`Banff, Alberta, Canada
`May 4-8, 2001
`
`Thalidomide: Mechanisms of Action and Clinical Outcomes
`Kenneth Anderson, MD
`Dana-Farber Cancer Institute
`________________________________________________________________________________________
`
`DR. RICHARD LUTES: This is Dr. Richard Lutes, reporting from the Eighth International Myeloma
`Workshop in Banff, Alberta. We are discussing the final session, "Thalidomide, Mechanisms of Action and
`Clinical Outcomes," and we welcome Dr. Kenneth Anderson of the Dana-Farber Cancer Institute in Boston.
`Good morning Dr. Anderson. To start with can you just give us your overview of thalidomide please?
`
`DR. KENNETH ANDERSON: Thalidomide is clearly a breakthrough in the therapy of multiple myeloma.
`Over two years ago it was used for the first time by doctors in Arkansas led by Dr. Bart Barlogie, and the
`observation in the clinic was that one-third of patients responded who literally responded to nothing else, in
`many cases having failed even two transplants. What's happened since is a flurry of activity to learn more
`about how to use thalidomide, to develop novel thalidomides that are even more potent that might have fewer
`side effects, and to rapidly move those new compounds from the bench or the laboratory to the clinic in
`trials with patients.
`
`DR. RICHARD LUTES: Can you give us an overview of the role of thalidomide first in refractory patients, and
`second then as up-front therapy?
`
`DR. KENNETH ANDERSON: Thalidomide in the initial study at the University of Arkansas achieved a
`response in approximately 30 percent of patients. As I mentioned earlier, many of these patients had failed
`high-dose therapy and were not treatable with any other conventional therapy. As is true of all the other
`agents we use to treat myeloma, when you use drugs earlier in the disease course, they work more
`effectively. Clearly tumor cells are sensitive to treatments early on after diagnosis, but they acquire drug
`resistance and have a more malignant phenotype with time. So thalidomide alone and together with other
`drugs, one of those being Decadron, has now been explored early in newly diagnosed multiple myeloma
`patients.
`
`At this session, Dr. Donna Weber of M.D. Anderson in Houston and Dr. Vincent Rajkumar of the Mayo
`Clinic each reported on the combination of thalidomide and Decadron, both in refractory patients but more
`importantly in up-front or newly diagnosed patients with myeloma. In the refractory setting, 40 percent to as
`many as half of the patients responded to thalidomide and Decadron and surprisingly, some of these
`patients had failed either Decadron or thalidomide alone. But fully half of such patients will respond to the
`combination. Even more exciting, when you use thalidomide together with Decadron in the early part of the
`disease course shortly after diagnosis, the response rates are much higher in the range of 70 to as high as
`80 percent rather than the third or 30 percent that we see in refractory disease.
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`DR. RICHARD LUTES: As almost any new drug becomes available, first it's used as a single and then in
`combination. And you mentioned the use of thalidomide with Decadron. What about other combinations?
`
`DR. KENNETH ANDERSON: Well, Dr. Barlogie at this session has described his experience of utilizing
`thalidomide as part of a combination chemotherapy program which does include high-dose therapy and
`transplantation and I'll let him address the special issues in that context. However, also at this session both
`Dr. Mort Coleman from New York and also Brian Drurie from Los Angeles describe the use of a three-drug
`combination, Biaxin, an antibiotic, Decadron and thalidomide. And seemingly at both sites the response
`rates to Biaxin, Decadron and thalidomide appear to be higher than would have been expected with either
`thalidomide or thalidomide and Decadron alone. A note of caution however is to mention that there are not
`large numbers of patients treated and while there may be increased responses we need further studies to
`confirm that possibility. The other cautionary note I would add is that Biaxin does enhance the side effects
`that were noted related to thalidomide. The reasons this is occurring are unclear, but the observation
`suggests that Biaxin affects the way thalidomide is metabolized by patients. Still, we don't know yet, so a
`cautionary note is to wait for further clinical trials before we can firmly conclude that the combination is in
`fact better in a randomized way than either thalidomide alone or thalidomide and Decadron.
`
`DR. RICHARD LUTES: Can you discuss your experience with the IMiDs please?
`
`DR. KENNETH ANDERSON: We've had the privilege of working with the new more-potent thalidomide
`analogues. They are called immunomodulatory drugs or IMiDs. In the clinic these drugs are much more
`potent against myeloma cells than thalidomide is directly and also by inhibiting cytokines, altering
`interactions of the myeloma cell with the bone marrow microenvironment, inhibiting angiogenesis, and
`stimulating the patient's own immune response against myeloma. So given that exciting prospect we
`moved rapidly from the bench to the bedside in a clinical trial, a phase I clinical trial that began in our center
`last October. Dr. Barlogie also has a similar ongoing phase I clinical trial, both of us trying to determine the
`maximally tolerated dose of the new ImiD, the dose that would be defined as the one that is tolerated with
`an acceptable side-effect profile. And then we will rapidly move on to a larger study in which we having
`known the correct dose will be able to test in a large number of patients its actual efficacy. The excitement
`so far reported both by Dr. Barlogie and myself in this session is that even in a phase I setting where we're
`simply trying to determine the right dose, both of us have noted marked anti-myeloma activity. Seeing
`activity in a phase I trial of a new drug is extremely unusual, so for both of us and for all doctors and patients
`it's a source of great hope and optimism.
`
`DR. RICHARD LUTES: Dr. Anderson, as the last speaker at this meeting, is there a take-home message
`that you'd like to leave for our audience?
`
`DR. KENNETH ANDERSON: Yes, I think there is. This meeting was really a landmark meeting in multiple
`myeloma. These sessions here presented cutting-edge and novel information about the cell of origin of
`myeloma, events that are important in the progression of disease in terms of the disease biology. It
`explored for the first time in depth the role of the marrow microenvironment in the development and
`progression of myeloma and so dealt with factors such as angiogenesis and others. It updated high-dose
`therapy and conventional-therapy strategies, and it integrated some of the new technologies that are now
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`available such as gene array and proteonomics. I think one of the major take-home messages from this
`meeting is for the first time in perhaps 30 or more years we have novel treatments now that are designed not
`only to target the tumor cell but to target the microenvironment as well. And excitingly these agents work
`when high-dose therapy has failed, so they clearly are providing for us an opportunity to treat patients and
`offer hope where previously we have been unable to do so.
`
`Also presented at this meeting were cutting-edge studies about immune treatments in myeloma, including
`vaccines and others that are finally progressing along quite well into the clinical trial setting. So I think the
`main take home message, and it would be for both patients, researchers, and caregivers alike is that the the
`spectrum of treatments that we are going to be having available for patients will vastly expand within the next
`year or two, and we can all expect a much better outcome for patients as a result.
`
`DR. RICHARD LUTES: Thank you Dr. Anderson for your comments.
`
`DR. KENNETH ANDERSON: Thank you.
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