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Předkládaná diplomová práce se zabývá terapií mnohočetného myelomu, který představuje nádorové onemocnění kostní dřeně vycházející z maligních plazmatických buněk. Zkoumá účinky chemoterapeutik bortezomibu, ixazomibu a carfilzomibu v různých koncentracích na myelomové linie RPMI-8226 a H929. Efekt jednotlivých látek je v první řadě sledován na základě míry proliferace a viability buněk po aplikaci chemoterapie a dále pomocí exprese genů (MICA a MICB) asociovaných s imunitní odpovědí NK buněk. K hodnocení míry exprese je použita qPCR analýza, jejíž výsledky jsou ověřeny na proteinové úrovni metodou průtokové cytometrie. Cílem práce je identifikace vhodného typu a koncentrace chemoterapie pro navazující experimenty s kombinovanou imunoterapií ex vivo připravenými NK buňkami., The master thesis deals with the therapy of multiple myeloma, which is a bone marrow tumour arising from malignant plasma cells. It investigates the effects of the chemotherapeutics bortezomib, ixazomib, and carfilzomib at various concentrations on the myeloma cell lines RPMI-8226 and H929. The impact of individual agents is firstly measured by the cell proliferation level and cell viability after chemotherapy treatment and then by gene expression (MICA and MICB) associated with the immune response of NK cells. The qPCR analysis is used to assess the expression level, and the results are verified at the protein level by flow cytometry. The thesis aims to identify the appropriate type and concentration of chemotherapy for follow-up experiments with ex vivo NK cell-prepared combination immunotherapy., Fakulta chemicko-technologická, 1. Prezentace výsledků diplomové práce. 2. Diskuze k posudkům vedoucího a oponenta diplomové práce. 3. Studentka zodpověděla všechny dotazy a připomínky k DP., Dokončená práce s úspěšnou obhajobou

Multiple available combinations of proteasome inhibitors, immunomodulators (IMIDs), and monoclonal antibodies are shifting the relapsed/refractory multiple myeloma (RRMM) treatment landscape. Lack of head-to-head trials of triplet regimens highlights the need for real-world (RW) evidence. We conducted an RW comparative effectiveness analysis of bortezomib (V), carfilzomib (K), ixazomib (I), and daratumumab (D) combined with either lenalidomide or pomalidomide plus dexamethasone (Rd or Pd) in RRMM. A retrospective cohort of patients initiating triplet regimens in line of therapy (LOT) ≥ 2 on/after 1/1/2014 was followed between 1/2007 and 3/2018 in Optums deidentified US electronic health records database. Time to next treatment (TTNT) was estimated using Kaplan-Meier methods; regimens were compared using covariate-adjusted Cox proportional hazard models. Seven hundred forty-one patients (820 patient LOTs) with an Rd backbone (VRd, n = 349; KRd, n = 218; DRd, n = 99; IRd, n = 154) and 348 patients (392 patient LOTs) with a Pd backbone (VPd, n = 52; KPd, n = 146; DPd, n = 149; IPd, n = 45) in LOTs ≥2 were identified. More patients ≥75 years received IRd (39.6%), IPd (37.8%), and VRd (36.7%) than other triplets. More patients receiving VRd/VPd were in LOT2 vs other triplets. Unadjusted median TTNT in LOT ≥ 2: VRd, 13.9; KRd, 8.7; IRd, 11.4; DRd, not estimable (NE); and VPd, 12.0; KPd, 6.7; IPd, 9.5 months; DPd, NE. In covariate-adjusted analysis, only KRd vs DRd was associated with a significantly higher risk of next LOT initiation/death (HR 1.72; P = 0.0142); no Pd triplet was significantly different vs DPd in LOT ≥ 2. Our data highlight important efficacy/effectiveness gaps between results observed in phase 3 clinical trials and those realized in the RW.

[Aim]: To evaluate the effectiveness and safety of ixazomib-lenalidomide-dexamethasone (IRd) in relapsed/refractory multiple myeloma in routine clinical practice. Patients & methods: Patient-level data from the global, observational INSIGHT MM and the Czech Registry of Monoclonal Gammopathies were integrated and analyzed., [Results]: At data cut-off, 263 patients from 13 countries were included. Median time from diagnosis to start of IRd was 35.8 months; median duration of follow-up was 14.8 months. Overall response rate was 73%, median progression-free survival, 21.2 months and time-to-next therapy, 33.0 months. Ixazomib/lenalidomide dose reductions were required in 17%/36% of patients; 32%/30% of patients discontinued ixazomib/lenalidomide due to adverse events., [Conclusion]: The effectiveness and safety of IRd in routine clinical practice are comparable to those reported in TOURMALINE-MM1.

Lack of head-to-head trials highlights a need for comparative real-world evidence of proteasome inhibitors plus Rd. Methods: In this retrospective, US population-representative EHR study of RRMM patients initiating IRd, KRd, or VRd in line of therapy (LOT) ≥2 between 1/2014 and 9/30/2018, 664 patients were treated in LOT ≥2 with: IRd, n = 168; KRd, n = 208; VRd, n = 357. Median age was 71/65/71 years; 67%/70%/75% had a frailtymodified score of intermediate/frail; 20%/28%/13% had high cytogenetic risk in I-/K-/V-Rd groups. Risk of PI-triplet discontinuation was lower for I- vs. K-Rd (HR: 0.71) and I- vs. V-Rd (HR: 0.85); unadjusted, median TTNTs (months): 12.7/8.6/14.2 (LOT ≥2) and 16.8/9.5/14.6 (LOT 2–3) (I-/K-/V-Rd). Adjusted TTNT was comparable between I-/K-/V-Rd in LOT ≥2 with a TTNT benefit among intermediate/ frail patients for I- (HR: 0.70; P=0.04) and V- (HR: 0.73; P<0.05) vs. K-Rd. I/K/V-Rd triplets were comparable in TTNT overall, but IRd and VRd were associated with longer TTNT in intermediate/frail patients than KRd. The results suggest a trial-efficacy/real-world-effectiveness gap, especially for KRd, underlining the limited generalizability of trial results where >50% of patients are excluded. Individualized treatment based on patient characteristics, such as frailty status, is especially pertinent in an elderly RRMM population.