Thalidomide-Induced Sinus Bradycardia

Patients with early-stage myeloma are typically observed without therapy until symptomatic disease occurs. However, they are at high risk of progression to symptomatic myeloma, with a median time to progression of approximately 1-2 years. We report the final results of a phase II trial of thalidomide as initial therapy for early-stage multiple myeloma in an attempt to delay progression to symptomatic disease. In total, 31 patients with smoldering or indolent multiple myeloma were studied at the Mayo Clinic. Two patients were deemed ineligible because they were found to have received prior therapy for myeloma, and were excluded from analyses except for toxicity. Thalidomide was initiated at a starting dose of 200 mg/day. Patients were followed-up monthly for the first 6 months and every 3 months thereafter. Of the 29 eligible patients, 10 (34%) had a partial response to therapy with at least 50% or greater reduction in serum and urine monoclonal (M) protein. When minor responses (25-49% decrease in M protein) were included, the response rate was 66%. Three patients had progressive disease while on therapy. Kaplan-Meier estimates of progression-free survival are 80% at 1 year and 63% at 2 years. Major grade 3-4 toxicities included two patients with somnolence and one patient each with neuropathy, deep-vein thrombosis, hearing loss, weakness, sinus bradycardia, and edema. Thalidomide has significant activity in early-stage myeloma and has the potential to delay progression to symptomatic disease. This approach must be further tested in randomized trials.

Thalidomide was administered to 83 patients with myelodysplastic syndrome (MDS), starting at 100 mg by mouth daily and increasing to 400 mg as tolerated. Thirty-two patients stopped therapy before 12 weeks (minimum period for response evaluation), and 51 completed 12 weeks of therapy. International Working Group response criteria for MDS were used to evaluate responses. Intent-to-treat (ITT) analysis classified all off-study patients as nonresponders. Off-study patients belonged to a higher risk category (P =.002) and had a higher percentage of blasts in their pretherapy bone marrow than patients who completed 12 weeks of therapy (P =.003). No cytogenetic or complete responses were seen, but 16 patients showed hematologic improvement, with 10 previously transfusion-dependent patients becoming transfusion independent. Responders had lower pretherapy blasts (P =.016), a lower duration of pretherapy platelet transfusions (P =.013), and higher pretherapy platelets (P =.003). Among responders, 9 had refractory anemia (RA); 5 had RA with ringed sideroblasts; and 2 had RA with excess blasts. By ITT analysis, 19% of patients (16 of 83) responded, and when only evaluable patients were analyzed, 31% (16 of 51) responded. It was concluded that thalidomide, as a single agent, is effective in improving cytopenias of some MDS patients, especially those who present without excess blasts. (Blood. 2001;98:958-965)