Multiple myeloma hypercalcemia

Hematologic malignancies such as multiple myeloma and, rarely, lymphomas are other causes of hypercalcemia. 

Corticosteroids have been useful in the treatment of acute leukemia, lymphoma, multiple myeloma, and other hematologic malignancies as well as in advanced breast cancer. In addition, they are effective as supportive therapy in the management of cancer-related hypercalcemia. The steroid hormones and related agents most useful in cancer therapy are listed in Table 55-5. 

Hypercalcemia is a hallmark of multiple myeloma because bone resorption occurs due to the activation of osteoclasts near myeloma cells by IL-6, soluble IL-6 receptor a, and interleukin-1/3 (B6). 

Light chains are filtered readily through the glomeruli and can be detected in urine, when the reabsorption capacity of the proximal tubule is exceeded. In addition to hypercalcemia, the clinical features of multiple myeloma include anemia, renal insufficiency, and osteolytic lesions revealed during radiologic examination. These lesions weaken the bone matrix and are prone to fractures. Patients are subject to recurrent infections. 

Monoclonal protein can be detected in serum, urine, or both in greater than 95% of patients with multiple myeloma (D16). Bone marrow plasma cells exceed 10%. Patients with advanced disease may excrete Bence-Jones proteins in urine. Both hypercalcemia and Bence-Jones proteinuria can contribute to renal failure (A6). 

This class of drugs is used to treat hypercalcemia in osteolytic bone cancer and metastasis in breast cancer, multiple myeloma, and Paget disease of the bone. It is used more frequently to inhibit bone resorption in postmenopausal women and therefore has the potential for widespread effects despite a relatively low risk of ADRs. 

Not surprisingly, subsequent reports established the danger of utilizing exogenous phosphate to treat hypercalcemia. A 46-year-old woman with multiple myeloma and a calcium of 17.8 mg/ dl was treated with oral and intravenous phosphate and developed acute kidney injury with abrupt cessation of calciuria [40]. A 40-year-old male with squamous cell carcinoma... 

Hypercalcemia occurs in 10% to 20% of individuals with cancer. Tumors most commonly cause hypercalcemia by producing PTHrP, which is secreted into the circulation and stimulates bone resorptions and/or by invasion of the bone by metastatic tumor, which produces local factors that stimulate bone resorption. PTHrP binds to the PTH receptor and is the principal mediator of humoral hypercalcemia of malignancy (HHM). Cytokines such as lymphotoxin, interleukin-1, tumor necrosis factor, and PTHrP appear to be important mediators of hypercalcemia in multiple myeloma and other hematological malignancies. Some lymphomas associated with acquired immunodeficiency syndrome or HTLV [ infections cause hypercalcemia by producing 1,25(0H)2D. It is estimated that 5% of patients with hypercalcemic cancer have coexisting primary hyperparathyroidism. 

B8 Bentzel, C. J., Carbone, P. P., and Rosenberg, L., The effect of prednisone on. calcium metabolism and Ca kinetics in patients with multiple myeloma and hypercalcemia. J. Clin. Invest. 43, 2132-2145 (1964). 

Ehe-existent kidney disease, particularly diabetic nephropathy with renal insufficiency, is the major risk factor. Conditions associated with decreased renal blood flow, including congestive heart failure and dehydration, also confer risk. The presence of multiple myeloma has been considered a relative contraindication for contrast use, but the risk appears to be associated with concomitant dehydration, renal insufficiency, or hypercalcemia rather than the diagnosis itself. Both... 

Glucocorticoids are usually effective in the treatment of hypercalcemia resulting from multiple myeloma, leukemia, lymphoma, sarcoidosis, and hypervitaminoses A and The mechanisms of... 

In this condition the renal tubules are unresponsive to antidiuretic hormone and, as such, the subject has polyuria. The condition may be congenital or acquired. Acquired nephrogenic diabetes insipidus can result from several causes, such as chronic renal disease, potassium deficiency including primary aldosteronism, drugs such as lithium, systemic diseases such as multiple myeloma, and chronic hypercalcemias, including hyperparathyroidism. The damage to the renal tubules... 

Calcitonin is indicated for patients with moderate to severe Paget s disease, characterized by abnormal and accelerated bone formation, and for patients with hypercalcemia associated with carcinoma multiple myeloma. 

Aplastic anemias (some forms) Complications of malignancy Hypercalcemia Hematologic malignancies Acute lymphoblastic leukemia Lymphomas Multiple myeloma Immune hemolytic anemia Immune thrombocytopenia Inflammatory bowel disease Transfusion reactions Allergic and Immune Diseases Acute hypersensitivity reactions Allergic rhinitis Anaphylaxis... 

Zoledronic acid is a bisphosphonate that causes inhibition of bone resorption. It is indicated in the treatment of hypercalcemia of malignancy treatment of patients with multiple myeloma and bone metastases from solid tumors in conjunction with standard antineoplastic therapy. 

The maximum recommended dose for the treatment of hypercalcemia of malignancy is 4 mg. A clinically significant deterioration in renal function occurs when single doses of this agent exceed 4 mg and the infusion duration is less than 15 minutes (52). It is recommended that patients be well hydrated before infusion. If serum calcium levels do not fall to normal levels, retreatment is appropriate, but retreatment is not recommended until 7 days have elapsed from the initial treatment. For the treatment of multiple myeloma and metastatic bone lesions, a 4-mg initial dose is recommended, followed by additional doses every 3 to 4 weeks for 9 to 15 months (prostate cancer, 15 months breast cancer, 12 months other solid tumors, 9 months). 

Pamidronate, a second-generation bisphosphonate, is 100-fold more potent than etidronate (Fig. 35.7) (6). It has been approved for the treatment of hypercalcemia of malignancy, for Paget s disease, and for osteolytic bone metastases of breast cancer and osteolytic lesions of multiple myeloma. When used to treat bone metastases, pamidronate decreases osteoclast recruitment, decreases osteoclast activity and increases osteoclast apoptosis (53). Erosive esophagitis has been reported with the use of pamidronate sodium. 

Hypercalcemia of malignancy is a common occurrence in solid tumors of the lung and breast as well as multiple myeloma and adult T-cell lymphoma/leukemia (26). The hypercalcemia associated with breast cancer is usually seen in late stages of the disease in patients with extensive bone metastases. In squamous cell carcinoma of the lung or kidney, however, hypercalcemia is not correlated with disease stage and is not necessarily associated with bone metastases. The hypercalcemia results from increased bone resorption, decreased bone formation and increased renal tubular calcium reabsorption. These findings suggest that some tumors may secrete humoral factors with PTH-like actions. 

In hospitalized patients, hypercalcemia of malignancy is the major cause of hypercalcemia (26,, , 54). In two separate studies, 9X of all cancer patients had hypercalcemia of malignancy (. 56). Hypercalcemia of malignancy is most common in solid tumors such as carcinomas of the lung, breast, kidney, pancreas and ovary, but also occurs with multiple myeloma and adult T-cell lymphoma/ leukemia. It has been estimated that there is approximately an equal distribution between humoral factors and metastatic bone tumors for causing hypercalcemia of malignancy (26,57,58). 

Aredia, pamidronate disodium (APD), is a bone-resorption inhibitor used to treat hypercalcemia associated with malignancy and osteolytic bone lesions associated with multiple myeloma, metastatic breast cancer, and moderate to severe Paget s disease of bone. Aredia, a member of the group of chemical compounds known as bisphosphonates, is an analog of pyrophosphate. Pamidronate disodium is designated chemically as phosphonic acid (3-amino-l-hydroxypropylidene) bis-, disodium salt, pentahydrate, (APD). 

Pamidronate is one of the first drugs that has been proven to reduce the incidence of skeletal complications of metastatic breast cancer and prostate cancer. It also relieves bone pain caused by metastatic bone lesions. Other indications include treatment of osteolytic bone lesions of multiple myeloma, moderate-to-severe hypercalcemia of malignancy, and moderate-to-severe bone lesions due to Paget s disease. 

Total Synthesis of Madindolines Madindo-lines are the selective inhibitors of interleukin 6 (IL-6), which is responsible for various lethal diseases like cancer cachexia, Castleman s disease,rheumatoid arthritis,hypercalcemia, and multiple myeloma. In 2005, Omura and Sunazuka published a total synthesis of madindolines via reductive amination. " The first-generation synthesis afforded the target compound in 7.8% overall yield in 19 linear steps (Scheme 39.53). 

---