Lower-Dose Thalidomide Effective in Relapsed or Refractory Multiple Myeloma, With Less Toxicity

ATLANTA—For patients with refractory or relapsed multiple myeloma, a lower dose of thalidomide (100 mg/d) offers similar efficacy to the higher dose (400 mg/d), but with fewer side effects. Ibrahim Yakoub-Agha, MD, of CHRU Lille, France, reported the results of IFM-01-02 at the 47th Annual Meeting of the American Society of Hematology (abstract 364), for the Intergroupe Francophone du Myelome.

Thalidomide has widely demonstrated effectiveness in patients with relapsed or refractory multiple myeloma. In a prior study, Dr. Yakoub-Agha observed that a higher incidence of thalidomide-related toxicity greater than grade 2 was directly related to both thalidomide dose intensity and cumulative dose. At the same time, overall survival and event-free survival were not related to the mean-daily thalidomide dose received during the initial 90-day treatment period.

The current prospective study was conducted to test noninferiority for the 100 mg thalidomide dose as compared with the 400 mg/d dose, and to assess dose-related toxicities, Dr. Yakoub-Agha said. In addition, given the poor prognosis of relapsed or refractory myeloma patients and the known potentiation of thalidomide by dexamethasone (Dex), the study protocol called for administration of the Thal/Dex combination for treatment failure, defined as progression at any time or stable disease after 3 months of thalidomide. The primary endpoint was 1-year overall survival.

Dr. Yakoub-Agha noted that, after the interim analysis, the original 160 patient per arm sample size was expanded to 200 patients. Included patients (195 patients at 400 mg/d; 205 patients at 100 mg/d) had received at least two lines of prior therapy or one line with an alkylating agent in the absence of alternative treatment. Patients relapsing after one line of intensive treatment (at least one autograft) could also be enrolled.

Median age was 67.5 years, and median time from diagnosis to randomization was 30 months. More than half of patients had prior intensive treatment. More patients (about 43%) were in ISS [International Staging System] I, with about 30% in ISS II and III. Similar proportions of patients in both arms had chromosome 13 deletions (n = 209).

Study Results

Reporting the first data of the final analysis, Dr. Yakoub-Agha stated that the inferiority hypothesis for the 100 mg/d dose was rejected. Although dexamethasone was added to treatment significantly more often in the 100 mg/d group (109 patients vs 90 patients for the 400 mg/d arm), overall survival at 1 year was sim-ilar between groups (73% 3% for 400 mg/d vs 69% 3% for 100 mg/d).

Side effects favored the 100 mg/d group, with somnolence significantly lower overall (61% vs 74% for 400 mg/d, P = .004) and in grades 2-4 (13% vs 33%, P < .001). Similarly, peripheral neuropathy was lower for the 100 mg/d arm (overall 60% vs 74% 400 mg/d, P = .004; grades 2-4 19% vs 32%, P = .05). Constipation was also reduced in the 100 mg/d group.

Dr. Yakoub-Agha commented that similar rates of deep thrombosis (about 8%) in the two groups may have been attributable to the protocol requirement that patients with prior thrombosis receive systemic oral anticoagulation.

He concluded, "Thalidomide 100 mg/d is comparable in terms of survival with 400 mg/d (with dexamethasone as salvage therapy in case of treatment failure in both arms) in patients with relapsed or refractory multiple myeloma. It is also better tolerated than 400 mg/d, with less somnolence, constipation, and peripheral neuropathy."

To the audience question, "Would you recommend, outside of a clinical trial, to begin treatment right away with 100 mg Thal/Dex?" Dr. Yakoub-Agha answered, "Yes. I think that would now be the new treatment combination."