Pokroky v léčbě mnohočetného myelomu, jehož incidence stoupá i u mladších ročníků, patří k jednomu z největších úspěchů onkologie posledních desetiletí. Díky tzv. biologickým či cíleným lékům se myelom změnil z prognosticky nepříznivé hematologické malignity na potenciálně kontrolovatelnou chorobu s možností vyléčení části pacientů. V současnosti představují páteřní léčbu cílené přípravky první, druhé a třetí generace, které v kombinaci s autologní transplantací kmenových buněk vedou k téměř 100% terapeutické odpovědi s více než 50% pravděpodobností dosažení kompletní remise. Medián přežití u mladších pacientů bez rizikových faktorů stoupá nad 10 let. U značné části nemocných je však efekt zástupců dostupných biologických přípravků zatím nedostatečný. Platí to zejména pro tzv. triple‑class refrakterní pacienty, tj. ty, kteří jsou refrakterní na léčbu všemi třemi třídami biologických léků (PI, IMIDy, protilátky anti‑CD38). Je proto nutné hledat nové léčebné možnosti.
Advances in the treatment of multiple myeloma, the incidence of which is increasing even in younger years, are one of the greatest achievements of oncology in recent decades. Thanks to the so‑called biological or targeted drugs, myeloma has changed from aprognostically unfavorable hematological malignancy to apotentially controllable disease with the possibility of curing some patients. At present, the first, second and third generation targeted preparations are the backbone treatments, which in combination with autologous stem cell transplantation led to almost 100% of the therapeutic response with more than 50% probability of achieving complete remission. The median survival in younger patients without risk factors rises above 10 years. However, in alarge part of patients, the effect of representatives of available biological preparations is still insufficient. This is especially true for so‑called triple‑class refractory patients, i.e. those who are refractory to all three classes of biological drugs (PI, IMIDs, anti‑CD38 antibodies). It is therefore necessary to look for new treatment options.
BACKGROUND: We have performed a head to head comparison of all-oral triplet combination of ixazomib, lenalidomide and dexamethasone (IRD) versus lenalidomide and dexamethasone (RD) in patients with relapsed and refractory multiple myeloma (RRMM) in the routine clinical practice. METHODS: A total of 344 patients treated with IRD (N = 127) or RD (N = 217) were selected for analysis from the Czech Registry of Monoclonal Gammopathies (RMG). Descriptive statistics were used to assess patient's characteristics associated with the respective therapy. The primary endpoint was progression free survival (PFS), secondary end points included response rates and overall survival (OS). Survival endpoints were plotted using Kaplan-Meier methodology at 95% Greenwood confidence interval. Univariable and multivariable Cox proportional hazards models were used to evaluate the effect of treatment regimens and the significance of uneven variables. Statistical tests were performed at significance level 0.05. RESULTS: In the whole cohort, median PFS for IRD was 17.5 and for RD was 11.5 months favoring the all-oral triplet, p = 0.005; in patients within relapse 1-3, the median PFS was 23.1 vs 11.6 months, p = 0.001. The hazard ratio for PFS was 0.67 (95% confidence interval [CI] 0.51-0.89, p = 0.006). The PFS advantage translated into improved OS for patients treated with IRD, median 36.6 months vs 26.0 months (p = 0.008). The overall response rate (ORR) was 73.0% in the IRD group vs 66.2% in the RD group with a complete response rate (CR) of 11.1% vs 8.8%, and very good partial response (VGPR) 22.2% vs 13.9%, IRD vs RD respectively. The IRD regimen was most beneficial in patients ≤75 years with ISS I, II, and in the first and second relapse. Patients with the presence of extramedullary disease did not benefit from IRD treatment (median PFS 6.5 months). Both regimens were well tolerated, and the incidence of total as well as grade 3/4 toxicities was comparable. CONCLUSIONS: Our analysis confirms the results of the TOURMALINE-MM1 study and shows benefit of all-oral triplet IRD treatment versus RD doublet. It demonstrates that the addition of ixazomib to RD improves key survival endpoints in patients with RRMM in a routine clinical setting.
- MeSH
- aplikace orální MeSH
- chemorezistence MeSH
- dexamethason farmakologie terapeutické užití MeSH
- doba přežití bez progrese choroby MeSH
- dospělí MeSH
- glycin analogy a deriváty farmakologie terapeutické užití MeSH
- Kaplanův-Meierův odhad MeSH
- lenalidomid farmakologie terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie mortalita patologie MeSH
- mnohočetný myelom farmakoterapie mortalita patologie MeSH
- následné studie MeSH
- prospektivní studie MeSH
- protokoly protinádorové kombinované chemoterapie farmakologie terapeutické užití MeSH
- registrace statistika a číselné údaje MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sloučeniny boru farmakologie terapeutické užití 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
- časopisecké články MeSH
- srovnávací studie MeSH
- Geografické názvy
- Česká republika MeSH
BACKGROUND: Maintenance therapy following autologous stem cell transplantation (ASCT) can delay disease progression and prolong survival in patients with multiple myeloma. Ixazomib is ideally suited for maintenance therapy given its convenient once-weekly oral dosing and low toxicity profile. In this study, we aimed to determine the safety and efficacy of ixazomib as maintenance therapy following ASCT. METHODS: The phase 3, double-blind, placebo-controlled TOURMALINE-MM3 study took place in 167 clinical or hospital sites in 30 countries in Europe, the Middle East, Africa, Asia, and North and South America. Eligible participants were adults with a confirmed diagnosis of symptomatic multiple myeloma according to International Myeloma Working Group criteria who had achieved at least a partial response after undergoing standard-of-care induction therapy followed by high-dose melphalan (200 mg/m2) conditioning and single ASCT within 12 months of diagnosis. Patients were randomly assigned in a 3:2 ratio to oral ixazomib or matching placebo on days 1, 8, and 15 in 28-day cycles for 2 years following induction, high-dose therapy, and transplantation. The initial 3 mg dose was increased to 4 mg from cycle 5 if tolerated during cycles 1-4. Randomisation was stratified by induction regimen, pre-induction disease stage, and response post-transplantation. The primary endpoint was progression-free survival (PFS) by intention-to-treat analysis. Safety was assessed in all patients who received at least one dose of ixazomib or placebo, according to treatment actually received. This trial is registered with ClinicalTrials.gov, number NCT02181413, and follow-up is ongoing. FINDINGS: Between July 31, 2014, and March 14, 2016, 656 patients were enrolled and randomly assigned to receive ixazomib maintenance therapy (n=395) or placebo (n=261). With a median follow-up of 31 months (IQR 27·3-35·7), we observed a 28% reduction in the risk of progression or death with ixazomib versus placebo (median PFS 26·5 months [95% CI 23·7-33·8] vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). No increase in second malignancies was noted with ixazomib therapy (12 [3%] patients) compared with placebo (eight [3%] patients) at the time of this analysis. 108 (27%) of 394 patients in the ixazomib group and 51 (20%) of 259 patients in the placebo group experienced serious adverse events. During the treatment period, one patient died in the ixazomib group and none died in the placebo group. INTERPRETATION: Ixazomib maintenance prolongs PFS and represents an additional option for post-transplant maintenance therapy in patients with newly diagnosed multiple myeloma. FUNDING: Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical Company.
- MeSH
- aplikace orální MeSH
- autologní transplantace MeSH
- časové faktory MeSH
- dvojitá slepá metoda MeSH
- glycin aplikace a dávkování škodlivé účinky analogy a deriváty MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom farmakoterapie chirurgie MeSH
- progrese nemoci MeSH
- protinádorové látky aplikace a dávkování škodlivé účinky MeSH
- sloučeniny boru aplikace a dávkování škodlivé účinky MeSH
- transplantace kmenových buněk * MeSH
- výsledek terapie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví 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
Substantial improvements in survival have been seen in multiple myeloma (MM) over recent years, associated with the introduction and widespread use of multiple novel agents and regimens, as well as the emerging treatment paradigm of continuous or long-term therapy. However, these therapies and approaches may have limitations in the community setting, associated with toxicity burden, patient burden, and other factors including cost. Consequently, despite improvements in efficacy in the rigorously controlled clinical trials setting, the same results are not always achieved in real-world practice. Furthermore, the large number of different treatment options and regimens under investigation in various MM settings precludes the feasibility of obtaining head-to-head clinical trial data, and there is a temptation to use cross-trial comparisons to evaluate data across regimens. However, multiple aspects, including patient-related, disease-related, and treatment-related factors, can influence clinical trial outcomes and lead to differences between studies that may confound direct comparisons between data. In this review, we explore the various factors requiring attention when evaluating clinical trial data across available agents/regimens, as well as other considerations that may impact the translation of these findings into everyday MM management. We also investigate discrepancies between clinical trial efficacy and real-world effectiveness through a literature review of non-clinical trial data in relapsed/refractory MM on novel agent-based regimens and evaluate these data in the context of phase 3 trial results for recently approved and commonly used regimens. We thereby demonstrate the complexity of interpreting data across clinical studies in MM, as well as between clinical studies and routine-care analyses, with the aim to help clinicians consider all the necessary issues when tailoring individual patients' treatment approaches.
- MeSH
- disparity zdravotní péče MeSH
- interpretace statistických dat * MeSH
- klinické zkoušky jako téma * MeSH
- komorbidita MeSH
- lidé MeSH
- mnohočetný myelom diagnóza epidemiologie mortalita terapie MeSH
- prognóza MeSH
- staging nádorů MeSH
- výsledek terapie MeSH
- výzkumný projekt MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
Ixazomib is the first oral proteasome inhibitor to enter the clinic. Given the efficacy of bortezomib in combination with cyclophosphamide and dexamethasone, we studied the combination of ixazomib, cyclophosphamide and dexamethasone (ICd) in newly diagnosed multiple myeloma (NDMM) and patients with measurable disease, irrespective of transplant eligibility, were enrolled. The phase 1 was to determine the maximum tolerated dose (MTD) of cyclophosphamide in the combination. Patients received ixazomib 4 mg (days 1, 8, 15), dexamethasone 40 mg (days 1, 8, 15, 22), and cyclophosphamide 300 or 400 mg/m2 days 1, 8, 15, 22; cycles were 28 days. We enrolled 51 patients, 10 in phase 1 and 41 patients in phase 2. The median age was 64.5 years (range: 41-88); 29% had high or intermediate risk FISH. The MTD was 400 mg/m2 of cyclophosphamide weekly. The best confirmed response in all 48 patients included ≥ partial response in 77%, including ≥ VGPR in 35%; 3 patients had a sCR. The response rate for all 48 evaluable patients at 4-cycles was 71%; the median time to response was 1.9 months. Common adverse events included cytopenias, fatigue and GI intolerance. ICd is a convenient, all oral combination that is well tolerated and effective in NDMM.
- MeSH
- cyklofosfamid aplikace a dávkování MeSH
- dexamethason aplikace a dávkování MeSH
- dospělí MeSH
- glycin aplikace a dávkování analogy a deriváty MeSH
- kombinovaná terapie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mnohočetný myelom diagnóza farmakoterapie mortalita MeSH
- protokoly protinádorové kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- sloučeniny boru aplikace a dávkování MeSH
- staging nádorů MeSH
- transplantace hematopoetických kmenových buněk MeSH
- výsledek terapie 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
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
BACKGROUND: The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. OBJECTIVE: The objective of this study was to quantitatively characterize the benefit-risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule. METHODS: We report early-phase study data and exposure-response analyses of TOURMALINE-MM1 data that support the selection of the recommended ixazomib dose and schedule. RESULTS: Single-agent ixazomib studies showed a favorable efficacy/safety profile with weekly versus twice-weekly dosing; a phase I/II study of ixazomib in combination with lenalidomide and dexamethasone (IRd) identified a weekly ixazomib dose that offered an acceptable efficacy/safety profile. In IRd exposure-response analyses from TOURMALINE-MM1, ixazomib systemic exposure was not a significant predictor of progression-free survival or probability of response. Significant associations were observed between ixazomib exposure and the probability of grade ≥3 anemia and thrombocytopenia, and grade ≥2 diarrhea, fatigue, nausea, peripheral neuropathy, and rash. Additionally, higher ixazomib exposure was associated with lower lenalidomide relative dose intensity. CONCLUSIONS: These analyses support a favorable benefit-risk profile for weekly ixazomib 4.0 mg on days 1, 8, and 15 of 28-day cycles, which was selected for the phase III TOURMALINE registration program. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov NCT00932698, NCT00963820, NCT01217957, NCT01564537.
- MeSH
- glycin aplikace a dávkování analogy a deriváty MeSH
- inhibitory proteasomu aplikace a dávkování MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- mnohočetný myelom farmakoterapie mortalita MeSH
- přežití bez známek nemoci MeSH
- protinádorové látky aplikace a dávkování MeSH
- sloučeniny boru aplikace a dávkování MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
- klinické zkoušky, fáze III MeSH
- práce podpořená grantem MeSH
Mukositida jako poškození orální části gastrointestinálního traktu je jednou z nejčastějších komplikací cytostatické a radiační léčby. Patogeneticky se nejedná jen o přímé poškození epitelu, ale o komplexní proces, který zahrnuje oxidativní stres, aktivaci řady transkripčních faktorů – např. jaderného faktoru kB (NF-kB), interakci řady cytokinů (TNF-a, IL-1, IL-6), mikrovaskulární poškození, indukci apoptózy v oblasti epitelu, ale i v dalších částech slizniční bariéry.
- Klíčová slova
- Kepivance,
- MeSH
- fibroblastový růstový faktor 7 farmakologie škodlivé účinky terapeutické užití MeSH
- hodnocení léčiv MeSH
- lidé MeSH
- mukozitida chemicky indukované terapie MeSH
- protinádorové látky škodlivé účinky MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- klinické zkoušky kontrolované MeSH
- MeSH
- cisplatina terapeutické užití MeSH
- deoxycytidin terapeutické užití MeSH
- fixní kombinace léků MeSH
- karcinom z přechodných buněk farmakoterapie patologie MeSH
- lidé MeSH
- metastázy nádorů farmakoterapie patologie MeSH
- nádory močového měchýře farmakoterapie patologie MeSH
- přežití MeSH
- Check Tag
- lidé MeSH
