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Phase III multiple myelomA

Masafumi Taniwaki, Mihoko Yoshida, Yosuke Matsumoto, Kazuho Shimura, Junya Kuroda, Hiroto Kaneko
Elotuzumab, targeting signaling lymphocytic activation molecule family 7 (SLAMF7), has been approved in combination with lenalidomide and dexamethasone (ELd) for relapsed/refractory multiple myeloma (MM) based on the findings of the phase III randomized trial ELOQUENT-2 (NCT01239797). Four-year follow-up analyses of ELOQUENT-2 have demonstrated that progression-free survival was 21% in ELd versus 14% in Ld. Elotuzumab binds a unique epitope on the membrane IgC2 domain of SLAMF7, exhibiting a dual mechanism of action: natural killer (NK) cell-mediated antibody-dependent cellular cytotoxicity (ADCC) and enhancement of NK cell activity...
2018: Mediterranean Journal of Hematology and Infectious Diseases
Nadia Khan, Brad Kahl
Resistance to apoptosis is one of the hallmarks of cancer and members of the B-cell lymphoma 2 (BCL-2) family of proteins are central regulators of apoptosis. Many cancers become resistant to chemotherapy and apoptosis by up-regulating BCL-2 and other family members, making these proteins attractive targets for cancer therapy. Venetoclax is an orally administered, small-molecule apoptosis stimulant that targets BCL-2 proteins by acting as a BCL-2 homology domain 3 (BH3) mimetic. The drug is approved in the USA and EU as a monotherapy for the for the treatment of certain patients with chronic lymphocytic leukemia (CLL) and is in phase III clinical development for multiple myeloma (MM), and in phase II or I/II clinical trials for acute myeloid leukemia, and several B-cell malignancies, including diffuse large B-cell lymphoma, Waldenstrom's macroglobulinaemia, follicular lymphoma, and mantle-cell lymphoma...
March 8, 2018: Targeted Oncology
Alina Striha, A John Ashcroft, Anna Hockaday, David A Cairns, Karen Boardman, Gwen Jacques, Cathy Williams, John A Snowden, Mamta Garg, Jamie Cavenagh, Kwee Yong, Mark T Drayson, Roger Owen, Mark Cook, Gordon Cook
BACKGROUND: Multiple myeloma (MM) is a plasma cell tumour with an approximate annual incidence of 4500 in the UK. Therapeutic options for patients with MM have changed in the last decade with the arrival of proteasome inhibitors and immunomodulatory drugs. Despite these options, almost all patients will relapse post first-line autologous stem cell transplantation (ASCT). First relapse management (second-line treatment) has evolved in recent years with an expanding portfolio of novel agents, driving response rates influencing the durability of response...
March 7, 2018: Trials
Chintan Shah, Rohit Bishnoi, Ankur Jain, Harini Bejjanki, Sican Xiong, Yu Wang, Fei Zou, Jan S Moreb
Carfilzomib is a second-generation proteasome inhibitor (PI) that is approved for patients with relapsed or refractory multiple myeloma (RRMM) who failed ≥1 prior lines of therapy. We performed a systematic review of carfilzomib literature with meta-analysis to determine cumulative incidence of cardiotoxicity. After the literature search, we included a total of 29 eligible phase I/II, phase II and phase III clinical trials which used carfilzomib. The cumulative incidence and overall odds ratios (OR) were calculated with random effect model, using 'R' software with metaphor package...
February 21, 2018: Leukemia & Lymphoma
Ivana N Micallef, Patrick J Stiff, Auayporn P Nademanee, Richard T Maziarz, Mitchell E Horwitz, Edward A Stadtmauer, Jonathan L Kaufman, John M McCarty, Rita Vargo, Peter D Cheverton, Martin Struijs, Brian Bolwell, John F DiPersio
The purpose of this report is to analyze long-term clinical outcomes of patients exposed to plerixafor plus granulocyte colony-stimulating factor (G-CSF) for stem cell mobilization. This was a study of patients with non-Hodgkin's lymphoma (NHL, n = 167) and multiple myeloma (MM, n = 163) who were enrolled in the long-term follow-up of 2 pivotal phase III studies (NCT00741325 and NCT00741780) of 240 µg/kg plerixafor plus 10 µg/kg G-CSF, or placebo plus 10 µg/kg G-CSF to mobilize and collect CD34+ cells for auto-HSCT...
February 1, 2018: Biology of Blood and Marrow Transplantation
Xiao-Na Jin, Bao-Zhen Zhou, Dang-Feng Zhang
OBJECTIVE: To explore the expression and clinical significance of VEGF, IL-17, β2-MG and IL-35 in patients with multiple myeloma. METHODS: A total of 83 patients with multiple myeloma (MM) from January 2012 to December 2016 were enrolled in MM group, 36 healthy subjects were enrolled in control group. The levels of IL-17, IL-35 and VEGF in serum were detected by ELISA. The levels of β2-MG in serum were measured by radioimmunoassay. The differences of different indexes between 2 groups were compared...
February 2018: Zhongguo Shi Yan Xue Ye Xue za Zhi
Kyriaki Tzogani, Elisabeth Penninga, Marie Louise Schougaard Christiansen, Doris Hovgaard, Sinan B Sarac, Jorge Camarero Jimenez, Isabel Garcia, Marta Lafuente, Arantxa Sancho-López, Tomas Salmonson, Christian Gisselbrecht, Francesco Pignatti
On May 20, 2016, a conditional marketing authorization valid through the European Union (EU) was issued for daratumumab as monotherapy for the treatment of adult patients with relapsed and refractory multiple myeloma, whose prior therapy included a proteasome inhibitor (PI) and an immunomodulatory drug (IMiD) and who had demonstrated disease progression on the last therapy. The review of daratumumab was conducted under the EMA's accelerated assessment program for drugs that are of major interest for public health, especially from the point of view of therapeutic innovation...
January 25, 2018: Oncologist
Jill M Comeau, Katherine Kelly, Gary W Jean
PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy and safety, cost, and place in therapy of elotuzumab for treatment of relapsed or refractory multiple myeloma (MM) are reviewed. SUMMARY: Elotuzumab is a humanized monoclonal antibody that targets the signaling lymphocytic activation molecule (SLAM) protein SLAMF7 and facilitates an antibody-dependent cellular cytotoxicity interaction between myeloma cells and natural killer cells. Elotuzumab has U.S...
January 15, 2018: American Journal of Health-system Pharmacy: AJHP
Kyriaki Tzogani, Paula van Hennik, Ita Walsh, Pieter De Graeff, Annika Folin, Jan Sjöberg, Tomas Salmonson, Jonas Bergh, Edward Laane, Heinz Ludwig, Christian Gisselbrecht, Francesco Pignatti
On August 28, 2015, a marketing authorization valid through the European Union was issued for panobinostat, in combination with bortezomib and dexamethasone, for the treatment of adult patients with relapsed and/or refractory multiple myeloma who have received at least two prior regimens including bortezomib and an immunomodulatory agent (IMiD).Panobinostat is an orally available histone deacetylase (HDAC) inhibitor that inhibits the enzymatic activity of HDAC proteins at nanomolar concentrations. HDAC proteins catalyze the removal of acetyl groups from the lysine residues of histones and some nonhistone proteins...
November 30, 2017: Oncologist
Zhaoyang Teng, Neeraj Gupta, Zhaowei Hua, Guohui Liu, Vivek Samnotra, Karthik Venkatakrishnan, Richard Labotka
The failure rate for phase III trials in oncology is high; quantitative predictive approaches are needed. We developed a model-based meta-analysis (MBMA) framework to predict progression-free survival (PFS) from overall response rates (ORR) in relapsed/refractory multiple myeloma (RRMM), using data from seven phase III trials. A Bayesian analysis was used to predict the probability of technical success (PTS) for achieving desired phase III PFS targets based on phase II ORR data. The model demonstrated a strongly correlated (R(2) = 0...
November 23, 2017: Clinical and Translational Science
Dimitrios C Ziogas, Evangelos Terpos, Efstathios Kastritis, Meletios A Dimopoulos
Carfilzomib is a second-generation proteasome inhibitor that binds selectively and irreversibly with the chymotrypsin-like site of the proteolytic core. Its initial approval by the Food and Drug Administration, as monotherapy for relapsed/refractory multiple myeloma (RR-MM), followed soon by a global authorization of its combination with dexamethasone or with lenalidomide plus dexamethasone for the treatment of RR-MM after 1-3 prior lines. In order to optimize its administration, carfilzomib is currently examined in different doses and regimens in relapsed/refractory as well as in newly diagnosed myeloma...
December 2017: Expert Opinion on Pharmacotherapy
Hannah A Blair
Intravenous daratumumab (DARZALEX® ) is a first-in-class human IgG1κ monoclonal antibody against CD38 available for use in patients with relapsed and/or refractory multiple myeloma. In phase I/II and II trials and a pooled analysis of these studies, daratumumab monotherapy induced an overall response (partial response or better) in approximately one-third of patients; responses were rapid, deep and durable. An overall survival (OS) benefit was seen with daratumumab monotherapy, including in patients with a minimal response or stable disease...
December 2017: Drugs
Sheridan M Hoy
Pomalidomide (Imnovid® ; Pomalyst® ), an analogue of thalidomide, is an immunomodulatory agent, with several mechanisms of action (both direct and indirect) thought to be involved in its anti-myeloma activity. Oral pomalidomide is available in several countries for use in combination with low-dose dexamethasone in adults with relapsed and refractory multiple myeloma. In multinational, phase II or III studies in patients with refractory, or relapsed and refractory multiple myeloma who had received ≥ 2 prior treatment regimens (including ≥ 2 cycles of both lenalidomide and bortezomib), pomalidomide plus low-dose dexamethasone was associated with prolonged progression-free survival (PFS) and overall survival and an improved overall response rate...
November 2017: Drugs
Massimo Offidani, Laura Corvatta
Monoclonal antibodies (mAb) represent a new frontier to treat newly diagnosed and relapsed-refractory multiple myeloma (MM). Elotuzumab, an mAb targeted SLAM7 in the plasma cells and natural killer cells surface, is the first mAb approved for the treatment of relapsed-refractory MM in combination with lenalidomide and dexamethasone. This approval was the final result of several preclinical and Phase I-II clinical studies leading to ELOQUENT-2 Phase III trial that demonstrated that elotuzumab adds a significant and durable value to standard therapy, paved the way of this new treatment strategy for MM...
November 1, 2017: Future Oncology
Kyriaki Tzogani, Jorge Camarero Jiménez, Isabel Garcia, Arantxa Sancho-López, Marc Martin, Alexandre Moreau, Pierre Demolis, Tomas Salmonson, Jonas Bergh, Edward Laane, Heinz Ludwig, Christian Gisselbrecht, Francesco Pignatti
On November 19, 2015, a marketing authorization valid through the European Union was issued for carfilzomib in combination with lenalidomide and dexamethasone for the treatment of adult patients with multiple myeloma (MM) who have received at least one prior therapy.In a phase III trial in patients with relapsed MM, median progression-free survival (PFS) for patients treated with carfilzomib in combination with lenalidomide and dexamethasone (CRd) was 26.3 months versus 17.6 months for those receiving lenalidomide and dexamethasone alone (hazard ratio = 0...
November 2017: Oncologist
Martin Kropff, Martin Vogel, Guido Bisping, Rudolf Schlag, Rudolf Weide, Wolfgang Knauf, Heinrich Fiechtner, Georgi Kojouharoff, Stephan Kremers, Wolfgang E Berdel
This phase III, open-label, randomized, controlled study aimed to evaluate the benefit of adding continuous low-dose oral cyclophosphamide to bortezomib-dexamethasone in patients with primary relapsed/refractory multiple myeloma. Patients were randomized 1:1 to receive up to eight 3-week cycles of bortezomib (1.3 mg/m2) and dexamethasone (20 mg; VD; n = 48) or bortezomib-dexamethasone plus oral cyclophosphamide (50 mg; VCD; n = 48). Median time to progression (primary endpoint) was slightly longer in the VD versus VCD group (12...
November 2017: Annals of Hematology
Fatimah Al-Ani, Martha Louzada
BACKGROUND: In newly diagnosed multiple myeloma (NDMM), autologous stem cell transplantation (ASCT) remains the standard approach for transplant-eligible patients. To control the inevitable relapse, post-transplant consolidation/maintenance strategies are commonly used. However, the benefit of post-transplant consolidation is still uncertain METHOD: We conducted a systematic review of phase II/III studies to compare the efficacy of post-ASCT consolidation plus lenalidomide maintenance (CON+LEN) vs lenalidomide maintenance alone (LEN alone) in NDMM...
December 2017: European Journal of Haematology
David C Johnson, Oleg Lenive, Jonathan Mitchell, Graham Jackson, Roger Owen, Mark Drayson, Gordon Cook, John R Jones, Charlotte Pawlyn, Faith E Davies, Brian A Walker, Christopher Wardell, Walter M Gregory, David Cairns, Gareth J Morgan, Richard S Houlston, Martin F Kaiser
Recent studies suggest that the evolutionary history of a cancer is important in forecasting clinical outlook. To gain insight into the clonal dynamics of multiple myeloma (MM) and its possible influence on patient outcomes, we analyzed whole exome sequencing tumor data for 333 patients from Myeloma XI, a UK phase 3 trial and 434 patients from the CoMMpass study, all of which had received immunomodulatory drug (IMiD) therapy. By analyzing mutant allele frequency distributions in tumors, we found that 17% to 20% of MM is under neutral evolutionary dynamics...
October 5, 2017: Blood
Neeraj Gupta, Huyuan Yang, Michael J Hanley, Steven Zhang, Rachael Liu, Shaji Kumar, Paul G Richardson, Tomas Skacel, Karthik Venkatakrishnan
BACKGROUND: The oral proteasome inhibitor ixazomib has been approved by regulatory authorities around the world, including in the United States and the European Union, for the treatment of patients with multiple myeloma (MM) who have received at least one prior therapy, based on the pivotal phase III TOURMALINE-MM1 study. OBJECTIVE: The objective of this study was to quantitatively characterize the benefit-risk profile of ixazomib in relapsed/refractory MM in support of the approved dose and schedule...
October 2017: Targeted Oncology
Evangelos Terpos, Marco Gobbi, Anna Potamianou, Marjolein Lahaye, Catherine Couturier, Michele Cavo
OBJECTIVES: This randomized, international, multicenter, open-label phase III study investigated the effects of experimental retreatment with subcutaneous bortezomib plus dexamethasone (VD) followed by prolonged bortezomib therapy vs. standard VD retreatment in patients with relapsed/refractory multiple myeloma. METHODS: Patients were randomized (2:1) to receive either experimental (n = 53) or standard (n = 27) retreatment, stratified by the number of prior therapy lines...
August 12, 2017: European Journal of Haematology
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