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Torino Myeloma Conference
April 22, 2004

Session I—Molecular Pathogenesis

The first morning’s session presented new findings on the molecular pathogenesis of multiple myeloma (MM). The major focus was identifying genetic markers that both identified the expected outcomes for potential groups, and perhaps even more exciting, identifying in individual patients or patient groups, markers that could allow for more “individualized” and tailored therapies.

Dr. P. L. Bergsagel presented on cyclin D dysregulation in multiple myeloma (MM). It seems that almost all MM tumors dysregulate at least 1 of the cyclin D genes (there are 3). Dr. Bergsagel compared the expression of cyclin D genes to a number of the typical chromosomal translocations in MM and found that 5 distinct classes of patients could be identified based on their cyclin D expression and chromosomal translocations. As the new research continues, it is hoped that patient outcomes will become more predictable based on in which group they reside and that more targeted treatment can be developed.

Dr. B. Van Ness presented the latest data emerging from the IMF-sponsored Bank on a Cure. The purpose of the Bank is to accumulate a DNA and genetic database with the eventual aim to identify through genetic testing, which patient should receive what treatment. In other words, ensure that each patient’s therapy is maximized for success. The Bank also hopes to extend their findings to identify risk factors in families to provide an early warning to families at risk for familial linkage of their multiple myeloma. To this end, Dr. Van Ness provided exciting data on melphalan, tumor necrosis factor, interleukin-10, and lymphotoxin, showing how the expression of these markers is likely linked with outcome in multiple myeloma and perhaps response to specific therapies.

Dr. B. Klein centered his presentation on communication signals in MM, more specifically in the bone marrow microenvironment. He was attempting to answer what promotes cell proliferation in bone in chronic disease and to this end, identified 2 growth factors in myeloma (called BAFF and APRIL). Inhibitors of BAFF and APRIL support death of myeloma cells suggesting a new avenue for research and hopefully treatments in the clinic.

Dr. Shaughnessy
A very interesting presentation was given by Dr. J. D. Shaughnessy, Jr. While abnormal karyotypes have emerged as a significant prognostic variable in predicting outcome in patients receiving high dose therapy and tandem stem cell transplants, abnormalities are seen in only about 30% of patients. Dr. Shaughnessy sought to identify distinct gene expression in patients that would have wide-spread application and high predictive relevance. His team reported on a group of 3 genes that collectively identified 4 groups  of patients and that could accurately predict outcome to therapy. Extending this concept, Dr. Shaughnessy suggested next steps included using the uncovered molecular mechanisms as insight for developing potential novel therapeutic approaches.

Dr. Avet-Loiseau
Dr. H. Avet-Loiseau continued the theme as the last speaker in the first morning session. He spoke of 3 levels of genetic heterogeneity in MM: ploidy, chromosome 13 abnormalities, and abnormalities based on 14q32 translocations. Dr. Avet-Loiseau presented fascinating data showing how genetic analyses can progressively reveal several subgroups within MM and discussed the need to move to large numbers of patients to validate his findings.

Session II—Phenotypic and Functional Abnormalities

The second morning session topic surrounded phenotypic and functional abnormalities in MM. Dr. A. Orfao began the session by presenting information on the different ways clonal plasma cells interact with the immune system in MM. While the presentation was complex, what was highlighted was that the immune system makes an early attempt to control monoclonal gammopathies, such as MM, but that this effort fails over time. Further studies may help better identify what goes wrong and perhaps provide another avenue for therapy.

Dr. M.M. Kawano continued the session with a close look at how the surface marker, known as CD45, plays a significant biological role in MM. Dr. Kawano studied a number of cell phenotypes, all with variations in CD45 expression. He found that the presence of CD45 is important for a myeloma cell to respond to interleukin-6, but that in the absence of CD45, myeloma cells still remain stable in bone marrow.

Dr. J. F. San Miguel, in his presentation, stressed the importance of immunophenotyping in MM. He took the audience through a series of supportive data illustrating how immunophenotyping has the following areas of value in MM: plasma cell infiltration; differentiation between MGUS and MM; minimal residual disease; gene expression/protein profiles; and lastly, perhaps the most relevant, identifying therapeutic intervention, especially with newly/recently emergent monoclonal antibodies.

Dr. J. Epstein switched gears, addressing the “myelomatous” environment. Specifically, Dr. Epstein focused on angiogenesis, osteoblast apoptosis, and osteoclastogenesis. He used a unique model in which a human bone was transplanted to a mouse. The bone was studied in the presence of myeloma cells, the mouse providing the overall environment. The effect of agents that blocked bone destruction were then evaluated, notably using bisphosphonates. The data reflected that inhibition of osteoclast formation has a profound anti-myeloma effect supporting the continued study of bisphosphonates in MM.

Dr. Croucher

Dr. P. Croucher continued the investigation of osteoclastic bone resorption and treatment of myeloma bonedisease. More specifically, Dr. Croucher studied the role of RANKL and osteoprotegerin (a decoy receptor for RANKL), and also how the bisphosphonate, zoledronic acid, inhibits the development of bone disease using a mouse model of MM. The information presented clearly suggested that targeting RANKL with the decoy receptor and use of zoledronic acid prevent the development of myeloma bone disease in the mouse model, and results in an anti-myeloma effect.

Dr. Pilarski

In finishing the morning sessions, Dr. L. M. Pilarski presented information on novel predictive indicators of disease outcome. Dr. Pilarski discussed how therapeutic modulation of RHAMM (a key receptor for hyaluronic acid) along with genetic modification of certain hyaluronan synthases may be able to abort the generation of aggressive clonal variants and inhibit malignant spread of disease.

Session III—Role of Microenvironment

The afternoon session opened addressing the role of the microenvironment in MM.

Dr. Amiot

Dr. M. Amiot was the first speaker and she continued discussion on CD45, a marker discussed during the earlier morning sessions, specifically looking at predictive outcomes of cells expressing high, low, or no CD45. Dr. Amiot presented that CD45- cells are predictive of poor prognosis and progressive disease. However, she identified a potential therapeutic strategy for these patients by blocking IGF-1R signaling.

Dr. Vacca

Dr. A. Vacca presented an intriguing discussion on angiogenesis and its role in MM. He provided information on the angioblastic cells in MM and the role of autocrine loops.
Dr. Vacca ended with a discussion on the role played by thalidomide as a downregulator of angiogenesis and vasoproliferation.

Dr. Van Reit
Dr. I. Van Riet discussed tumor cell – endothelial cell interactions and the role of tyrosine kinase receptors and their inhibitors on those interactions. Dr. Van Riet presented data on both in vitro (measuring microvessel density) and in vivo studies (tumor load and survival). The outcome of his findings clearly demonstrated the critical role played by tyrosine kinases and in tumor cell – endothelial interaction and that interference of those interactions with tyrosine kinase inhibitors can result in decreased tumor loads and increased survival.

Dr. C. S. Mitsiades studied the mechanisms of tumor survival in a mouse model. He identified 4 signaling pathways that support tumor survival and identified inhibitors of those pathways that may function at multiple levels and thus provide an additive or synergistic effect. The areas of interest involve pathways affected by proteosome inhibitors, by heat shock protein 90, by histone deacetylases, and inhibitors of the IGF-1R signal cascade. Dr. Mitisiades indicated that a phase 1 clinical trial is underway to evaluate these inhibitors.

Dr. Caligaris-Cappio

Dr. F. Caligaris-Cappio continued discussion of the microenvironment in MM, stressing the importance of a hypoxic environment. He also presented data on compound MG132 and its ability to induce apoptosis in cell lines and cells taken from patients with MM.

Dr. Guiliani

Dr. N. Giuliani finished the first afternoon session with further discussion of RANKL and osteoprotegerin (OPG). Dr. Guiliani presented information about the imbalance of the RANKL/OPG system and concluded that blocking bone resorption induced by RANKL may decrease tumor burden as well as bone destruction in patients with MM.

Session IV—Role of Immunosurveillance

Dr. M. Dhodapkar opened the second afternoon session by discussing the role of the natural killer T-cells (NKT) and their ability to recognize certain glycolipid antigens. The relevance of these findings is that NKT cells in patients with MM are defective, but can be restored using dendritic cells pulsed with NKT ligand (galactosylceramide), an observation that may hold a promise of a future therapy in MM.

Dr. Mellstedt

Dr. H. Mellstedt presented findings on natural and adaptive idiotype reactive
T-cells. Data indicate that a fraction of patients with myeloma mount spontaneous CD4 and CD8 idiotype-specific immunity. Mechanisms to harness idiotype reactive T-cells are really just emerging, but it is hoped that someday idiotype mechanisms will enhance the immune system of patients with MM.

Dr. Massai

Dr. M. Massai spoke of the role of the mevalonate pathway and the impact of zoledronic acid. Dr. Massai’s data reflected the ever-widening appreciation of how bisphosphonates can participate as therapy for MM, illustrating its effects on bone and also an antitumor effect that may be mediated through certain T-cells.

Dr. D. E. Joshua ended the afternoon session by taking a closer look at T-cells and dendritic cells in myeloma. Dr. Joshua presented information related to idiotypic response and dysfunctional dendritic cells in patients with MM. He provided a basic foundation using interleukin-12 plus antigen as a means to expand immunoreactive cells in MM.

For more information regarding these sessions, look for the complete proceedings from the Multiple Myeloma 2004 meeting to be published after the conclusion of this conference.

April 23, 2004

April 24, 2004

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