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This session looked at novel therapies, targeting not only the myeloma cell but also the marrow microenvironment.

Presentations included in this session were as follows:

Role of Novel Therapies Targeting The Myeloma Cell And Its Microenvironment: Dr. Ken Anderson

Novel agents targeting MM cells in the BM, including Thalidomide (Thal) and Immunomodulatory Analogs Thal/IMiDs induce G1 growth arrest/apoptosis of drug resistant MM cells via inhibiting NF-κB and activating caspase 8; inhibit adhesion of MM cells to BM stromal cells (SCs); inhibit bioactivity and/or secretion in MM cells, and/or BMSCs of cytokines; inhibit angiogenesis; induce T cell and NK cell anti-MM immunity; and decrease human MM cell growth in a SCID mouse model.

IMiD (Revamid) is more potent in preclinical studies and achieved stable disease or response in 79% of patients in Phase I study of relapsed refractory MM without somnolence, constipation, or neuropathy; it achieved responses, including CRs, in phase II trials. Phase III trial is comparing Dex/placebo versus Revimid/placebo in relapsed MM.

The proteosome inhibitor PS-341 (Velcade) inhibits 26S proteosome activity; induces apoptosis via caspase-8, 9, and 3 in drug resistant MM cells; downregulates adhesion molecules and binding of MM cells and MMSCs; blocks constitutive and adhesion-induced NFκb dependent cytokine cytokine secretion in BMSCs; and inhibits angiogenesis. PS-341 downregulates growth and survival gene transcription; and induces apoptotic, ubiquitin/proteosome, and stress response gene transcripts. Proeomics shows that PS-341 inhibits DNA repair kinases, and it can overcome resistance to DNA damaging agents. PS-341 induced cleavage of gp130 may account for MM sensistivity. PS-341 inhibits human MM cell growth, decreases angiogenesis, and prolongs survival in SCID mice. Anti-MM activity was observed in phase I trials, and a phase II trial of PS-341 in refractory relapsed MM achieved 35% responses (10% CR, near CR). Responses were durable (12 months) and associated with clinical benefit: improved quality of life; increased hemoglobin and decreased transfusions; stable renal function; and increase in normal immunoglobulin levels. PS-341 is being compared with Dex in phase III trial for relapsed MM.

Other agents include Arsenic Trioxide, 2-Methoxyestradinol, and Lysophosphatidic Acid Acyltransferase-β Inhibitors. Novel agents targeting MM cell signalling cascades include VEGFR tyrosine kinase inhibitor PTK787/ZK222584. Farnesyl-transferase Inhibitors; Historic Deacetylase Inhibitors suberoylanilide hydroxamic acid and cinnamyl hyroxamic acid LAQ824; and Heat Shock Protein 90 Inhibitors alone or to enhance response to PS-341.

Novel agents targeting BM include IκB Kinase Inhibitor PS-1145 and p38 MAPK inhibitor which do not inhibit growth of isolated MM cells, but do block tumor growth and cytokine secretion in BM. Novel agents targeting cell surface receptors include Tumor Necrosis Factor -Related /Apoptosis-Inducing Ligand/APo2 Ligand; Insulin-like growth factor -1 receptor inhibitors to overcome cytokine-induced growth, survival, and drug resistance: Statins to disrupt upstream lipid raft and downstream growth signalling; and anti-CD20 against CD20+ MM Cells. These novel agents, used alone or in combination with conventional or other novel agents, offer great promise to improve patient outcome in myeloma. Importantly, gene array and proteomic evaluation samples from patients treated with these novel agents will define molecular mechanisms of tumor cell sensitivity versus resistance, thereby providing the framework for developing next generation more potent, selective and less toxic, targeted MM therapies.

The Role of Arsenic Trioxide in Multiple Myeloma: Dr. Mohamad Hussein

Dr. Hussein discussed experience with Arsenic Trioxide in clinical trials for multiple myleoma.

The patients were heavily pretreated (17 of 24 had >=2 prior chemo regimens).

Another trial combined Arsenic Trioxide, Ascorbic Acid and Dexamethasone..

41% had at least a partial response, 41% stable and 18% with disease progression.

Dr. Hussein concluded that the regimen was well tolerated and showed some benefit.

Dr. Hussein concluded that the regimen was well tolerated and showed some benefit.

The Proteosome Inhibitor Bortezomib In Multiple Myeloma: Dr. Paul Richardson

Dr. Richardson discussed the role of the recently-approved proteosome inhibitor Bortezomib in the treatment of multiple myeloma.

Dr. Richardson explained the mechanisms of action.

202 patients were enrolled in the "Summit" trial.

202 patients were enrolled in the "Summit" trial.

There was a 35% overall response rate, with another 24% of patients showing stable disease.

Dr. Richardson presented the conclusions from the trial, which suggest that Bortezomib (a.k.a. PS-341, Velcade™) is a useful drug in the treatment of heavily pretreated patients.

Using gene array chips, there are findings emerging about which patients are more likely to respond to this agent.

Dr. Richardson presented the conclusions from the trial, which suggest that Bortezomib (a.k.a. PS-341, Velcade™) is a useful drug in the treatment of heavily pretreated patients.

Dr. Richardson presented the conclusions from the trial, which suggest that Bortezomib (a.k.a. PS-341, Velcade™) is a useful drug in the treatment of heavily pretreated patients.

Dr. Richardson presented the conclusions from the trial, which suggest that Bortezomib (a.k.a. PS-341, Velcade™) is a useful drug in the treatment of heavily pretreated patients.

Results Of Thalidomide And IMiDs In Multiple Myeloma: Dr. Meletios Dimopoulos

Dr. Dimopoulos discussed the role of the Thalidomide and the Immunomulatory Drugs (IMiDs) in the treatment of multiple myeloma. He began by discussing the mechanisms of action.

30% of pretreated patients had an objective response to single agent thalidomide.

There remains significant ambiguity about the appropriate dose.

Response rates when combining thalidomide with dexamethasone is over 50%.

Event Free and Overall Survival was shown to be superior for Thalidomide-Dexamethasone versus Conventional Chemotherapy.

Increased response rates in pretreated patients were achieved by combining Thalidomide-Dexamethasone with various Chemotherapies.

There are also a number of studies evaluating Thalidomide-based regimens for up-front therapy.

Deep Vein Thrombosis has been an issue to varying degrees in various Thalidomide-based regimens.

This issue is under investigation to identify patients at risk and potential interventions.

Thalidomide is being evaluated for potential benefit in virtually all disease phases.

Thalidomide analogs, IMiDs, show promise to deliver the benefits without the most troublesome toxicities (i.e., somnolence, constipation and neuropathy).

Clinical trials are underway to evaluate the IMiDs, which along with all of the very good results achieved thus far and the trials still in progress with thalidomide bodes well for the patient community.

Farnesyl Transferase Inhibitors (PTIs) In Multiple Myeloma: Dr. Melissa Alsina

Dr. Alsina presented finding about the potential use of FTIs in multiple myeloma.

FTIs target the Ras Oncogene.

This oncogene is a potential target because of the evidence that it plays a role in multiple myeloma.

The gene affects proteins that play a role in IL-6 signal transduction, which is an important cytokine in myeloma.

There is evidence that FTI-R115777 is effective invtro.

...causing apoptosis (cell death) in myeloma cell lines in the lab.

FTIs have also been tested in mouse models.

...with some encouraging results.

Clinical trials are underway to evaluate FTIs for treating myeloma.

FTIs trials are open to relapsed/refractory myeloma patients.

43 patients were entered into the trial.

The major side effects observed are listed below:

Responses were disappointing.

The patient shown below showed stabilization of IgG and improved hemoglobin.

FTIs inhibit protein farnesylation in bone marrow and peripheral blood mononuclear cells from multiple myeloma patients.

FTIs surpress FTase activity in the bone marrow of multiple myeloma patients

...and they affect tumor survival signaling pathways.

Unfortunately, the trial did not succeed in establishing a link between inhibition or farnesylation and disease stabilization, although the treatment did seem to induce disease stablization, albeit not disease reduction.

The regimen is well-tolerated and achieves the desired effect on the microenvironment, it appears to have an affect on disease stablization that is independent of this effect.

NFκB:  A New Therapeutic Target For Overcoming Drug Resistance: Dr. James Berenson

Dr. Berenson discussed promising findings showing the potential of NFκB as a potential target for new therapies aimed at overcoming drug resistance in multiple myeloma. NFκB plays a key role in the disease process, as explained below:

Dr. Berenson explained how NFκB plays a role in gene activation.

...and in DNA binding activity.

Active myeloma cells appear to have higher activity of NFκB DNA binding.

Velcade™ reduces NFκB translocation...

...which may play a role in its anti-myeloma effect.

Velcade™ appears to have a synergistic effect with melphalan.

Melphalan is being tested as a treatment in combination with Velcade™ in a Phase I trial for relapsing myeloma.

Dr. Berenson presented results garnered from 15 patients participating in this trial, showing encouraging results in halting disease progression/relapse.

Neuropathy continues to be an issue with Velcade™, although primarily in patients who had neuropathy before commencing treatment as a result of prior therapies.

Arsenic Trioxide also impacts NFκB DNA binding activity

Dr. Berenson presented findings from a trial involving 7relapsing myeloma patients given Arsenic Trioxide in combination with Vitamin C and steroids..

The patients were all heavily pretreated and resistant to multiple regimens

Despite their history, there were some encouraging responses to this new combination therapy..

Based on these results, the trials are progressing to a multi-center Phase II study.

Dr Berenson concluded that NFκB plays a key role in the development of drug resistance in myeloma and that the newer drugs, which block NFκB DNA binding show real promise in treating relapsed/refractory disease-- definitely good news for patients!

The panel then responded to questions from the audience.

Please note that the Unknown Patient is a patient, not a doctor and not a scientist. This summary represents a layman's view of what was said at the conference and should form a basis for raising awareness of issues that could be discussed with a qualified professional. In no way should anything contained in this report be taken as medical advice or form the basis for action without first consulting a qualified medical professional who is familiar with your specific medical situation.