Advances in Hematologic Malignancies Issue 2, Spring 2013
Patients with multiple myeloma are commonly diagnosed with hypercalcemia. In fact, hypercalcemia is one of the four diagnostic "CRAB" criteria (calcium elevation, renal insufficiency, anemia, or bone disease) used to distinguish smoldering myeloma and monoclonal gammopathies of undetermined significance from active, symptomatic multiple myeloma. About 10 to 15 percent of patients with multiple myeloma present with hypercalcemia at the time of initial diagnosis, while more than 25 percent will be found to have hypercalcemia at some point during the trajectory of their disease, usually at the time of disease progression and relapse.
Hypercalcemia in myeloma is multifactorial, but is ultimately caused by bone destruction from osteolytic tumor lesions and is most commonly observed in patients with extensive bone involvement by neoplastic plasma cells. Calcium leeched from bones within these lytic lesions enters the extracellular fluid and may then be insufficiently excreted by the kidneys, so that renal insufficiency is another risk factor for hypercalcemia. Symptoms associated with hypercalcemia may be subtle or dramatic, and can include: nausea and vomiting; confusion or depression; myalgias and arthralgias; dry mouth; polydipsia; anorexia; constipation; abdominal pain; and, eventually, coma. In patients with myeloma, a hypercalcemia diagnosis is often indicative of uncontrolled disease.
Not all patients with extensive bony destruction by myeloma have hypercalcemia. This clinical observation suggested to investigators that the pathophysiology of hypercalcemia in patients with multiple myeloma was complicated, and there have been major advances in understanding this complex pathophysiology in recent years.
Interactions between the myeloma cells and the myeloma microenviroment play a fundamental role. Osteoclasts are stimulated to resorb bone by cytokines released by the myeloma/marrow microenvironment, and chief among the osteoclast-activating factor cytokines is Receptor Activator of Nuclear Factor Kappa-B Ligand (RANKL), a member of the Tumor Necrosis Factor (TNF) ligand/receptor superfamily. RANKL is a key mediator of osteoclast differentiation and activation and is overexpressed in the myeloma marrow microenvironment. In contrast, osteoprotegerin (OPG), which acts as a decoy receptor antagonist for RANKL, is downregulated in myeloma lesions. Thus, there is a net increase in RANKL and a decrease in OPG in multiple myeloma, leading to osteoclast hyperactivity.
Although RANKL/OPG are critical, there are many other cytokines involved in multiple myeloma hypercalcemia pathophysiology. These include macrophage inflammatory protein-1α (MIP-1 α), Dickkopf 1 (DKK1),vascular endothelial growth factor (VEGF), Wnt, TGF-β, RUNX2/Cbfal1, and interleukins 3 and 6. MIP-1α signaling through its cell surface receptors on bone cells enhances interactions between myeloma and marrow stromal cells, leading to a vicious cycle in which the myeloma and microenvironment further upregulate RANKL, worsening bone destruction and increasing growth of tumor cells. Expression of some of these proteins by myeloma cells also results in decreased osteoblastic function, decreasing the ability of the bone to heal.
Generally, hypercalcemia is treated with hydration and either a bisphosphonate or RANKL inhibitor, as well as addressing the underlying cause. This multi-pronged therapeutic approach can result in rapid correction of laboratory abnormalities and dramatic improvement in patient symptoms.
An important first step in the treatment of hypercalcemia is to replenish fluids, since hypercalcemia increases filtration across the renal glomerular membrane, interferes with urine concentration, and causes diuresis and hypovolemia. Therefore, aggressive fluid resuscitation is necessary to reverse the hypovolemia and improve urinary calcium excretion. Additionally, diuretics and corticosteroids are often used to treat the hypercalcemia patient. Forced diuresis with loop diuretics can help avoid fluid overload and also increase urinary calcium absorption, and corticosteroids can both decrease calcium absorption from the gut and promote renal excretion. In severe cases and in patients with advanced myeloma-related kidney disease, hemodialysis may be necessary.
Administrating an anti-hypercalcemic medication is the next step. Calcitonin has a rapid onset of action and inhibits bone resorption without the risk of nephrotoxicity, but its ability to decrease calcium is modest and transient. Bisphosphonates, by contrast, are potent osteoclastic inhibitors with durable activity. The most common bisphosphonates used for hypercalcemia in myeloma include zoledronic acid (Zometa) or pamidronate (Aredia). When administered for an extended period of time, bisphosphonates are associated with osteonecrosis of the jaw (ONJ), a difficult complication of which dental professionals are increasingly aware. Bisphosphonates are also associated with renal toxicity and hypocalcemia.
Denosumab, a fully human monoclonal antibody that antagonizes RANKL signaling and decreases osteoclast activity, is the newest therapy for hypercalcemia. Denosumab is approved by the U.S. Food and Drug Administration for osteoporosis and to prevent skeletal metastases in solid tumors, but it is not yet approved for myeloma, though several studies have indicated it is effective and its use can be considered in bisphosphonate-refractory disease. Older therapies such as plicamycin, gallium are often mentioned in textbooks, but are rarely used in contemporary clinical practice.
Hypercalcemia is usually an ominous indication that either the myeloma disease has relapsed or that the patient is not responding to current therapy. It is, therefore, important to give systemic myeloma therapy as soon as possible to prevent recurrence of hypercalcemia.
Dana-Farber currently has more than a dozen active and enrolling
clinical trials for patients with relapsed or refractory myeloma, including studies with the activin receptor antagonist antibody
sotatercept (ACE-011), the c-Met/VEGFR2 tyrosine kinase inhibitor
cabozantinib (XL184), the oral proteasome inhibitors
ixazomib (MLN9708) and
marizomib (NPI-0052), the hypoxia-activated compound
CXCR4 antibody BMS-936564, the deacetylase inhibitors
ACY-1215 and panobinostat, an
anti-CD38 monoclonal antibody, the BRAF inhibitor
vemurafenib, the anti-B-cell activating factor
tabalumab (LY 2127399), and
— Kimberly Noonan, RN, NP, and Kathleen Colson, RN, of the Dana-Farber/Brigham and Women's Cancer Center (DF/BWCC) Jerome Lipper Multiple Myeloma Center, with Melissa Cochran, MS, NP, of the DF/BWCC Adult Stem Cell Transplantation Program