Introduction Waldenström’s macroglobulinemia (WM) is characterized by the presence of lymphoplasmacytic cells in the bone marrow and the secretion of IgM monoclonal protein in the serum, indicating that WM cells present a high protein turnover, 1-3 leading us to hypothesize that inhibition of its turnover might be responsible for induction of apoptosis in malignant cells, such as using proteasome inhibitors. 4,5 The major activity of proteasome inhibitors is through targeting the IL-6 and NF-KB signaling pathways that are critical regulators of survival and proliferation in B-cell malignancies including WM. 6-8 Specifically, we have demonstrated that NF-KB is constitutively activated in WM primary cells; and recently found that this could be related to overexpression of microRNA-155. 9 One of the most extensively studied proteasome inhibitors is bortezomib. Bortezomib inhibits the ubiquitin-26S proteasome pathway, which regulates the turnover of a vast number of intracellular proteins, and has become an exciting target in a variety of malignancies, most notably multiple myeloma. 10 The proper functioning of this system is crucial for cell cycle regulation, gene transcription, and signal transduction. Inhibition of the proteasome effectively increases the presence of IKBA and prevents NF-KB release to the nucleus. Based on its activity in multiple myeloma, single-agent bortezomib was tested in WM in phase II trials and achieved 40%-80% responses, 11 indicating that proteasome activity is critical for the survival of WM cells. Other proteasome inhibitors have recently been developed including NPI- 0052 (Salinosporamide A, Nereus Inc, San Diego, CA). 12 NPI-0052 has a different chemical structure, toxicity profile, and mechanism of action than bortezomib. It regulates all three activities of the proteasome, and apoptosis mediated by this agent appears to be predominately through the caspase-8 cell death cascade. 13 Proteasome Inhibition Exerts Antitumor Activity in Waldenström’s Macroglobulinemia We previously evaluated the anti-tumor activity of proteasome inhibitors in WM and found that the novel proteasome inhibitor NPI-0052 inhibits proliferation and induces apoptosis in WM cell lines and CD19+ primary WM cells. 14 We then demonstrated that the combination of NPI-0052 and bortezomib leads to synergistic cytotoxicity on WM cell lines, IgM secreting cell lines, and patient cells. These two agents lead to inhibition of nuclear translocation of p65 NF-KB, targeting both the canonical and noncanonical NF-KB pathway, with synergistic induction of caspase-dependent and -independent apoptosis as shown by caspase-3, -8, -9 as well as PARP cleavage, release of Smac/DIABLO and AIF from the mitocondria, and activation of terminal UPR. This study therefore begins to delineate the role of the canonical and noncanonical NF-KB pathways in WM. 14 Role of Proteasome Inhibition in Waldenström’s Macroglobulinemia Aldo M. Roccaro, Antonio Sacco, Xavier Leleu, Abdel Kareem Azab, Feda Azab, Judith Runnels, Xiaoying Jia, Hai T. Ngo, Molly Melhem, Anne-Sophie Moreau, Irene M. Ghobrial The paradigm for the treatment of monoclonal gammophaties has dramatically changed: based on the understanding of the complex interaction between tumor cells and bone marrow microenvironment and the signaling pathways that are deregulated in this process, a number of novel therapeutic agents are now available. For example, 3 novel agents with a targeted anti–multiple myeloma activity, have been FDA approved for the treatment of this disease, namely bortezomib, thalidomide, and lenalidomide. The success of targeted therapy in myeloma has led to the development and investigation of more than 30 new compounds in this disease and in other plasma cell dyscrasias such as Waldenström’s macroglobulinemia (WM), both in the preclinical settings and as part of clinical trials. Among them the role of proteasome inhibitors has been widely dissected providing the preclinical basis for clinical trials of combinations of proteasome inhibitors in WM. Clinical Lymphoma & Myeloma, Vol. 9, No. 1, 94-96, 2009; DOI: 10.3816/CLM.2009.n.025 Keywords: Angiogenesis, Bortezomib, Immune response, NPI-0052, Waldenström Medical Oncology, Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA Supported in part by the Kirsch Laboratory for WM, International Waldenstrom Macroglobulinemia Foundation, Leukemia and Lymphoma Society and NIH R21 CA112904-01. Meeting date: October 15-19, 2008; Published date: March 18, 2009 Address for correspondence: Irene M. Ghobrial, MD, Medical Oncology, Dana-Farber Cancer Institute, 44 Binney Street, Mayer 548A, Boston, MA, 02115 Fax: 617-632-4862; e-mail: irene_ghobrial@dfci.harvard.edu This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA. Electronic forwarding or copying is a violation of US and international copyright laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1557-9190, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA. www.copyright.com 978-750-8400. Abstract 94 | Clinical Lymphoma & Myeloma March 2009