NEW ORLEANS—A combination of oral thalidomide(Drug information on thalidomide) (Thalomid) and dexamethasone(Drug information on dexamethasone) is sufficiently active in newly diagnosed multiple myeloma that current intravenous regimens are no longer required for most patients, S. Vincent Rajkumar, MD, associate professor of medicine, Mayo Clinic, Rochester, Minnesota, said at the 40th Annual Meeting of the American Society of Clinical Oncology (abstract 6508).
The logic of this phase III trial derived from a series of clinical studies that established the activity of thalidomide and dexamethasone as single agents in relapsed multiple myeloma, together with observed synergy of the two agents in preclinical studies. The activity of thalidomide is believed to reflect the importance of angiogenesis in myeloma, and the inhibitory role that thalidomide plays in this process.
Two smaller phase II trials with this drug combination, involving 50 and 40 patients, had shown response rates of 64% and 72%, respectively (Rajkumar et al: J Clin Oncol 20:1319, 2002; Weber et al J Clin Oncol 21:16, 2003). Accordingly, a phase III trial, E1A00, was organized under the aegis of the Eastern Oncology Cooperative Group, to compare the efficacy of the thalidomide/dexamethasone combination with that of dexamethasone alone, as first-line therapy.
In all, 207 patients newly diagnosed with multiple myeloma, symptomatic and untreated, were randomized to receive either thalidomide 200 mg/d plus dexamethasone 40 mg/d, on days 1-4, 9-12, and 17-20, or dexamethasone alone at the same dosage. Therapy was repeated monthly for a total of 4 months, at which time patients had the option of continuing the same dosing schedule or going off therapy to receive a stem cell transplant. All patients also received monthly bisphosphonate therapy—pamidronate (Aredia) or zoledronic acid(Drug information on zoledronic acid) (Zometa).
Response was defined as a 50% reduction in both serum and urine M protein levels within four cycles of treatment; in the event serum M protein levels were not measurable, response was defined as a 90% reduction in the urinary level.
At the time of the ASCO presentation, 196 patients were evaluable, with responses seen in 58 of 98 patients (59%) in the thalidomide/dexamethasone arm, compared with 40 of 98 patients (41%) treated with dexamethasone alone (P = .011). When including those patients for whom no urine measurements were made of the M protein, so that determinations had been made only on the serum levels, the response rates were 68% and 46%, in the presence and absence of thalidomide, respectively.
Response was rapid, with a median time of 1.1 months in both treatment arms. There were three complete responses in the thalidomide/dexamethasone arm, and none in the dexamethasone-alone arm. There were very few instances of disease progression during the 4-month treatment period, including 3% of patients receiving the combined therapy and 5% of those receiving dexamethasone alone.
A key cautionary note derived from the higher frequency of deep venous thromboses (DVTs grade 3 or higher) in the combined arm (16% vs 3% on dexamethasone alone). These bore no significant association with age, degree of response, or time during the treatment period. With respect to nonhematologic toxicities, 67% of patients on the combined arm experienced events of grade 3 or higher during the 4-month period, compared with 42% on dexamethasone alone. These toxicities were manageable, however, and did not result in a higher mortality rate (7% in the combined arm vs 11% in the dexamethasone-alone arm).
Dr. Rajkumar concluded that the trial provides solid evidence that combined thalidomide/dexamethasone treatment is an effective induction therapy in newly diagnosed myeloma, with responses superior to those characteristic of dexamethasone alone. These advantages, however, must be weighed against the higher frequency of DVTs seen with the combined treatment. Patients receiving this therapy should also receive routine anticoagulant prophylaxis, in the form of either low molecular weight heparin(Drug information on heparin) or full-dose coumadin, to reduce the probability of DVTs in this context.
Most importantly, both induction regimes showed sufficient efficacy as to obviate the need for traditional intravenous chemotherapies such as vincristine/Adriamycin/dexamethasone (VAD).
Future study will include further examinations of the dosage levels, particularly that of dexamethasone, to see whether equivalent efficacies can be achieved while reducing the incidence of adverse events. Also, thalidomide will be compared with a related compound, CC-5013, as agents in combined therapy with dexamethasone, since preliminary observations indicate that patients may vary in their relative responsiveness to these various combinations.
