Session Two: Emerging data on the use of Thalidomide in the treatment of Waldenstrom's Macroglobulinemia
- Targeted therapy for the plasma cell malignancies (Multiple Myeloma and Waldenstrom's macroglobulinemia), Kenneth C. Anderson, MD
Dana-Farber Cancer Institute, Boston, MA
- Thalidomide Therapy in Waldenstrom's Macroglobulinemia, Meletios A. Dimopoulos, MD, Alexandra Hospital, University of Athens
Athens, Greece
- Biaxin, Low dose Thalidomide and Dexamethasone are highly active in Waldenstrom's Macroglobulinemia and Multiple Myeloma, Morton Coleman, MD, Cornell University, New York, NY

Targeted therapy for the plasma cell malignancies (Multiple Myeloma and Waldenstrom's Macroglobulinemia)
Kenneth C. Anderson, MD, Dana-Farber Cancer Institute, Boston, MA

In dealing with cancers, we have traditionally concentrated on the malignant cells themselves. In recent years, we have begun to consider also the neighborhood in which tumors live. We have, for example, begun to examine the process of angiogenesis, the creation of the delivery system for the blood these tumors require. Thus in WM, we can attack the malignant cells, or we can try to treat the disease by changing the environment surrounding the tumor cells in the bone marrow.

To find ways of effectively but safely changing that environment, we follow a three-fold process. First, in the laboratory we look for mechanisms to make the environment inhospitable to the tumor. Then we try what we have discovered in the laboratory on patients in clinical trials, to see whether the results are the same in the living organism as they are in the Petri dish. Finally, we go back to the laboratory to see whether we can explain why patients are (or are not) responding in the way they do.

In the case of multiple myeloma, we have the experience of about fourteen thousand (14,000) patients. The median survival period has been between four and five years. Few if any have been cured.
Blood vessels abound in the presence of tumors. We know that thalidomide can inhibit the formation of blood vessels. So we use thalidomide to try to reduce the blood supply and thus starve the tumor. We use it to prevent the tumor from inducing the blood vessel growth it would normally cause. Additionally, there are other known effects of thalidomide on multiple myeloma. It can induce dormancy in the MM cell. And it increases the natural killer cells which attack MM. It may also reduce the effectiveness of cellular defenses such as CD59.

Trials in mice have shown that animals with myeloma show greatly extended survival when treated with thalidomide. Some even last through the normal life span of the mouse; we might well consider them cured. The mechanism seems to be the inhibition of blood vessel growth.

Thalidomide is but one of similar compounds. New ones, called IMiD's, are being developed. Of these, the one we call IMiD3 seems to hold particular promise of being more effective than thalidomide with reduced side effects.

Another promising drug is the proteasome inhibitor PS 341. It, too, shuts off the switch that produces Interleukin 6 (IL-6) and thus causes the growth of blood vessels to supply the tumor. PS 341 not only inhibits new vessel growth, but also kills MM cells directly. And from what we now know, it seems to have the same effect on Waldenstrom's cells.

Phase I trials on PS 341 are currently well underway. While the purpose of Phase I is to test the safety and permissible dose of a treatment, both of two MM patients responded dramatically. MM patients who have shown resistance to other treatments have now been enrolled in Phase II trials of the drug. They have been given eight cycles, and most have responded well over up to six months of treatment. The drug seems sometimes to result in complete remission.

There is evidence that these compounds may work even better in combination therapy. IMiD1, in combination with decadron (a corticosteroid), etc., has led to the best yet killing of multiple myeloma. It seems to work even better when combined with PS 341.

Newer treatments for diseases of the bone marrow, then, focus not only on the malignant cells themselves, but on controlling the surrounding environment in the marrow.

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Thalidomide therapy in Waldenstrom's Macroglobulinemia

Meletios A. Dimopoulos, MD, Alexandra Hospital, University of Athens
Athens, Greece

The traditional chemotherapies, most of them alkylating agents, can develop responses in fifty to seventy-five percent (50-75%) of patients on first administration. After relapse, they may be used again, but the response rates diminish. Almost all patients gradually develop resistance to such chemotherapy.

Many non-standard combinations of therapy have been tried to get around this limitation. One of them is that same Thalidomide that caused such horrible results in pregnancies years ago. A number of trials have been undertaken, and it has proven effective in related diseases, particularly in resistant multiple myeloma.

In one such trial, Waldenstrom's patients in need of treatment were given two hundred (200) milligrams per day for fourteen (14) days. At the end of that period, the dosage was doubled to four hundred (400) milligrams. Assuming the side effects were not too great, the dose was raised again two weeks later by the same amount, to six hundred (600) milligrams per day. Since many of the participants were unable to stand the higher doses, no conclusions could be drawn concerning how response related to dosage. At the end of the period, all were placed on a maintenance dose of one hundred (100) milligrams per day.

Of the twenty patients, half of whom had previously undergone chemotherapy, five (5) showed partial response, and five (5) achieved stabilization of the disease, neither improving dramatically nor getting worse. Ten (10) showed no effect on disease progression; most of these were long-term patients.

The side effects were varied but troublesome and affected in one way or another all patients in the study. Among them we find constipation, somnolence, fatigue, depression and abnormal blood clots. Most disturbing was the development of peripheral neuropathy. Side effects seemed more common in the elderly. Only five (5) patients could handle the full six hundred (600) milligram daily dose, most of them of younger age. More to the point, perhaps, the duration of disease remission was short; in most cases the effect lasted two months or less.

It appears, then, that thalidomide as a single agent is not too successful in treating WM, though it does have some effect. It would probably be best used in prolonged low-dosage administration. It may, however, be more useful in combination with other agents.

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Biaxin, Low dose Thalidomide, and dexamethasone are highly active in Waldenstrom's macroglobulinemia and Multiple Myeloma
Morton Coleman, MD, Cornell University, New York, NY

Thalidomide, when used alone, does give a few responses in multiple myeloma patients. But it is not a comfortable regimen, and most responses are not startling -- though in one study two (2) subjects did show greater than ninety percent (90%) response.

It is also known that biaxin, an antibiotic, produced some positive results, though not in patients who had developed resistance to prior chemotherapy regimens. So a decision was made to try a triple cocktail. We would combine biaxin, a low dose of Thalidomide (thus hopefully avoiding some of its less comfortable side effects) and dexamethasone(a corticosteroid).

Fifty-five (55) patients were recruited for this study, of whom six (6) had not MM but WM, Waldenstrom's macroglobulinemia. Sixteen percent (16%) were previously untreated; most of the rest had been heavily treated in the past. Thirty-one (31) were male, twenty-four (24) female. Ten were under fifty-five (55) years of age, twenty-one (21) were in the age range 55-69, and twenty-four (24) were older. Forty (40) of those patients were evaluated, the rest either withdrawing, being wrongly diagnosed, or otherwise unevaluable. Thirteen percent (13%) showed complete remission, forty percent (40%) were near complete remissions (still had a monoclonal spike, but normal immunoglobulin levels), thirteen percent (13%) had major response (75% or better reduction in monoclonal immunoglobulin), twenty-seven percent (27%) showed partial response with over fifty percent (50%) immunoglobulin reduction, and three individuals did not respond. Improvement in hemoglobin and bone marrow generally mirrored these results. There was relatively little toxicity.

Since the completion of this study, ten (10) WM patients have been treated with this BLT-D regimen. All had received prior therapy. Roughly eighty percent (80%) responded, results being roughly comparable to those in the prior group. There has been slightly more nerve damage.

This is by nature an ongoing procedure. Thalidomide must be taken daily, the others weekly or so, or relapse can be expected in about five (5) weeks. It is also toxic. Eventually every patient shows neuropathy (nerve damage). There is some blood clotting, and heart rhythm problems. In sum, the BLT-D regimen is more effective than the sum of the individual drugs if taken alone; but it is also more toxic than any by itself.

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