83 results on '"Pawel Robak"'
Search Results
2. Bortezomib for the Treatment of Hematologic Malignancies: 15 Years Later
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Pawel Robak and Tadeusz Robak
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Therapeutics. Pharmacology ,RM1-950 - Abstract
Abstract Bortezomib is a dipeptidyl boronic acid that selectively inhibits the ubiquitin proteasome pathway, which plays a role in the degradation of many intracellular proteins. It is the first-in-class selective and reversible inhibitor of the 26S proteasome, with antiproliferative and antitumor activity. It exerts its anti-neoplastic action mainly via the inhibition of the nuclear factor-κB pathway components associated with cell proliferation, apoptosis, and angiogenesis. The drug has revolutionized the treatment of multiple myeloma and, more recently, mantle cell lymphoma. In 2003, bortezomib received accelerated approval from the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma and in 2008 for patients with previously untreated multiple myeloma. In 2006, bortezomib was approved for the treatment of refractory/relapsed mantle cell lymphoma and, in 2014, for previously untreated mantle cell lymphoma. Bortezomib has also demonstrated clinical efficacy both as a single drug and in combination with other agents in light chain amyloidosis, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, and peripheral T-cell lymphomas. Furthermore, continued clinical studies are required to confirm its value for patients with indolent and aggressive B-cell non-Hodgkin lymphomas and acute leukemias.
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- 2019
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3. Heterogenous mutation spectrum and deregulated cellular pathways in aberrant plasma cells underline molecular pathology of light-chain amyloidosis
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Zuzana Chyra, Tereza Sevcikova, Petr Vojta, Janka Puterova, Lucie Brozova, Katerina Growkova, Jana Filipova, Martina Zatopkova, Sebastian Grosicki, Agnieszka Barchnicka, Wieslaw Wiktor Jedrzejczak, Anna Waszczuk-Gajda, Alexandra Jungova, Aneta Mikulasova, Marian Hajduch, Martin Mokrejs, Ludek Pour, Martin Stork, Lubica Harvanova, Martin Mistrik, Gabor Mikala, Pawel Robak, Anna Czyz, Jakub Debski, Lidia Usnarska-Zubkiewicz, Artur Jurczyszyn, Lukas Stejskal, Gareth Morgan, Fedor Kryukov, Eva Budinska, Michal Simicek, Tomas Jelinek, Matous Hrdinka, and Roman Hajek
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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4. Current Status of Older and New Purine Nucleoside Analogues in the Treatment of Lymphoproliferative Diseases
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Pawel Robak, Ewa Lech-Maranda, Tadeusz Robak, and Anna Korycka
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Fludarabine ,Cladribine ,Pentostatin ,Clofarabine ,Nelarabine ,Forodesine ,Purine nucleoside analogues ,Mechanism of action ,Clinical application ,Organic chemistry ,QD241-441 - Abstract
For the past few years more and more new cytotoxic agents active in the treatment of hematological malignancies have been synthesized and become available for either in vitro studies or clinical trials. Among them the class of antineoplastic drugs belonging to the purine nucleoside analogues group (PNAs) plays an important role. Three of them: pentostatin (DCF), cladribine (2-CdA) and fludarabine (FA) were approved by Food and Drug Administration (FDA) for the treatment of hematological malignancies. Recently three novel PNAs: clofarabine (CAFdA), nelarabine (ara-G) and forodesine (immucillin H, BCX-1777) have been synthesized and introduced into preclinical studies and clinical trials. These agents seem to be useful mainly for the treatment of human T-cell proliferative disorders and they are currently undergoing clinical trials in lymphoid malignancies. However, there are also several studies suggesting the role of these drugs in B-cell malignancies. This review will summarize current knowledge concerning the mechanism of action, pharmacologic properties, clinical activity and toxicity of PNAs accepted for use in clinical practice, as well as new agents available for clinical trials.
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- 2009
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5. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study
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Philippe Moreau, Halyna Pylypenko, Sebastian Grosicki, Ievgenii Karamanesht, Xavier Leleu, Grigoriy Rekhtman, Zvenyslava Masliak, Pawel Robak, Dixie-Lee Esseltine, Huaibao Feng, William Deraedt, Helgi van de Velde, and Bertrand Arnulf
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2015
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6. Immunotherapy combinations for chronic lymphocytic leukemia: advantages and disadvantages
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Pawel Robak and Tadeusz Robak
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Pharmacology ,Clinical Biochemistry ,Drug Discovery - Abstract
In the last few years, BTK inhibitors, PI3K inhibitors, and venetoclax have been approved for clinical use against chronic lymphocytic leukemia (CLL), both as single agents, and in combination. This article summarizes recent achievements in the treatment of patients with CLL, and pays special attention to novel targeted drugs and monoclonal antibodies (Mabs). A literature search was conducted of the PubMed and Google Scholar databases. Rituximab and obinutuzumab have been combined with chemotherapy, and more recently, with BTK inhibitors, PI3K inhibitors, and venetoclax. These agents have demonstrated high activity in treatment naïve (TN) and relapsed or refractory (RR) CLL. Immunochemotherapy regimens are currently considered in TN younger patients with
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- 2022
7. Melflufen or pomalidomide plus dexamethasone for patients with multiple myeloma refractory to lenalidomide (OCEAN): a randomised, head-to-head, open-label, phase 3 study
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Fredrik H Schjesvold, Meletios-Athanasios Dimopoulos, Sosana Delimpasi, Pawel Robak, Daniel Coriu, Wojciech Legiec, Luděk Pour, Ivan Špička, Tamas Masszi, Vadim Doronin, Jiri Minarik, Galina Salogub, Yulia Alekseeva, Antonio Lazzaro, Vladimir Maisnar, Gábor Mikala, Laura Rosiñol, Anna Marina Liberati, Argiris Symeonidis, Victoria Moody, Marcus Thuresson, Catriona Byrne, Johan Harmenberg, Nicolaas A Bakker, Roman Hájek, Maria-Victoria Mateos, Paul G Richardson, Pieter Sonneveld, Fredrik Schjesvold, Anna Nikolayeva, Waldemar Tomczak, Ludek Pour, Ivan Spicka, Gabor Mikala, Laura Rosinol, Tatiana Konstantinova, Anargyros Symeonidis, Moshe Gatt, Arpad Illes, Haifaa Abdulhaq, Moez Dungarwalla, Sebastian Grosicki, Roman Hajek, Xavier Leleu, Alexander Myasnikov, Paul G. Richardson, Irit Avivi, Dries Deeren, Mercedes Gironella, Miguel Teodoro Hernandez-Garcia, Joaquin Martinez Lopez, Muriel Newinger-Porte, Paz Ribas, Olga Samoilova, Eric Voog, Mario Arnao-Herraiz, Estrella Carrillo-Cruz, Paolo Corradini, Jyothi Dodlapati, Miquel Granell Gorrochategui, Shang-Yi Huang, Matthew Jenner, Lionel Karlin, Jin Seok Kim, Agnieszka Kopacz, Nadezhda Medvedeva, Chang-Ki Min, Roberto Mina, Katrin Palk, Ho-Jin Shin, Sang Kyun Sohn, Jason Tache, Achilles Anagnostopoulos, Jose-Maria Arguiñano, Michele Cavo, Joanne Filicko, Margaret Garnes, Janusz Halka, Kathrin Herzog-Tzarfati, Natalia Ipatova, Kihyun Kim, Maria-Theresa Krauth, Irina Kryuchkova, Mihaela Cornelia Lazaroiu, Mario Luppi, Andrei Proydakov, Alessandro Rambaldi, Milda Rudzianskiene, Su-Peng Yeh, Maria Magdalena Alcalá-Peña, Adrian Alegre Amor, Hussain Alizadeh, Maurizio Bendandi, Gillian Brearton, Randall Brown, Jim Cavet, Najib Dally, Miklos Egyed, José Ángel Hernández-Rivas, Ain Kaare, Jean-Michel Karsenti, Janusz Kloczko, William Kreisle, Je-Jung Lee, Sigrid Machherndl-Spandl, Sudhir Manda, Ivan Moiseev, Jan Moreb, Zsolt Nagy, Santosh Nair, Albert Oriol-Rocafiguera, Michael Osswald, Paula Otero-Rodriguez, Valdas Peceliunas, Torben Plesner, Philippe Rey, Giuseppe Rossi, Don Stevens, Celia Suriu, Corrado Tarella, Anke Verlinden, Alain Zannetti, Hematology, and Oncopeptides
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Published Online ,See Comment page e82 ,Malignancies ,University of ,Department of Hematology ,Hematology - Abstract
Background Melphalan flufenamide (melflufen), an alkylating peptide-drug conjugate, plus dexamethasone showed clinical activity and manageable safety in the phase 2 HORIZON study. We aimed to determine whether melflufen plus dexamethasone would provide a progression-free survival benefit compared with pomalidomide plus dexamethasone in patients with previously treated multiple myeloma. Methods In this randomised, open-label, head-to-head, phase 3 study (OCEAN), adult patients (aged ≥18 years) were recruited from 108 university hospitals, specialist hospitals, and community-based centres in 21 countries across Europe, North America, and Asia. Eligible patients had an ECOG performance status of 0–2; must have had relapsed or refractory multiple myeloma, refractory to lenalidomide (within 18 months of randomisation) and to the last line of therapy; and have received two to four previous lines of therapy (including lenalidomide and a proteasome inhibitor). Patients were randomly assigned (1:1), stratified by age, number of previous lines of therapy, and International Staging System score, to either 28-day cycles of melflufen and dexamethasone (melflufen group) or pomalidomide and dexamethasone (pomalidomide group). All patients received dexamethasone 40 mg orally on days 1, 8, 15, and 22 of each cycle. In the melflufen group, patients received melflufen 40 mg intravenously over 30 min on day 1 of each cycle and in the pomalidomide group, patients received pomalidomide 4 mg orally daily on days 1 to 21 of each cycle. The primary endpoint was progression-free survival assessed by an independent review committee in the intention-to-treat (ITT) population. Safety was assessed in patients who received at least one dose of study medication. This study is registered with ClinicalTrials.gov, NCT03151811, and is ongoing. Findings Between June 12, 2017, and Sept 3, 2020, 246 patients were randomly assigned to the melflufen group (median age 68 years [IQR 60–72]; 107 [43%] were female) and 249 to the pomalidomide group (median age 68 years [IQR 61–72]; 109 [44%] were female). 474 patients received at least one dose of study drug (melflufen group n=228; pomalidomide group n=246; safety population). Data cutoff was Feb 3, 2021. Median progression-free survival was 6·8 months (95% CI 5·0–8·5; 165 [67%] of 246 patients had an event) in the melflufen group and 4·9 months (4·2–5·7; 190 [76%] of 249 patients had an event) in the pomalidomide group (hazard ratio [HR] 0·79, [95% CI 0·64–0·98]; p=0·032), at a median follow-up of 15·5 months (IQR 9·4–22·8) in the melflufen group and 16·3 months (10·1–23·2) in the pomalidomide group. Median overall survival was 19·8 months (95% CI 15·1–25·6) at a median follow-up of 19·8 months (IQR 12·0–25·0) in the melflufen group and 25·0 months (95% CI 18·1–31·9) in the pomalidomide group at a median follow-up of 18·6 months (IQR 11·8–23·7; HR 1·10 [95% CI 0·85–1·44]; p=0·47). The most common grade 3 or 4 treatment-emergent adverse events were thrombocytopenia (143 [63%] of 228 in the melflufen group vs 26 [11%] of 246 in the pomalidomide group), neutropenia (123 [54%] vs 102 [41%]), and anaemia (97 [43%] vs 44 [18%]). Serious treatment-emergent adverse events occurred in 95 (42%) patients in the melflufen group and 113 (46%) in the pomalidomide group, the most common of which were pneumonia (13 [6%] vs 21 [9%]), COVID-19 pneumonia (11 [5%] vs nine [4%]), and thrombocytopenia (nine [4%] vs three [1%]). 27 [12%] patients in the melflufen group and 32 [13%] in the pomalidomide group had fatal treatment-emergent adverse events. Fatal treatment-emergent adverse events were considered possibly treatment related in two patients in the melflufen group (one with acute myeloid leukaemia, one with pancytopenia and acute cardiac failure) and four patients in the pomalidomide group (two patients with pneumonia, one with myelodysplastic syndromes, one with COVID-19 pneumonia). Interpretation Melflufen plus dexamethasone showed superior progression-free survival than pomalidomide plus dexamethasone in patients with relapsed or refractory multiple myeloma., Oncopeptides AB
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- 2022
8. MicroRNA in Multiple Myeloma - A Role in Pathogenesis and Prognostic Significance
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Anna Puła, Tadeusz Robak, and Pawel Robak
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Pharmacology ,Regulation of gene expression ,Bortezomib ,Organic Chemistry ,Biology ,Prognosis ,Biochemistry ,Microvesicles ,Gene Expression Regulation, Neoplastic ,Pathogenesis ,MicroRNAs ,Drug Discovery ,Gene expression ,microRNA ,Cancer research ,medicine ,Humans ,Molecular Medicine ,Gene silencing ,RNA Interference ,Epigenetics ,Multiple Myeloma ,medicine.drug - Abstract
Multiple myeloma (MM) is a common malignant hematological malignancy. Recently, interest has grown in the role of non-coding regions in disease pathogenesis. MicroRNAs (miRNAs) are small non-coding RNAs containing 19-25 bases that play a crucial role in messenger RNA silencing and post-transcriptional regulation of gene expression. Several miRNAs demonstrate markedly dysregulated expression in MM, suggesting that they may act as both tumor suppressors and oncogenes. microRNAs are also reportedly involved in the regulation of other epigenetic mechanisms of gene expression. Additionally, some miRNAs have been associated with drug resistance, and therefore a further exploration of their activity may lead to its reversal. Moreover, miRNA expression patterns in either MM cells or serum exosomes have been shown to be good prognostic markers. This review describes the roles of miRNAs in MM and examines their potential to predict MM prognosis and play a role in novel therapeutic strategies.
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- 2021
9. Bone lesions in hairy cell leukemia: Diagnosis and treatment
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Piotr Kupnicki, Dorota Jesionek-Kupnicka, Tadeusz Robak, Aaron Polliack, and Pawel Robak
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Pathology ,medicine.medical_specialty ,medicine.medical_treatment ,Osteolysis ,Pathogenesis ,03 medical and health sciences ,Femoral head ,0302 clinical medicine ,Bone Marrow ,Positron Emission Tomography Computed Tomography ,medicine ,Humans ,Hairy cell leukemia ,Cladribine ,Leukemia, Hairy Cell ,business.industry ,Incidence (epidemiology) ,Disease Management ,Hematology ,General Medicine ,medicine.disease ,Combined Modality Therapy ,Magnetic Resonance Imaging ,Tumor Burden ,Radiation therapy ,medicine.anatomical_structure ,030220 oncology & carcinogenesis ,Disease Susceptibility ,Bone marrow ,Bone Diseases ,Complication ,business ,030215 immunology ,medicine.drug - Abstract
Skeletal involvement is a rare complication of hairy cell leukemia (HCL) with an incidence of approximately 3%. Bone lesions are commonly lytic, and the most common sites of involvement are the femoral head and neck. Skeletal involvement is typically associated with high tumor burden and bone marrow infiltration. However, isolated cases of skeletal disease without splenomegaly or bone marrow involvement are occasionally reported. This review focuses on skeletal lesions in HCL, particularly the pathogenesis, clinical symptoms, diagnostic methods, and treatment approach. A literature review of the MEDLINE database for articles in English concerning hairy cell leukemia, skeletal symptoms, bone involvement was conducted via PubMed. Publications from January 1970 to May 2020 were scrutinized. Additional relevant publications were obtained by reviewing the references from the chosen articles.
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- 2020
10. Multifocal osteolytic lesions in hairy cell leukemia—the importance of PET/CT in diagnosis and assessment
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Tadeusz Robak, Piotr Kupnicki, Dorota Jesionek-Kupnicka, Aaron Polliack, and Pawel Robak
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medicine.medical_specialty ,Pathology ,PET-CT ,Hematology ,business.industry ,Internal medicine ,medicine ,Hairy cell leukemia ,General Medicine ,medicine.disease ,business - Published
- 2020
11. Different MAF translocations confer similar prognosis in newly diagnosed multiple myeloma patients
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Krzysztof Jamroziak, Artur Jurczyszyn, Chor Sang Chim, Monika Długosz-Danecka, Deepu Madduri, Julia Kelman, Max Bittrich, Michel Delforge, Klaus Martin Kortüm, Gabor Mikala, Ariel Kleman, Jorge J. Castillo, Maria-Victoria Mateos, Adam J. Olszewski, Saurabh Chhabra, Pawel Robak, Lidia Usnarska-Zubkiewicz, Anna Waszczuk-Gajda, Iwona Hus, Sarah Goldman-Mazur, David Jayabalan, Julio Davila Valls, Irit Avivi, Rebecca Silbermann, Norbert Grząśko, Stuart L. Goldberg, David H. Vesole, Yael C Cohen, Ruben Niesvizky, Piotr Mazur, Anna Suska, Verónica González-Calle, Laura Rosiñol, Alessandro Gozzetti, Łukasz Szukalski, Jacek Czepiel, Jakub Radocha, Parameswaran Hari, Daniel Coriu, Izabela Kozłowska, Aimee Chappell, Peter Barth, and Massimo Gentile
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Oncology ,Cancer Research ,medicine.medical_specialty ,Translocation ,Chromosomal translocation ,Newly diagnosed ,Transplantation, Autologous ,survival ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Humans ,Medicine ,Multiple myeloma ,Retrospective Studies ,16) ,MAF ,myeloma ,t(14 ,20) ,business.industry ,Hematopoietic Stem Cell Transplantation ,Small sample ,Hematology ,Prognosis ,medicine.disease ,Treatment Outcome ,030220 oncology & carcinogenesis ,Multiple Myeloma ,business ,Large group ,030215 immunology - Abstract
The MAF translocations, t(14;16) and t(14;20), are considered as adverse prognostic factors based on few studies with small sample sizes. We report on their prognostic impact in a large group of 254 patients - 223 (87.8%) with t(14;16) and 31 (12.2%) with t(14;20). There were no intergroup differences in survival estimates. Median progression-free survival was 16.6 months for t(14;16) and 24.9 months for t(14;20) (
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- 2020
12. Cobimetinib alone and plus venetoclax with/without atezolizumab in patients with relapsed/refractory multiple myeloma
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Fredrik Schjesvold, Bruno Paiva, Vincent Ribrag, Paula Rodriguez-Otero, Jesus F. San-Miguel, Pawel Robak, Markus Hansson, Maika Onishi, Habib Hamidi, Vikram Malhi, Monique Dail, Apurva Javery, Grace Ku, and Marc S. Raab
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Cancer Research ,Oncology ,Hematology - Abstract
Introduction Mitogen-activated protein kinase pathway mutations are present in >50% of patients with relapsed/refractory (R/R) multiple myeloma (MM). MEK inhibitors show limited single-agent activity in R/R MM; combination with B-cell lymphoma-2 (BCL-2) and programmed death-ligand 1 inhibition may improve efficacy. This phase Ib/II trial (NCT03312530) evaluated safety and efficacy of cobimetinib (cobi) alone and in combination with venetoclax (ven) with/without atezolizumab (atezo) in patients with R/R MM. Patients and Methods Forty-nine patients were randomized 1:2:2 to cobi 60 mg/day on days 1–21 (n = 6), cobi 40 mg/day on days 1–21 + ven 800 mg/day on days 1–28 with/without atezo 840 mg on days 1 and 15 of 28-day cycles (cobi-ven, n = 22; cobi-ven-atezo, n = 21). Safety run-in cohorts evaluated cobi-ven and cobi-ven-atezo dose levels. Results Any-grade common adverse events (AEs) with cobi, cobi-ven, and cobi-ven-atezo, respectively, included diarrhea (33.3%, 81.8%, 90.5%) and nausea (16.7%, 50.0%, 66.7%); common grade ≥3 AEs included anemia (0%, 22.7%, 23.8%), neutropenia (0%, 13.6%, 38.1%), and thrombocytopenia (0%, 18.2%, 23.8%). The overall response rate for all-comers was 0% (cobi), 27.3% (cobi-ven), and 28.6% (cobi-ven-atezo), and 0%, 50.0%, and 100%, respectively, in patients with t(11;14)+. Biomarker analysis demonstrated non-t(11;14) patient selection with NRAS/KRAS/BRAF mutation or high BCL-2/BCL-2-L1 ratio (>52% of the study population) could enrich for responders to the cobi-ven combination. Conclusions Cobi-ven and cobi-ven-atezo demonstrated manageable safety with moderate activity in all-comers, and higher activity in patients with t(11;14)+ MM, supporting a biomarker-driven approach for ven in MM.
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- 2022
13. Pretreatment Serum Levels of IL-1 Receptor Antagonist and IL-4 Are Predictors of Overall Survival in Multiple Myeloma Patients Treated with Bortezomib
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Damian Mikulski, Janusz Szemraj, Aleksandra Łosiewicz, Dariusz Jarych, Pawel Robak, Tadeusz Robak, Izabela Dróżdż, Edyta Węgłowska, Ewelina Perdas, Wojciech Fendler, and Małgorzata Misiewicz
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medicine.drug_class ,bortezomib ,IL-13 ,IL-1Ra ,IL-4 ,multiple myeloma ,OS ,PFS ,Article ,medicine ,Overall survival ,Multiple myeloma ,Interleukin 4 ,oncology_oncogenics ,business.industry ,Bortezomib ,General Medicine ,medicine.disease ,Receptor antagonist ,Interleukin 13 ,Cancer research ,Medicine ,business ,medicine.drug - Abstract
Multiple myeloma (MM) is characterized by the malignant proliferation of monoclonal plasma cells in the bone marrow with an elevation in monoclonal paraprotein, renal impairment, hypercalcemia, lytic bony lesions, and anemia. Immune cells and associated cytokines play a significant role in MM growth, progression, and dissemination. While some cytokines and their clinical significance are well described in MM biology, others remain relatively unknown. The present study examines the influence on progression-free survival (PFS) and overall survival (OS) by the serum levels of 27 selected cytokines in 61 newly diagnosed MM patients receiving first-line therapy with bortezomib-based regimens. The measurements were performed using a Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay and a MAGPIX Multiplex Reader, based on the Bio-Plex® 200 System (Bio-Rad). The following levels were determined: IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12, IL-13, IL-15, IL-17, Eotaxin, FGF, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1, MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α, and VEGF. Most patients received a VCD chemotherapy regimen (bortezomib, cyclophosphamide, and dexamethasone). In the final multivariate model, IL-13 cytokine level (HR 0.1411, 95% CI: 0.0240–0.8291, p = 0.0302) and ASCT (HR 0.3722, 95% CI: 0.1826–0.7585, p = 0.0065) significantly impacted PFS. Furthermore, ASCT (HR 0.142, 95% CI: 0.046–0.438, p = 0.0007), presence of bone disease at diagnosis (HR 3.826, 95% CI: 1.471–9.949, p = 0.0059), and two cytokine levels—IL-1Ra (HR 1.017, 95% CI: 1.004–1.030, p = 0.0091) and IL-4 (HR 0.161, 95% CI: 0.037–0.698, p = 0.0147)—were independent predictors of OS. Three clusters of MM patients were identified with different cytokine profiles. In conclusion, serum pretreatment levels of IL-13 and IL-4 are predictors of better PFS and OS, respectively, whereas IL-1Ra pretreatment levels negatively impact OS in MM patients treated with bortezomib-based chemotherapy. Cytokine signature profile may have a potential influence on the outcome of patients treated with bortezomib.
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- 2021
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14. Prognostic Value of Resistance Proteins in Plasma Cells from Multiple Myeloma Patients Treated with Bortezomib-Based Regimens
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Kacper Kościelny, Karolina Juszczak, Dariusz Jarych, Tadeusz Robak, Damian Mikulski, Pawel Robak, Izabela Dróżdż, Małgorzata Misiewicz, Wojciech Fendler, and Janusz Szemraj
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Oncology ,medicine.medical_specialty ,XBP1 ,MAFb ,survival ,Article ,PFS ,Text mining ,Internal medicine ,hemic and lymphatic diseases ,medicine ,POMP ,Multiple myeloma ,Bortezomib ,business.industry ,bortezomib ,OS ,General Medicine ,medicine.disease ,PSMB5 ,multiple myeloma ,medicine.anatomical_structure ,Proteasome ,MAFB ,Medicine ,cMAF ,Bone marrow ,prognosis ,business ,medicine.drug - Abstract
While multiple myeloma (MM) treatment with proteasome inhibitors and other agents yields encouraging results, primary and secondary resistance remains an emerging problem. An important factor in such treatment resistance is the overexpression of several proteins. The present study comprehensively evaluates the expression of POMP, PSMB5, NRF2, XBP1, cMAF and MAFb proteins in plasma cells isolated from the bone marrow of 39 MM patients treated with bortezomib-based regimens using an enzyme-linked immunosorbent assay (ELISA). The proteins were selected on the basis of previous laboratory and clinical studies in bortezomib-treated MM patients. It was found that the expression of the investigated proteins did not significantly differ between bortezomib-sensitive and bortezomib-refractory patients. However, the expression of some proteins correlated with overall survival (OS), this was significantly shorter in patients with higher POMP expression (HR 2.8, 95% CI: 1.1–7.0, p = 0.0277) and longer in those with higher MAFB expression (HR 0.32, 95% CI: 0.13–0.80, p = 0.0147). Our results indicate that a high expression of POMP and MAFB in MM plasma cells may serve as predictors of OS in MM patients treated with bortezomib-based regimens. However, further studies are needed to determine the role of these factors in effective strategies for improving anti-myeloma therapy.
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- 2021
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15. Prognostic Value of Resistance Proteins in Plasma Cells From Multiple Myeloma Patients Treated With Bortezomib
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Pawel Robak, Szemraj, Mikulski, Drozdz, K, Juszczak, D. Jarych, Robak, Kościelny, and Fendler
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business.industry ,MAFB ,Bortezomib ,Cancer research ,Medicine ,business ,medicine.disease ,Value (mathematics) ,Multiple myeloma ,oncology_oncogenics ,medicine.drug - Abstract
While multiple myeloma (MM) treatment with proteasome inhibitors and other agents yields encouraging results, primary and secondary resistance remains an emerging problem. An important factor in such treatment resistance is the overexpression of several proteins. The present study comprehensively evaluates the expression of POMP, PSMB5, NRF2, XBP1, cMAF and MAFb proteins in plasma cells isolated from the bone marrow of 39 MM patients treated with bortezomib-based regimens using enzyme-linked immunosorbent assay (ELISA). The proteins were selected on the basis of previous laboratory and clinical studies in bortezomib treated MM patients. It was found that the expression of the investigated proteins did not significantly differ between bortezomib-sensitive and bortezomib-refractory patients. However, the expression of some proteins correlated with overall survival (OS); this was significantly shorter in patients with higher POMP expression (HR 2.8, 95% CI: 1.1-7.0, p = 0.0277) and longer in those with higher MAFB expression (HR 0.32, 95% CI: 0.13-0.80, p = 0.0147). Our results indicate that high expression of POMP and MAFB in MM plasma cells may serve as predictors of OS in MM patients treated with bortezomib-based regimens. However, further studies are needed to determine the role of these factors in effective strategies for improving anti-myeloma therapy.
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- 2021
16. OAB-010: Atlas: a phase 3 randomized trial of carfilzomib, lenalidomide, and dexamethasone versus lenalidomide alone after stem-cell transplant for multiple myeloma
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Andrzej Jakubowiak, Tomasz Wrobel, Krzysztof Jamroziak, Tadeusz Kubicki, Pawel Robak, Jarosław Czyz, Agata Tyczynska, Agnieszka Druzd-Sitek, Krzysztof Giannopoulos, Adam Nowicki, Anna Lojko-Dankowska, Magdalena Matuszak, Lidia Gil, Bartosz Pula, Justyna Rybka, Lidia Usnarska-Zubkiewicz, Olga Czabak, Andrew Stefka, Benjamin Derman, and Dominik Dytfeld
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Cancer Research ,Oncology ,Hematology - Published
- 2022
17. Efficacy of daratumumab monotherapy in real-world heavily pretreated patients with relapsed or refractory multiple myeloma
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Anna Pasternak, Krzysztof Giannopoulos, Dominik Dytfeld, Krzysztof Warzocha, Wanda Knopinska-Posluszny, Patrycja Zielinska, Adam Walter-Croneck, Lidia Usnarska-Zubkiewicz, Jadwiga Hołojda, Krzysztof Jamroziak, Dorota Hawrylecka, Monika Mordak-Domagala, Pawel Robak, Agnieszka Szeremet, Małgorzata Wojciechowska, Michal Osowiecki, Jan Maciej Zaucha, Aleksander Salomon-Perzyński, and Marcin Wójtowicz
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Male ,Oncology ,medicine.medical_specialty ,medicine.medical_treatment ,Antineoplastic Agents ,Disease-Free Survival ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Internal medicine ,medicine ,Humans ,030212 general & internal medicine ,Adverse effect ,Multiple myeloma ,Aged ,Aged, 80 and over ,business.industry ,Antibodies, Monoclonal ,Daratumumab ,Refractory Multiple Myeloma ,General Medicine ,Immunotherapy ,Middle Aged ,medicine.disease ,ADP-ribosyl Cyclase 1 ,Treatment Outcome ,Tolerability ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Proteasome inhibitor ,Female ,Neoplasm Recurrence, Local ,Multiple Myeloma ,business ,medicine.drug - Abstract
Purpose Daratumumab is a promising new agent for relapsed/refractory multiple myeloma (RRMM). However, there are limited data on its clinical activity and tolerability in the real-world patients. The purpose of this study is to determine the efficacy and toxicity profile of daratumumab monotherapy in the real-life setting. Patients and methods Thirty RRMM patients treated with daratumumab who had previously received at least three treatment lines including a proteasome inhibitor and an immunomodulatory drug or had been double refractory (DR MM) were included to the Polish Myeloma Group observational study. Results The objective response rate to daratumumab was 42.8%. Median progression-free survival (PFS) and overall survival reached 9.5 and 13.8 months, respectively. Importantly, patients with DR-MM had a significantly shorter PFS than other patients (median PFS of 4.1 vs. 12.1 months). Daratumumab was generally well tolerated, however two patients had their therapy interrupted due to adverse events. Conclusion Daratumumab monotherapy has significant activity and good tolerance in heavily pretreated RRMM patients.
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- 2019
18. Mantle cell lymphoma: therapeutic options in transplant-ineligible patients
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Martin Dreyling, Pawel Robak, Tadeusz Robak, and Piotr Smolewski
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Bendamustine ,Oncology ,Cancer Research ,Vincristine ,medicine.medical_specialty ,Lymphoma, Mantle-Cell ,Transplantation, Autologous ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Autologous stem-cell transplantation ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Bortezomib ,business.industry ,Hematopoietic Stem Cell Transplantation ,Induction chemotherapy ,Induction Chemotherapy ,Hematology ,Prognosis ,medicine.disease ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Rituximab ,Mantle cell lymphoma ,business ,030215 immunology ,medicine.drug - Abstract
Management of patients with newly diagnosed mantle cell lymphoma (MCL) depends on the age and fitness of the patient. For younger patients, the commonly accepted standard of care is a high-dose cytarabine-based induction chemotherapy followed by autologous stem cell transplantation (ASCT). In newly diagnosed patients with MCL ineligible for intensive therapy and ASCT, the standard-of-care has generally been R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), followed by rituximab, maintenance. In recent years, bendamustine-based therapy has been increasingly adopted for older MCL patients and more recently, vincristine has been replaced by bortezomib in the R-CHOP combination as VR-CAP for previously untreated patients. Novel targeted agents now offer more promise than traditional chemotherapy or immunochemotherapy for both previously treated and untreated disease, and should also improve outcomes for older MCL patients. Here, we review standard therapies currently in use and novel agents that may soon be available for MCL patients and particularly for those unsuitable for ASCT.
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- 2019
19. Bortezomib for the Treatment of Hematologic Malignancies: 15 Years Later
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Tadeusz Robak and Pawel Robak
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Antineoplastic Agents ,Review Article ,Immunoglobulin light chain ,030226 pharmacology & pharmacy ,Lymphoplasmacytic Lymphoma ,Bortezomib ,03 medical and health sciences ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,medicine ,Humans ,Drug Approval ,Multiple myeloma ,Randomized Controlled Trials as Topic ,030203 arthritis & rheumatology ,Pharmacology ,United States Food and Drug Administration ,Cell growth ,business.industry ,lcsh:RM1-950 ,Waldenstrom macroglobulinemia ,medicine.disease ,United States ,lcsh:Therapeutics. Pharmacology ,Treatment Outcome ,Proteasome ,Hematologic Neoplasms ,Cancer research ,Mantle cell lymphoma ,business ,Proteasome Inhibitors ,medicine.drug - Abstract
Bortezomib is a dipeptidyl boronic acid that selectively inhibits the ubiquitin proteasome pathway, which plays a role in the degradation of many intracellular proteins. It is the first-in-class selective and reversible inhibitor of the 26S proteasome, with antiproliferative and antitumor activity. It exerts its anti-neoplastic action mainly via the inhibition of the nuclear factor-κB pathway components associated with cell proliferation, apoptosis, and angiogenesis. The drug has revolutionized the treatment of multiple myeloma and, more recently, mantle cell lymphoma. In 2003, bortezomib received accelerated approval from the US Food and Drug Administration for the treatment of relapsed/refractory multiple myeloma and in 2008 for patients with previously untreated multiple myeloma. In 2006, bortezomib was approved for the treatment of refractory/relapsed mantle cell lymphoma and, in 2014, for previously untreated mantle cell lymphoma. Bortezomib has also demonstrated clinical efficacy both as a single drug and in combination with other agents in light chain amyloidosis, lymphoplasmacytic lymphoma/Waldenstrom macroglobulinemia, and peripheral T-cell lymphomas. Furthermore, continued clinical studies are required to confirm its value for patients with indolent and aggressive B-cell non-Hodgkin lymphomas and acute leukemias.
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- 2019
20. Dose and drug changes in chronic lymphocytic leukemia cell response in vitro: A comparison of standard therapy regimens with two novel cyclin-dependent kinase inhibitors
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Pawel Robak, Małgorzata Rogalińska, Małgorzata Kubczak, Tomaš Gucký, Vladmir Krystof, Aleksandra Szustka, Jerzy Z. Blonski, and Małgorzata Misiewicz
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Male ,Cancer Research ,Cell Survival ,Chronic lymphocytic leukemia ,Cell ,Antineoplastic Agents ,Biochemistry ,Flow cytometry ,necrosis ,chemistry.chemical_compound ,anticancer agents ,Cyclin-dependent kinase ,alkylator ,Cell Line, Tumor ,Antineoplastic Combined Chemotherapy Protocols ,Genetics ,Tumor Cells, Cultured ,Medicine ,Humans ,Propidium iodide ,Molecular Biology ,Protein Kinase Inhibitors ,biology ,medicine.diagnostic_test ,Dose-Response Relationship, Drug ,business.industry ,viability ,apoptosis ,cyclin-dependent kinase inhibitor ,Articles ,Cell cycle ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Cyclin-Dependent Kinases ,medicine.anatomical_structure ,Oncology ,chemistry ,Apoptosis ,monoclonal antibody ,biology.protein ,Cancer research ,Molecular Medicine ,chronic lymphocytic leukemia ,Rituximab ,Female ,business ,in vitro cell incubations ,medicine.drug - Abstract
Chronic lymphocytic leukemia (CLL) treatment is improving; however, some patients do not respond to therapy. Due to the high heterogeneity in disease development, there is an urgent need for personalization of therapy. In the present study, the response of leukemic mononuclear cells to anticancer drugs used for CLL treatment (cladribine + mafosfamide; CM or CM combined with rituximab; RCM) was compared with the response to new cyclin‑dependent kinase (CDK) inhibitors: BP14 and BP30. Viable apoptotic and necrotic cells were quantified by flow cytometry using propidium iodide and Yo‑Pro stains. CDK inhibitors were studied in several doses to determine the reduction of necrosis and simultaneous increase of apoptosis in leukemic cell incubations with anticancer agents. The distinct cell response to applied doses/anticancer agents was observed. Results obtained in the current manuscript confirmed that modulation of doses is important. This was particularly indicated in results obtained at 24 h of cells incubation with anticancer agent. While an important time for analysis of anticancer response efficacy (monitoring of apoptosis induction potential) seems to be 48 h of cells exposition to anticancer agents. High variability in response to the drugs revealed that both the nature and the dose of the anticancer agents could be important in the final effect of the therapy. The present findings support the thesis that personalized medicine, before drug administration in the clinic, could be important to avoid the application of ineffective therapy.
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- 2019
21. Drug resistance in multiple myeloma
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Pawel Robak, Tadeusz Robak, Janusz Szemraj, and Izabela Dróżdż
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0301 basic medicine ,DNA repair ,Antineoplastic Agents ,Drug resistance ,03 medical and health sciences ,0302 clinical medicine ,Plasma Cell Myeloma ,medicine ,Humans ,Radiology, Nuclear Medicine and imaging ,Epigenetics ,Multiple myeloma ,Lenalidomide ,business.industry ,Bortezomib ,General Medicine ,medicine.disease ,Multiple drug resistance ,030104 developmental biology ,Oncology ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Cancer research ,Multiple Myeloma ,business ,medicine.drug - Abstract
Multiple myeloma (MM, plasma cell myeloma) is a malignant hematologic disease characterized by the clonal proliferation of malignant plasma cells. The treatment of MM has changed dramatically in recent years, with the introduction of new drugs into therapeutic strategies, both in the front line setting and in relapsed refractory disease. However, most patients eventually relapse and often demonstrate multiple drug resistance. Therefore there is still an urgent and unmet need to define the molecular mechanisms of resistance for available drugs in order to enhance the use of existing treatments and design more effective therapies. Genetic abnormalities are well known to play a central role in MM resistance to available drugs, and epigenetic aberrations mainly affecting the patterns of DNA methylation and histone modifications of genes, especially tumor suppressors, can be involved in the resistance mechanism. Moreover, defects in the mechanisms of apoptosis, senescence and DNA repair could also contribute to drug resistance. In addition, mutations or alterations in the expression of the drug target can influence response to therapy. Achieving a better understanding of the pathways and protein expression involved in MM drug resistance and the development of novel therapeutic strategies are important goals for further progress in the treatment of MM. This review gives a critical overview of the role of cellular, microenvironmental and molecular mechanisms of drug resistance in MM.
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- 2018
22. The Prognostic Value of Whole-Blood PSMB5, CXCR4, POMP, and RPL5 mRNA Expression in Patients with Multiple Myeloma Treated with Bortezomib
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Pawel Robak, Aleksandra Kotkowska, Piotr Smolewski, Wojciech Fendler, Janusz Szemraj, Izabela Dróżdż, Małgorzata Misiewicz, Dariusz Jarych, Konrad Stawiski, Tadeusz Robak, Damian Mikulski, and Edyta Węgłowska
- Subjects
0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,TXN ,RPL5 ,PSMB5 ,CXCR4 ,lcsh:RC254-282 ,Article ,03 medical and health sciences ,0302 clinical medicine ,Autologous stem-cell transplantation ,immune system diseases ,Internal medicine ,hemic and lymphatic diseases ,Gene expression ,medicine ,biochemistry ,cardiovascular diseases ,POMP ,neoplasms ,Multiple myeloma ,Whole blood ,Bortezomib ,business.industry ,allergology ,bortezomib ,medicine.disease ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,XBP1 ,Multiple drug resistance ,multiple myeloma ,refractory ,030104 developmental biology ,030220 oncology & carcinogenesis ,gene expression ,business ,medicine.drug - Abstract
Proteasome inhibitors, like bortezomib, play a key role in the treatment of multiple myeloma (MM), however, most patients eventually relapse and eventually show multiple drug resistance, and the molecular mechanisms of this resistance remain unclear. The aim of our study is to assess the expression of previously described genes that may influence the resistance to bortezomib treatment at the mRNA level (ABCB1, CXCR4, MAF, MARCKS, POMP, PSMB5, RPL5, TXN, and XBP1) and prognosis of MM patients. mRNA expression was determined in 73 MM patients treated with bortezomib-based regimens (30 bortzomib-sensitive and 43 bortezomib-refractory patients) and 11 healthy controls. RPL5 was significantly down-regulated in multiple myeloma patients as compared with healthy controls. Moreover, POMP was significantly up-regulated in MM patients refractory to bortezomib-based treatment. In multivariate analysis, high expression of PSMB5 and CXCR and autologous stem cell transplantation were independent predictors of progression-free survival, and high expression of POMP and RPL5 was associated with shorter overall survival.
- Published
- 2021
23. P-210: Oral ixazomib (Ixa), IV daratumumab (Dara), and dexamethasone (dex; IDd) in relapsed/refractory multiple myeloma (RRMM) patients (pts) with 1–3 prior therapies: phase 2 study interim analysis (IA)
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Richard Labotka, Meletios-Athanasios Dimopoulos, Jeffrey Matous, Suman Kambhampati, Roman Hájek, Sosana Delimpasi, Lionel Karlin, Jesus G. Berdeja, Andrzej Pluta, Kaveri Suryanarayan, Petr Pavlicek, Ajeeta B Dash, Robert Z. Orlowski, Argiris Symeonidis, Sebastian Grosicki, Sonja Zweegman, Jan Straub, Pawel Robak, Cyrille Touzeau, Luděk Pour, Viralkumar Bhanderi, and Philip Twumasi-Ankrah
- Subjects
Cancer Research ,medicine.medical_specialty ,Anemia ,business.industry ,Daratumumab ,Phases of clinical research ,Hematology ,medicine.disease ,Interim analysis ,Sudden death ,Gastroenterology ,Ixazomib ,Discontinuation ,chemistry.chemical_compound ,Regimen ,Oncology ,chemistry ,Internal medicine ,medicine ,business - Abstract
Background: Proteasome inhibitors (PIs) & monoclonal antibodies are backbones of RRMM treatment;Ixa is approved with lenalidomide-dex for pts with ≥1 prior therapy, & Dara is approved in various regimens, including with bortezomib-dex (DVd). In CASTOR (DVd vs Vd), Vd was limited to 8 cycles;however, prolonged PI therapy is associated with improved outcomes. The IDd regimen with oral Ixa may enable longer-term PI therapy than with DVd. We evaluate IDd using a treat-to-progression approach. Methods: Ixa/Dara-naive RRMM pts receive Ixa 4 mg (days 1, 8, 15), Dara 16 mg/kg (days 1, 8, 15, 22, cycles 1–2;days 1, 15, cycles 3–6;day 1, cycles 7+), & dex 20 mg (days 1, 2, 8, 9, 15, 16, 22, 23) in 28-day cycles. The primary endpoint is ≥ very good partial response (VGPR) rate;secondary endpoints include overall response rate (ORR), progression-free survival (PFS), time to progression (TTP), overall survival (OS), & safety. We report data from the 2nd IA, conducted after ~50% of PFS events had occurred (data cutoff: 1/1/2021). Results: 61 pts were enrolled (median age 69 y, 19.7% aged ≥75 y;19.7% International Staging System stage III;26.2% high-risk cytogenetics [del(17p), t(4;14), t(14;16)], 42.6% expanded high-risk cytogenetics [high-risk &/or amp1q21]);59.0/26.2/14.8% of pts had received 1/2/3 prior lines. At data cutoff, pts had received a median of 16 IDd cycles;37.7% were ongoing. Relative dose intensity (RDI) of Ixa, Dara, & dex was 20%) TEAEs were diarrhea (39.3%), anemia (27.9%), thrombocytopenia (26.2%), & fatigue (21.3%);common (>5%) G≥3 TEAEs were pneumonia (11.5%), thrombocytopenia (11.5%), & anemia (8.2%). Infections & Infestations TEAEs were seen in 57.4% of pts (G≥3 24.6%) and were serious in 26.2%, including pneumonia (9.8%) and COVID-19/pneumonia (4.9%). Rate of peripheral neuropathy (PN) was 18.0% (1.6% G≥3). PN was 28.6% & 12.5%in pts with & without history of PN, respectively. Study drug dose modifications, reductions & discontinuations due to TEAEs were required in 57.4% (Ixa 36.1%, Dara 34.4%, dex 41.0%), 32.8%, & 9.8%of pts, respectively. Four pts died on study due to sudden death, COVID-19 pneumonia, septic shock, & COVID-19 (none were considered study drug-related). Conclusion: These IA data suggest IDd has a positive risk-benefit profile in RRMM pts, with a ≥VGPR rate of 30.5%, median PFS of 17.0 m, & a low rate of discontinuation due to TEAEs. The final analysis of this ongoing study is expected in 2022.
- Published
- 2021
24. Heterogenous mutation spectrum and deregulated cellular pathways in aberrant plasma cells underline molecular pathology of light-chain amyloidosis
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Jana Filipova, Martin Mistrik, Ludek Pour, Martin Mokrejs, Gabor Mikala, Lucie Brozova, Artur Jurczyszyn, Roman Hájek, Lukas Stejskal, Michal Simicek, Martin Stork, Katerina Growkova, Zuzana Chyra, Martina Zatopkova, Petr Vojta, Pawel Robak, Jakub Dębski, Marian Hajduch, Anna Czyż, Agnieszka Barchnicka, Matous Hrdinka, Eva Budinská, Tereza Sevcikova, Janka Puterova, Aneta Mikulasova, Lidia Usnarska-Zubkiewicz, Tomas Jelinek, Wiesław Wiktor Jędrzejczak, Fedor Kryukov, Lubica Harvanova, Sebastian Grosicki, Alexandra Jungova, Anna Waszczuk-Gajda, and Gareth J. Morgan
- Subjects
Amyloid ,Plasma Cells ,Immunoglobulin light chain ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,medicine ,AL amyloidosis ,Humans ,Immunoglobulin Light-chain Amyloidosis ,Pathology, Molecular ,Letters to the Editor ,Multiple myeloma ,030304 developmental biology ,0303 health sciences ,Mutation ,biology ,Chemistry ,Molecular pathology ,Amyloidosis ,AL AMYLOIDOSIS ,Hematology ,medicine.disease ,3. Good health ,030220 oncology & carcinogenesis ,biology.protein ,Cancer research ,Immunoglobulin Light Chains ,Antibody - Abstract
Light-chain (AL) amyloidosis (ALA) is a rare but fatal monoclonal gammopathy (MG) causing organ and tissue damage resulting from the deposition of misfolded immunoglobulin free light chains in the form of amyloid fibrils.1 In some cases, ALA coexists with multiple myeloma (MM) (ALA+MM), which is the second most common blood cancer and is caused by the proliferation of clonal plasma cells (PC).2 Due to insufficient knowledge of ALA and ALA+MM biology, therapeutic options have mirrored treatment regimens of MM, which focus on the elimination of clonal PC.3,4 We investigated the mutation and gene expression profiles in clonal aberrant PC (aPC) in order to better understand ALA and ALA+MM etiology and to clarify the molecular differences between individual MG diagnoses.
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- 2021
25. Once-per-week selinexor, bortezomib, and dexamethasone versus twice-per-week bortezomib and dexamethasone in patients with multiple myeloma (BOSTON): a randomised, open-label, phase 3 trial
- Author
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Vesselina Goranova-Marinova, Eirini Katodritou, Mamta Garg, Michael G. Kauffman, Paul G. Richardson, Lingling Li, Monica Galli, Sosana Delimpasi, Sebastian Grosicki, Jelena Bila, Galina Salogub, Dinesh Kumar Sinha, Holger W. Auner, Larry D. Anderson, Sybiryna Korenkova, Don A. Stevens, Melina Arazy, Reuben Benjamin, Supratik Basu, Jacqueline Jeha, Moshe Yair Levy, Artur Jurczyszyn, Nizar J. Bahlis, Jean Richard Saint-Martin, Jatin P. Shah, Hang Quach, Anna M. Liberati, Tuphan Kanti Dolai, Iryrna Kriachok, Roman Hájek, Anita A. Joshi, Darrell White, Michele Cavo, Sundar Jagannath, Meletios A. Dimopoulos, Xavier Leleu, Hanna Oliynyk, Pawel Robak, Maryana Simonova, Ganna Usenko, Ludek Pour, Maria V. Mateos, Ivan Spicka, Moshe E. Gatt, Atanas Radinoff, Craig T. Wallington-Beddoe, Jeevan Kumar, Vishnuvardhan Peddagali, Halyna Pylypenko, Thierry Facon, Christopher P. Venner, Donna E. Reece, Sharon Shacham, Maria Gavriatopoulou, Yi Chai, Mercedes Gironella, Vadim A Doronin, P. Moreau, Karyopharm, Grosicki S., Simonova M., Spicka I., Pour L., Kriachok I., Gavriatopoulou M., Pylypenko H., Auner H.W., Leleu X., Doronin V., Usenko G., Bahlis N.J., Hajek R., Benjamin R., Dolai T.K., Sinha D.K., Venner C.P., Garg M., Gironella M., Jurczyszyn A., Robak P., Galli M., Wallington-Beddoe C., Radinoff A., Salogub G., Stevens D.A., Basu S., Liberati A.M., Quach H., Goranova-Marinova V.S., Bila J., Katodritou E., Oliynyk H., Korenkova S., Kumar J., Jagannath S., Moreau P., Levy M., White D., Gatt M.E., Facon T., Mateos M.V., Cavo M., Reece D., Anderson L.D., Saint-Martin J.-R., Jeha J., Joshi A.A., Chai Y., Li L., Peddagali V., Arazy M., Shah J., Shacham S., Kauffman M.G., Dimopoulos M.A., Richardson P.G., and Delimpasi S.
- Subjects
Male ,medicine.medical_treatment ,Kaplan-Meier Estimate ,030204 cardiovascular system & hematology ,Gastroenterology ,Dexamethasone ,multiple myeloma, Selinexor, dexamethasone ,Bortezomib ,0302 clinical medicine ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,030212 general & internal medicine ,Multiple myeloma ,11 Medical and Health Sciences ,education.field_of_study ,General Medicine ,Middle Aged ,Progression-Free Survival ,Hydrazines ,XPO1 ,Female ,Multiple Myeloma ,Life Sciences & Biomedicine ,medicine.drug ,Adult ,medicine.medical_specialty ,Adolescent ,Population ,Antineoplastic Agents ,Drug Administration Schedule ,03 medical and health sciences ,Medicine, General & Internal ,Internal medicine ,General & Internal Medicine ,medicine ,Humans ,Progression-free survival ,education ,Aged ,Chemotherapy ,Science & Technology ,business.industry ,Triazoles ,medicine.disease ,EFFICACY ,Regimen ,Proteasome inhibitor ,business ,PERIPHERAL NEUROPATHY - Abstract
Summary Background Selinexor combined with dexamethasone has shown activity in patients with heavily pre-treated multiple myeloma. In a phase 1b/2 study, the combination of oral selinexor with bortezomib (a proteasome inhibitor) and dexamethasone induced high response rates with low rates of peripheral neuropathy, the main dose-limiting toxicity of bortezomib. We aimed to evaluate the clinical benefit of weekly selinexor, bortezomib, and dexamethasone versus standard bortezomib and dexamethasone in patients with previously treated multiple myeloma. Methods This phase 3, randomised, open-label trial was done at 123 sites in 21 countries. Patients aged 18 years or older, who had multiple myeloma, and who had previously been treated with one to three lines of therapy, including proteasome inhibitors, were randomly allocated (1:1) to receive selinexor (100 mg once per week), bortezomib (1·3 mg/m2 once per week), and dexamethasone (20 mg twice per week), or bortezomib (1·3 mg/m2 twice per week for the first 24 weeks and once per week thereafter) and dexamethasone (20 mg four times per week for the first 24 weeks and twice per week thereafter). Randomisation was done using interactive response technology and stratified by previous proteasome inhibitor therapy, lines of treatment, and multiple myeloma stage. The primary endpoint was progression-free survival in the intention-to-treat population. Patients who received at least one dose of study treatment were included in the safety population. This trial is registered at ClinicalTrials.gov , NCT03110562 . The trial is ongoing, with 55 patients remaining on randomised therapy as of Feb 20, 2020. Findings Of 457 patients screened for eligibility, 402 were randomly allocated—195 (49%) to the selinexor, bortezomib, and dexamethasone group and 207 (51%) to the bortezomib and dexamethasone group—and the first dose of study medication was given between June 6, 2017, and Feb 5, 2019. Median follow-up durations were 13·2 months [IQR 6·2–19·8] for the selinexor, bortezomib, and dexamethasone group and 16·5 months [9·4–19·8] for the bortezomib and dexamethasone group. Median progression-free survival was 13·93 months (95% CI 11·73–not evaluable) with selinexor, bortezomib, and dexamethasone and 9·46 months (8·11–10·78) with bortezomib and dexamethasone (hazard ratio 0·70 [95% CI 0·53–0·93], p=0·0075). The most frequent grade 3–4 adverse events were thrombocytopenia (77 [39%] of 195 patients in the selinexor, bortezomib, and dexamethasone group vs 35 [17%] of 204 in the bortezomib and dexamethasone group), fatigue (26 [13%] vs two [1%]), anaemia (31 [16%] vs 20 [10%]), and pneumonia (22 [11%] vs 22 [11%]). Peripheral neuropathy of grade 2 or above was less frequent with selinexor, bortezomib, and dexamethasone (41 [21%] patients) than with bortezomib and dexamethasone (70 [34%] patients; odds ratio 0·50 [95% CI 0·32–0·79], p=0·0013). 47 (24%) patients in the selinexor, bortezomib, and dexamethasone group and 62 (30%) in the bortezomib and dexamethasone group died. Interpretation A once-per-week regimen of selinexor, bortezomib, and dexamethasone is a novel, effective, and convenient treatment option for patients with multiple myeloma who have received one to three previous lines of therapy. Funding Karyopharm Therapeutics.
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- 2020
26. Cytokine and Chemokine Profile in Patients with Multiple Myeloma Treated with Bortezomib
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Damian Mikulski, Edyta Węgłowska, Dariusz Jarych, Piotr Smolewski, Ewa Wawrzyniak, Wojciech Fendler, Tadeusz Robak, Małgorzata Misiewicz, Janusz Szemraj, Pawel Robak, Magdalena Ferlińska, and Izabela Dróżdż
- Subjects
Male ,0301 basic medicine ,medicine.medical_specialty ,Chemokine ,Article Subject ,Anemia ,medicine.medical_treatment ,Immunology ,Gastroenterology ,Bortezomib ,Pathogenesis ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,Pathology ,medicine ,Humans ,RB1-214 ,In patient ,Chemokine CCL4 ,Chemokine CCL2 ,Multiple myeloma ,Aged ,biology ,Tumor Necrosis Factor-alpha ,business.industry ,Interleukin-8 ,Interleukin-9 ,Cell Biology ,Middle Aged ,medicine.disease ,Discontinuation ,Interleukin 1 Receptor Antagonist Protein ,030104 developmental biology ,Cytokine ,030220 oncology & carcinogenesis ,biology.protein ,Cytokines ,Female ,Chemokines ,Multiple Myeloma ,business ,Research Article ,medicine.drug - Abstract
The aim of the study was to determine the levels of selected cytokines and chemokines in the serum of multiple myeloma (MM) patients treated with bortezomib-based regimens. A total of 71 MM patients were examined: 41 with primary refractory disease (17) or early relapse (28), and 30 who were bortezomib sensitive with no progression for at least six months. Patients who demonstrated CR or PR after bortezomib-based therapies longer than six months after treatment discontinuation were designated bortezomib sensitive. Serum cytokine levels were assayed with Bio-Rad Bio-Plex Pro Human Cytokine 27-Plex Assay on the MAGPIX Multiplex Reader and the Bio-Plex® 200 System (Bio-Rad). Higher levels of MIP-1α and lower levels of MIP-1β and IL-9 were associated with better responses to bortezomib-based treatment, and higher levels of IL-1ra and IL-8 were associated with bone involvement. MCP-1 was elevated in patients with hemoglobin<10 g/dl compared to those without anemia. The levels of IL-8, MIP-1α, and TNF-α were significantly higher in patients with renal insufficiency. Only MIP-1α was elevated in patients with hypercalcemia compared to patients with normal calcium levels. In conclusion, distinct cytokines are involved in the pathogenesis of MM and may play a prominent role in the prediction of treatment response. However, a single measurement of serum cytokines should be interpreted with caution and further studies are needed.
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- 2020
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27. OCEAN: A randomized Phase III study of melflufen + dexamethasone to treat relapsed refractory multiple myeloma
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Pawel Robak, Pieter Sonneveld, Fredrik Schjesvold, Johan Aschan, Ludek Pour, and Hematology
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0301 basic medicine ,Oncology ,Cancer Research ,medicine.medical_specialty ,Phenylalanine ,Dexamethasone ,03 medical and health sciences ,0302 clinical medicine ,Refractory ,Recurrence ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Clinical endpoint ,Overall survival ,Humans ,Lenalidomide ,Melphalan ,Multiple myeloma ,Randomized Controlled Trials as Topic ,business.industry ,General Medicine ,medicine.disease ,Pomalidomide ,Progression-Free Survival ,Thalidomide ,030104 developmental biology ,Clinical Trials, Phase III as Topic ,Drug Resistance, Neoplasm ,030220 oncology & carcinogenesis ,Relapsed refractory ,business ,Multiple Myeloma ,medicine.drug - Abstract
Melflufen is a novel peptide–drug conjugate that rapidly delivers a cytotoxic payload into tumor cells. It has emerged as a potential new multiple myeloma treatment, particularly for late-stage forms of the disease. Here we describe the rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melflufen + dexamethasone versus pomalidomide + dexamethasone. Eligible patients with relapsed refractory multiple myeloma have received 2–4 previous treatments and are refractory to both lenalidomide and their last treatment. Patients are excluded if they have previously received pomalidomide. The primary endpoint is progression-free survival, and key secondary endpoints include overall response rate, duration of response and overall survival.
- Published
- 2020
28. Novel Drugs for Multiple Myeloma
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Tadeusz Robak and Pawel Robak
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business.industry ,Cancer research ,medicine ,medicine.disease ,business ,Multiple myeloma - Published
- 2019
29. A multicenter retrospective study of 223 patients with t(14;16) in multiple myeloma
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Aimee Chappell, K. Martin Kortüm, Sarah Goldman-Mazur, Peter Barth, Rebecca Silbermann, Ariel Kleman, Sebastian Grosicki, Adam J. Olszewski, David Jayabalan, Julio Davila Valls, Irit Avivi, Daniel Coriu, Maria V. Mateos, Alessandro Gozzetti, Iwona Hus, Yael Cohen, Max Bittrich, Deepu Madduri, Julia Kelman, Stuart L. Goldberg, Gabor Mikala, Krzysztof Jamroziak, Chor S. Chim, Ruben Niesvizky, Saurabh Chhabra, Pawel Robak, Artur Jurczyszyn, Norbert Grząśko, Parameswaran Hari, Izabela Kozłowska, David H. Vesole, Massimo Gentile, Michel Delforge, Verónica González-Calle, Laura Rosiñol, Jorge J. Castillo, Monika Długosz-Danecka, Lidia Usnarska-Zubkiewicz, Anna Waszczuk-Gajda, Łukasz Szukalski, Jacek Czepiel, Jakub Radocha, and Anna Suska
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Male ,medicine.medical_specialty ,Scoring system ,Adverse outcomes ,Female ,Humans ,Middle Aged ,Multiple Myeloma ,Progression-Free Survival ,Retrospective Studies ,Translocation, Genetic ,Translocation ,Newly diagnosed ,03 medical and health sciences ,0302 clinical medicine ,Genetic ,Internal medicine ,Medicine ,Progression-free survival ,Multiple myeloma ,business.industry ,Retrospective cohort study ,Hematology ,medicine.disease ,Multicenter study ,030220 oncology & carcinogenesis ,Cohort ,business ,030215 immunology - Abstract
The t(14;16) translocation, found in 3%-5% of newly diagnosed (ND) multiple myeloma (MM), has been associated with adverse outcomes. However, the studies establishing the characteristics of t(14;16) included solely small cohorts. The goal of the current international, multicenter (n = 25 centers), retrospective study was to describe the characteristics and outcomes of t(14;16) patients in a large, real-world cohort (n = 223). A substantial fraction of patients had renal impairment (24%) and hemoglobin10 g/dL (56%) on initial presentation. Combined therapy of both immunomodulatory drug and proteasome inhibitor (PI) in the first line was used in 35% of patients. Autologous stem cell transplantation was performed in 42% of patients. With a median follow up of 4.1 years (95% CI 3.7-18.7), the median progression-free survival (PFS) and overall survival (OS) from first line therapy were 2.1 years (95% CI 1.5-2.4) and 4.1 years (95% CI 3.3-5.5), respectively. Worse OS was predicted by age 60 years (HR = 1.65, 95% CI [1.05-2.58]), as well as revised International Scoring System (R-ISS) 3 (vs R-ISS 2; HR = 2.59, 95% CI [1.59-4.24]). In conclusion, based on the largest reported cohort of t(14;16) patients, quarter of this subset of MM patients initially presents with renal failure, while older age and the R-ISS 3 predict poor survival.
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- 2019
30. OCEAN (OP-103): Melflufen Plus Dexamethasone (Dex) Versus Pomalidomide (Pom) and Dex in Relapsed/Refractory Multiple Myeloma (RRMM) - Impact of Prior Treatments Analysis
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Pawel Robak, Meletios-Athanasios Dimopoulos, Fredrik Schjesvold, Maria-Victoria Mateos, Kajsa Larsson, Marcus Thuresson, Jakob Lindberg, Roman Hájek, Paul G. Richardson, and Pieter Sonneveld
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Pomalidomide ,Biochemistry ,Internal medicine ,Relapsed refractory ,medicine ,business ,Multiple myeloma ,Dexamethasone ,medicine.drug - Abstract
Background: With new standard-of-care and novel treatment options available in MM, outcomes have improved; however, patients (pts) eventually become refractory to multiple drug classes (Gandhi et al. Leukemia. 2019;33:2266). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumor cells. In the United States, melflufen + dex received accelerated approval in RRMM based on results from the phase 2 HORIZON study (Richardson et al. J Clin Oncol. 2021;39:757). In the phase 3, randomized, OCEAN study (NCT03151811), melflufen + dex significantly reduced the risk of disease progression vs pom + dex (progression-free survival [PFS]: hazard ratio [HR], 0.79 [95% CI, 0.64-0.98; P=0.031]) in RRMM (Oncopeptides. Press release. July 8, 2021). This subgroup analysis of OCEAN investigates the impact of prior treatments on efficacy outcomes. Methods: Eligible pts received 2-4 prior lines of therapy (LoT) including lenalidomide (len) and a proteasome inhibitor (PI) and were refractory to len (within 18 mo of randomization) and to their last LoT. Stratified by age, number of prior LoTs, and International Staging System score, pts were randomized 1:1 to 28-d cycles of melflufen 40 mg intravenously on d1 or pom 4 mg orally (PO) daily on d1 to d21. All pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts received therapy until disease progression or unacceptable toxicity. The primary endpoint was PFS, assessed by an Independent Review Committee per International Myeloma Working Group Uniform Response Criteria. Key secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. Subgroup analyses by prior therapy received were prespecified prior to the start of the study. Results: At data cutoff (Feb 3, 2021), 495 pts were randomized to receive melflufen (n=246) or pom (n=249). Among these, 125 pts (51%) and 120 pts (48%) had a prior stem cell transplant (SCT), 43 pts (17%) and 43 pts (17%) were on len for PFS and OS by prior therapy received are shown in the Figure. Significant PFS benefit with melflufen (vs pom) was observed in pts without a prior SCT (HR, 0.59 [95% CI, 0.44-0.79]; P Conclusion: In OCEAN, melflufen + dex showed superior PFS, but not OS, compared with pom + dex. PFS benefit with melflufen was consistent across clinically relevant subgroups, primarily in pts without a prior SCT, with ongoing analyses aimed at determining factors driving this benefit. Figure 1 Figure 1. Disclosures Dimopoulos: BeiGene: Honoraria; Takeda: Honoraria; Janssen: Honoraria; BMS: Honoraria; Amgen: Honoraria. Schjesvold: Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Schain: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Nordics Nanovector: Current holder of individual stocks in a privately-held company; Oncopeptides: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Adaptive Biotechnologies: Consultancy; SkyliteDX: Honoraria; Bayer: Consultancy; AbbVie: Honoraria. Mateos: Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Robak: Medical University of Lodz: Current Employment; Celgene: Honoraria, Research Funding; Amgen: Honoraria; Janssen: Honoraria. Hájek: Pharma MAR: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Richardson: AbbVie: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; Sanofi: Consultancy; Celgene/BMS: Consultancy, Research Funding; Regeneron: Consultancy; GlaxoSmithKline: Consultancy; Protocol Intelligence: Consultancy; Oncopeptides: Consultancy, Research Funding; Secura Bio: Consultancy; Karyopharm: Consultancy, Research Funding; AstraZeneca: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Lindberg: Affibody: Membership on an entity's Board of Directors or advisory committees; Camurus: Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Oncopeptides: Current Employment, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses. Thuresson: Oncopeptides AB: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Larsson: Oncopeptides AB: Current Employment; Alnylam Pharmaceuticals Inc.: Current holder of individual stocks in a privately-held company, Ended employment in the past 24 months. Sonneveld: Amgen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; SkylineDx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. OffLabel Disclosure: Yes, this is a subgroup analysis of a phase 3 investigational study of melflufen in patients with RRMM refractory to lenalidomid.
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- 2021
31. OCEAN (OP-103): Melflufen/Dexamethasone (Dex) Compared with Pomalidomide (Pom)/Dex in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM) - Subgroup Analysis By Prior Alkylator Exposed/Refractory Status
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Meletios-Athanasios Dimopoulos, Fredrik Schjesvold, Maria-Victoria Mateos, Johan Harmenberg, Catriona Byrne, Marcus Thuresson, Pawel Robak, Pieter Sonneveld, Paul G. Richardson, and Roman Hájek
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Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Subgroup analysis ,Cell Biology ,Hematology ,Pomalidomide ,medicine.disease ,Biochemistry ,Refractory ,Internal medicine ,Relapsed refractory ,medicine ,In patient ,business ,Dexamethasone ,Multiple myeloma ,medicine.drug - Abstract
Background: Most pts with MM will be exposed to alkylators throughout their disease course as part of a multidrug regimen or as high-dose melphalan (HDM) conditioning prior to undergoing an autologous stem cell transplant (SCT). MM invariably relapses and can become refractory to prior treatments. Outcomes are poor for pts with RRMM, highlighting the need for effective agents with novel mechanisms of action (Kumar et al. Leukemia. 2017;31:2443). Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate (PDC) that targets aminopeptidases and thereby rapidly releases alkylating agents inside tumor cells. Previously reported analyses from the phase 2 HORIZON study of melflufen + dex in pts with RRMM show that melflufen is active in pts who have prior exposure to alkylator therapy, and safety signals were not impacted by prior alkylator exposure (Rodriguez-Otero, et al. ASCO . 2021; Poster 8048). Topline results from the phase 3 randomized OCEAN study demonstrated the primary endpoint was met, with superior progression-free survival (PFS) for melflufen + dex vs pom + dex in pts with RRMM (hazard ratio [HR] 0.79 [95% CI, 0.64-0.98]) (Oncopeptides. Press release. July 8, 2021). In this analysis, the clinical activity of melflufen is examined in a subset of pts from OCEAN exposed to prior alkylator therapy. Methods: Eligible pts with RRMM had received 2-4 prior lines of therapy (LoTs), including lenalidomide (len) and a proteasome inhibitor, and were refractory to len (within 18 mo of randomization) and to the last LoT. Pts were stratified by age, number of prior LoTs, and International Staging System score, and were randomized 1:1 to receive 28-d cycles of melflufen 40 mg intravenously (d1) or pom 4 mg orally (PO; daily, d1 to 21); all pts received dex 40 mg (20 mg for pts ≥75 y) PO on d1, 8, 15, and 22. Pts were treated until disease progression or unacceptable toxicity. The primary endpoint was PFS. Key secondary endpoints were overall survival (OS), overall response rate (ORR), and safety. Refractoriness was defined as disease that failed to achieve a minimal response or progressed while on primary or salvage therapy or within 60 d of last dose. Efficacy was analyzed by alkylator exposure or refractory status with/without SCT in prior LoTs. Results: At the data cutoff of Feb 3, 2021, 495 pts were randomized to receive melflufen (n=246) or pom (n=249) in the intention-to-treat population, with 125 pts (51%) and 120 pts (48%) having received a prior SCT. In the melflufen and pom groups, 29 pts (12%) and 36 pts (14%) were not exposed to a prior alkylator, whereas 217 pts (88%) and 213 pts (86%) were exposed to prior alkylators; 139 (57%) and 138 (55%) were exposed to a prior alkylator but not refractory and 78 (32%) and 75 (30%) were refractory to a prior alkylator, respectively. The majority of pts exposed to prior alkylators received cyclophosphamide (melflufen, 59%; pom, 58%), standard dose melphalan (melflufen, 25%; pom, 26%), and/or HDM (melflufen, 46%; pom, 44%). Melflufen was associated with increased PFS compared with pom in pts not exposed to prior alkylators (HR, 0.44 [95% CI, 0.24-0.83]) and in pts without a prior SCT who were exposed to an alkylator (HR, 0.60 [95% CI, 0.43-0.84]) or exposed but not refractory to an alkylator (HR, 0.53 [95% CI, 0.33-0.84]), with a trend for increased PFS in pts refractory to an alkylator without a prior SCT (HR, 0.69 [95% CI, 0.43-1.12]; Figure). Similar trends in OS were seen in in pts without a prior SCT who were exposed to an alkylator (HR, 0.76 [95% CI, 0.51-1.14]) or refractory to an alkylator (HR, 0.59 [95% CI, 0.33-1.07]). In pts with a prior SCT, pom was generally associated with improved PFS and OS, regardless of alkylator exposed or refractory status. ORR was significantly higher in the melflufen group compared with the pom group for pts not exposed to prior alkylators (59% vs 22%; P=.0029) and numerically higher in pts without prior SCT who were exposed (38% vs 28%; P=.1677), exposed but not refractory (44% vs 32%; P=.2061), and refractory (30% vs 24%; P=.5481) to prior alkylators. Conclusion: Melflufen + dex was associated with higher PFS, OS, and ORR compared with pom + dex in pts with RRMM without prior SCT, but not in pts with prior SCT. These results support the use of melflufen + dex in pts with RRMM without prior SCT, including pts who are exposed or refractory to prior alkylators, without HDM exposure from prior SCT. Figure 1 Figure 1. Disclosures Sonneveld: SkylineDx: Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Mateos: AbbVie: Honoraria; Regeneron: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sea-Gen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bluebird bio: Honoraria; GSK: Honoraria; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene - Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Honoraria, Membership on an entity's Board of Directors or advisory committees. Robak: Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Research Funding; Medical University of Lodz: Current Employment. Schjesvold: AbbVie: Honoraria; Adaptive Biotechnologies: Consultancy; Schain: Honoraria; Bayer: Consultancy; SkyliteDX: Honoraria; Oncopeptides: Consultancy, Current holder of individual stocks in a privately-held company, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Nordics Nanovector: Current holder of individual stocks in a privately-held company; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene/BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria. Hajek: Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria. Richardson: Sanofi: Consultancy; AbbVie: Consultancy; Karyopharm: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; AstraZeneca: Consultancy; Protocol Intelligence: Consultancy; GlaxoSmithKline: Consultancy; Secura Bio: Consultancy; Janssen: Consultancy; Takeda: Consultancy, Research Funding; Regeneron: Consultancy; Celgene/BMS: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding. Harmenberg: Oncopeptides AB: Consultancy, Current equity holder in publicly-traded company, Divested equity in a private or publicly-traded company in the past 24 months, Other: Travel, Accommodations, Expenses . Thuresson: Oncopeptides AB: Consultancy, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Byrne: Oncopeptides AB: Current Employment, Current holder of stock options in a privately-held company; BMS: Current holder of individual stocks in a privately-held company. Dimopoulos: BMS: Honoraria; Janssen: Honoraria; Beigene: Honoraria; Takeda: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Yes, this abstract includes a subgroup analysis of a phase 3 investigational study of melflufen in patients with RRMM refractory to lenalidomide
- Published
- 2021
32. Safety and Preliminary Efficacy Results from a Phase Ib/II Study of Cobimetinib As a Single Agent and in Combination with Venetoclax with or without Atezolizumab in Patients with Relapsed/Refractory Multiple Myeloma
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Paula Rodriguez-Otero, Wan-Jen Hong, Roman Hájek, Aparna Raval, Sameer Deshpande, Markus Hansson, Joaquin Martinez-Lopez, Vincent Ribrag, Jorge D. Gallo, Marc S. Raab, Fredrik Schjesvold, Adrián Alegre Amor, Vikram Malhi, Maika Onishi, and Pawel Robak
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Oncology ,Cobimetinib ,medicine.medical_specialty ,Venetoclax ,business.industry ,Immunology ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,chemistry.chemical_compound ,chemistry ,Atezolizumab ,Internal medicine ,Relapsed refractory ,medicine ,Single agent ,In patient ,business ,Multiple myeloma - Abstract
Introduction: MAPK pathway mutations are present in more than 50% of patients (pts) with relapsed/refractory multiple myeloma (RRMM; Xu et al. Oncogenesis 2017; Kortum et al. Blood 2016). While MEK inhibitors have demonstrated limited single-agent activity in RRMM, combination with BCL-2 inhibition with or without PD-L1 inhibition may improve efficacy, by shifting the apoptotic balance towards cell death and increasing CD8+ T cell recognition and enhancing the anti-tumor immune response. We conducted a Phase Ib/II study of cobimetinib (C) as a single agent and in novel combinations with venetoclax (V) with or without atezolizumab (A) in pts with RRMM (NCT03312530). Methods: Pts with RRMM who had received 3-5 prior therapies, including a proteasome inhibitor and an immunomodulatory drug, were enrolled. Safety run-in (SRI) cohorts, SRI 1 and SRI 2, evaluated the safety of C+V and C+V+A, respectively. Pts were then randomized 1:2:2 to C (Arm A), C+V (Arm B), or C+V+A (Arm C). Pts received C 60 mg PO daily on Day (D) 1-21 (Arm A), or C 40 mg PO daily on D1-21 and V 800 mg PO daily on D1-28 (SRI 1, Arm B) and A 840 mg IV on D1 and D15 (SRI 2, Arm C) on 28-day cycles. Responses were assessed using IMWG 2016 criteria. Pharmacokinetic (PK) analyses were performed. Exploratory biomarker assessments included cytogenetics, mutational analysis, and PD-L1 and BCL-2 family expression (RNAseq). Results: As of May 6 2020, 49 pts were enrolled (SRI 1, n=6; SRI 2, n=6; Arm A, n=6; Arm B, n=16; Arm C, n=15). Median age was 65 years (range 44-79), 63% were male, 94% had ECOG PS 0-1, and 47% had ISS II/III disease. Median prior lines of therapy was 4 (range 3-5), with prior ASCT in 43% and prior daratumumab in 41% of pts. 24% of pts had high-risk cytogenetics (del(17p), t(4;14), t(14;16)), 20% were t(11;14) positive, 51% had RAS mutations (KRAS, NRAS, BRAF, NF-1), and 31% had high PD-L1 expression. The most common adverse events (AEs) of any grade (Gr; C/C+V/C+V+A) were diarrhea (33%/82%/91%), nausea (17%/50%/67%), anemia (17%/46%/57%), neutropenia (0/32%/57%), thrombocytopenia (0/27%/33%), blood creatine phosphokinase increase (17%/32%/24%), and rash (50%/14%/33%). The most common Gr 3-4 AEs were neutropenia (0/14%/38%), anemia (0/23%/24%), thrombocytopenia (0/18%/24%), and pneumonia (0/14%/14%). The most common serious AE was pneumonia (0/23%/14%). Two AEs of tumor lysis syndrome (TLS) were reported, with 1 meeting Howard criteria for laboratory TLS (t(11;14) pt on C+V, no dose interruption). Treatment discontinuation due to AEs was noted in 17%, 18%, and 14% of C, C+V, and C+V+A pts, respectively. At a median follow-up of 13.4 months (mo), there were 27 (55%) deaths overall (4 [67%]/14 [64%]/9 [43%]). The leading cause of death was progressive disease (PD; 2 [50%]/11 [79%]/7 [78%]). Two treatment-related deaths were observed (C+V: pneumonia; C+V+A: general physical health deterioration in the setting of PD). Overall survival (OS) for C, C+V, and C+V+A was 12.9, 12.4, and 23.3 mo respectively, and comparable with historical OS in 3L+ pts (Usmani et al. Oncologist 2016; Kumar et al. Leukemia 2017). No clinically relevant drug-drug interactions were identified between C, V, and A based on preliminary PK analysis. The overall response rate (ORR; ≥partial response) was 0% (0/6) for C, 27% (6/22) for C+V, and 29% (6/21) for C+V+A (Figure A). Compared with the non-t(11;14) pts, responses to C+V and C+V+A were higher among t(11;14) pts, with an ORR of 50% (2/4) and 100% (5/5), respectively. Median duration of response was 11.5 mo for C+V (range 2-18) versus 5.1 mo for C+V+A pts (range 2-15), with individual pt characteristics likely contributing to the observed difference. Prolonged disease stability and durable responses were noted in a subset of pts, irrespective of t(11;14) and/or RAS mutation status (Figure B/C). At data cut-off, 4 pts remain on treatment, 3 of whom are t(11;14) positive and 1 who is t(11;14) negative and RAS wild-type but BCL2/BCL2L1 (BCL-XL) high (log2≥2.3). Conclusions: C, C+V and C+V+A demonstrated manageable safety and tolerability in heavily pretreated pts with RRMM. Preliminary efficacy results show moderate activity of the combinations in all-comers and higher activity in t(11;14) pts, supporting a biomarker-driven approach in the development of V in MM. Further biomarker analyses may provide insight into the pt subgroups that may benefit from combined MAPK and BCL-2 inhibition, and the contribution of PD-L1 inhibition. Disclosures Schjesvold: Novartis, Amgen, Celgene, Takeda, Janssen, Oncopeptides, MSD, Sanofi: Consultancy; Celgene, Amgen, Janssen, Oncopeptides: Research Funding; Amgen, Celgene, Takeda, Janssen,Novartis, SkyliteDX, Oncopeptides, Sanofi: Honoraria. Ribrag:Roche/Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; arGEN-X-BVBA: Research Funding; BAY1000394 studies on MCL: Patents & Royalties; Immune Design: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Eisai: Honoraria; AZD: Honoraria, Other; Pharmamar: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; F. Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Expenses; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; MSD: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy, Current equity holder in publicly-traded company, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; argenX: Current equity holder in publicly-traded company, Research Funding; Institut Gustave Roussy: Current Employment; Nanostring: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Rodriguez-Otero:GlaxoSmithKline: Consultancy, Current Employment, Current equity holder in publicly-traded company, Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Kite: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company); Abbvie: Consultancy, Honoraria; Medscape: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria; Oncopeptides: Consultancy, Honoraria. Robak:Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, F. Hoffmann-La Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria. Hansson:Amgen, Celgene, Takeda, Janssen Cilag: Consultancy. Hajek:Celgene, Novartis, Amgen, Takeda, Janssen, BMS: Research Funding; Takeda, Amgen, Oncopeptides, Sanofi, Janssen, Novartis, Celgene: Honoraria; BMS, Takeda, Amgen, Oncopeptides, Sanofi, Janssen: Membership on an entity's Board of Directors or advisory committees. Amor:Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene-BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Martinez-López:Janssen, BMS, Sanofi, Novartis, Incyte, F. Hoffmann-La Roche and Amgen: Honoraria, Other: Advisory boards; Hosea and Altum: Membership on an entity's Board of Directors or advisory committees; Janssen, Novartis, BMS, Incyte: Consultancy. Onishi:Genentech, Inc.: Current Employment, Current equity holder in publicly-traded company; F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Gallo:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Raval:F. Hoffmann-La Roche: Current Employment, Current equity holder in publicly-traded company. Deshpande:Syneos Health: Current Employment. Malhi:Genentech, Inc.: Current Employment; F. Hoffmann-La Roche: Current equity holder in publicly-traded company. Hong:F. Hoffmann-La Roche: Current equity holder in publicly-traded company; Genentech, Inc.: Current Employment. Raab:Amgen: Membership on an entity's Board of Directors or advisory committees; Heidelberg Pharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding. OffLabel Disclosure: Venetoclax (ABT-199/GDC-0199) is a highly selective, potent, oral B-cell lymphoma-2 (BCL-2) inhibitor. Cobimetinib (GDC-0973/RG7420) is an orally bioavailable small molecule inhibitor of mitogen-activated protein kinase kinase 1 (MAP2K1 or MEK1). Atezolizumab (RG7446/MPDL-3280A) is a monoclonal antibody directed against programmed death-1 ligand-1 (PD-L1).
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- 2020
33. Early Mortality in Patients with Multiple Myeloma Treated with Novel Agents - Analysis from Polish Myeloma Study Group
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Anna Waszczuk-Gajda, Lidia Usnarska-Zubkiewicz, Agnieszka Barchnicka, Grzegorz Helbig, Szymon Fornagiel, Dariusz Woszczyk, Pawel Robak, Grzegorz Charliński, Bartosz Małecki, Mirosław Markiewicz, A. Czyż, Janusz Kloczko, Agnieszka Kolkowska, Sebastian Grosicki, Jan Maciej Zaucha, Agata Tyczyńska, Tadeusz Robak, Jarosław Czyż, Artur Jurczyszyn, Anna Kopińska, Dominik Dytfeld, Iwona Hus, Jadwiga Hołojda, Anna Masternak, Jaroslaw Piszcz, Lidia Gil, Tomasz Wróbel, and Grzegorz W. Basak
- Subjects
medicine.medical_specialty ,business.operation ,business.industry ,Immunology ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Octapharma ,Biochemistry ,Thalidomide ,Regimen ,Novel agents ,Internal medicine ,Cohort ,Medicine ,In patient ,business ,Multiple myeloma ,medicine.drug - Abstract
Background Although the introduction of novel agents improved the survival outcomes in patients with multiple myeloma (MM), some patients died within one year (early mortality, EM) following diagnosis. In this study, we evaluated the EM rate, and investigated the risk factors associated with EM in MM patients. Aims In this study we investigated risk factors associated with EM in MM patients initially treated with novel-agent containing regimen. Methods We conducted a multicenter (15 Polish sites) retrospective study a cohort of symptomatic MM pts diagnosed between October 2006 and November 2019 and living < 365 days (d) after diagnosis. All pts were dead at the time of the analysis. Data were collected from medical registries and databases. Mortality rate and cause at 2, 6, and 12 months following diagnosis was evaluated. Clinical staging was performed using the International Staging System (ISS). Response to treatment was evaluated according to the International Myeloma Working Group (IMWG) consensus criteria (2016). Statistical analysis was performed using R-studio v.1.3.959. and significant levels were set at p Results Of the 197 pts were included in the study, 112 (57%) male and the median age at diagnosis was 69 y (41-91). The MM type of 100 patients (52%) was Immunoglobulin (Ig) G, 24% of patients was IgA, 15% of patients had light chain disease, and 3% of patients IgM or IgD. At diagnosis, renal impairment (RI) was present in 43%, extramedullary disease (EMD) in 15% of the pts; 15% were in stage I, 10% in stage II, 60% in stage III (ISS) and 15% not done. Fluorescent in situ hybridization analysis was performed in 59 pts, 69% presenting high-risk cytogenetic abnormalities (HRC) [t(4;14), t(14;16), t(14;20) or del17p]. 54% pts were >2 comorbidities at diagnosis. Heart disease was presented at diagnosis in 57% pts and diabetes in 22% pts. First-line treatment (1stL), 41% of the pts patients were bortezomib-based (Bor) regimens, 25% Bor with thalidomide (VT)-based, 22% IMiD-based and 13% others. Response evaluation showed an overall response rate (ORR) of 44% (3% CR; 14% VGPR; 27% PR). 46% pts survived < 2 months, 29%; 2-6 months and 25%: 6-12 month. Median time until death was 2.5 month; 31% of pts died directly from progression disease (PD), and 69% from other causes [infection in 66%, cardiovascular complications in 27%, RI in 8%]. In our study, age > 65 y (HR 1.67; 95% CI 1.24-2.26; p=0.0007), and >75 y (HR 1.5; 95% CI 1.10-2.03; p=0.0087), >2 comorbidities (p=0.002), heart disease (HR 2.12; 95% CI 1.57-2.85; p < 0.0001), RI (HR 0.7; 95% CI 0.53-0.95; p=0.029), dependence of dialysis (HR 1.50; 95% CI 1.05-2.14; p=0.029) were associated with increased risk of death. Mortality predictive value showed HRC (p=0.05), lactate dehydrogenase levels (HR 0.65; 95% CI 0.38-1.1; p=0.002), and >PR (HR 0.30; 95% CI 0.21-0.43; p Conclusions IMWG response criteria are not adequate to predict short-term outcome in the era of novel agents. Infections and refractory disease were the leading contributors to early death in our pts cohort. These data may provide new opportunities to define patient-adapted treatment strategies in order to decrease EM and improve overall survival in MM. Disclosures Wrobel: BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Research Funding; Janssen: Honoraria. Robak:Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, F. Hoffmann-La Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria. Robak:Bristol Meyers Squibb: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Honoraria, Research Funding; Takeda: Consultancy; GSK: Research Funding; UTX-TGR: Research Funding; Acerta: Research Funding; BioGene: Honoraria, Research Funding; Morphosys: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Medical University of Lodz: Current Employment; UCB: Honoraria, Research Funding; Pfizer: Research Funding; Momenta: Consultancy; Sandoz: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding.
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- 2020
34. Novel synthetic drugs currently in clinical development for chronic lymphocytic leukemia
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Tadeusz Robak and Pawel Robak
- Subjects
0301 basic medicine ,Antineoplastic Agents ,Pharmacology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,hemic and lymphatic diseases ,Animals ,Humans ,Medicine ,Bruton's tyrosine kinase ,Pharmacology (medical) ,Molecular Targeted Therapy ,Dinaciclib ,Copanlisib ,biology ,Venetoclax ,business.industry ,Drugs, Investigational ,General Medicine ,Alvocidib ,Leukemia, Lymphocytic, Chronic, B-Cell ,Duvelisib ,030104 developmental biology ,chemistry ,Drug Design ,030220 oncology & carcinogenesis ,Ibrutinib ,biology.protein ,Cancer research ,Acalabrutinib ,business - Abstract
Over the last few years, several new synthetic drugs, particularly Bruton's tyrosine kinase (BTK), phosphatidylinositol 3-kinase (PI3K) and BCL-2 inhibitors have been developed and investigated in chronic lymphocytic leukemia (CLL). Areas covered: This review highlights key aspects of BTK, PI3K and BCL-2 inhibitors that are currently at various stages of preclinical and clinical development in CLL. A literature review of the MEDLINE database for articles in English concerning CLL, B-cell receptor, BCL-2 antagonists, BTK inhibitors and PI3K inhibitors, was conducted via PubMed. Publications from 2000 through July 2017 were scrutinized. The search terms used were acalabrutinib, ACP-196, BGB-3111, ONO-4059, GS-4059, duvelisib, IPI-145, TGR-1202, copanlisib, Bay 80-6946, buparlisib, BKM-120, BCL-2 inhibitors, venetoclax, ABT-263, navitoclax, CDK inhibitors, alvocidib, flavopiridol, dinaciclib, SCH 727,965, palbociclib, PD-0332991, in conjunction with CLL. Conference proceedings from the previous five years of the ASH and EHA Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: The use of new synthetic drugs is a promising strategy for the treatment of CLL. Data from ongoing and future clinical trials will aid in better defining the status of new drugs in the treatment of CLL.
- Published
- 2017
35. Personalized therapy tests for the monitoring of chronic lymphocytic leukemia development
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Małgorzata Rogalińska, Zofia M. Kiliańska, Henryk Piekarski, Tadeusz Robak, Aneta Koceva-Chyła, Paweł Góralski, Jerzy Z. Blonski, Pawel Robak, and Jan Barciszewski
- Subjects
0301 basic medicine ,Cancer Research ,Chronic lymphocytic leukemia ,Purine analogue ,Peripheral blood mononuclear cell ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Mafosfamide ,hemic and lymphatic diseases ,medicine ,Cladribine ,personalized therapy ,business.industry ,apoptosis ,Articles ,Cell cycle ,medicine.disease ,Fludarabine ,anticancer drugs ,030104 developmental biology ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Cancer research ,chronic lymphocytic leukemia ,Rituximab ,cell signal inhibitors ,business ,medicine.drug - Abstract
There is individual variation in the course of disease development and response to therapy of patients with chronic lymphocytic leukemia (CLL). Novel treatment options for CLL include a new generation of purine analogs, antibodies and inhibitors of specific cell signaling pathways, which typically induce apoptosis or necrosis. A prospective analysis of patient blood samples revealed that a combination of four tests allowed the most appropriate and effective type of treatment to be selected prior to drug administration, and for the analysis of leukemic cell sensitivity to anticancer drug(s) during disease development. The comparative analysis of blood from the stable and progressive form of CLL in an individual patient revealed diversity in the response to anticancer agents. CLL peripheral blood mononuclear cells were incubated with cladribine + mafosfamide (CM), fludarabine + mafosfamide, CM + rituximab, rituximab alone (Rit) or kinetin riboside (RK). A combination of cell viability, differential scanning calorimetry (DSC) profiles of nuclear preparations and poly(ADP-ribose) polymerase 1 (PARP-1) protein expression analysis of the leukemic cells was performed to evaluate the anticancer effects of the tested agents during CLL development. The results of the present study indicate that such studies are effective in determining the most appropriate anticancer drug and could monitor disease progression on an individual level. In addition, the results of the current study suggest that CLL progression leads to diversification of the cellular drug response. The most efficient apoptosis inducer for the patient was purine analog RK when the disease was stable, while the CM combination was the most effective agent for the progressive form of disease.
- Published
- 2017
36. The Value of Serum MicroRNA Expression Signature in Predicting Refractoriness to Bortezomib-Based Therapy in Multiple Myeloma Patients
- Author
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Tadeusz Robak, Damian Mikulski, Dariusz Jarych, Wojciech Fendler, Monika Siemieniuk-Ryś, Janusz Szemraj, Konrad Stawiski, Piotr Smolewski, Małgorzata Misiewicz, Izabela Dróżdż, Pawel Robak, and Edyta Węgłowska
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,Refractory period ,efficacy ,miR-181a-5p ,Drug resistance ,miR-376c-3p ,lcsh:RC254-282 ,Article ,resistance ,Refractory ,immune system diseases ,hemic and lymphatic diseases ,Internal medicine ,microRNA ,medicine ,Multiple myeloma ,Univariate analysis ,Bortezomib ,business.industry ,bortezomib ,lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,sensitivity ,medicine.disease ,multiple myeloma ,refractory ,Proteasome inhibitor ,miR-215-5p ,business ,medicine.drug - Abstract
Bortezomib is the first-in-class proteasome inhibitor, commonly used in the treatment of multiple myeloma (MM). The mechanisms underlying acquired bortezomib resistance in MM are poorly understood. Several cell-free miRNAs have been found to be aberrantly regulated in MM patients. The aim of this pilot study was to identify a blood-based miRNA signature that predicts bortezomib-based therapy efficacy in MM patients. Thirty MM patients treated with bortezomib-based regimens were studied, including 19 with refractory disease and 11 who were bortezomib sensitive. Serum miRNA expression patterns were identified with miRCURY LNA miRNA miRNome PCR Panels I+II (Exiqon/Qiagen). Univariate analysis found a total of 21 miRNAs to be differentially expressed in patients with MM according to bortezomib sensitivity. Multivariate logistic regression was created and allowed us to discriminate refractory from sensitive patients with a very high AUC of 0.95 (95%CI: 0.84&ndash, 1.00), sensitivity, specificity and accuracy were estimated as 0.95, 0.91, and 0.93. The model used expression of 3 miRNAs: miR-215-5p, miR-181a-5p and miR-376c-3p. This study is the first to demonstrate that serum expression of several miRNAs differs between patients who are bortezomib refractory and those who are sensitive which may prove useful in studies aimed at overcoming drug resistance in MM treatment.
- Published
- 2020
37. Pomalidomide, bortezomib, and dexamethasone (PVd) in lenalidomide (LEN)-pretreated relapsed refractory multiple myeloma: Subanalysis of patients with renal impairment in OPTIMISMM
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Filiz Vural, Meral Beksac, Eva Casal Mendez, Tsvetan Biyukov, Abraham S. Kanate, Pawel Robak, Monica Galli, Lara Grote, Alessandra Larocca, Albert Oriol, Paul G. Richardson, Larry D. Anderson, Katja Weisel, Meletios A. Dimopoulos, Ruiyun Jiang, Jindriska Lindsay, Münci Yağcı, Fredrik Schjesvold, Anna Marina Liberati, and Shankar Srinivasan
- Subjects
Oncology ,Cancer Research ,medicine.medical_specialty ,business.industry ,Bortezomib ,Standard treatment ,medicine.disease ,Pomalidomide ,Internal medicine ,Relapsed refractory ,Medicine ,Until Disease Progression ,business ,Multiple myeloma ,Dexamethasone ,medicine.drug ,Lenalidomide - Abstract
e20562 Background: Upfront LEN until disease progression is a standard treatment (Tx) in multiple myeloma (MM). Data are limited on optimal Tx after first-line LEN, especially in LEN-refractory patients (pts), a growing population. In OPTIMISMM (phase 3, NCT01734928), PVd significantly improved median PFS at first relapse in relapsed refractory MM (RRMM) pts, of whom 100% were LEN pretreated and 57% were LEN refractory (median, 20.7 vs 11.6 mos; HR = 0.54 [95% CI, 0.36-0.82]; P = .0027) vs Vd (Richardson, 2019). Pd has shown efficacy and safety in RRMM pts with moderate or severe renal impairment (RI), including those on dialysis (Dimopoulos, 2018). However, outcomes with second-line PVd in RRMM pts with RI have not been assessed. Here we report efficacy and safety of PVd vs Vd at first relapse by renal status (CrCl < 60 vs ≥ 60 mL/min). Methods: Pts received PVd or Vd (1:1) in 21-day (D) cycles (C); POM 4 mg/D on D1-14 (PVd arm only); BORT 1.3 mg/m2 on D1, 4, 8, 11 of C1-8 and on D1, 8 of C9+; and DEX 20 mg/D (10 mg/D for pts aged > 75 yrs) on days of and after BORT. Pts on dialysis were excluded. Results: Of 559 pts enrolled, 226 (40%) had 1 prior line of therapy; of whom 28% had CrCl < 60 mL/min and 4% had severe RI (CrCl < 30 mL/min). In pts with CrCl < 60 mL/min (PVd vs Vd), median age was 74 vs 73 yrs. In pts with CrCl ≥ 60 mL/min (PVd vs Vd), median age was 62 vs 64 yrs. A higher proportion of pts with baseline CrCl < 60 (23% vs 43%) than ≥ 60 mL/min (7% vs 8%) had ISS stage III at study entry. Data cutoff was Oct 26, 2017. Median PFS was improved with PVd in both renal groups (Table). ORR significantly improved regardless of renal status. Depth of response also improved with PVd vs Vd; ≥ VGPR occurred in 54% vs 21% in the CrCl < 60 mL/min group and 64% vs 23% in the CrCl ≥ 60 mL/min group. Myelosuppression was the most common grade 3/4 TEAE (Table). Conclusions: Second-line PVd led to improved vs Vd in pts with RRMM and RI; however, the PFS difference was not statistically significant. Safety was consistent for PVd with no new signals in pts with RI. These findings further support the earlier use of POM-based Tx in RRMM pts, including those with mild to moderate RI. Clinical trial information: NCT01734928. [Table: see text]
- Published
- 2020
38. Multiple myeloma in patients up to 30 years of age: a multicenter retrospective study of 52 cases
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Jorge J. Castillo, K. Martin Kortüm, Chor S. Chim, Mark A. Fiala, Ravi Vij, Vibor Milunovic, Max Bittrich, Julio Dávila, Edvan de Queiroz Crusoe, Roman Hájek, Katarzyna Wiśniewska-Piąty, David H. Vesole, Jieqi Liu, Pawel Robak, Anna Waszczuk-Gajda, Hareth Nahi, Małgorzata Raźny, Daria Zawirska, David Jayabalan, and Artur Jurczyszyn
- Subjects
Adult ,Male ,Cancer Research ,medicine.medical_specialty ,Scoring system ,Adolescent ,Population ,Gastroenterology ,03 medical and health sciences ,Young Adult ,0302 clinical medicine ,Autologous stem-cell transplantation ,Internal medicine ,Antineoplastic Combined Chemotherapy Protocols ,Outcome Assessment, Health Care ,medicine ,Humans ,In patient ,education ,Child ,Multiple myeloma ,Retrospective Studies ,education.field_of_study ,business.industry ,Patient Selection ,Age Factors ,Hematopoietic Stem Cell Transplantation ,Disease Management ,Retrospective cohort study ,Hematology ,medicine.disease ,Combined Modality Therapy ,Young age ,Treatment Outcome ,Oncology ,Novel agents ,030220 oncology & carcinogenesis ,Cytogenetic Analysis ,Female ,business ,Multiple Myeloma ,030215 immunology - Abstract
A small proportion of patients with multiple myeloma (MM) are diagnosed at a very young age. The clinicopathological characteristics and prognosis of these patients are not well known. This analysis included 52 patients diagnosed with MM at the age of ≤30 years (range: 8-30 years). 68% of patients had International Scoring System (ISS) 1 MM; 22% presented with the light chain-only disease, and 48% with elevated serum lactate dehydrogenase (LDH). 85% of patients were treated with novel agents, and 62% received front-line autologous stem cell transplantation (ASCT). Overall response rate (ORR) to front-line treatment and ASCT were 71% and 90%, respectively. The group was followed-up for the median period of 86 months. The median overall survival (OS) was 166 months (95% CI: 53-222), with 5-year OS rate of 77% (95% CI: 61.0-87.9). This findings suggest that the prognosis in young MM patients may be as good if not better than in the general population of MM patients.
- Published
- 2018
39. Prognostic indicators in primary plasma cell leukaemia : a multicentre retrospective study of 117 patients
- Author
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David Jayabalan, Dorotea Fantl, Renata Guzicka-Kazimierczak, Grzegorz Charliński, Wanda Knopinska-Posluszny, Agnieszka Druzd-Sitek, Mark A. Fiala, Agnieszka Kopacz, Agnieszka Barchnicka, Jakub Radocha, Waldemar Sawicki, Norbert Grząśko, Roman Hájek, Iwona Hus, Michel Delforge, Anders Waage, Alessandro Gozzetti, Jorge J. Castillo, Xavier Leleu, Artur Jurczyszyn, Irit Avivi, Andrew Yee, Thomas Guerrero-Garcia, David H. Vesole, Erden Atilla, Julio Dávila, Jieqi Liu, Pawel Robak, Marek Rodzaj, Giuseppe Mele, Valentine Richez, Agoston Gyula Szabo, Anna Waszczuk-Gajda, and Anna Masternak
- Subjects
Adult ,Male ,medicine.medical_specialty ,Multivariate analysis ,survival ,Disease-Free Survival ,Leukemia, Plasma Cell ,Prognostic score ,03 medical and health sciences ,myeloma ,plasma cell leukaemia ,prognosis ,therapeutic response ,0302 clinical medicine ,Autologous stem-cell transplantation ,Internal medicine ,medicine ,Humans ,In patient ,Autografts ,Aged ,Retrospective Studies ,Aged, 80 and over ,business.industry ,Retrospective cohort study ,Hematology ,Middle Aged ,Plasma cell leukaemia ,Peripheral blood ,Confidence interval ,Survival Rate ,030220 oncology & carcinogenesis ,Female ,business ,Stem Cell Transplantation ,030215 immunology - Abstract
We report a multicentre retrospective study that analysed clinical characteristics and outcomes in 117 patients with primary plasma cell leukaemia (pPCL) treated at the participating institutions between January 2006 and December 2016. The median age at the time of pPCL diagnosis was 61 years. Ninety-eight patients were treated with novel agents, with an overall response rate of 78%. Fifty-five patients (64%) patients underwent upfront autologous stem cell transplantation (ASCT). The median follow-up time was 50 months (95% confidence interval [CI] 33; 76), with a median overall survival (OS) for the entire group of 23 months (95% CI 15; 34). The median OS time in patients who underwent upfront ASCT was 35 months (95% CI 24·3; 46) as compared to 13 months (95% CI 6·3; 35·8) in patients who did not receive ASCT (P = 0·001). Multivariate analyses identified age ≥60 years, platelet count ≤100 × 109 /l and peripheral blood plasma cell count ≥20 × 109 /l as independent predictors of worse survival. The median OS in patients with 0, 1 or 2-3 of these risk factors was 46, 27 and 12 months, respectively (P < 0·001). Our findings support the use of novel agents and ASCT as frontline treatment in patients with pPCL. The constructed prognostic score should be independently validated.
- Published
- 2018
40. Subcutaneous versus intravenous bortezomib in patients with relapsed multiple myeloma: subanalysis of patients with renal impairment in the phase III MMY-3021 study
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Dixie-Lee Esseltine, Sebastian Grosicki, Xavier Leleu, William Deraedt, Pawel Robak, Grigoriy B Rekhtman, Bertrand Arnulf, Ievgenii Karamanesht, Philippe Moreau, Helgi van de Velde, Huaibao Feng, Halyna Pylypenko, and Zvenyslava Masliak
- Subjects
medicine.medical_specialty ,business.industry ,Bortezomib ,Treatment outcome ,Urology ,Hematology ,medicine.disease ,Surgery ,Medicine ,In patient ,Online Only Articles ,business ,Multiple myeloma ,medicine.drug - Abstract
Renal impairment is a common presenting feature in multiple myeloma (MM) and an estimated 50% of patients are affected during the course of their disease.[1][1] Moderate and/or severe renal impairment/failure is associated with poorer survival.[2][2]–[4][3] Subanalyses of phase III studies in
- Published
- 2015
41. Emerging antibody-drug conjugates for treating lymphoid malignancies
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Tadeusz Robak, Anna Wolska-Washer, Pawel Robak, and Piotr Smolewski
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0301 basic medicine ,Drug ,medicine.medical_specialty ,Antibody-drug conjugate ,Immunoconjugates ,Lymphoma ,media_common.quotation_subject ,Antineoplastic Agents ,Pharmacology ,Lorvotuzumab mertansine ,03 medical and health sciences ,0302 clinical medicine ,Drug Delivery Systems ,Internal medicine ,medicine ,Denintuzumab mafodotin ,Animals ,Humans ,Pharmacology (medical) ,media_common ,Pinatuzumab vedotin ,Inotuzumab ozogamicin ,Hematology ,Leukemia ,business.industry ,Antibodies, Monoclonal ,Polatuzumab vedotin ,030104 developmental biology ,030220 oncology & carcinogenesis ,business ,Multiple Myeloma ,medicine.drug - Abstract
Antibody-drug conjugates (ADC) are monoclonal antibodies (Mabs) attached to biologically active drugs through specialized chemical linkers. They deliver and release cytotoxic agents at the tumor site, reducing the likelihood of systemic exposure and therefore toxicity. These agents should improve the potency of chemotherapy by increasing the accumulation of cytotoxic the drug within or near the neoplastic cells with reduced systemic effects. Areas covered: A literature review was conducted of the MEDLINE database PubMed for articles in English examining Mabs, B-cell receptor pathway inhibitors and immunomodulating drugs. Publications from 2000 through April 2017 were scrutinized. Conference proceedings from the previous five years of the American Society of Hematology, European Hematology Association, American Society of Clinical Oncology, and ACR/ARHP Annual Scientific Meetings were searched manually. Additional relevant publications were obtained by reviewing the references from the chosen articles. Expert opinion: Newer ADCs show promise as treatment for several hematologic malignancies, especially lymphoma, multiple myeloma, and leukemia. However, definitive data from ongoing and future clinical trials will aid in better defining the status of these agents in the treatment of these diseases.
- Published
- 2017
42. Pro-apoptotic effect of an anti-CD37 scFv-Fc fusion protein, in combination with the anti-CD20 antibody, ofatumumab, on tumour cells from B-cell malignancies
- Author
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Scott Stromatt, Agata Majchrzak, Pawel Robak, Piotr Smolewski, Małgorzata Misiewicz, Aleksandra Mędra, Tadeusz Robak, Barbara Cebula-Obrzut, and Magdalena Witkowska
- Subjects
Cancer Research ,Cell Survival ,Tetraspanins ,Recombinant Fusion Proteins ,Antineoplastic Agents ,Apoptosis ,Biology ,Antibodies, Monoclonal, Humanized ,Ofatumumab ,Antibodies ,Mice ,chemistry.chemical_compound ,Antigens, Neoplasm ,Cell Line, Tumor ,hemic and lymphatic diseases ,medicine ,Animals ,Humans ,Cytotoxic T cell ,Cytotoxicity ,Cells, Cultured ,B cell ,Membrane Potential, Mitochondrial ,B-Lymphocytes ,Caspase 3 ,Integrin beta1 ,Antibodies, Monoclonal ,Drug Synergism ,Leukemia, Lymphocytic, Chronic, B-Cell ,Caspase 9 ,Immunoglobulin Fc Fragments ,medicine.anatomical_structure ,Oncology ,chemistry ,Cell culture ,Monoclonal ,Immunology ,biology.protein ,Cancer research ,Antibody ,Apoptosis Regulatory Proteins ,Ex vivo ,Single-Chain Antibodies - Abstract
SMIP-016, a new anti-tumour agent, is a mouse/human chimeric fusion protein built on the ADAPTIR™ (modular protein therapeutic) platform targeting human CD37. In this study, for the first time, we examined pro-apoptotic activity of SMIP-016 in combination with monoclonal anti-CD20 antibody, ofatumumab (HuMax-CD20) in de novo chronic lymphocytic leukaemia (CLL) cells and in different B-cell neoplasm-derived lines. In CLL cells SMIP-016 exerted significant cytotoxicity (versus control - p=0.01). In the in vitro models, SMIP-016 was also distinctly active against Raji line (Burkitt lymphoma; BL) (versus control - p=0.007), Riva-1 line (diffuse large B-cell lymphoma; DLBCL) (versus control - p=0.002) and RPMI 8226 line (multiple myeloma cells; MM) (versus control - p=0.03). In studies combining SMIP-016 and ofatumumab, the cytotoxicity against CLL cells was significantly higher than the agents used alone (p
- Published
- 2014
43. New Therapies for Chronic Lymphocytic Leukemia
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Pawel Robak and Tadeusz Robak
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Cancer Research ,Oncology ,business.industry ,Chronic lymphocytic leukemia ,Cancer research ,medicine ,Molecular Medicine ,medicine.disease ,business - Published
- 2014
44. Characteristics and outcomes of patients with multiple myeloma aged 21-40years versus 41-60years:a multi-institutional case-control study
- Author
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Jorge J. Castillo, Pawel Robak, Małgorzata Wojciechowska, Lidia Usnarska-Zubkiewicz, Kristian Thidemann Andersen, Sebastian Grosicki, Alessandro Gozzetti, David Jayabalan, Małgorzata Raźny, Dariusz Woszczyk, Marcin Rymko, David H. Vesole, Tomas Pika, Hanna Ciepłuch, Ruben Niesvizky, Artur Jurczyszyn, Renata Guzicka-Kazimierczak, Leo Rasche, Irit Avivi, Krzysztof Mądry, Sujitha Yadlapati, Hareth Nahi, Monika Joks, and Wanda Knopinska-Posluszny
- Subjects
Lytic lesions ,Male ,Adult ,medicine.medical_specialty ,Hematopoietic Stem Cell Transplantation/methods ,myeloma ,outcomes ,survival ,transplantation ,young ,Case-Control Studies ,Chromosome Aberrations ,Female ,Hematopoietic Stem Cell Transplantation ,Humans ,L-Lactate Dehydrogenase ,Middle Aged ,Multiple Myeloma ,Neoplasm Staging ,Survival Rate ,Transplantation, Autologous ,Treatment Outcome ,Young Adult ,Age Factors ,Hematology ,03 medical and health sciences ,0302 clinical medicine ,Elevated lactate dehydrogenase ,Internal medicine ,medicine ,Autologous transplantation ,Multiple Myeloma/diagnosis ,Stage (cooking) ,L-Lactate Dehydrogenase/blood ,Multiple myeloma ,Transplantation ,business.industry ,Incidence (epidemiology) ,Advanced stage ,Case-control study ,medicine.disease ,Surgery ,myeloma young survival outcomes transplantation population survival patterns Hematology ,030220 oncology & carcinogenesis ,business ,Autologous ,030215 immunology - Abstract
We compared the outcomes of multiple myeloma (MM) patients aged 21–40 and 41–60 years in the novel agent era. This case-control study included 1089 patients between 2000 and 2015. Cases and controls were matched for sex, International Staging System (ISS) stage and institution. There were 173 patients in the younger group and 916 patients in the older group. Younger patients presented with a higher incidence of lytic lesions (82% vs. 72%; P = 0·04) and high-risk cytogenetic abnormalities (83% vs. 68%; P = 0·007), but lower rate of elevated lactate dehydrogenase (21% vs. 44%; P
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- 2016
45. Troska Kościoła katolickiego o osoby z niepełnosprawnością
- Author
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Paweł Robak
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kościół katolicki ,niepełnosprawność ,godność ,wsparcie ,cierpienie ,Law - Abstract
Kościół katolicki w swojej działalności kieruje się przede wszystkim misją wsparcia każdego człowieka. W sposób szczególny wsparciem otacza osoby z niepełnosprawnością. Pokazuje, że pomimo dysfunkcji, słabości i ograniczeń osobom takim powinna przysługiwać taka sama godność, jak i pełnosprawnym. Zadanie opieki nad wiernymi powierzone zostało biskupom. Aby jeszcze lepiej dotrzeć do wiernych, Kościół kieruje swoją pomoc poprzez działanie instytucji mu podległych. Nauczanie Kościoła nakazuje pełne włączanie niepełnosprawnych w życie lokalnych społeczności, jakimi są parafie oraz w życie instytucji na szczeblu ponad parafialnym. Artykuł ma na celu przekrojowe ukazanie nauczania oraz form wsparci,a jakie Kościół katolicki oferuje swoim wiernym, a w sposób szczególny osobom niepełnosprawnym.
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- 2022
- Full Text
- View/download PDF
46. The Prognostic Impact of t(14;16) in Multiple Myeloma: A Multicenter Retrospective Study of 213 Patients. Is It Time to Revise the Revised ISS?
- Author
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Krzysztof Jamroziak, Andrew Yee, Laura Rosinol Dachs, Alessandro Gozzetti, David Jayabalan, Max Bittrich, Deepu Madduri, Parameswaran Hari, Izabela Kozłowska, Julia Kelman, Anna Suska, Stuart L. Goldberg, Artur Jurczyszyn, Sarah Goldman-Mazur, Irit Avivi, Łukasz Szukalski, Massimo Gentile, David H. Vesole, Veronica Gonzalez De La Calle, Anna Waszczuk-Gajda, Julio Dávila, Iwona Hus, Ruben Niesvizky, Ariel Kleman, Yael C Cohen, Jorge J. Castillo, Lidia Usnarska-Zubkiewicz, Saurabh Chhabra, Pawel Robak, Norbert Grząśko, Jakub Radocha, Aimee Chappell, and Daniel Coriu
- Subjects
Oncology ,medicine.medical_specialty ,business.industry ,Immunology ,Treatment outcome ,Disease progression ,Retrospective cohort study ,Cell Biology ,Hematology ,medicine.disease ,Biochemistry ,Chemotherapy regimen ,Osteolytic lesion ,Transplantation ,03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,Internal medicine ,medicine ,business ,Survival analysis ,Multiple myeloma ,030215 immunology - Abstract
Introduction One of the strongest predictors of outcome in multiple myeloma (MM) patients are the intrinsic genetic abnormalities in the malignant plasma cells. t(14;16)(q32;q23) deregulates the c-musculoaponeurotic fibrosarcoma (c-MAF) oncogene. Due to the relative rarity of t(14;16) [ Methods We retrospectively analyzed 213 patients with t(14;16) from 24 clinical centers in Germany, Italy, Spain, Israel, Poland, Romania, Czech Republic and the United States. Diagnosis and clinical responses were based on the International Myeloma Working Group criteria. The t(14;16) was detected by double color fluorescence in situ hybridization using bone marrow samples. Baseline characteristics at diagnosis, patient treatment and clinical outcomes were collected using unified forms. Overall survival (OS) was defined as the period between the date of diagnosis and the date of death or last observation. Progression-free survival (PFS) was defined as the period between the date of diagnosis and either the date of the first relapse, of the last observation or death of any causes. Cox proportional hazard regression analysis was applied to assess risk factors of death. Survival curves were plotted by the Kaplan-Meier method and compared using log-rank and Breslow-Gehan-Wilcoxon tests. Results We analyzed a total of 213 patients, mean age 62.1 years (range 32 to 90), including 91 (42.7%) males. Immunoglobulin isotype included IgG (n=98, 46.0%), IgA (n=60, 28.2%) and IgM (n=1, 0.5%), light chain only in 47 cases (22.1%). ISS stage at diagnosis included: stage III (n=78, 36.6%), stage II (n=81, 38.0%) and stage I (n=47, 22.1%); for R-ISS: stage III (n=79, 37.1%), stage II (n=71, 33.3%), stage I (n=10, 4.7%). For stage is unknown for the remaining patients. Hypercalcemia was present in 38 cases (17.8%), anemia (2 mg/dl) in 54 (25.4%) patients. In 104 (48.8%) cases osteolytic lesions were present. The t(14;16) was associated with other aberrations in 134 (62.9%), in 35 (16.4%) patients with del17p. First line treatment for MM with t(14;16) included PIs + chemotherapy in 72 patients (36%), PIs + IMIDs in 39 patients (20%) or chemotherapy + PIs + IMIDs in 25 patients (13%). Overall response rate was 67%. Median PFS was 31 months (CI 95% 28-40.3 months; Figure 1, panel A). Median OS was 88 months (CI 95% 49-177 months; Figure 1, panel B). 5-year OS from MM diagnosis was 55% (46-63%), whereas 10-year OS reached 44% (31-56%). Median OS for stage I was not reached, for stage II was 62 months (95%CI 38-177 months) and for stage III was 32 months (95% CI 18-88 months). Patients in ISS stage I had better OS than stage III patients (p Patients treated with combined therapy of IMIDs, PIs ± chemotherapy had better survival than patients treated with IMIDs or PIs alone or chemotherapy alone (p=0.044; Figure 3, panel A). Patients after auto-PBSCT (median OS not reached, n=62, 29.1%), especially tandem auto-PBSCT (median OS not reached, n=18, 8.5%) performed better OS than patients without transplant (median OS: 42.1 months [95%CI 27- 62 months], p Patients with additional del17p exhibited worse OS than patient with single t(14;16) mutation (median OS 42 vs 107 months, p=0.043; Figure 2, panel B). Conclusion This is the largest report of myeloma patients with t(14;16). Patients with t(14;16) and del17p had a worse prognosis than patients with t(14;16) alone. The use of auto-PBSCT, especially in the subgroup who received planned tandem auto-PBSCT, is associated with better survival. Combined therapy with PIs and IMIDs improved the overall survival in t(14;16) patients, which may suggests, that this high-risk prognostic feature might be partially overcome by the use of new-drug therapies. This study of 213 patients indicates that t(14;16) is not as severe adverse factor as compared to the original IMWG R-ISS analysis (n= 84), which suggests that the revised ISS may require updating. Disclosures Castillo: Genentech: Consultancy; Abbvie: Consultancy, Research Funding; Millennium: Research Funding; Pharmacyclics: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Niesvizky:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Amgen Inc.: Consultancy, Research Funding. Rosinol Dachs:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria. Cohen:Janssen: Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Neopharm Israel: Consultancy, Honoraria; Medisson Israel: Consultancy, Honoraria, Research Funding. Hari:Spectrum: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria; Amgen Inc.: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding. Goldberg:COTA Inc.: Employment, Equity Ownership.
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- 2018
47. Toward personalized therapy for chronic lymphocytic leukemia
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Paweł Góralski, Agnieszka Janus, Ida Franiak-Pietryga, Tadeusz Robak, Małgorzata Rogalińska, Pawel Robak, Zofia M. Kiliańska, Jerzy Z. Blonski, Marek Mirowski, Henryk Piekarski, and Henryk Maciejewski
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Male ,Cancer Research ,Cyclophosphamide ,Microarray ,Cell Survival ,medicine.medical_treatment ,Chronic lymphocytic leukemia ,Biology ,Antibodies, Monoclonal, Murine-Derived ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,Gene expression ,Tumor Cells, Cultured ,medicine ,Humans ,Precision Medicine ,Cladribine ,Aged ,Oligonucleotide Array Sequence Analysis ,Cell Nucleus ,Pharmacology ,Bedside to Bench Report ,Calorimetry, Differential Scanning ,Immunotherapy ,Middle Aged ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Molecular biology ,Leukemia ,Treatment Outcome ,Proto-Oncogene Proteins c-bcl-2 ,Oncology ,Drug Resistance, Neoplasm ,Monoclonal ,Molecular Medicine ,Rituximab ,Transcriptome ,medicine.drug - Abstract
The differences in clinical course of chronic lymphocytic leukemia could have an impact on variations in a patient’s response to therapy. Our published results revealed that thermal transition (95 ± 5°C) in differential scanning calorimetry profiles appear to be characteristic for the advanced stage of CLL. Moreover, a decrease/loss of this transition in nuclei from leukemic cells exposed to drugs ex vivo could indicate their diverse efficacy. It seems that the lack of changes in thermal profile could predict patient’s drug resistance. In this study, we demonstrate the results obtained after drug treatment of leukemic cells by calorimetry, apoptosis-related parameters involved in expression of genes using cDNA microarray and western blot. These data were compared with the patients’ clinical parameters before and after RCC therapy (rituximab + cladribine + cyclophosphamide). The complementary analysis of studied cases with opposite clinical response (CR or NR) revealed a strong relationship between clinical data, differences in thermal scans and apoptosis-related gene expression. We quantified expression of eight of apoptosis-related 89 genes, i.e., NOXA, PUMA, APAF1, ESRRBL1, CASP3, BCL2, BCL2A1 and MCL1. Particular differences in NOXA and BCL2 expression were revealed. NOXA expression in cells of patients who achieved a complete response to RCC therapy was 0.44 times higher in comparison to control ones. Interestingly, in the case of patients who did not respond to immunotherapy, NOXA expression was highly downregulated (RQ = 4.39) as compared with untreated cells. These results were confirmed by distinct cell viability, protein expression as well as by differences in calorimetry profiles.
- Published
- 2013
48. A Targeted Therapy for Protein and Lipid Kinases in Chronic Lymphocytic Leukemia
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Pawel Robak and T Robak
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Chronic lymphocytic leukemia ,Biochemistry ,Phosphatidylinositol 3-Kinases ,chemistry.chemical_compound ,Drug Discovery ,Agammaglobulinaemia Tyrosine Kinase ,Humans ,Syk Kinase ,Medicine ,Protein Kinase Inhibitors ,Protein Kinase C ,Phosphoinositide-3 Kinase Inhibitors ,Pharmacology ,business.industry ,Sunitinib ,Organic Chemistry ,Intracellular Signaling Peptides and Proteins ,Protein-Tyrosine Kinases ,Alvocidib ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,Cyclin-Dependent Kinases ,Axitinib ,src-Family Kinases ,Imatinib mesylate ,chemistry ,Ibrutinib ,Cancer research ,Molecular Medicine ,business ,Protein Kinases ,Tyrosine kinase ,Bosutinib ,medicine.drug - Abstract
Protein kinases (PKs) and lipid kinases (LKs) are good choices for targets of signal transduction therapy as these enzymes are involved in signaling pathways, and are often related to the pathogenesis of lymphoid malignancies. The attractiveness of PKs and LKs as drug able targets is enhanced by the fact that they are enzymes whose biological activity can be turned off by drugs that block their catalytic site. In the last few years small molecular kinase inhibitors (KIs) have been synthesized and become available for preclinical studies and clinical trials. The first KI, introduced into clinical practice in 1998, was imatinib mesylate, which became the first choice drug in chronic myeloid leukemia. More recently, several KIs have been developed to target the proximal B-cell receptor (BCR) signaling pathway including spleen tyrosine kinase inhibitor (Fostamatinib) and Bruton's tyrosine kinase inhibitors (Ibrutinib, AVL-263). These agents are currently evaluated in early clinical trials in chronic lymphocytic leukemia (CLL) and other diseases. Cyclin-dependent kinase (Cdk) inhibitors, flavopiridol (alvocidib), BMS-387032 (SNS-032), sunitinib and sorafenib are currently under evaluation in clinical trials for relapsed/refractory CLL. Multi-tyrosine kinase inhibitors including vandetanib (ZD6474) bosutinib (SKI-606), TKI258 (CHIR-258), pazopanib (GW786034) and axitinib (AG013736) have been also developed for the treatment of lymphoid malignancies. Phosphatidylinositol 3-kinases (PI3K ) are a family of lipid kinases that mediate signals from cell surface receptors. CAL-101 (GS-1101) is an oral PI3Kδ-specific inhibitor which has shown preclinical and clinical activity against CLL. This article summarizes recent achievements in the mechanism of action, pharmacological properties and clinical activity and toxicity of PK and LK inhibitors in CLL.
- Published
- 2012
49. Antibody therapy alone and in combination with targeted drugs in chronic lymphocytic leukemia
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Tadeusz Robak, Jerzy Z. Blonski, and Pawel Robak
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0301 basic medicine ,Chronic lymphocytic leukemia ,Antineoplastic Agents ,Ofatumumab ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,immune system diseases ,Obinutuzumab ,hemic and lymphatic diseases ,Antineoplastic Combined Chemotherapy Protocols ,medicine ,Humans ,Molecular Targeted Therapy ,Protein Kinase Inhibitors ,CD20 ,Clinical Trials as Topic ,biology ,business.industry ,Antibodies, Monoclonal ,Hematology ,medicine.disease ,Leukemia, Lymphocytic, Chronic, B-Cell ,030104 developmental biology ,Treatment Outcome ,Oncology ,chemistry ,030220 oncology & carcinogenesis ,Ibrutinib ,Immunology ,Cancer research ,biology.protein ,Alemtuzumab ,Rituximab ,Idelalisib ,business ,medicine.drug - Abstract
The development of non-chemotherapeutic agents, including monoclonal antibodies (mAbs) and other targeted drugs, makes chemotherapy-free treatment an attractive option for chronic lymphocytic leukemia (CLL). The classical mAb, rituximab, has been authorized for use in both first-line and second-line therapy for CLL. New mAbs directed against CD20, ofatumumab, and obinutuzumab (GA-101) have also been approved for the treatment of this disease. Recently, several new mAbs with potential benefits over the approved anti-CD20 antibodies have been developed for use in CLL. Anti-CD37, anti-CD19, and anti-CD40 mAbs are in early clinical trials and show promise in treating CLL. In addition, the combination of mAbs with B-cell receptor signaling pathway inhibitors and immunomodulatory drugs makes the chemotherapy-free option a reality today. Combinations of antibodies with targeted drugs like ibrutinib, idelalisib, or lenalidomide are expected to replace chemotherapy-based combinations for treating CLL in the near future. However, phase III trials should confirm the benefit of these new treatment strategies and establish their exact place in the therapeutic armamentarium for CLL.
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- 2016
50. Management of Multiple Myeloma with Second-Generation Antibody-Drug Conjugates
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Pawel Robak and Tadeusz Robak
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0301 basic medicine ,Indatuximab ravtansine ,Immunoconjugates ,medicine.drug_class ,Antineoplastic Agents ,Pharmacology ,Monoclonal antibody ,Lorvotuzumab mertansine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Pharmacology (medical) ,Multiple myeloma ,Lenalidomide ,biology ,Bortezomib ,business.industry ,Antibodies, Monoclonal ,General Medicine ,medicine.disease ,030104 developmental biology ,030220 oncology & carcinogenesis ,biology.protein ,Antibody ,Neoplasm Recurrence, Local ,business ,Multiple Myeloma ,Biotechnology ,medicine.drug ,Conjugate - Abstract
The antibody-drug conjugate (ADC) is a combination of a cytotoxic agent and monoclonal antibodies (mAbs) through a stable specialized chemical linker. After ADC binds to the target antigen, the conjugate is internalized and toxin is released, leading to the death of a target cell. Lorvotuzumab mertansine, indatuximab ravtansine, and milatuzumab-doxorubicin are currently under clinical development for use in multiple myeloma (MM). Preliminary data from recent studies indicate that these agents induce responses in patients with relapsed and/or refractory MM and have an acceptable safety profile.
- Published
- 2016
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