Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The prolonged administration of bisphosphonates can reduce the frequency of morbid skeletal events in patients with metastatic breast carcinoma or multiple myeloma. The development of more potent bisphosphonates will simplify current therapeutic schemes and could improve the therapeutic effectiveness of bisphosphonate therapy. Zoledronate (CGP-42446) is the most potent of the clinically tested compounds. It is a cyclic third-generation bisphosphonate that is 100-850 times more active than pamidronate in several in vivo and in vitro pharmacological test systems. The first therapeutic trial with zoledronate has been performed in patients with tumor-induced hypercalcemia (corrected calcium [Ca] > 2.75 mmol/L after rehydration). In a Phase I multicenter trial, it was shown that a single infusion was already effective at dose levels of 0.02 and 0.04 mg of zoledronate/kg bodyweight, thus 1.2 and 2.4 mg total dose for an average 60-kg individual. Five of 5 patients became normocalcemic after a dose of 0.02 mg/kg, and 14 of 15 (93%) after a dose of 0.04 mg/kg. The median time to normalization of serum Ca was 2 days and the median duration of action was 33 days, suggesting that zoledronate has a faster onset and a longer duration of action than other clinically tested bisphosphonates. Zoledronate was well tolerated; the only side effect was an increase in body temperature in 30% of the cases, which was probably not drug-related in many patients. A Phase I trial also has been initiated in patients with lytic bone metastases. Zoledronate was given as monthly short infusions (5-30 minutes) at doses between 0.1-8.0 mg. There was an analgesic effect and even at low doses (2 mg and above), the effects on the biochemical markers of bone resorption appeared to be greater than after 90-mg pamidronate infusions. These initial human data suggest that zoledronate can be administered as convenient short intravenous infusions and lead to a more marked and a more prolonged inhibition of bone resorption than is currently possible with available compounds. Future trials will have to determine whether prolonged treatment with this extremely potent bisphosphonate also can have a greater effect on the morbidity of bone metastases.
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PMID:Clinical research update: zoledronate. 936 40

In a double blind randomized study, the bisphosphonate drug Pamidronate (Aredia) significantly protected Durie-Salmon stage III multiple myeloma patients from osteolytic bone disease. In the patient sub-group on salvage chemotherapy. Pamidronate treatment was also significantly associated with prolonged survival. To test if this drug could induce direct antitumor effects, we exposed myeloma cells to increasing concentrations of Pamidronate or a more potent bisphosphonate, Zoledronate. A concentration- and time-dependent cytotoxic effect was detected on four of five myeloma cell lines as well as three specimens obtained directly from myeloma patients. Zoledronate-induced cytotoxicity was significantly greater than that of Pamidronate. Cytotoxicity could not be explained by bisphosphonate-induced chelation of extracellular calcium or secondary decrease in production of the myeloma growth factor interleukin-6. Morphological examination, DNA electrophoresis and cell cycle analysis indicated that the bisphosphonate-induced cytotoxic effect consisted of a combination of cytostasis and apoptotic myeloma cell death. Enforced expression of BCL-2 protected against the apoptotic death but not against cytostasis. Most cytotoxic effects were seen between 10 and 100 microM of drug. The results suggest a possible direct anti-tumor effect in myeloma patients treated with bisphosphonates which may participate in their significantly increased survival. This hypothesis should now be further tested in clinical trials.
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PMID:In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. 951 85

Metastatic bone disease is a frequent cause of morbidity in advanced cancer patients with a subsequent high incidence of skeletal complications (fractures, hypercalcemia, spinal cord compression) and severe pain. The osteolytic process is mainly characterized by an osteoclastic activity of bone resorption and inflammatory activity provoked by various cytokines and prostaglandins. Bisphosphonates represent a new class of drugs with inhibitory activity on bone resorption and on inflammatory processes which revealed themselves to be efficacious in a series of clinical conditions such as tumour-induced hypercalcemia, Paget's disease, osteoporosis and metastatic bone disease. The aim of this review of the literature is to show the analgesic efficacy of the different bisphosphonates in phase III studies carried out on patients with metastatic bone disease. Medline and Cancerlit database from January 1984 to February 1998 have been considered. From the analysis of the published studies it appears that bisphosphonates and, in particular, intravenous Disodium Pamidronate, are not only able to slow down the progression of the disease and to reduce the onset of skeletal complications but also have an analgesic effect and the possibility of improving the quality of life, above all in patients with osteolytic metastases due to breast cancer and multiple myeloma. Bisphosphonates represent a further valid therapy to add to an already consolidated list of therapies such as radio, chemo and endocrine therapy, analgesic drugs, orthopaedic and physiatric in the pain management of patients with bone metastases. These drugs meet with the patients' compliance, are well-tolerated as well as having a good cost/efficacy profile. It still remains to be seen if the newer and more potent bisphosphonates such as Ibandronate and Zoledronate can be administered differently from the intravenous route such as by mouth or by patch which are readily accepted by the patient and, moreover, if these more potent drugs are able to prevent or delay the onset and/or the progression of bone metastases.
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PMID:The role of bisphosphonates in the treatment of painful metastatic bone disease: a review of phase III trials. 987 May 69

Metastatic bone disease develops as a result of the many interactions between tumour cells and bone cells. This leads to disruption of normal bone metabolism, with the increased osteoclast activity seen in most, if not all, tumor types providing a rational target for treatment. The clinical course of metastatic bone disease in multiple myeloma, breast and prostate cancers is relatively long, with patients experiencing sequential skeletal complications over a period of several years. These include bone pain, fractures, hypercalcaemia, and spinal cord compression, all of which may profoundly impair a patient's quality of life. External beam radiotherapy and systemic endocrine and cytotoxic treatments are the mainstay of treatment in advanced cancers. However, it is now clear that the bisphosphonates provide an additional treatment strategy, which reduces both the symptoms and complications of bone involvement. Pamidronate (Aredia(TM)) is the most widely evaluated bisphosphonate and is recommended for most patients with multiple myeloma or breast cancer with bone metastases. Current research aims include the evaluation of new potent bisphosphonates such as zoledronic acid (Zometa(TM)). It is hoped that this compound is not only more convenient and easier to administer but also more effective in inhibiting skeletal morbidity. Zometa may also have some direct anticancer activity. Preclinical studies with Zometa have demonstrated its potential in malignant bone disease. Clinical studies in treatment of hypercalcemia of malignancy have been completed, as have Phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled Phase III trials are now ongoing to establish the efficacy and safety of Zometa in treatment of bone metastases in patients with osteolytic and osteoblastic lesions. Additionally, new specific molecules such as osteoprotogerin have been developed that are based on our improved understanding of the cellular signalling mechanisms involved in cancer induced bone disease. These potent molecules are now entering clinical trials. Ongoing research is aimed at trying to define the optimum route, dose, schedule and type of bisphosphonate in metastatic bone disease and their use in the prevention and treatment of osteoporosis in cancer patients. In vitro suggestions of direct anti-cancer activity and some promising clinical data in early breast cancer have resulted in considerable interest in the possible adjuvant use of bisphosphonates to inhibit the development of bone metastases.
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PMID:Optimising treatment of bone metastases by Aredia(TM) and Zometa(TM). 1111 66

Preclinical studies with zoledronic acid (Zometa; Novartis Pharmaceuticals Corp, East Hanover, NJ) have shown its potential in malignant bone disease. Clinical studies in the treatment of hypercalcemia of malignancy have been completed, as have phase I and II trials in patients with cancer and pre-existing bone metastases. Three randomized, double-blind, controlled phase III trials are ongoing to establish the efficacy and safety of zoledronic acid in the treatment of osteolytic and osteoblastic bone metastases. In one study, 4 mg zoledronic acid is compared with the standard therapy, 90 mg pamidronate, in treatment of osteolytic lesions in patients with breast cancer and multiple myeloma. Two other studies, one in patients with prostate cancer and bone metastases and another in patients with non-small cell lung cancer and other tumor types, are placebo-controlled. The primary end point in all three studies is the frequency of skeletal complications resulting from bone metastases. Adjuvant trials that assess the ability of zoledronic acid to prevent or reduce the incidence of bone metastases in patients at high risk for future skeletal metastasis are also planned or ongoing. The rationale and design of these ongoing and planned studies is discussed.
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PMID:The role of zoledronic acid in cancer: clinical studies in the treatment and prevention of bone metastases. 1134 60

Zoledronic acid (Zometa, Novartis Pharmaceuticals Corp, East Hanover, NJ) is a new, highly potent bisphosphonate that may provide improved management of skeletal complications in cancer patients with bone metastases. A total of 383 cancer patients with osteolytic bone lesions was evaluated in two phase I studies and one phase II study of zoledronic acid. The phase I studies used two dosing regimens, either a 5-minute monthly intravenous infusion of 0.1 to 8 mg administered for 3 or more months or a single 30 to 60 second intravenous bolus of 1 to 16 mg. Zoledronic acid was well tolerated in the two phase I studies and a maximum tolerated dose was not reached in either study. A dose-dependent decrease in urinary markers of bone resorption was observed with the monthly 5-minute infusion. A single intravenous bolus of doses ranging from 2 to 16 mg zoledronic acid suppressed biochemical markers of bone resorption for up to 8 weeks. The phase II study evaluated a 5-minute infusion of 0.4, 2, or 4 mg zoledronic acid and a 2-hour infusion of 90 mg pamidronate in 280 patients with bone metastases and multiple myeloma or breast cancer. Significantly fewer patients receiving the 2 and 4 mg doses of zoledronic acid or 90 mg pamidronate required radiation therapy to bone than those patients receiving a 0.4 mg dose of zoledronic acid. Only 30% to 35% of patients in the 2 and 4 mg zoledronic acid groups or in the pamidronate group experienced any skeletal related event compared with 46% in the 0.4 mg zoledronic acid group. Adverse events consistent with an acute phase reaction were observed with both bisphosphonates. No new, unexpected adverse events were observed with this novel bisphosphonate. These studies support the further evaluation of zoledronic acid in cancer patients with osteolytic metastases. Doses of 0.4 mg or less are ineffective, while rapid infusion of more than 8 mg may increase the risk of renal dysfunction. A 4 mg dose given as a brief infusion appears to offer an excellent benefit/risk ratio for further evaluation in phase III trials.
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PMID:Zoledronic acid in cancer patients with bone metastases: results of Phase I and II trials. 1134 62

Bisphosphonates (BPs) are potent inhibitors of osteoclast-mediated bone resorption, and it is well accepted that tumor cells in bone, especially breast cancer and myeloma cells, can stimulate osteoclast formation and activity leading to the release of growth factors or cytokines, which will further stimulate cancer cells' growth and their secretion of osteolytic factors. BPs are now the standard treatment for cancer hypercalcemia, for which a dose of 90 mg of pamidronate or 1500 mg of clodronate is recommended; the former compound is more potent and has a longer lasting effect. Repeated pamidronate infusions exert clinically relevant analgesic effects in more than half of patients with metastatic bone pain. Recent data suggest that non-responding patients should perhaps be treated with higher doses. The optimal dose actually remains to be defined, especially as it is thought that it is probably a function of the disease stage. Regular pamidronate infusions can also achieve a partial objective response according to conventional UICC criteria and they can almost double the objective response rate to chemotherapy. Lifelong administration of oral clodronate to patients with breast cancer metastatic to bone reduces the frequency of morbid skeletal events by more than one-fourth. Two double-blind randomized placebo-controlled trials comparing monthly 90 mg pamidronate infusions to placebo infusions for 1-2 years in addition to hormone or chemotherapy in patients with at least one lytic bone metastasis have shown that the mean skeletal morbidity rate could be reduced by 30-40%. The results obtained with intravenous BPs are generally viewed as better than those obtained with oral clodronate. However, preference can be given to the oral route when BPs are started early in the process of metastatic bone disease in a patient receiving hormone therapy. According to the recently published ASCO guidelines, pamidronate 90 mg i.v. delivered over 2 h every 3-4 weeks can be recommended in patients with metastatic breast cancer who have imaging evidence of lytic destruction of bone and who are concurrently receiving systemic therapy with hormonal therapy or chemotherapy. Furthermore, the ASCO Panel considered it "reasonable" to start i.v. BPs in women with localized pain whose bone scans were abnormal and plain radiographs normal, but not when an abnormal bone scan is asymptomatic. The pertinence of these criteria is discussed below. Because BPs are providing supportive care, reducing the rate of skeletal morbidity but evidently not abolishing it, the criteria for stopping their administration have to be different from those used for classic antineoplastic drugs, and they should not be stopped when metastatic bone disease is progressing. However, criteria to determine whether and for how long an individual patient benefits from their administration are lacking. New biochemical markers of bone resorption might help identify those patients continuing to benefit from therapy. Even better results have been achieved in patients with multiple myeloma, and the general consensus is that BPs should be started as soon as the diagnosis of lytic disease is made in myeloma patients. On the other hand, data are scanty in prostate cancer, but large-scale trials with potent BPs are ongoing or planned in such patients. Similar results to those achieved with pamidronate have been obtained with monthly 6-mg infusions of the newer BP ibandronate in patients with breast cancer metastatic to bone. The tolerance of ibandronate could be better, and the drug has the potential to be administered as a 15- to 30-min infusion. Zoledronate can also be administered safely as a 15-min 4-mg infusion, and large scale phase III trials have just been completed. These newer BPs will simplify the current therapeutic schemes and improve the cost-effectiveness ratio; they also have the potential to improve the therapeutic efficacy, at least in patients with an aggressive osteolytic disease or when given as adjuvant therapy. For that matter, initial data with clodronate indicate that they have the potential to prevent the development of bone metastases, but the use of BPs in the adjuvant setting must still be viewed as experimental.
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PMID:Bisphosphonates for cancer patients: why, how, and when? 1213 23

The purpose of this report is to summarize information on drugs recently approved by the U.S. Food and Drug Administration. Three drugs have recently been approved: Gleevec (imatinib mesylate) at a starting dose of 400 or 600 mg daily for the treatment of malignant unresectable and/or metastatic gastrointestinal stromal tumors; Mesnex (mesna) tablets as a prophylactic agent to reduce the incidence of ifosfamide-induced hemorrhagic cystitis, and Zometa (zoledronic acid) for the treatment of patients with multiple myeloma and for patients with documented bone metastases from solid tumors, in conjunction with standard antineoplastic therapy. Prostate cancer should have progressed after treatment with at least one hormonal therapy. The recommended dose and schedule is 4 mg infused over 15 minutes every 3-4 weeks. These three drugs represent three different types of drug approval: Gleevec is an accelerated approval and supplemental new drug application (NDA); Mesnex tablets represent an oral formulation of a drug approved 14 years ago as an intravenous formulation, and Zometa represents a standard NDA for a noncytotoxic, supportive-care drug. Information provided includes rationale for drug development, study design, efficacy and safety results, and pertinent literature references.
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PMID:U.S. Food and Drug Administration drug approval summaries: imatinib mesylate, mesna tablets, and zoledronic acid. 1240 1

Bone disease characterised by osteolytic lesions, pathological fractures and hypercalcaemia is an important clinical feature in multiple myeloma. Pain, decreased performance status, and the need for palliative radiotherapy and surgical interventions are common sequelae. Bisphosphonates act primarily on osteoclasts to inhibit excessive bone resorption, and have therefore been investigated in myeloma patients to ameliorate the clinical consequences of the bone disease. Bisphosphonates are currently the therapy of choice in myeloma patients with hypercalcaemia. In long-term management, both oral clodronate and intravenous pamidronate are effective in reducing skeletal-related events. Zoledronic acid seems to be as effective as pamidronate. Whether bisphosphonates have antimyeloma activity is currently unknown. Cost-benefit analyses have shown reasonable efficacy with acceptable costs. Bisphosphonate therapy is now accepted as an important part of care in myeloma patients, although much still has to be learned in order to optimise this therapy in multiple myeloma.
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PMID:Bisphosphonate therapy in multiple myeloma: past, present, future. 1293 Mar 27

Bone metastases are a common feature of a variety of solid tumors and are associated with substantial skeletal morbidity, including severe bone pain and pathologic fractures. Treatment with bisphosphonates, primarily pamidronate, is the current standard of care for patients with breast cancer and multiple myeloma who have predominantly osteolytic lesions. However, until recently no bisphosphonate had demonstrated efficacy in patients with osteoblastic lesions, which are common during the progression of prostate cancer and other solid tumors. Zoledronic acid, a potent, new-generation, nitrogen-containing bisphosphonate, has demonstrated significant benefits for patients with bone metastases resulting from a broad range of primary tumors, including multiple myeloma and breast, lung, kidney, and prostate cancers, and other solid tumors. Benefits include a decreased incidence of pathologic fractures and longer time to the first skeletal complication. Zoledronic acid is the first and only bisphosphonate to be proved effective in patients with all types of bone lesions, from osteolytic to osteoblastic, and therefore represents an important therapeutic advancement in the treatment of bone metastases.
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PMID:Broad clinical activity of zoledronic acid in osteolytic to osteoblastic bone lesions in patients with a broad range of solid tumors. 1256 47


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