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 antitumorózní 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
Gain/amplification of 1q21 (≥3 copies), a chromosomal abnormality frequently observed in multiple myeloma, can negatively affect prognosis, due to its involvement in resistance to anti-myeloma therapy and disease progression. In this updated subgroup analysis of the randomized, Phase 3 IKEMA study (NCT03275285) in relapsed/refractory multiple myeloma (RRMM), we evaluated progression-free survival (PFS) and depth of response with the anti-CD38 antibody isatuximab plus carfilzomib-dexamethasone (Isa-Kd) versus Kd, in 1q21+ patients and related subgroups, at long-term follow-up (44.2 months). Our analysis included patients with 1q21+ (≥3 copies, with/without high-risk chromosomal abnormality [HRCA]), isolated 1q21+ (≥3 copies, without HRCA), gain(1q21) (3 copies, with/without HRCA), and amp(1q21) (≥4 copies, with/without HRCA). PFS benefit was achieved with Isa-Kd versus Kd in patients with 1q21+ (HR 0.58, 95% CI: 0.37-0.92), with isolated 1q21+ (HR 0.49, 95% CI: 0.27-0.92), with gain(1q21), or amp(1q21), consistent with the overall population and prior interim 1q21+ subgroup analyses. Median PFS with Isa-Kd versus Kd was 25.8 versus 16.2 months in 1q21+ patients and 38.2 versus 16.2 months in patients with isolated 1q21+. Clinically meaningful, higher rates of very good partial response or better, complete response or better (≥CR), minimal residual disease (MRD) negativity, and MRD negativity and ≥CR were reached with Isa-Kd versus Kd in patients with 1q21+, isolated 1q21+, gain(1q21), or amp(1q21). In Isa-Kd and Kd, the MRD negativity and ≥CR rate was 29.3% versus 15.4% in 1q21+ patients, 36.2% versus 12.9% in patients with isolated 1q21+, 27.9% versus 13.5% in patients with gain(1q21), and 31.3% versus 20.0% in patients with amp(1q21), respectively. In conclusion, addition of Isa to Kd in triplet combination therapy has shown PFS benefit and deeper responses, compared with Kd, in 1q21+ patients at higher risk of progression, including patients with isolated 1q21+, gain(1q21), and amp(1q21), thus supporting Isa-Kd an effective treatment option for patients with RRMM.
Melphalan flufenamide (melflufen), a first-in-class alkylating peptide-drug conjugate, plus dexamethasone was approved in Europe for use in patients with triple-class refractory relapsed/refractory multiple myeloma (RRMM) with ≥3 prior lines of therapy and without prior autologous stem cell transplantation (ASCT) or with a time to progression >36 months after prior ASCT. The randomized LIGHTHOUSE study (NCT04649060) assessed melflufen plus daratumumab and dexamethasone (melflufen group) versus daratumumab in patients with RRMM with disease refractory to an immunomodulatory agent and a proteasome inhibitor or who had received ≥3 prior lines of therapy including an immunomodulatory agent and a proteasome inhibitor. A partial clinical hold issued by the US Food and Drug Administration for all melflufen studies led to financial constraints and premature study closure on February 23rd 2022 (data cut-off date). In total, 54 of 240 planned patients were randomized (melflufen group, N=27; daratumumab group, N=27). Median progression-free survival (PFS) was not reached in the melflufen group versus 4.9 months in the daratumumab group (Hazard Ratio: 0.18 [95% Confidence Interval, 0.05-0.65]; P=0.0032) at a median follow-up time of 7.1 and 6.6 months, respectively. Overall response rate (ORR) was 59% in the melflufen group versus 30% in the daratumumab group (P=0.0300). The most common grade ≥3 treatment-emergent adverse events in the melflufen group versus daratumumab group were neutropenia (50% vs. 12%), thrombocytopenia (50% vs. 8%), and anemia (32% vs. 19%). Melflufen plus daratumumab and dexamethasone demonstrated superior PFS and ORR versus daratumumab in RRMM and a safety profile comparable to previously published melflufen studies.
- MeSH
- autologní transplantace MeSH
- dexamethason terapeutické užití MeSH
- fenylalanin * analogy a deriváty MeSH
- inhibitory proteasomu MeSH
- lidé MeSH
- melfalan * analogy a deriváty MeSH
- mnohočetný myelom * diagnóza farmakoterapie MeSH
- monoklonální protilátky * MeSH
- nádory plazmocelulární * MeSH
- neutropenie * MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze III MeSH
- randomizované kontrolované studie MeSH
- Geografické názvy
- Spojené státy americké MeSH
Melphalan flufenamide (melflufen), a first-in-class, alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 or 40 mg) and dexamethasone (40 mg with daratumumab; 20 mg followed by 40 mg with bortezomib; dose reduced if aged ≥75 years) in triplet combination with daratumumab (16 mg/kg; daratumumab arm) or bortezomib (1.3 mg/m2; bortezomib arm) in patients with relapsed/refractory MM refractory to an immunomodulatory agent and/or a proteasome inhibitor and who had received one to four prior lines of therapy. Primary objectives were to determine the optimal dose of melflufen in triplet combination (phase I) and overall response rate (phase IIa). In total, 33 patients were treated in the daratumumab arm and 23 patients received therapy in the bortezomib arm. No dose-limiting toxicities were reported at either melflufen dose level with either combination. With both triplet regimens, the most common grade ≥3 treatment-emergent adverse events were thrombocytopenia and neutropenia; thrombocytopenia was the most common treatment-emergent adverse event leading to treatment discontinuation. In the daratumumab arm, patients receiving melflufen 30 mg remained on treatment longer than those receiving the 40-mg dose. In the daratumumab arm, the overall response rate was 73% and median progression-free survival was 12.9 months. Notably, in the bortezomib arm, the overall response rate was 78% and median progression-free survival was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in relapsed/refractory MM.
- MeSH
- bortezomib terapeutické užití MeSH
- dexamethason terapeutické užití MeSH
- fenylalanin * analogy a deriváty MeSH
- lidé MeSH
- melfalan * analogy a deriváty MeSH
- mnohočetný myelom * diagnóza farmakoterapie MeSH
- monoklonální protilátky * MeSH
- nádory plazmocelulární * MeSH
- neutropenie * chemicky indukované MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky MeSH
- senioři MeSH
- trombocytopenie * MeSH
- Check Tag
- lidé MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- klinické zkoušky, fáze I MeSH
- klinické zkoušky, fáze II MeSH
Aim: We pooled data from three observational studies (INSIGHT MM, UVEA-IXA and REMIX) to investigate the real-world effectiveness of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory myeloma. Materials & methods: INSIGHT MM was a prospective study conducted in countries across Europe, Asia and North/Latin America while UVEA-IXA and REMIX were multicenter, retrospective/prospective studies conducted in Europe. Patients who had received IRd as ≥2nd line of therapy were analyzed. Primary outcomes were time-to-next treatment (TTNT) and progression-free survival (PFS). Results: Overall, 564 patients were included (median follow-up: 18.5 months). Median TTNT and PFS were 18.4 and 19.9 months; both outcomes were numerically longer for earlier versus later lines. Median treatment duration was 14.0 months. Overall response rate was 64.6%. No new safety concerns were noted. Conclusion: The effectiveness of IRd in routine practice appears similar to the efficacy observed in TOURMALINE-MM1. IRd benefit in earlier versus later lines was consistent with previous reports.
- MeSH
- dexamethason terapeutické užití MeSH
- glycin * analogy a deriváty MeSH
- lenalidomid terapeutické užití MeSH
- lidé MeSH
- mnohočetný myelom * farmakoterapie MeSH
- multicentrické studie jako téma MeSH
- prospektivní studie MeSH
- protokoly antitumorózní kombinované chemoterapie škodlivé účinky terapeutické užití MeSH
- retrospektivní studie MeSH
- sloučeniny boru terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- MeSH
- antibakteriální látky aplikace a dávkování farmakologie terapeutické užití MeSH
- dexamethason terapeutické užití MeSH
- diagnostické zobrazování metody MeSH
- diferenciální diagnóza MeSH
- klinické laboratorní techniky metody MeSH
- lidé MeSH
- nozokomiální pneumonie farmakoterapie MeSH
- oxygenoterapie MeSH
- pneumonie * diagnóza farmakoterapie klasifikace MeSH
- rentgendiagnostika hrudníku metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
- MeSH
- adrenalin terapeutické užití MeSH
- dexamethason aplikace a dávkování terapeutické užití MeSH
- diferenciální diagnóza MeSH
- infekce respiračními syncytiálními viry patologie MeSH
- infekce viry z čeledi Paramyxoviridae patologie MeSH
- laryngitida * diagnóza farmakoterapie mikrobiologie MeSH
- lidé MeSH
- nebulizátory a vaporizátory MeSH
- stupeň závažnosti nemoci MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- přehledy MeSH
Pooperační nevolnost a zvracení (PONV) je častou pooperační komplikací, která postihuje 20-30 % dětí, u vysoce rizikových výkonů stoupá incidence až k 80 %. PONV vedle subjektivního dyskomfortu zvyšuje pooperační morbiditu a ohrožuje dítě dehydratací, dehiscencí operační rány a následným krvácením. Dochází k prodloužení pobytu na dospávacím pokoji a celkové doby hospitalizace. Management PONV spočívá v identifikaci rizikových pacientů a zahájení adekvátní prevence. Lékem volby je dexametazon nebo ondansetron, u vysoce rizikových dětí jejich kombinace. V případě selhání prevence je indikace k podání antiemetika z jiné farmakologické skupiny.
Postoperative nausea and vomiting (PONV) is a common postoperative complication with overall incidence of 20-30 %, however, with high risk procedures it increases up to 80 %. PONV is the main cause of the patient ́s discomfort, worsens perioperative morbidity and put the child at risk of dehydratation, dehiscence of surgical wound and bleeding. PONV prolongs the lenght of stay (PACU, in-hospital care). The cornerstone of PONV management is the identification of high risk pediatric patients and an adequate pre-operative pharmacological prevention. Dexamethasone and ondansetron (or their combination) are the first line medications. In case of failure, rescue therapy should be provided with other pharmacological agents.
- MeSH
- antiemetika MeSH
- dexamethason aplikace a dávkování terapeutické užití MeSH
- dítě MeSH
- lidé MeSH
- ondansetron aplikace a dávkování terapeutické užití MeSH
- pooperační nevolnost a zvracení * diagnóza farmakoterapie prevence a kontrola MeSH
- rizikové faktory MeSH
- Check Tag
- dítě MeSH
- lidé MeSH
- Publikační typ
- přehledy MeSH
BACKGROUND: Dose modifications in response to adverse events (AEs) can maintain tumor response and improve therapy tolerability. We conducted a post-hoc analysis of the efficacy and safety of reduced selinexor doses in the BOSTON trial (NCT03110562). PATIENTS AND METHODS: Efficacy, safety, and quality of life (QoL) in 195 patients with relapsed/refractory multiple myeloma randomized to once-weekly (QW) selinexor (100 mg), QW subcutaneous bortezomib (1.3 mg/m2), and twice-weekly dexamethasone (20 mg) were compared between patients with dose reductions and those without. RESULTS: In total, 126 patients (65%) had selinexor dose reductions (median dose 71.4 mg/wk). In patients with dose reductions versus those without median progression-free survival was 16.6 months (95% CI 12.9-not evaluable [NE]) versus 9.2 months [95% CI 6.8-15.5]), overall response rate was 81.7% (95% CI 73.9-88.1%) versus 66.7% (95% CI 54.3-77.6%), ≥very good partial response was (51.6% [95% CI 42.5-60.6%] vs. 31.9% [95% CI 21.2-44.2]), median duration of response was not reached (95% CI 13.8-NE) versus 12.0 months (95% CI 8.3-NE), and time to next treatment was 22.6 months (95% CI 14.6-NE) versus 10.5 months (95% CI 6.3-18.2). Mean best change from baseline on the EORTC QLQ-C30 Global Health Status/QoL scale was 10.0 ± 20.5 versus 4.0 ± 20.9. Duration-adjusted AE rates that were lower after selinexor dose reduction included thrombocytopenia (62.5% before vs. 47.6% after), nausea (31.6% vs. 7.3%), fatigue (28.1% vs. 9.9%), decreased appetite (21.5% vs. 6.4%), anemia (17.9% vs. 10.3%), and diarrhea (12.9% vs. 5.2%). CONCLUSION: Appropriate dose reductions in response to AEs of the 100 mg selinexor starting dose in the BOSTON study were associated with improved efficacy, reduced AE rates and improved QoL.
- MeSH
- dexamethason terapeutické užití MeSH
- kvalita života * MeSH
- lidé MeSH
- mnohočetný myelom * farmakoterapie MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- vysazování léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- randomizované kontrolované studie MeSH
- MeSH
- dexamethason terapeutické užití MeSH
- humanizované monoklonální protilátky terapeutické užití MeSH
- lidé MeSH
- lokální recidiva nádoru farmakoterapie MeSH
- mnohočetný myelom * farmakoterapie MeSH
- protokoly antitumorózní kombinované chemoterapie terapeutické užití MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- dopisy MeSH
