Two Studies Solidify Thalidomide’s Value in Managing Multiple Myeloma

NEW ORLEANS—Thalidomide’s value in managing multiple myeloma has been solidified by reports from two cancer centers presented at the ASH meeting.

Thalidomide is “the first agent in years to get a response in multiple myeloma, and a durable remission in a significant percentage of patients,” noted Ramen Desikan, MD, of the of the Myeloma and Transplantation Research Center, University of Arkansas for Medical Sciences in Little Rock. Dr. Desikan explained that thalidomide has a number of antitumor properties, including the potential to reduce microvessel density (shown to be associated with survival in multiple myeloma), to effect immune modulation, and to alter adhesion molecules and cytokine effects.

Dramatic responses are possible, he said, describing a patient with refractory disease who had achieved less than a partial remission with intensive treatment supported by both autologous and allogenic stem cell transplants. After disease progression, the patient was treated with salvage chemotherapy and then alpha-interferon, which did not alter the disease course. He was then started on thalidomide and responded well, with serum IgA dropping from 8,000 mg/dL to less than 400 mg/dL with this therapy, Dr. Desikan reported. Bone marrow from this patient showed reduction in plasmacytosis and decreased microvasculature. “Following this, we evaluated thalidomide seriously as a phase II agent,” Dr. Desikan explained.

Phase II Study

The study enrolled 180 patients with advanced multiple myeloma from December 1997 to May 1999 at a dose schedule of 200 mg p.o. daily with escalation by 200 mg every 2 weeks to a maximum dose of 800 mg. Three-quarters of patients achieved the third dose level and half achieved the full dose.

Pertinent patient and disease characteristics were as follows:

mean age 58 years, with a range of 35 to 80 years, and 40% over 60;

B2 microglobulin 3.1 mg/L (median), but very high in 23%;

C-reactive protein 0.9 mg/L (median);

creatinine 1.1 mg/dL (median);

median duration of prior standard therapy 36 months;

bone marrow plasmacytosis > 30% in 28% of patients;

abnormal cytogenetics in 67%, including chromosome deletion 13 in 42%; and

prior high-dose therapy in 77%, including 53% with tandem transplants.

The total response rate (at least 25% tumor regression)was 36% (64 of 180 patients). This included complete responses in four patients, and maximum paraprotein responses by at least 90% in 18 patients, by 75% in 14 patients, by 50% in 16 patients, and by 25% in 13 patients. Minimal levels of response were observed in 36% of the patients, at a median time to response of 1 month; at least 50% paraprotein response (achieved in 30%) was noted at 2 months median. For a drop of 75%, patients needed to be treated for 3 months. “In a sense, you have to be on this drug long enough before abandoning this treatment,” emphasized Dr. Desikan.

Paraprotein Responses

Paraprotein responses were associated with resolution of bone marrow plasmacytosis in 60% of patients who had at least a 90% paraprotein reduction; only 34% of patients achieving a lesser paraprotein response had resolution of plasmacytosis (P = .03).

Additionally, there were significant increases in hemoglobin and declines in creatinine among paraprotein responders. Bone marrow microvessel density declined significantly in patients achieving at least 90% paraprotein reduction (P = .02) whereas changes in nonresponders were not significant.

Forty-nine of the 180 patients are still enrolled in the study. Ninety-five have progressed, and 45 could not tolerate thalidomide. There were six deaths on the study, one possibly related to toxicity. Most toxicities were grades 1 and 2 and were easily reversed. These were mainly somnolence, fatigue, and constipation. Since myelosuppression was virtually absent, thalidomide may potentially be combined with chemotherapy, Dr. Desikan pointed out.

With a median follow-up of 8 months, the median event-free survival was 5 months and overall survival was 13 months. “Of note, more than 50% of responders are still free from progression (now at 13 months), so median time to disease progression has not been achieved,” he reported.

By multivariate analysis, patients with a low labeling index were more likely to respond to treatment than patients with a high labeling index. As for features predicting for outcome, higher bone marrow plasmacytosis and deletion 13 heralded an inferior outcome.

Activity Confirmed

A study from M.D. Anderson Cancer Center in Houston also confirmed the activity of thalidomide in resistant myeloma with modest side effects and showed improved results with the addition of dexamethasone.

Donna M. Weber, MD, reported on 22 patients with primary refractory disease and 22 patients with refractory relapse. Patients received 200 mg daily, escalating in 200-mg increments every 2 weeks to 800 mg. Patients were treated for 3 months unless there was clear and rapid disease progression. Before receiving thalidomide, patients were resistant to pulse dexamethasone alone, cyclophosphamide (Cytoxan, Neosar) with pulse dexamethasone (Ak-Dex, Dalalone, Decadrol), hyperCVAD (twice daily cyclophosphamide, vincristine [Oncovin], Adriamycin [doxorubicin], and dexamethasone), or myeloablative therapy with autologous stem cell transplant.

Partial response was defined as a reduction of 50% or more in serum myeloma protein and/or a 75% reduction in Bence Jones protein. This was achieved in 7 of 22 patients (32%) with primary resistant disease and 4 of 22 (18%) with disease in refractory relapse. Nine additional patients had tumor mass reductions between 25% and 50%, and all responses occurred with doses of 400 mg or lower. The median time to remission was short (1.1 months), reported Dr. Weber.

Common Side Effects

Common side effects included constipation (66%), sedation (60%), pruritic rash or dry skin (47%), numbness, tremor, mood change (38%), and edema (20%). Upper respiratory infection or pneumonia occurred in 16% and neutropenia in 13% of patients. Patients receiving more than 400 mg had approximately twice the incidence of side effects, she reported.

Twenty-seven of the 33 nonresponders were treated with a combination of daily thalidomide plus intermittent dexamethasone (20 mg/m² q.d. p.o. × 4 days on days 1-4, 9-12, 17-20. This combination produced responses in nine additional patients for an overall response rate to either thalidomide alone or to the combination with dexamethasone of 45% (20 of 44 patients).

Dr. Weber said future studies should focus on combinations of thalidomide with dexamethasone and other active agents, as well as treatment of patients with earlier phases of disease.