Since their introduction to the clinic 10 years ago, proteasome inhibitors have become the cornerstone of anti-multiple myeloma therapy. Despite significant progress in understanding the consequences of proteasome inhibition, the unique activity of bortezomib is still unclear. Disappointing results from clinical trials with bortezomib in other malignancies raise the question of what makes multiple myeloma so sensitive to proteasome inhibition. Successful administration of bortezomib in various immunological disorders that exhibit high antibody production suggests that the balance between protein synthesis and degradation is a key determinant of sensitivity to proteasome inhibition because a high rate of protein production is a shared characteristic in plasma and myeloma cells. Initial or acquired resistance to bortezomib remains a major obstacle in the clinic as in vitro data from cell lines suggest a key role for the β5 subunit mutation in resistance; however the mutation was not found in patient samples. Recent studies indicate the importance of selecting for a subpopulation of cells that produce lower amounts of paraprotein during bortezomib therapy.

• Klíčová slova
• Autoimmune diseases, Bortezomib, Multiple myeloma, Proteostasis, Resistance, Ubiquitin-proteasome system,
• MeSH
• autoimunitní nemoci farmakoterapie   metabolismus   MeSH
• bortezomib MeSH
• kyseliny boronové terapeutické užití   MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   metabolismus   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyraziny terapeutické užití   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• bortezomib MeSH
• kyseliny boronové MeSH
• protinádorové látky MeSH
• pyraziny MeSH

Bortezomib represents a novel biological and targeted treatment modality with excellent treatment results in multiple myeloma patients. Bortezomib has also been successfully used several times in heavily pre-treated patients with myeloma relapse or progression after allogeneic stem cell transplantation. Its immunomodulatory effect, mediated, for instance, through the selective apoptosis of alloreactive T-lymphocytes and inhibition of the nuclear factor kappa B, brings the potential of graft versus host disease management, while the immunological anti-tumour effect remains preserved. Apart from thrombocytopenia, neurotoxicity most likely potentiated by concomitant and long-term use of cyclosporine is the major side effect of the treatment. The impact and modulation of graft versus host disease remains controversial in clinical practice. Bortezomib is effective and feasible in the post-transplant setting.

• MeSH
• bortezomib MeSH
• homologní transplantace MeSH
• inhibitory proteas terapeutické užití   MeSH
• kombinovaná terapie MeSH
• kyseliny boronové terapeutické užití   MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   terapie   MeSH
• nemoc štěpu proti hostiteli farmakoterapie   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyraziny terapeutické užití   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• bortezomib MeSH
• inhibitory proteas MeSH
• kyseliny boronové MeSH
• protinádorové látky MeSH
• pyraziny MeSH

BACKGROUND: Previous results from an interim analysis of an open-label, randomized, phase 3 study demonstrated that bortezomib combined with pegylated liposomal doxorubicin (PLD) was superior to bortezomib monotherapy in patients with relapsed/refractory multiple myeloma who had previously received one or more lines of therapy. Protocol-defined final survival data from that study are provided here. METHODS: Patients were randomized (1:1) to receive either bortezomib alone (1.3 mg/m(2) intravenously on days 1, 4, 8, and 11 of every 21-day cycle) or bortezomib-PLD (bortezomib plus PLD 30 mg/m(2) intravenously on day 4). The primary endpoint was the time to progression. Secondary efficacy endpoints included overall survival (OS), progression-free survival, and the overall response rate. RESULTS: In total, 646 patients (bortezomib-PLD, n = 324; bortezomib alone, n = 322) were randomized between December, 2004, and March, 2006. On the clinical cutoff date (May 16, 2014) for the final survival analysis, at a median follow-up of 103 months, 79% of patients had died (bortezomib-PLD group: 253 of 324 patients; 78%; bortezomib alone group: 257 of 322 patients; 80%). The median OS in the bortezomib-PLD group was 33 months (95% confidence interval [CI], 28.9-37.1) versus 30.8 months (95% CI, 25.2-36.5) in the bortezomib alone group (hazard ratio, 1.047; 95% CI, 0.879-1.246; P = .6068). Salvage therapies included conventional and novel drugs, which were well balanced between the two treatment groups. CONCLUSIONS: Despite inducing a superior time to progression, long-term follow-up revealed that PLD-bortezomib did not improve OS compared with bortezomib alone in patients with relapsed/refractory multiple myeloma. The inability to sustain the early observed survival advantage may have been caused by the effects of subsequent lines of therapy, and underscores the need for long-term follow-up of phase 3 trials while recognizing the challenge of having adequate power to detect long-term differences in OS. Cancer 2016;122:2050-6. © 2016 American Cancer Society.

• Klíčová slova
• bortezomib, doxorubicin, multiple myeloma, pegylated liposomal doxorubicin, survival,
• MeSH
• bortezomib aplikace a dávkování   terapeutické užití   MeSH
• doxorubicin aplikace a dávkování   analogy a deriváty   terapeutické užití   MeSH
• intravenózní podání MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• mnohočetný myelom farmakoterapie   mortalita   MeSH
• polyethylenglykoly aplikace a dávkování   terapeutické užití   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   terapeutické užití   MeSH
• rozvrh dávkování léků MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• bortezomib MeSH
• doxorubicin MeSH
• liposomal doxorubicin MeSH Prohlížeč
• polyethylenglykoly MeSH

UNLABELLED: According to the criteria for multiple myeloma, systemic AL-amyloidosis may be divided into primary systemic AL-amyloidosis, where monoclonal gametopathy is present but the criteria for multiple myeloma are not satisfied, and systemic AL-amyloidosis with underlying multiple myeloma. There is a continuous transition between the two units. The present paper describes treatment of patients with established systemic AL-amyloidosis who satisfy the 2003 International Myeloma Working Groups criteria for symptomatic multiple myeloma (confirmed monoclonal immunoglobulin, clonal plasmocytes confirmed in the bone marrow and at least one clinical symptom of myeloma - confirmed amyloid). From 2009, a total of 10 patients with AL-amyloidosis and underlying multiple myeloma have been treated at our centre with combined bortezomib-containing regimens. The cohort includes 5 women and 5 men. Median age of these AL-amyloidosis patients at the diagnosis was 65.5 years. All 10 patients were treated with a combination of 3 drugs, bortezomib, cyclophosphamide and dexamethasone or bortezomib, doxorubicin a dexamethasone. Two of the 10 patients died during the first month of treatment. Treatment response cannot be evaluated in these patients. Haematological treatment response was evaluable in 8 patients only. Monoclonal immunoglobulin disappearance with negative urine and serum immunofixation and normalization of free light chain immunoglobulins was observed in six of the 8 patients. Treatment response according to the current IMWG was evaluated as very good partial remission (VGPR) as we did not perform bone marrow testing after the treatment to confirm complete remission according to the current criteria. One of the 8 evaluated patients died due to disease progression in the third month of treatment and there was no haematological treatment response in one who was considered to have a stable disease. Organ treatment response was evaluated in patients who were followed up for longer than 3 months of treatment only. Organ treatment response (reduced cardiac impairment) was not evaluable in a patient who had heart transplantation and then received chemotherapy. A total of 5 (83%) of the 6 evaluated patients fulfilled the criteria of organ treatment response. CONCLUSION: Our small cohort showed a high number of haematological treatment responses (VGPR in 75% of patients) as well as organ treatment response in patients with systemic AL-amyloidosis who were treated with bortezomib-containing treatment regimens.

• MeSH
• amyloidóza komplikace   farmakoterapie   MeSH
• bortezomib MeSH
• cyklofosfamid aplikace a dávkování   MeSH
• dexamethason aplikace a dávkování   MeSH
• doxorubicin aplikace a dávkování   MeSH
• kyseliny boronové aplikace a dávkování   MeSH
• lidé MeSH
• mnohočetný myelom komplikace   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• pyraziny aplikace a dávkování   MeSH
• senioři MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• Názvy látek
• bortezomib MeSH
• cyklofosfamid MeSH
• dexamethason MeSH
• doxorubicin MeSH
• kyseliny boronové MeSH
• pyraziny MeSH

BACKGROUND: Multiple myeloma is the second most prevalent and mostly fatal hematologic cancer. Further advances have been made in understanding the mechanisms involved in the myeloma pathogenesis and elucidation of critical signalling pathways as therapeutical targets. Proteasome inhibitors are the example of this new approach and bortezomib is the first agent in this class to enter clinical trials. METHODS AND RESULTS: In 6 hematological centers in Czech Republic 29 patients with refractory/relapsed myeloma had been treated with bortezomib (Velcade, Millennium Pharmaceuticals) in 2004. The initial dose 1.3 mg/m2 of Velcade was given, in 1 case the dose was adjusted due to pre-existing renal failure to 1 mg/m2. The response was achieved in 17 patients (59%). Four patients had complete, 11 partial and two minor responses. In 5 cases stabilization of disease was observed and 6 patients progressed during the therapy. CONCLUSIONS: Unfortunately, one patient died immediately after the start of therapy due to sepsis. The most common adverse events were thrombocytopenia, anaemia, neuropathy, gastrointestinal complication, renal failure and fatigue. Grade 4 adverse events occurred in 37.9% of patients (4x thrombocytopenia, 2x gastrointestinal, 2x renal failure, 1x sepsis, leucopenia, hepatopathy and anaemia, respectively). Peripheral neuropathic pain of grade 3 was reported in 4 cases, in one patient therapy had to be interrupted due to this complication. We confirmed promising results of phase II trials.

• MeSH
• bortezomib MeSH
• dospělí MeSH
• inhibitory proteas terapeutické užití   MeSH
• kyseliny boronové terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   MeSH
• protinádorové látky terapeutické užití   MeSH
• pyraziny terapeutické užití   MeSH
• recidiva MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• anglický abstrakt MeSH
• časopisecké články MeSH
• multicentrická studie MeSH
• Názvy látek
• bortezomib MeSH
• inhibitory proteas MeSH
• kyseliny boronové MeSH
• protinádorové látky MeSH
• pyraziny MeSH

We report on six cases of skin lesions induced by bortezomib in patients treated for relapsed multiple myeloma. The folliculitis-like rash appeared in the second cycle of bortezomib therapy. Therapy with prednisone led to rapid resolution of the skin lesions. Prednisone 10 mg before each infusion of bortezomib was necessary to prevent recurrence of the rash while antihistamines alone were ineffective.

• MeSH
• bortezomib MeSH
• cetirizin terapeutické užití   MeSH
• dexamethason terapeutické užití   MeSH
• exantém chemicky indukované   farmakoterapie   MeSH
• imunokompromitovaný pacient MeSH
• imunosupresiva terapeutické užití   MeSH
• kombinovaná terapie MeSH
• kyseliny boronové škodlivé účinky   terapeutické užití   MeSH
• léková dermatitida farmakoterapie   etiologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   terapie   MeSH
• nesedativní H1-antihistaminika terapeutické užití   MeSH
• prednison terapeutické užití   MeSH
• protinádorové látky škodlivé účinky   terapeutické užití   MeSH
• pyraziny škodlivé účinky   terapeutické užití   MeSH
• transplantace periferních kmenových buněk MeSH
• záchranná terapie MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• bortezomib MeSH
• cetirizin MeSH
• dexamethason MeSH
• imunosupresiva MeSH
• kyseliny boronové MeSH
• nesedativní H1-antihistaminika MeSH
• prednison MeSH
• protinádorové látky MeSH
• pyraziny MeSH

BACKGROUND: Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival. RESULTS: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion. CONCLUSIONS: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).

• MeSH
• antigeny CD38 antagonisté a inhibitory   MeSH
• bortezomib aplikace a dávkování   škodlivé účinky   MeSH
• chemorezistence MeSH
• dexamethason aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• intravenózní infuze MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• recidiva MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antigeny CD38 MeSH
• bortezomib MeSH
• daratumumab MeSH Prohlížeč
• dexamethason MeSH
• monoklonální protilátky MeSH

Proteasome inhibition is a modern and surprisingly successful approach how to cancer treatment. Bortezomib (Velcade®) is a first-in-class proteasome inhibitor and has been approved for first-line treatment of multiple myeloma and second-line treatment of mantle cell lymphoma. There have been almost 200 clinical trials with bortezomib, both as a single agent and in combination with other drugs, for various cancers, as listed in the US National Cancer Institute database. However, bortezomib's mechanism of action remains elusive despite enormous progress in our knowledge of the cell biology of the ubiquitin-proteasome system (UPS) and bortezomib-induced signaling events in cancer cells. This review maps a rapidly growing and open body of research in both areas.

• MeSH
• bortezomib MeSH
• inhibitory proteas farmakologie   MeSH
• inhibitory proteasomu MeSH
• kyseliny boronové farmakologie   MeSH
• lidé MeSH
• nádory farmakoterapie   patologie   MeSH
• proteasomový endopeptidasový komplex metabolismus   MeSH
• protinádorové látky farmakologie   MeSH
• pyraziny farmakologie   MeSH
• ubikvitin metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• bortezomib MeSH
• inhibitory proteas MeSH
• inhibitory proteasomu MeSH
• kyseliny boronové MeSH
• proteasomový endopeptidasový komplex MeSH
• protinádorové látky MeSH
• pyraziny MeSH
• ubikvitin MeSH

Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0-27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P<0.0001) and improved the overall response rate (83.8% versus 63.2%; P<0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% con fidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.

• MeSH
• bortezomib aplikace a dávkování   MeSH
• chemorezistence MeSH
• dexamethason aplikace a dávkování   MeSH
• dospělí MeSH
• hodnocení výsledků zdravotní péče metody   statistika a číselné údaje   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru MeSH
• mnohočetný myelom farmakoterapie   patologie   MeSH
• monoklonální protilátky aplikace a dávkování   MeSH
• následné studie MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• reziduální nádor diagnóza   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• bortezomib MeSH
• daratumumab MeSH Prohlížeč
• dexamethason MeSH
• monoklonální protilátky MeSH

In the phase 3 BOSTON study, patients with multiple myeloma (MM) after 1-3 prior regimens were randomized to once-weekly selinexor (an oral inhibitor of exportin 1 [XPO1]) plus bortezomib-dexamethasone (XVd) or twice-weekly bortezomib-dexamethasone (Vd). Compared with Vd, XVd was associated with significant improvements in median progression-free survival (PFS), overall response rate (ORR), and lower rates of peripheral neuropathy, with trends in overall survival (OS) favoring XVd. In BOSTON, 141 (35.1%) patients had MM with high-risk (presence of del[17p], t[4;14], t[14;16], or ≥4 copies of amp1q21) cytogenetics (XVd, n = 70; Vd, n = 71), and 261 (64.9%) exhibited standard-risk cytogenetics (XVd, n = 125; Vd, n = 136). Among patients with high-risk MM, median PFS was 12.91 months for XVd and 8.61 months for Vd (HR, 0.73 [95% CI, (0.4673, 1.1406)], p = 0.082), and ORRs were 78.6% and 57.7%, respectively (OR 2.68; p = 0.004). In the standard-risk subgroup, median PFS was 16.62 months for XVd and 9.46 months for Vd (HR 0.61; p = 0.004), and ORRs were 75.2% and 64.7%, respectively (OR 1.65; p = 0.033). The safety profiles of XVd and Vd in both subgroups were consistent with the overall population. These data suggest that selinexor can confer benefits to patients with MM regardless of cytogenetic risk. ClinicalTrials.gov identifier: NCT03110562.

• MeSH
• bortezomib škodlivé účinky   terapeutické užití   MeSH
• cytogenetické vyšetření MeSH
• dexamethason škodlivé účinky   terapeutické užití   MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• hydraziny škodlivé účinky   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mnohočetný myelom farmakoterapie   genetika   MeSH
• protinádorové látky škodlivé účinky   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• triazoly škodlivé účinky   terapeutické užití   MeSH
• výsledek terapie MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• bortezomib MeSH
• dexamethason MeSH
• hydraziny MeSH
• protinádorové látky MeSH
• selinexor MeSH Prohlížeč
• triazoly MeSH