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Torino Myeloma Conference
April 24, 2004

Session IX—New Drugs

Dr. K. Anderson opened the first morning session on new drugs. Dr. Anderson spoke on the biology of treatment for MM. This was an exciting and very forward-looking presentation that was closed with the emphatic view that the “end is in sight”. Dr. Anderson focused on the new treatment directions in MM and the new paradigm for treatment. He took the audience through a discussion of the mechanisms of action for Thalidomide and Revlimid and for Velcade. He discussed the concept of drugs that inhibit vascular endothelial growth factor (VEGF), those that target the myeloma tumor cell directly, and those that kill the myeloma cell when it is in the bone marrow microenvironment. The entire concept of treating myeloma is at the forefront of change as we now look to sequentially stress the myeloma cell at all stages of its existence, to weaken it, re-weaken it, and eventually kill it. Dr. Anderson closed saying that in the very near future, we will be able to specifically construct therapies based on the individual patient and reconstruct these therapies as the patient responds to treatment.

Dr. Richardson

Dr. P. G. Richardson followed with an instructive presentation on Thalidomide and Revlimid. He presented data on the need to individualize Thalidomide dose to reduce toxicity. He reviewed some of the existing data with Thalidomide as a prelude to discussion of the Thalidomide analogue, cc-5013 (Revlimid). Revlimid, phase I data were presented showing substantial activity in relapsed/refractory disease. This activity occurred in the absence of much of the toxicity observed with the parent compound (constipation, somnolence, and neuropathy). In his phase I study, 63% of patients had >25% reduction in serum paraprotein and responses were observed in 46% of patients who had received prior Thalidomide. Dr. Richardson finished with discussion of Actimid, another analogue of Thalidomide with greater potency and a more tolerable side effect profile than Thalidomide.

Dr. S. Jagannath discussed his results combining Velcade (V) and dexamethasone (D) as front-line therapy in MM. Dr. Jagannath described the mechanism of action of V and explained that its action in MM is not completely explained by its activity as a proteosome inhibitor. He next took the audience through preliminary data illustrating use of V+D front-line. Though the data compiled to date (and presented) are not yet complete, near complete and partial responses were observed in patients treated with V+D. Dr. Jagannath concluded that there is efficacy in V+D in front-line therapy; it is well tolerated, and worthy of larger study in newly diagnosed patients with MM.

Dr. Zangari

Dr. M. Zangari presented early phase data on use of Velcade (V) in combination with Thalidomide (T) and dexamethasone (D) in MM patients relapsing after autologous transplantation. He reported on 73 patients, most with prior exposure to Thalidomide and the majority with deletion of chromosome 13. This was a dose escalation study, with an overall response of 70% by cycle 8. Adverse events included fatigue and neuropathy. The time to 50% or better response occurred independent of cytogenetic status or prior Thalidomide use. These studies are continuing.

Dr. S.V. Rajkumar’s presentation was provided by his colleague, Dr. Kyle. The topic was use of Thalidomide in newly diagnosed and asymptomatic MM. Dr. Kyle offered the rational for considering Thalidomide and presented early data from the Mayo Clinic ( Rochester , MN , USA ) and M.D. Anderson Cancer Center ( Houston , TX , USA ), and predicted increasing use of Thalidomide in newly diagnosed patients, especially in combination with dexamethasone. Dr. Kyle next discussed a new trial (phase III) in which the Thalidomide analogue, Revlimid, is being evaluated with dexamethasone. Discussion turned to early treatment for smoldering MM. Early data were provided illustrating potential benefit of Thalidomide in asymptomatic MM. The presentation ended with a description of another study, this one comparing Thalidomide plus zoledronic acid to zoledronic acid alone in asymptomatic MM.

Dr. R. Alexanian’s presentation was provided by his colleague, Dr. Donna Weber. Dr. Weber presented on Thalidomide (T) and dexamethasone (D) as primary treatment for MM and the added role of bortezomib.  Dr. Weber started by comparing data on the use of T+D in untreated MM; data was obtained from both the Mayo Clinic ( Rochester , MN , USA ) and M.D. Anderson Cancer Center ( Houston , TX , USA ). She indicated that overall response was reasonable but that with T+D, deep vein thrombosis (DVT) was sufficiently frequent to warrant including a prophylactic anticoagulant. She next reviewed a series of studies in which bortezomib (B) was added to therapy that included doxirubicin; T+D; or melphalan. Specific data were presented of a study consisting of B+T+D in untreated patients, showing a high 74% response rate and rapid onset of time to remission (less than 1 month). She reflected that further trials are necessary to define optimum combinations of drugs for patients with newly diagnosed as well as resistant MM.

Dr. Palumbo

Dr. A. Palumbo finished the first morning session with a presentation on the use of melphalan (M), Thalidomide (T), and predinsone (P) in newly diagnosed patients with MM. He provided data from an ongoing international, prospective, randomized trial in myeloma patients >65 years of age and compared 2 treatment arms: M/P vs. M/P/T.

At the outset, Dr. Palumbo cautioned that addition of T to M/P resulted in increased adverse events, mostly constipation and neuropathy, and that these events generally appear within the first 2 months of treatment. Increased infections on M/P/T use were addressed by the addition of an antibiotic; DVT was addressed by the addition of an anticoagulant. Response rates were improved in M/P/T vs. M/P, with a partial response (PR) of 80%; complete response (CR) plus near complete response (NCR) were 39% in the M/P/T group and only 6% in the M/P group. Follow up at 13 months showed a relapse rate of 80% for the M/P group and only 20% for the M/P/T group. These studies continue.

Session X—Immunotherapy

Dr. Munshi

The second morning session of Immunotherapy was opened by Dr. N. C. Munshi, who spoke on dendritic cell (DC)-based vaccination in MM. Dr. Munshi explained the concept of using DCs (cells that present antigens to the immune system) attached to antigens from myeloma cells, or, in fact, physically fused with myeloma cells, as a means to enhance a patient’s immune response to their tumor. He also described other ways of developing these DC-based vaccines that could make them even more effective. He closed his presentation with evidence that this treatment direction, though not new in concept, has reached the stage of development where vaccine models can finally move into clinical trials. He cautioned, however, that there are still many questions to answer before DC-based vaccines become an active part of therapy for MM.

Dr. Yi

Dr. Q. Yi continued the discussion of intranodal vaccination of idiotype-pulsed (a special antigen of myeloma cells) mature dendritic cells in MM. Dr. Yi presented his technique for developing this vaccine and provided proof that the concept can work. He next discussed how this type of vaccination could have application in patients with indolent or smoldering MM and described next steps in clinical development.

Dr. F. Stevenson provided an update on DNA vaccines. DNA vaccines are best visualized as combining the DNA of a myeloma cell antigen with other DNA in such a way that the tumor cell DNA can be injected back into the patient in a form that will help the patient develop an immune response to his or her myeloma cells. It is a very complex undertaking and technically there have been numerous obstacles to overcome. However, Dr. Stevenson believes that many of these obstacles have been or soon will be addressed. She announced that a clinical trial of a DNA vaccine is now under way (not in MM) to fully test the concept and she believes that application to MM, though not near-tern, is getting closer.

Dr. Lemoli

Dr. R.M. Lemoli closed the presentation and the conference with discussion of dendritic cell (DC)-based vaccines. While similar in basic concept to the presentations by Drs. Munshi and Yi, Dr. Lemoli’s vaccine is prepared differently. Instead of using a broad, general range of DCs, Dr. Lemoli isolates specific DCs from the blood (CD14+ cells) and grows them in culture before they are ready for use. He presented data showing that this vaccine can induce an immune response in patients. He cautioned that much still needs to be accomplished before this type of vaccine is ready for common use 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 22, 2004

April 23, 2004

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