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`Highlights from the VIIIth International Myeloma Workshop
`Banff, Alberta, Canada
`May 4-8, 2001
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`Clinical Implications
`Bart Barlogie, MD
`Arkansas Cancer Research Center, Little Rock, Arkansas
`________________________________________________________________________________________
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`This is Dr. Richard Lutes, reporting at the Eighth International Myeloma Workshop in Banff, Alberta. We
`have the pleasure of speaking with Dr. Bart Barlogie of the Arkansas Cancer Research Center. Welcome Dr.
`Barlogie.
`
`DR. BART BARLOGIE: Good morning.
`
`DR. RICHARD LUTES: We'd like to discuss thalidomide, but first can you give us a short refresher course
`on the role of angiogenesis in myeloma?
`
`DR. BART BARLOGIE: We really didn't know much about angiogenesis until thalidomide entered clinical
`investigation. Angiogenesis, of course, was stimulated through the exciting work of Judah Folkman's on
`endostatin and angiostatin, the two agents he evaluated in solid-tumor models. And then attention was also
`paid to some of the liquid tumors, the leukemias, and multiple myeloma. It became apparent to everybody's
`surprise that in the setting of extensive marrow involvement there was quite a bit of vascularity in patients
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`with multiple myeloma. But the focus was then really intensified and research was intensified once
`thalidomide as an anti-angiogenesis drug entered the clinic, and it is now well established in multiple
`myeloma that the bone marrow microenvironment plays a very important role in the expansion and survival of
`myeloma cells.
`Strictly antiangiogenic approaches have not been tested because whether it's thalidomide or some of the
`other putatively antiangiogenic drugs, they all seem to have other mechanisms of action as well. And until
`the time that strictly antiangiogenic molecules are entering the clinic such as endostatin, we will not really
`know whether this mechanism by itself will produce substantial antitumor activity.
`
`DR. RICHARD LUTES: Can you summarize what we know currently about the mechanism of action of
`thalidomide?
`
`DR. BART BARLOGIE: When we performed the early trial we were keen on demonstrating that patients
`who were responding to therapy had a reduction in the so-called microvessel density in the marrow. And we
`wanted to know what would happen in other patients who actually had a persistence of their increased
`microvessel density. More mechanistic investigations in various laboratories have shown that thalidomide
`exerts a number of other properties among which foremost are immunomodulatory properties. There are
`interactions that tumor cells have with the bone-marrow microenvironment, that is adhesion of myeloma
`cells to stromal cells as they are being disrupted by thalidomide. Thalidomide also has ways of making the
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`myeloma cells more susceptible to other agents including dexamethasone. So there's a whole plethora of
`effects that may all be operating in a given patient and may be different from one patient to another. And we
`now have model systems such as the SCID-Hu mouse into which one can implant primary human myeloma
`cells. One can begin to investigate how thalidomide and other agents actually work.
`
`DR. RICHARD LUTES: I'd like to review the experience of yourself and others in the patients. First, let's
`talk about the role of thalidomide in refractory patients.
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`DR. BART BARLOGIE: After we reported in the New England Journal several years ago an activity of about
`30 percent or 35 percent mainly in patients who had relapsed following one or two transplants, this
`experience has been confirmed worldwide. When we had a meeting about thalidomide that included Dr.
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`Folkman, he said this was probably the fastest evaluation of a new drug in a systemic malignancy setting.
`He was very surprised how rapidly this caught on, and this is a testimony obviously to the dearth of new
`agents that we had in myeloma and to the activity of this compound in this disease.
`
`We have since evaluated another hundred patients with multiple myeloma in the refractory disease state,
`and this is to be published shortly in Blood and confirming our earlier observations that about a third of
`patients respond, about 10 percent to 15 percent achieve complete remission, and some of these complete
`remissions are so durable that there are patients who relapsed from a transplant two or three years ago who
`are in a sustained state of disease control. We have recognized in those refractory disease trials that the
`dose actually does play a role. So in contrast to some of the studies currently ongoing in less heavily pre-
`treated patients, we have found that the dose of thalidomide does impact the response rate and response
`duration. Patients in our trial who received more than 400 milligrams had a higher response rate and longer
`duration of disease control.
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`There are several studies ongoing in various institutions evaluating thalidomide in conjunction with
`glucocorticoids in the refractory disease setting but also up front. We will be reporting at this meeting on
`thalidomide being combined with a combination of cytotoxic agents such as DT-PACE, an acronym that
`stands for dexamethasone, thalidomide, cisplatin, Adriamycin, cyclophosphamide and etoposide, and that
`combination is highly effective in the aggressive fulminant disease and brings about complete responses in
`about 20 percent of patients. We have gone on to evaluate the role of thalidomide for the up-front
`management of patients with myeloma in the randomized trial, total therapy to where we have an intensive
`remission induction followed by two cycles of high-dose therapy and followed by consolidation
`chemotherapy and then maintenance interferon. In up- front, all patients are randomized to receive 400
`milligrams of thalidomide or not. The data are still blinded, we have treated over 300 patients and
`collectively for both arms combined the induction response is about 40 percent and after two cycles of high-
`dose therapy we are looking at a complete remission rate on the order of 70 percent. So these are very
`good numbers, and we should know probably in a year about the role or the contribution to the success that
`thalidomide makes.
`
`DR. RICHARD LUTES: Dr. Barlogie, can you discuss IMiDs and how they differ from thalidomide and what
`the clinical trial status is currently?
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`DR. BART BARLOGIE: There are several congeners that have been designed to reduce the toxicity of
`thalidomide, which is dose dependent and comprises mainly sedative effects, polyneuropathy, constipation,
`tremors and the like. And they are acute-dose and cumulative-dose related. Celgene Corporation has
`designed a number of newer compounds. The the one currently in clinical trials is ImiD, and this has gone
`through a phase I/II evaluation at Dana- Farber Cancer Center and at our institution. At the Farber it is in the
`setting of refractory myeloma but without prior transplant, and at our institution in patients who have had
`previous thalidomide who have had a relapse following high-dose therapy.
`
`We have now treated 12 patients on a dose-escalation schedule beginning at 5 milligrams daily to 10
`milligrams, 25 and 50 milligrams. We have seen now at the 25- and 50-milligram dose, especially at the 50-
`milligram dose, three out of three responses, and overall we have seen six out of 12 patients who had more
`than 25-percent tumor-mass reduction. And we have seen three who had more than a 50-percent reduction.
`The sedative effects were nonexistent. Seven patients who had previously been treated with thalidomide
`were included in the trial. Some of them did have thalidomide-related neuropathy which did not worsen,
`which actually did improve on the IMiD investigation. So our current impression with relatively short follow-
`up of several months, two or three months, we see that the tolerance of the IMiD is much improved, and I
`think this drug holds great promise for eventual up- front management of myeloma patients as well.
`
`DR. RICHARD LUTES: Excellent. Dr. Barlogie, given your extensive experience with thalidomide, are there
`specific patient-management issues that we should be aware of?
`
`DR. BART BARLOGIE: Well, I think the most important issue is that thalidomide and other new agents be
`evaluated as part of the well- designed clinical trials. We and my colleagues working in the field of myeloma
`basic and clinical research see more and more patients who have been given thalidomide as up-front
`treatment by their primary physicians. And that is a practice I would not condone. I think we need to
`evaluate very carefully what thalidomide's role is. We don't really know the exact dosing, we know that
`lower doses, as low as 50 milligrams in newly diagnosed patients, in those with smoldering disease, do
`have an antitumor effect. We don't know whether it's important to keep a patient chronically on thalidomide
`or whether it is appropriate to have dose disruption for several months to allow for recovery from toxicities,
`and so on. The trials in Europe are under way to evaluate melphalan, prednisone vis a vis melphalan and
`thalidomide. The French myeloma investigators are looking at thalidomide as a maintenance strategy after
`transplant, and so on. I think there is clearly toxicity from thalidomide, and as the IMiD and other related
`compounds are being evaluated and show comparable or even greater antitumor activity, then they have a
`great potential to replace thalidomide. Whether these newer compounds work through similar mechanisms
`is currently being investigated.
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`DR. RICHARD LUTES: And can you tell us a little bit about Dr. Weber's presentation on thalidomide in
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`untreated patients?
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`DR. BART BARLOGIE: Dr. Weber from the M.D. Anderson Hospital has together with Dr. Alexanian and
`her other colleagues used thalidomide in conjunction with dexamethasone based on trials initially in
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`refractory disease. And in a refractory disease setting thalidomide itself was no longer active,
`dexamethasone was no longer active, and the combination then was applied and brought about responses
`in about 20 percent or so of patients. When used up front Dr. Weber as well as Dr. Rajkumar of the Mayo
`Clinic have seen responses using 50-percent-reduction criteria in about 70 percent of patients. Complete
`remissions however have been rare, and so while the overall response rate using this 50-percent-reduction
`criteria is encouraging, the absence of complete remission is bothersome, and it would indicate that as with
`dexamethasone there is also in the case of thalidomide a tumor-resistant subpopulation that seems to
`escape the antitumor effects of thalidomide.
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`We have recognized in our program that chromosome 13 deletion is an adverse feature for benefit from
`thalidomide in both response and duration of response. And these kinds of qualitative studies have to be
`performed in order to determine at the genetic level which types of myeloma respond well to thalidomide and
`combinations of thalidomide, vis a vis those that need more intensive approaches. In our DT-PACE
`combination therapy program, the chromosome 13 deletion, present in about 20 percent of newly diagnosed
`patients, was not an adverse feature. So maybe there are means to overcome this very grave prognostic
`subgroup, which has a survival of a year to a year and a half. It is this group of patients that I think that
`would benefit when recognized up-front for new treatment approaches, where it would be appropriate to apply
`fundamentally new agents with even unknown mechanisms of action. These patients represent a well-
`defined subgroup so that it should be possible in short order to discover whether new agents have activity or
`not. And if they do have activity in such a high-risk setting then it can be hoped that they would be even
`much more effective in the more benign non-chromosome 13 deletion group.
`
`DR. RICHARD LUTES: We want to thank you Dr. Bart Barlogie, Arkansas Cancer Center, for your
`comments.
`
`DR. BART BARLOGIE: My pleasure, thank you.
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