9.7 mg/dl. She expired due to a cardiac arrest.

PTH secretion from tumors with acinar cell differentiation outside of the pancreas has not been described. Cinacalcet was ineffective and it is doubtful that the malignant cells had calcium-sensing receptors. Calcitonin was effective initially, but she eventually developed tachyphylaxis. Use of denosumab later in the treatment course has resulted in significant improvement in calcium despite worsening PTH levels.

Denosumab is effective in the treatment of paraneoplastic PTH-mediated hypercalcemia and should be considered in patients who have resistance to bisphosphonate therapy.

Hypercalcemia is a metabolic complication in some patients with malignancy, often seen in later-stage malignancies, and often predicts a poor prognosis. The most common causes include tumor secretion of parathyroid hormone–related peptide, excess production of 1,25-dihydroxy vitamin D, and osteolytic cytokine production. However, the etiology is not always mediated by malignancy, and other causes such as PTH-mediated hypercalcemia should be considered. This chapter reviews the etiology of hypercalcemia associated with malignancy and proposed mechanisms. It also discusses appropriate evaluation and treatment strategies.

Disturbances in calcium and phosphorus homeostasis are commonly encountered when caring for cancer patients. These may result from the malignancy itself or as a complication of treatment. A thorough understanding of pathophysiologic processes, whereby the tumor or its therapy result in abnormalities of calcium and phosphorus balance, is essential to managing cancer patients. Disturbances resulting in hypercalcemia can be divided into four types: tumor production of parathyroid hormone related peptide (PTHrP) known as humoral hypercalcemia of malignancy (HHM), local osteolytic hypercalcemia mediated by cytokine production most commonly seen in multiple myeloma or breast cancer, calcitriol production, and ectopic parathyroid hormone secretion. HHM makes up 80% of cancer-related hypercalcemia. The most common solid organ malignancies are squamous cell carcinomas most frequently from lung, head and neck, and skin. Adult T-cell leukemia/lymphoma cells also produce PTHrP. Lymphomas, leukemias and gastrointestinal stromal tumors result in hypercalcemia from calcitriol production. Hypocalcemia can occur with osteoblastic metastases, tumor lysis syndrome, hypomagnesemia, cisplatin, axitinib, 5-fluorouracil with low dose leucovorin, estramustine, nab-paclitaxel, high dose interleukin 2 and agents used to treat hypercalcemia, such as bisphosphonates and denosumab. Tumor lysis syndrome whether from treatment or spontaneous can lead to hyperphosphatemia and is the most common oncologic emergency. Prophylaxis with fluids, allopurinol or rasburicase is important to reduce risk of acute kidney injury. Hypophosphatemia can be caused by tumor production of fibroblast growth factor-23; and Fanconi syndrome from medications, lymphoma or multiple myeloma. Other drugs used to treat cancers may also lower serum phosphorus concentration including: BCR-ABL tyrosine kinase inhibitors, anaplastic lymphoma kinase (ALK) inhibitors, eribulin, high-dose estrogens, and mammalian target of rapamycin (mTOR) inhibitors.

Parathyroid independent hypercalcemia is characterized by suppressed parathyroid hormone (PTH) in the presence of hypercalcemia.

Well known causes and mechanisms are redistribution of calcium from the skeleton, by malignant diseases; inadequately increased intestinal calcium uptake mediated by increased vitamin D activity, and reduced renal elimination due to medications. Frequent and infrequent causes are discussed, and more recent mechanistic models presented in this review.

Most hypercalcemic conditions are stable and in equilibrium between the different organs, whereas the utmost severe cases are characterized by rapid rising calcium levels and renal failure, resulting in a vicious circle where a disequilibrium state is developed. Management and treatment depends on the underlying condition and severity.

The aim of this review is to discuss non-parathyroid hypercalcemic conditions as seen in the modern clinic, with a focus on areas where recent gain of knowledge has been achieved.