BACKGROUND: In multiple myeloma (MM), improving our understanding of routine clinical practice and the effectiveness of agents outside of clinical trials is important. TOURMALINE-MM1 data resulted in approval of ixazomib for MM patients who have received ≥ 1 prior therapy. PATIENTS AND METHODS: UVEA-IXA comprised a retrospective chart review in the early access program, and a prospective 1-year follow-up period. Eligible patients had had a biochemical and/or symptomatic relapse after 1-3 prior lines of therapy; no anti-MM therapy for > 3 cycles at the start of ixazomib therapy; and an Eastern Cooperative Oncology Group performance score of 0-2. Lenalidomide- or proteasome inhibitor (PI)-refractory patients were ineligible. Primary endpoints were response and progression-free survival (PFS). RESULTS: Of 357 enrolled patients, 309 were evaluable; most patients received ixazomib alongside lenalidomide (98%) and dexamethasone (97%); 61% had received 2-3 prior lines of therapy. Median PFS was 15.6 months (95% confidence interval [CI]: 12.0-20.6) in all evaluable patients, and 19.6 (95% CI: 12.1-27.0) and 13.9 (95% CI: 10.1-18.1) months in patients who received 1 and ≥ 2 prior lines of therapy, respectively. The overall response rate was 67% in all evaluable patients, and 72% and 63%, respectively, in patients who received 1 and ≥ 2 prior lines of therapy. Median overall survival was 35.5 months. The ixazomib safety profile was consistent with previous reports. CONCLUSION: This study supports ixazomib-based therapy as an effective and tolerable treatment in the real-world. Outcomes were favorable in patients with 1 or ≥ 2 prior lines of therapy who were not lenalidomide- or PI-refractory.

• MeSH
• dexamethason terapeutické užití   MeSH
• glycin analogy a deriváty   MeSH
• lenalidomid terapeutické užití   MeSH
• lidé MeSH
• lokální recidiva nádoru farmakoterapie   MeSH
• mnohočetný myelom * MeSH
• prospektivní studie MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   MeSH
• retrospektivní studie MeSH
• sloučeniny boru * MeSH
• uvea MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Ixazomib je první perorální inhibitor proteazomu, jenž je v kombinaci s lenalidomidem a dexametazonem indikován k léčbě pacientů s mnohočetným myelomem, kteří podstoupili alespoň jednu předchozí linii léčby. Souhlas ke klinickému užití ixazomibu byl vydán na základě výsledků studie TOURMALINE-MM1, dvojitě zaslepené, placebem kontrolované studie fáze III, která prokázala významné zlepšení přežití bez progrese u výhradně perorálně podávané kombinace ixazomibu a lenalidomidu s dexametazonem proti samotnému lenalidomidu s dexametazonem (medián 20,6 vs. 14,7 měsíce; poměr rizika 0,74; p = 0,01; medián sledování 14,7 měsíce). Doplnění kombinace lenalidomidu s dexametazonem o ixazomib je nemocnými velmi dobře tolerováno a nemá nepříznivý vliv na jejich kvalitu života. V práci hodnotíme účinnost, bezpečnost, farmakokinetiku a údaje o kvalitě života, které lze sledovat u ixazomibu a zabýváme se úlohou této perorální účinné látky v léčbě pacientů s relabujícím/refrakterním mnohočetným myelomem, včetně pacientů s vysoce rizikovými cytogenetickými abnormalitami a léčbou u výrazně předléčených pacientů.

Ixazomib is the first and only oral proteasome inhibitor, indicated for the treatment of multiple myeloma in combination with lenalidomide and dexamethasone in patients who have received at least one prior therapy. The approval is based on the results of the randomized, double-blind, placebo-controlled phase III TOURMALINE-MM1 trial that demonstrated statistically significant improvement in progression-free survival in patients treated with the all-oral triplet combination of ixazomib plus lenalidomide and dexamethasone compared to patients in the lenalidomide and dexamethasone arm (20.6 months vs 14.7 months in the control group; hazard ratio 0.74; p = 0.01; median follow-up 14.7 months). The addition of ixazomib to a regimen of lenalidomide and dexamethasone is generally well tolerated with no negative impact on patient-reported quality of life. In this review, we highlight the efficacy, safety, pharmacokinetics and patient-reported quality of life data of ixazomib. We focus on the role of ixazomib in the treatment of patients with relapsed/refractory multiple myeloma including patients with high-risk cytogenetic features as well as heavily pretreated patients.

• Klíčová slova
• ixazomib,
• MeSH
• dexamethason aplikace a dávkování   škodlivé účinky   MeSH
• glycin analogy a deriváty   farmakologie   terapeutické užití   MeSH
• imunologické faktory MeSH
• inhibitory angiogeneze farmakologie   terapeutické užití   MeSH
• inhibitory proteas farmakologie   terapeutické užití   MeSH
• klinická studie jako téma MeSH
• klinické zkoušky, fáze III jako téma MeSH
• lidé MeSH
• mnohočetný myelom * farmakoterapie   MeSH
• protinádorové látky farmakologie   terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• sloučeniny boru farmakologie   terapeutické užití   MeSH
• thalidomid aplikace a dávkování   škodlivé účinky   analogy a deriváty   analogy a deriváty   farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH

Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval [CI], 0.321-0.918; P = .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95% CI, 0.462-0.888; P = .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI, 0.492-1.240), and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI, 0.474-0.928). IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537.

• MeSH
• chemorezistence MeSH
• chromozomální aberace * MeSH
• dexamethason aplikace a dávkování   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• glycin aplikace a dávkování   analogy a deriváty   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   genetika   MeSH
• přežití bez známek nemoci MeSH
• proporcionální rizikové modely MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• senioři MeSH
• sloučeniny boru aplikace a dávkování   MeSH
• thalidomid aplikace a dávkování   analogy a deriváty   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

Real-world data on regimens for relapsed/refractory multiple myeloma (RRMM) represent an important component of therapeutic decision-making. This multi-centric, retrospective, observational study conducted by the treating physicians evaluated the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in 155 patients who received ixazomib via early access programs in Greece, the UK, and the Czech Republic. Median age was 68 years; 17% had an Eastern Cooperative Oncology Group performance status ≥ 2; median number of prior therapies was 1 (range 1-7); 91%, 47%, and 17% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Median duration of exposure to ixazomib was 9.6 months. Overall response rate was 74%, including 35% very good partial response or better (16% complete response). Median progression-free survival (PFS) was 27.6 months (27.6 and 19.9 months in patients with 1 or > 1 prior lines, respectively). IRd treatment for ≥ 6 months was associated with longer PFS (hazard ratio 0.06). Fourteen patients (9%) discontinued IRd due to adverse events/toxicity in the absence of disease progression. Peripheral neuropathy was reported in 35% of patients (3% grades 3-4). These findings support the results of the phase III TOURMALINE-MM1 trial in a broader real-world RRMM population.

• MeSH
• dexamethason aplikace a dávkování   škodlivé účinky   MeSH
• dospělí MeSH
• glycin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• lenalidomid aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• mnohočetný myelom farmakoterapie   mortalita   MeSH
• přežití bez známek nemoci MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   MeSH
• recidiva MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sloučeniny boru aplikace a dávkování   škodlivé účinky   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 III MeSH
• multicentrická studie MeSH
• pozorovací studie MeSH

BACKGROUND: Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma. METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups. CONCLUSIONS: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).

• MeSH
• aplikace orální MeSH
• dexamethason aplikace a dávkování   MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• exantém chemicky indukované   MeSH
• glycin aplikace a dávkování   škodlivé účinky   analogy a deriváty   MeSH
• Kaplanův-Meierův odhad MeSH
• kvalita života MeSH
• lidé středního věku MeSH
• lidé MeSH
• mnohočetný myelom farmakoterapie   MeSH
• přežití bez známek nemoci MeSH
• proporcionální rizikové modely MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• sloučeniny boru aplikace a dávkování   škodlivé účinky   MeSH
• thalidomid aplikace a dávkování   analogy a deriváty   MeSH
• trombocytopenie chemicky indukované   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
• srovnávací studie MeSH

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