Bortezomib in the front-line treatment of multiple myeloma

Primary glioblastoma multiforme is an aggressive brain tumor that has no cure. Current treatments include gross resection of the tumor, radiation and chemotherapy. Despite valiant efforts, prognosis remains dismal. A promising new technique involves the use of oncolytic viruses that can specifically replicate and lyse in cancers, without spreading to normal tissues. Currently, these are being tested in relevant preclinical models and clinical trials as a therapeutic modality for many types of cancer. Results from recent clinical trials with oncolytic viruses have revealed the safety of this approach, although evidence for efficacy remains elusive. Oncolytic viral strategies are summarized in this review, with a focus on therapies used in brain tumors.     

Bortezomib in the front-line treatment of multiple myeloma

Front-line therapy for multiple myeloma is rapidly evolving with the development of new, highly active regimens based on novel agents such as bortezomib. Bortezomib-based regimens are demonstrating substantial efficacy both as induction prior to stem cell transplantation and as treatment for patients ineligible for transplant, offering rapid and durable responses with consistently high rates of complete response, a surrogate end point for improved overall survival. Combinations of bortezomib plus established and novel agents, such as melphalan-prednisone, dexamethasone, doxorubicin, thalidomide-dexamethasone and, most recently, lenalidomide-dexamethasone, are proving superior to or more promising than previous standards of care. Importantly, these regimens are demonstrating enhanced activity across the front-line population, including patients with renal impairment, high-risk cytogenetics and advanced bone disease. Impressive Phase 3 results with bortezomib-melphalan-prednisone, bortezomib-dexamethasone and bortezomib-thalidomide-dexamethasone should facilitate the establishment of these highly effective regimens as key therapies for newly diagnosed myeloma.     

Bortezomib in multiple myeloma: treatment approach and outcomes

Because multiple myeloma (MM) remains incurable, new therapeutic approaches are needed. Proteasome inhibition represents a new therapeutic strategy with the potential to inhibit multiple pathogenic pathways in MM. In phase I trials, the novel proteasome inhibitor bortezomib demonstrated encouraging activity in patients with advanced MM. In the SUMMIT phase II trial, 202 heavily pre-treated patients with relapsed and refractory MM received bortezomib 1.3 mg/m² twice weekly for 2 weeks, followed by a 1-week rest. The overall response rate, defined as complete + partial + minimal responses (CR + PR + MR), was 35%, with CR or near-CR in 10% of patients. Median duration of response was 12 months and median duration of survival 16 months for all patients. Adverse effects included manageable gastrointestinal symptoms, thrombocytopaenia, and peripheral neuropathy. Thrombocytopaenia and neuropathy were generally reversible and occurred mainly in patients who already had these toxicities at time of enrollment. In the CREST phase II trial, 54 patients with relapsed or refractory MM after first-line therapy were randomised to receive bortezomib 1.0 mg or 1.3 mg/m², twice weekly for 2 weeks, followed by a 1-week rest. Overall response rates were 33% at the 1.0 mg dose and 50% at the 1.3 mg dose. Toxicities were similar to those seen in SUMMIT, with nausea, diarrhoea and peripheral neuropathy occurring more frequently at the higher dose level. In conclusion, the results of the SUMMIT and CREST trials show that bortezomib is highly active in patients with relapsed and refractory MM. A large phase III trial comparing bortezomib with dexamethasone in relapsed MM patients was recently stopped after a pre-specified interim analysis showed a statistically significant improvement in time to disease progression for patients receiving bortezomib. Studies testing bortezomib as front-line therapy are ongoing.     

Bortezomib,doxorubicin and dexamethasone in advanced multiple myeloma

BackgroundBortezomib has shown significant activity in myeloma. In this multicenter trial, we assessed for the first time the combination of bortezomib, doxorubicin and low-dose dexamethasone (PAd) in the treatment of relapsed/refractory myeloma.Patients and methodsSixty-four patients were treated for a median of four 28-day cycles (1–6). Bortezomib was given at 1.3 mg/m² (days 1, 4, 8, 11) and dexamethasone at 40 mg (days 1–4); 34 patients receive doxorubicin at 20 mg/m² (days 1, 4) while 30 patients pegylated liposomal doxorubicin at 30 mg/m² (day 1).ResultsFifty-eight percent of patients had undergone prior autologous transplantation, 70% prior anthracycline and 27% prior bortezomib-based regimens. Forty-three patients (67%) achieved at least a partial response including 16 (25%) with at least a very good partial response. One-year event-free survival was 34% after PAd and 31% after the previous line of therapy (hazard ratio 1.20, 95% confidence interval 0.76–1.90, P = 0.43). One-year overall survival from the start of PAd was 66%. Grade 3–4 toxic effects included thrombocytopenia (48%), neutropenia (36%), infections (15%), anemia (13%), gastrointestinal disturbances (11%) and peripheral neuropathy (10%). Two patients had grade 3–4 cardiac heart failure.ConclusionsPAd is an active salvage therapy with manageable toxicity in patients with relapsed/refractory myeloma.     

Bortezomib in multiple myeloma: systematic review and clinical considerations

We conducted a systematic review to determine the appropriate use of bortezomib alone or in combination with other agents in patients with multiple myeloma (mm). We searched medline, embase, the Cochrane Library, conference proceedings, and the reference lists of included studies. We analyzed randomized controlled trials and systematic reviews if they involved adult mm patients treated with bortezomib and if they reported on survival, disease control, response, quality of life, or adverse effects.Twenty-six unique studies met the inclusion criteria. For patients with previously untreated mm and for candidates for transplantation, we found a statistically significant benefit in time to progression [hazard ratio (hr): 0.48, p < 0.001; and hr: 0.63, p = 0.006, respectively] and a better response with a bortezomib than with a non-bortezomib regimen (p < 0.001). Progression-free survival was longer with bortezomib and thalidomide than with thalidomide alone (p = 0.01). In non-candidates for transplantation, a significant benefit in overall survival was observed with a bortezomib regimen (hr compared with a non-bortezomib regimen: 0.61; p = 0.008), and in transplantation candidates receiving bortezomib, the response rate was improved after induction (p = 0.004) and after a first transplant (p = 0.016).In relapsed or refractory mm, overall survival (p = 0.03), time to progression (hr: 1.82; p = 0.000004), and progression-free survival (hr: 1.69; p = 0.000026) were significantly improved with bortezomib and pegylated liposomal doxorubicin (compared with bortezomib alone), and bortezomib monotherapy was better than dexamethasone alone (hr: 0.77; p = 0.027). Bortezomib combined with thalidomide and dexamethasone was better than either bortezomib monotherapy or thalidomide with dexamethasone (p < 0.001).In previously untreated or in relapsed or refractory mm patients, bortezomib-based therapy has improved disease control and, in some patients, overall survival.     

Bortezomib in combination with dexamethasone for relapsed multiple myeloma

Fifteen patients with advanced multiple myeloma were scheduled to receive bortezomib 1.3 mg/m2 IV days 1, 4, 8, and 11 every 3 weeks for eight cycles in combination with dexamethasone. One patient (7%) achieved a complete response, 10 (67%) a partial response, and one (7%) a minor response (MR) resulting in an overall response rate (> or = MR) of 80% (9/9 with > or = 2nd untreated and 3/6 with refractory relapse). Responses occurred after a median of 3 weeks and were independent of conventional prognostic parameters including deletion of chromosome 13. Adverse events, mainly myelosuppression, neuropathy and fatigue, were manageable.     

硼替佐米治疗多发性骨髓瘤发生药物性肝损害四例

 目的　观察硼替佐米治疗多发性骨髓瘤（MM）所致的肝脏损害甚至肝衰竭情况。方法　硼替佐米引起肝脏损害4例MM患者均为复发、难治性,男3例,女1例;年龄46～60岁;κ轻链型 2例 ,非分泌型1例,lgGλλ双克隆型1例 ;ⅢB期 3例,ⅢA期1例。结果　4例患者在硼替佐米治疗前肝功能均正常,在化疗中出现肝脏损害,谷氨酸氨基转移酶升高（为化疗前的2～80倍）,天冬氨酸氨基转移酶升高（为化疗前的1.5～70倍）,2例患者胆红素、碱性磷酸酶升高,1例患者γ-谷氨酰转肽酶升高。给予保肝及严重者停用硼替佐米后肝功能恢复正常。结论　硼替佐米在治疗MM时可引起肝脏损害。     

Bortezomib: a valuable new antineoplastic strategy in multiple myeloma

Although the treatment of multiple myeloma has improved over the past decade, the disease remains incurable. Bortezomib, a first-in-class selective proteasome inhibitor, was approved in the United States in 2003 and the European Union in 2004 for the treatment of relapsed and refractory multiple myeloma in patients who have received at least 2 prior therapies and demonstrated disease progression on the last therapy. In vitro, bortezomib induces apoptosis of multiple myeloma cells and inhibits cell adhesion within the bone marrow microenvironment. Preclinical and clinical data have shown that bortezomib enhances sensitivity and reverses resistance to standard therapeutic agents used in multiple myeloma. The efficacy and safety of bortezomib was established in patients with relapsed and/or refractory disease. In a large phase III trial in patients with relapsed multiple myeloma, median time to progression and overall survival were significantly improved with bortezomib compared with high-dose dexamethasone. Importantly, the preliminary results of several phase I and II studies are also showing high antimyeloma activity of bortezomib alone or in combination with dexamethasone or cytotoxic agents such as doxorubicin, melphalan, or thalidomide in patients with newly diagnosed multiple myeloma. Ideally, the introduction of bortezomib will result in a significant improvement in the future management of multiple myeloma.     

Bortezomib and its role in the management of patients with multiple myeloma

The multicatalytic proteinase complex, or proteasome, is responsible for the majority of regulated eukaryotic protein turnover through the ubiquitin–proteasome pathway. Bortezomib (Velcade^®, Millennium Pharmaceuticals, Inc.), the first drug specifically designed to target the proteasome, has recently entered the clinical arena. Previous preclinical studies showed that bortezomib had a unique cytotoxicity profile and that proteasome inhibition in vivo could be achieved safely with concomitant antitumor efficacy. In clinical studies, bortezomib has shown remarkable single-agent activity against relapsed and refractory multiple myeloma in both Phase I and II trials. Based on the latter, bortezomib has been approved by the US Food and Drug Administration for patients who have received two prior regimens and progressed on the second of these. Early results with bortezomib as a front-line therapy for multiple myeloma have shown a high response rate and further studies are ongoing. Preclinical studies support the possibility that modulation of proteasome function has great potential as a strategy for chemosensitization. Preliminary clinical trial results suggest that combinations using standard chemotherapeutics with bortezomib may have higher response rates in multiple myeloma than bortezomib as a single agent. Furthermore, these combinations may be able to recapture a response in patients whose disease was previously resistant to the standard agent, or bortezomib, or both. If borne out by additional studies, these results suggest that older treatment paradigms, in which drugs were used once but then discarded from the armamentarium upon disease progression, may need to be reassessed. Bortezomib may provide significant benefits to patients both alone and in combination with other agents and at several time points during the natural history of multiple myeloma.     

硼替佐米在多发性骨髓瘤治疗中的应用

硼替佐米通过抑制蛋白酶体的活性而抑制核因子-κB（NF-κB）的功能,具有选择性抗骨髓瘤活性。在新诊断、难治、复发多发性骨髓瘤患者中的应用,显示出了其他药物无可比拟的优势,具有缓解率高,能延长患者生存期等特点。尽管其副作用常见,但是可以控制。     

Bortezomib and its role in the management of patients with multiple myeloma

The multicatalytic proteinase complex, or proteasome, is responsible for the majority of regulated eukaryotic protein turnover through the ubiquitin-proteasome pathway. Bortezomib (Velcade, Millennium Pharmaceuticals, Inc.), the first drug specifically designed to target the proteasome, has recently entered the clinical arena. Previous preclinical studies showed that bortezomib had a unique cytotoxicity profile and that proteasome inhibition in vivo could be achieved safely with concomitant antitumor efficacy. In clinical studies, bortezomib has shown remarkable single-agent activity against relapsed and refractory multiple myeloma in both Phase I and II trials. Based on the latter, bortezomib has been approved by the US Food and Drug Administration for patients who have received two prior regimens and progressed on the second of these. Early results with bortezomib as a front-line therapy for multiple myeloma have shown a high response rate and further studies are ongoing. Preclinical studies support the possibility that modulation of proteasome function has great potential as a strategy for chemosensitization. Preliminary clinical trial results suggest that combinations using standard chemotherapeutics with bortezomib may have higher response rates in multiple myeloma than bortezomib as a single agent. Furthermore, these combinations may be able to recapture a response in patients whose disease was previously resistant to the standard agent, or bortezomib, or both. If borne out by additional studies, these results suggest that older treatment paradigms, in which drugs were used once but then discarded from the armamentarium upon disease progression, may need to be reassessed. Bortezomib may provide significant benefits to patients both alone and in combination with other agents and at several time points during the natural history of multiple myeloma.     

Bortezomib and the increased incidence of herpes zoster in patients with multiple myeloma

BackgroundBortezomib has significantly advanced the treatment of patients with multiple myeloma (MM). However, considering that most patients with MM are elderly, bortezomib-related morbidity should be thoroughly studied to ensure the safe use of this drug. Herpes zoster has been reported as a possible adverse event associated with bortezomib because a major target of bortezomib, nuclear factor—κB, is known to be involved with T-cell immunity.Patients and MethodsWe performed a retrospective analysis of the incidence of herpes zoster among 282 patients treated with a bortezomib-containing regimen.ResultsDuring the patients' pre-bortezomib treatment (median, 2.14 years), the incidence of herpes zoster was 11% (31 of 282 patients). However, after the patients were treated with bortezomib, the incidence increased to 22.3% (63 of 282 patients), of which almost all occurrences were within the first 3 cycles (median duration, 41 days). The time interval from diagnosis to bortezomib initiation date was shorter in herpes zoster—positive patients than in herpes zoster—negative patients (2.14 ± 1.87 years vs. 3.38 ± 2.95 years; P = .002). Disease duration, previous herpes zoster infection, disease stage and type of myeloma, and the type and intensity of previous treatments failed to show any relationship with herpes zoster. These findings suggest that longer history of disease and treatments did not affect the occurrence of herpes zoster, nor did the type of bortezomib regimens or their toxicities.ConclusionBortezomib can increase the incidence of herpes zoster regardless of disease duration, previous treatments, and concomitantly administered drugs. Thus, the occurrence of herpes zoster should be monitored during bortezomib treatment.     

A novel orally active proteasome inhibitor induces apoptosis in multiple myeloma cells with mechanisms distinct from Bortezomib

Bortezomib therapy has proven successful for the treatment of relapsed and/or refractory multiple myeloma (MM); however, prolonged treatment is associated with toxicity and development of drug resistance. Here, we show that the novel proteasome inhibitor NPI-0052 induces apoptosis in MM cells resistant to conventional and Bortezomib therapies. NPI-0052 is distinct from Bortezomib in its chemical structure, effects on proteasome activities, mechanisms of action, and toxicity profile against normal cells. Moreover, NPI-0052 is orally bioactive. In animal tumor model studies, NPI-0052 is well tolerated and prolongs survival, with significantly reduced tumor recurrence. Combining NPI-0052 and Bortezomib induces synergistic anti-MM activity. Our study therefore provides the rationale for clinical protocols evaluating NPI-0052, alone and together with Bortezomib, to improve patient outcome in MM.     

血管内皮生长因子与多发性骨髓瘤

多发性骨髓瘤(MM)是目前仍缺乏根治手段的浆细胞肿瘤,与骨髓微环境异常密切相关.研究表明,血管内皮生长因子(VEGF)是肿瘤微环境中血管形成最重要的生长因子,直接参与MM的发病和进展.目前正在MM患者中开展VEGF相关途径的靶向治疗.