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Multiple Myeloma, Bortezomib

Massimo Nabissi, Maria Beatrice Morelli, Massimo Offidani, Consuelo Amantini, Silvia Gentili, Alessandra Soriani, Claudio Cardinali, Pietro Leoni, Giorgio Santoni
Several studies showed a potential anti-tumor role for cannabinoids, by modulating cell signaling pathways involved in cancer cell proliferation, chemo-resistance and migration. Cannabidiol (CBD) was previously noted in multiple myeloma (MM), both alone and in synergy with the proteasome inhibitor bortezomib, to induce cell death. In other type of human cancers, the combination of CBD with Δ9-tetrahydrocannabinol (THC) was found to act synergistically with other chemotherapeutic drugs suggesting their use in combination therapy...
October 18, 2016: Oncotarget
Jana Jakubikova, Danka Cholujova, Teru Hideshima, Paulina Gronesova, Andrea Soltysova, Takeshi Harada, Jungnam Joo, Sun-Young Kong, Raphael E Szalat, Paul G Richardson, Nikhil C Munshi, David M Dorfman, Kenneth C Anderson
Specific niches within the tumor bone marrow (BM) microenvironment afford a sanctuary for multiple myeloma (MM) clones due to stromal cell-tumor cell interactions, which confer survival advantage and drug resistance. Defining the sequelae of tumor cell interactions within the MM niches on an individualized basis may provide the rationale for personalized therapies. To mimic the MM niche, we here describe a new 3D co-culture ex-vivo model in which primary MM patient BM cells are co-cultured with mesenchymal stem cells (MSC) in a hydrogel 3D system...
October 13, 2016: Oncotarget
P Fabbrini, K Finkel, M Gallieni, G Capasso, M Cavo, A Santoro, S Pasquali
Acute kidney injury (AKI) is a frequent complication of multiple myeloma and is associated with increased short-term mortality. Additionally, even a single episode of AKI can eventually lead to end-stage renal disease (ESRD), significantly reducing quality of life and long-term survival. In the setting of multiple myeloma, severe AKI (requiring dialysis) is typically secondary to cast nephropathy (CN). Renal injury in CN is due to intratubular obstruction from precipitation of monoclonal serum free light chains (sFLC) as well as direct tubular toxicity of sFLC via stimulation of nuclear factor (NF)κB inflammatory pathways...
October 18, 2016: Journal of Nephrology
Jesús F San-Miguel, Vania T M Hungria, Sung-Soo Yoon, Meral Beksac, Meletios A Dimopoulos, Ashraf Elghandour, Wieslaw W Jedrzejczak, Andreas Günther, Thanyaphong N Nakorn, Noppadol Siritanaratkul, Robert L Schlossman, Jian Hou, Philippe Moreau, Sagar Lonial, Jae H Lee, Hermann Einsele, Monika Sopala, Bourras-Rezki Bengoudifa, Florence Binlich, Paul G Richardson
BACKGROUND: Panobinostat plus bortezomib and dexamethasone significantly increased median progression-free survival compared with placebo plus bortezomib and dexamethasone in the phase 3 PANORAMA 1 trial. Here, we present the final overall survival analysis for this trial. METHODS: PANORAMA 1 is a randomised, placebo-controlled, double-blind, phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma with one to three previous treatments...
October 14, 2016: Lancet Haematology
Shun-Quan Wu, Wen-Yan Niu, Ya-Ping Li, Hao-Bo Huang, Rong Zhan
The oncogene B-cell-specific Moloney murine leukemia virus insertion site‑1 (Bmi‑1) is overexpressed in multiple myeloma (MM). Our previous study demonstrated that Bmi‑1 silencing sensitized MM cells to bortezomib. Translational regulation has emerged as a prominent underlying mechanism of Bmi‑1 regulation, particularly via microRNA targeting. The present study determined that Bmi‑1 may be directly targeted by miR‑203 using a luciferase assay. In addition, enforced expression of miR-203 led to significant downregulation of Bmi‑1 protein and mRNA expression levels...
October 12, 2016: Molecular Medicine Reports
Shigeo Hashimoto, Takashi Kuroha, Toshio Yano, Naoko Sato, Tatsuo Furukawa
Five cases were treated by adding daily low-dose thalidomide (50 mg) to bortezomib and dexamethasone therapy for refractory multiple myeloma. This therapy was effective in four cases, with an improvement of bone pain and regression of M-protein. One case was treated with cyclophosphamide, thalidomide, and dexamethasone, adding bortezomib after starting the three-drug combination therapy. This patient has remained in a stable disease state since the beginning of this therapy. Regarding the other four cases, a partial response and a prolonged survival for approximately one year were noted...
2016: Internal Medicine
Soushi Ibata, Tsutomu Sato, Hiroyuki Kuroda, Yasuhiro Nagamachi, Satoshi Iyama, Akihito Fujimi, Yusuke Kamihara, Yuichi Konuma, Masahiro Yoshida, Ayumi Tatekoshi, Akari Hashimoto, Hiroto Horiguchi, Kaoru Ono, Kazuyuki Murase, Kohichi Takada, Koji Miyanishi, Masayoshi Kobune, Yasuo Hirayama, Junji Kato
PURPOSE: Consolidation/maintenance therapy induces deep remission in patients with multiple myeloma (MM); however, the most suitable regimen has been under investigation. The combination therapy with bortezomib, lenalidomide and dexamethasone (VRD) is a powerful regimen for relapsed/refractory as well as newly diagnosed MM as an induction therapy. However, severe adverse events (AEs) may become a problem when VRD is introduced without dose reduction as a consolidation/maintenance therapy...
October 13, 2016: Cancer Chemotherapy and Pharmacology
Maria-Victoria Mateos, Albert Oriol, Joaquín Martínez-López, Ana-Isabel Teruel, Enrique Bengoechea, Luis Palomera, Felipe de Arriba, Dixie-Lee Esseltine, Andrew Cakana, Lixia Pei, Helgi van de Velde, Jesus San Miguel
: Bortezomib-melphalan-prednisone (VMP) is a standard-of-care for previously untreated, transplant-ineligible multiple myeloma (MM). Here, we compared outcomes between VMP regimens in the VISTA trial (9-cycle VMP schedule, including 4 cycles of twice weekly bortezomib) and the PETHEMA/GEM05 trial (less intensive 6-cycle VMP schedule with 1 cycle of twice weekly and 5 cycles of weekly bortezomib, then bortezomib-based maintenance). A total of 113 patient pairs matched by propensity score (estimated using logistic regression and incorporating eight exposure/outcome-related parameters) were included in this retrospective analysis...
October 14, 2016: Annals of Hematology
Prahlad V Raninga, Giovanna Di Trapani, Slavica Vuckovic, Kathryn F Tonissen
Multiple myeloma (MM) is an incurable plasma B cell malignancy. Despite recent advancements in anti-MM therapies, development of drug resistance remains a major clinical hurdle. DJ-1, a Parkinson's disease-associated protein, is upregulated in many cancers and its knockdown suppresses tumor growth and overcomes chemoresistance. However, the role of DJ-1 in MM remains unknown. Using gene expression databases we found increased DJ-1 expression in MM patient cells, which correlated with shorter overall survival and poor prognosis in MM patients...
October 12, 2016: Apoptosis: An International Journal on Programmed Cell Death
Shanmugapriya Thangavadivel, Claudia Zelle-Rieser, Angelika Olivier, Benno Postert, Gerold Untergasser, Johann Kern, Andrea Brunner, Eberhard Gunsilius, Rainer Biedermann, Roman Hajek, Ludek Pour, Wolfgang Willenbacher, Richard Greil, Karin Jöhrer
The bone marrow microenvironment plays a decisive role in multiple myeloma progression and drug resistance. Chemokines are soluble mediators of cell migration, proliferation and survival and essentially modulate tumor progression and drug resistance. Here we investigated bone marrow-derived chemokines of naive and therapy-refractory myeloma patients and discovered that high levels of the chemokine CCL27, known so far for its role in skin inflammatory processes, correlated with worse overall survival of the patients...
October 8, 2016: Oncotarget
Seok Jin Kim, Soo-Mee Bang, Yoon Seok Choi, Deog-Yeon Jo, Jin Seok Kim, Hyewon Lee, Hyeon Seok Eom, Dok Hyun Yoon, Cheolwon Suh, Je-Jung Lee, Junshik Hong, Jae Hoon Lee, Youngil Koh, Kihyun Kim, Sung-Soo Yoon, Chang-Ki Min
BACKGROUND: Bendamustine may be a potential treatment option for patients with myeloma, but little is known about the utility of bendamustine as a salvage treatment, especially in Asian patients. METHODS: We performed a multicenter retrospective study of patients with relapsed or refractory myeloma who received bendamustine and prednisone. RESULTS: The records of 65 heavily pre-treated patients, who had undergone bortezomib and lenalidomide treatment (median number of previous treatments: 5), were analyzed...
September 2016: Blood Research
Daniele Tibullo, Nunzia Caporarello, Cesarina Giallongo, Carmelina Daniela Anfuso, Claudia Genovese, Carmen Arlotta, Fabrizio Puglisi, Nunziatina L Parrinello, Vincenzo Bramanti, Alessandra Romano, Gabriella Lupo, Valeria Toscano, Roberto Avola, Maria Violetta Brundo, Francesco Di Raimondo, Salvatore Antonio Raccuia
Multiple myeloma (MM) is a clonal B-cell malignancy characterized by an accumulation of clonal plasma cells (PC) in the bone marrow (BM) leading to bone destruction and BM failure. Despite recent advances in pharmacological therapy, MM remains a largely incurable pathology. Therefore, novel effective and less toxic agents are urgently necessary. In the last few years, pomegranate has been studied for its potential therapeutic properties including treatment and prevention of cancer. Pomegranate juice (PGJ) contains a number of potential active compounds including organic acids, vitamins, sugars, and phenolic components that are all responsible of the pro-apoptotic effects observed in tumor cell line...
October 1, 2016: Nutrients
Shaji K Kumar, Betsy R LaPlant, Craig B Reeder, Vivek Roy, Alese E Halvorson, Francis Buadi, Morie A Gertz, P Leif Bergsagel, Angela Dispenzieri, Melanie A Thompson, Jamie Crawley, Prashant Kapoor, Joseph Mikhael, Keith Stewart, Suzanne R Hayman, Yi L Hwa, Wilson Gonsalves, Thomas E Witzig, Sikander Ailawadhi, David Dingli, Ronald S Go, Yi Lin, Candido E Rivera, S Vincent Rajkumar, Martha Q Lacy
Proteasome inhibitors have become an integral part of myeloma therapy. Considerable efforts have gone into optimizing this therapeutic approach in order to obtain maximal proteasome inhibition with least toxicity. Ixazomib is the first oral proteasome inhibitor to enter the clinic and has been studied as a single agent as well as in various combinations. The current trial was designed to examine the efficacy and toxicity of combining two different doses of ixazomib (4 mg and 5.5mg given weekly for 3 of 4 weeks) with 40 mg weekly of dexamethasone, in relapsed myeloma...
October 4, 2016: Blood
Valentina Marchica, Fabrizio Accardi, Paola Storti, Cristina Mancini, Eugenia Martella, Benedetta Dalla Palma, Marina Bolzoni, Katia Todoerti, Magda Marcatti, Chiara Schifano, Sabrina Bonomini, Gabriella Sammarelli, Antonino Neri, Maurilio Ponzoni, Franco Aversa, Nicola Giuliani
The skin is a possible site of extramedullary localization in multiple myeloma (MM) patients; however, the mechanisms involved in this process are poorly understood. We describe the case of a refractory MM patient who developed a cutaneous localization under bortezomib treatment and we further expanded observations in other eight MM patients. We focused on the expression of genes involved in plasma cell skin homing, including CCR10, which was highly expressed. Moreover, we observed a lack of CXCR4 surface expression and the down-regulation of ICAM1/CD54 throughout the progression of the disease, suggesting a possible mechanism driving the escape of MM cells from the bone marrow into the skin...
October 3, 2016: International Journal of Hematology
Yoichi Imai, Eri Ohta, Shu Takeda, Satoko Sunamura, Mariko Ishibashi, Hideto Tamura, Yan-Hua Wang, Atsuko Deguchi, Junji Tanaka, Yoshiro Maru, Toshiko Motoji
Multiple myeloma (MM) is a relapsed and refractory disease, one that highlights the need for developing new molecular therapies for overcoming of drug resistance. Addition of panobinostat, a histone deacetylase (HDAC) inhibitor, to bortezomib and dexamethasone improved progression-free survival (PFS) in relapsed and refractory MM patients. Here, we demonstrate how calcineurin, when inhibited by immunosuppressive drugs like FK506, is involved in myeloma cell growth and targeted by panobinostat. mRNA expression of PPP3CA, a catalytic subunit of calcineurin, was high in advanced patients...
April 21, 2016: JCI Insight
Katia Beider, Evgenia Rosenberg, Hanna Bitner, Avichai Shimoni, Merav Leiba, Maya Koren-Michowitz, Lena Ribakovsky, Shiri Klein, Devorah Olam, Hanna Wald, Lola Weiss, Michal Abraham, Eithan Galun, Amnon Peled, Arnon Nagler
PURPOSE: To explore the functional consequences of possible cross-talk between the CXCR4/CXCL12 and the S1P pathways in multiple myeloma (MM) cells and to evaluate the effect of S1P targeting with FTY720 modulator as a potential anti-MM therapeutic strategy. EXPERIMENTAL DESIGN AND RESULTS: S1P targeting with FTY720 induces MM cell apoptosis. The combination of FTY720 with SPHK1 inhibitor SKI-II results in synergistic inhibition of MM growth. CXCR4/CXCL12-enhanced expression correlates with reduced MM cell sensitivity to both FTY720 and SKI-II inhibitors, and with SPHK1 co-expression in both cell lines and primary MM bone marrow samples, suggesting regulative cross-talk between CXCR4/CXCL12 and SPHK1 pathways in MM cells...
October 3, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Paola Neri, Nizar J Bahlis, Claudia Paba-Prada, Paul Richardson
Survival outcomes of patients with Multiple Myeloma (MM) have improved over the last decade due to the introduction of novel agents such as the immunomodulatory drugs thalidomide, lenalidomide (Len) and pomalidomide, and the proteasome inhibitors bortezomib (BTZ) and carfilzomib [1, 2]. However, despite these major advances, MM remains largely incurable and almost all patients relapse and require additional therapy [3]. The successful introduction of next generation novel agents including oral proteasome inhibitors, deacetylase inhibitors, and especially monoclonal antibodies as part of immunotherapy promises to further improve outcome...
2016: Cancer Treatment and Research
Guillemette Fouquet, Francesca Gay, Eileen Boyle, Sara Bringhen, Alessandra Larocca, Thierry Facon, Xavier Leleu, Antonio Palumbo
Multiple myeloma (MM) is a disease of the elderly, with a median age at diagnosis of approximately 70 years old, and more than 30 % of patients aged >75 years. This latter and very elderly population is going to significantly rise in the near future given the increase in life expectancy in Western countries, and, most importantly, global health status of elderly patients is improving, justifying appropriate treatments. Changes in treatment paradigm from the old melphalan-prednisone regimen used since the 1970s to its use as a backbone in a nontransplant setting since the late 1990s have highlighted different subgroups in elderly MM...
2016: Cancer Treatment and Research
N An, X Li, M Shen, S L Chen, Z X Huang
Objective: To investigate the efficacy and outcome in newly diagnosed multiple myeloma (MM) patients with renal insufficiency using bortezomib- or thalidomide-based regimens as front line treatment. Method: Sixty-nine newly diagnosed MM patients with renal insufficiency were retrospectively analyzed from August 2006 to August 2014. Results: ① Among thirty-nine patients with bortezomib based regimens (the bortezomib group), the overall response rate (ORR) was 89.7% and complete response (CR) plus near CR(nCR) rate was 41...
October 1, 2016: Zhonghua Nei Ke za Zhi [Chinese Journal of Internal Medicine]
Katarzyna Baranowska, Kristine Misund, Kristian K Starheim, Toril Holien, Ida Johansson, Sagar Darvekar, Glenn Buene, Anders Waage, Geir Bjørkøy, Anders Sundan
Cells degrade proteins either by proteasomes that clinically are targeted by for example bortezomib or carfilzomib, or by formation of autophagosomes and lysosomal degradation that can be inhibited by hydroxychloroquine (HCQ). Multiple myeloma is unique among cancers because proteasomal inhibition has good clinical effects. However, some multiple myeloma patients display intrinsic resistance to the treatment and most patients acquire resistance over time. We hypothesized that simultaneous targeting both arms of protein degradation could be a way to improve treatment of multiple myeloma...
September 23, 2016: Oncotarget
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