Mechanisms and Management of Hypercalcemia in Multiple Myeloma

Pathophysiologic Mechanisms

Myeloma cells and bone marrow stromal cells produce multiple cytokines that stimulate osteoclast activity, including interleukin-1, interleukin-6, tumor necrosis factor, and receptor activator of nuclear factor kappa B-ligand (RANKL) 1
The increased osteoclast activity leads to excessive bone resorption, releasing calcium from the bone matrix into the bloodstream 2

Symptoms of hypercalcemia depend on severity and may include increased urination, increased thirst, nausea, confusion, vomiting, and muscle pain 3
Hypercalcemia is one of the CRAB criteria (hypercalcemia, renal insufficiency, anemia, and bone lesions) used to diagnose symptomatic multiple myeloma requiring treatment 4
Conventional radiographs reveal abnormalities consisting of lytic lesions, osteoporosis, or fractures in 79% of patients with multiple myeloma at diagnosis 1

Bisphosphonates (zoledronic acid or pamidronate) are the most effective therapy for hypercalcemia in multiple myeloma 3
Aggressive hydration with normal saline is an essential first step in treatment 2, 3
Diuretics (e.g., furosemide) should only be administered after correction of intravascular volume 3
Denosumab may be considered in patients with hypercalcemia refractory to bisphosphonates or with renal insufficiency 3