Bone disease multiple myeloma

Bisphosphonates have been shown to be highly effective in osteoporosis, cancer bone metastasis, multiple myeloma, and Paget s disease of bone. While generally very well tolerated, these drugs do have potential adverse effects. Recently, the association of long-term high dose bisphosphonate treatment with osteonecrosis of the jaw has been described. This is a potentially serious side effect seen mostly in patients with multiple myeloma or... 

Boyd, K., Morgan, G., Davies, F., Wu, P., Gregory, W., Bell, S.E., Szubert, A., Navarro-Coy, N., Drayson, M., Owen, R.G., Feyler, S., Ashcroft, J., et al. (2011). Does zoledronic acid (ZOL) reduce skeletal-related events (SREs) and improve progression-free survival (PFS) in patients (Pts) with multiple myeloma (MM) with or without bone disease MRC myeloma IX study results J Clin Oncol 29(Suppl.) abstr 8010, 506pp. 

Autologous transplantation is commonly used in non-Hodgkin s lymphoma, Hodgkin s disease, multiple myeloma, and a relatively small subset of patients with solid tumors. A number of laboratory techniques are evolving to allow the bone marrow harvested for autologous transplantation to expand in the laboratory prior to infusion and to cleanse the marrow of potential malignant ceU contamination. 

G29. Gutman, A. B., Tyson, T. L., and Gutman, E. B., Serum calcium, inorganic phosphorus and phosphatase activity in hyperparathyroidism, Paget s disease, multiple myeloma and neoplastic diseases of the bones. Arch. Intern. Med. 57, 379-413 (1936). 

Multiple myeloma is a malignancy of plasma cells that is characterized by an abnormal production of a monoclonal protein. Features of the disease include bone lesions, anemia, and... 

The primary goal in the treatment of multiple myeloma is to decrease tumor burden and minimize complications associated with the disease. A watch and wait approach is an option for asymptomatic patients who have no lytic lesions in the bone. Once symptoms occur, treatment is required. Chemotherapy can be used to reduce tumor burden in patients with symptomatic disease, but increasingly, immunomodula-tors such as thalidomide and dexamethasone are initial therapy. Almost all patients will become refractory to initial treatment and will require the use of salvage therapies such as bortezomib. Autologous stem cell transplantation prolongs overall survival in patients who can tolerate high-dose chemotherapy and may be the treatment of choice for many patients. 

Bone disease is a common manifestation of multiple myeloma. Bisphosphonates should be initiated in symptomatic patients with bone lesions to slow osteopenia and reduce the fracture risk associated with the disease. Pamidronate and zolendronic acid have equivalent efficacy in the management of osteolytic lesions, but because of relative ease of administration, zolendronic acid is used most frequently.43 The use of zolendronic acid decreases pain and bone-related complications and improves quality of life. The suggestion that bisphosphonates have direct antimyeloma activity, based on the ability to inhibit NF-kB signaling, remains controversial. Recent cases of osteonecrosis of the jaw have been a major concern. Risk factors are unclear, but osteonecrosis of the jaw is more common in patients receiving intravenous administration of bisphosphonates and having dental procedures performed. It is recommended that patients... 

Leukemia, lymphoma, Hodgkin s disease, or multiple myeloma / Generalized malignancy / Chronic renal failure of nephritic syndrome / Patients receiving immunosuppressive therapy / Organ or bone marrow transplant recipients... 

Metastatic bone disease (MBD) is characterized by very high levels of bone turnover in regions proximal to the tumour [33]. Bone resorption inhibitors such as bisphosphonates represent the current standard of care for the treatment of bone metastases primarily due to breast or prostate cancer and multiple myeloma. It has been proposed that other strong anti-resorptives such as a Cat K inhibitor could be useful in the treatment of bone metastases. Evidence for this has been presented in the form of a preclinical MBD model in which human breast cancer cells are implanted into nude mice. Treatment with a Cat K inhibitor gave a significantly lower area of breast cancer-mediated osteolytic lesions in the tibia [34]. In a separate study, the efficacy of a Cat K inhibitor in the reduction in tumour-induced osteolysis was found to be enhanced in the presence of the bisphosphonate zolendronic acid [35,36]. When prostate cancer cells were injected into the tibia of SCID mice, treatment with a Cat K inhibitor both prevented and diminished the progression of cancer growth in bone [37]. 

Inhibition of IGF-IR autophosphorylation by NVP-ADW742 results in a plethora of pro-apoptotic molecular events that may account for its effectiveness as a single agent and in enhancing the antitumor activity of a broad spectrum of chemotherapeutic and anticancer targeted agents. Initial in vivo proof-of-concept of the potential therapeutic benefit of blocking IGF-IR kinase activity in tumor cells was obtained in an orthotopic multiple myeloma (MM) model of bone and bone marrow disease. In this mice model, MM... 

Unlabeled Uses Prevention and treatment of discoid lupus erythematosus, erythema multiforme, graft vs host reactions following bone marrow transplantation, rheumatoid arthritis treatment of Behget s syndrome, Crohn s disease, G1 bleeding, multiple myeloma, pruritus, recurrent aphthous ulcers in HIV patients, wasting syndrome associated with HIV or cancer... 

This plasma cell malignancy is one of the models of neoplastic disease in humans because it arises from a single tumor stem cell, and the tumor cells produce a marker protein (myeloma immunoglobulin) that allows the total body burden of tumor cells to be quantified. Multiple myeloma principally involves the bone marrow and the surrounding bone, causing bone pain, lytic lesions, bone fractures, and anemia as well as an increased susceptibility to infection. 

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). 

Serum IL-6 levels are usually very low or not measurable prior to middle age. However, subsequent IL-6 dysregulation results in increased production such that it is readily measurable in older persons even in the absence of inflammation. It has been suggested that dysregulation of IL-6 gene expression may be related to increased autoantibody production and the presence of benign paraproteinemia, both of which are commonly present in the elderly (Rl). Moreover, increased IL-6 levels may be responsible for the age-associated development of malignant B-cell tumors. In addition, Ershler (E4) noted that increased IL-6 has been associated with alteration of amyloid precursor protein, as is present in Alzheimer s disease, and stimulation of postmenopausal bone resorption. IL-6 has also been implicated in multiple myeloma, lymphoma, rheumatoid arthritis, Castleman s disease, and cardiac myxoma (E4). 

Nevertheless, phosphonocarboxylate derivatives have been considered for treatment of diseases characterized by excessive osteoclast-mediated bone resorption. For example, it has been demonstrated that 3-PEHPC treatment in the 5T2MM model of multiple myeloma prevents the development of myeloma bone disease in vivo and reduces the myeloma burden by inhibiting osteoclastic bone resorption [29]. Similarly, it has been shown that 3-PEHPC dose-dependently increases apoptosis in human myeloma cells similar to risedronate. However, while risedronate causes apoptosis and induces cell cycle arrest in the S-phase, no cell cycle arrest was detected after treatment with 3-PEHPC due to its different mechanism of action [30]. 

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. 

Uses. Three bisphosphonates (alendronate, etidronate, risedronate) are currently licensed in the UK for the treatment of osteoporosis (zoledronate is also effective), and the others are used in Paget s disease of bone, and hypercalcaemia due to cancer (pamidronate, clodronate, zoledronate). Bisphosphonates may also provide benefit for neoplastic disease that has spread to bone evidence indicates that clodronate by mouth and pamidronate i.v. are effective in the secondary prevention of bone metastases due to multiple myeloma and breast cancer. 

There are several acquired hematological disorders which have an increased synthesis of Hb-F [summarized in (H37, K13)], Thus, an elevated level of Hb-F is frequently observed in, for example, Fanconi s anemia, megaloblastic anemia, polycythemia vera, various types of leukemia, multiple myeloma and lymphomas, macroglobulinemia, and metastatic disease of the bone marrow. The chemical heterogeneity of the Hb-F in some of these disorders (aplastic anemia, Fanconi s anemia, and various forms of leukemia) has been studied (H60, R29). In many instances, the to ratio is similar to that found in the normal newborn. This is particularly striking for patients with various forms of leukemia, and the Hb-F which is produced in increased quantities in these disorders invariably has a °y to y ratio of about 3 1. This newborn ratio of °y to y chains in Hb-F may be a common factor in these diseases as perhaps another example of fetal characteristics in red cells of patients with leukemia, it supports the hypothesis that these cells may be of fetal origin (H25). 

Bisphosphonates are widely used for the prevention and treatment of osteopenia and osteoporosis and for the reduction of skeletal complications in patients with malignant bone disease. Several oral bisphosphonates, including alendronate, risedronate, and ibandronate, are approved worldwide for the treatment of osteoporosis in postmenopausal women, as are intravenous (i.v.) formulations of ibandronate (3 mg quarterly) and zoledronic acid (5 mg annually). Several i.v. bisphosphonates are available for the treatment of the skeletal complications that frequently occur in malignant disease, such as hypercalcaemia of malignancy (HCM), multiple myeloma, and bone metastases associated with solid tumours. Pamidronate is approved worldwide for the treatment of HCM, multiple myeloma, and breast cancer bone metastases. Although not registered for oncology indications in the United States, i.v. ibandronate is widely available elsewhere for HCM and breast cancer bone metastases. 

AE = Adverse event BC = Breast cancer CLOD = Clodronate EHDP = Etidronate HCM = Hypercalcaemia of malignancy IBN = Ibandronate i.v = Intravenous LC = Lung cancer MM = Multiple myeloma OST = Other solid tumours (renal, head and neck, thyroid, other) PDB = Paget s disease of bone PAM = Pamidronate PC = Prostatecancer PLA = Placebo PMO = Postmenopausal osteoporosis RIS = Risedronate ZOL = Zoledronicacid. 

Immunosuppressants are drugs capable of suppressing immune responses. They are used to treat autoimmune disease, aUergy, multiple myeloma, and chronic nephritis, and in organ transplantation. For example, immunosuppressants that are used to provide maintenance immunosuppression in solid organ and bone marrow transplant patients include cyclosporine, everoHmus (Ever), mycophe-nolic acid (MPA), Siro, and Tac (Figure 33-13). 

Abildgaard N, Brixen K, Kristensen JE, Eriksen EF, Nielsen JL, Heickendorff L. Comparison of five bio-chemical markers of bone resorption in multiple myeloma elevated pre-treatment levels of S-ICTP and U-Ntx are predictive of early progression of the bone disease during standard chemotherapy. Br J Hematoi 2003 120 235-42. 

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