Abstract
Introduction: Thalidomide is usually administered orally continuously once daily and has shown remarkable activity in about 30% of patients with heavily pretreated multiple myeloma (MM). Moreover, there is considerable interest in the administration of thalidomide-containing combinations as primary treatment of MM. With such regimens at least 60% of patient achieve an objective response. Thalidomide can cause a variety of side effects whose incidence and severity may be related to the maximum dose and duration of thalidomide treatment. Furthermore, this drug may be poorly tolerated by older patients. We designed a phase II study for the primary treatment of elderly patients (≥ 75 years of age) with MM which was based on intermittent oral administration of melphalan, thalidomide and dexamethasone.
Patients and Methods: This ongoing multicenter study was initiated in February 2003 and includes patients with symptomatic myeloma ≥75 years of age regardless of performance status, renal function, and comorbidities. Treatment consists of melphalan (M) 8mg/m2 days 1–4, dexamethasone (D) 12mg/m2 p.o. after breakfast on days 1–4 and 14–18 and thalidomide (T) 300 mg p.o. at bedtime on days 1–4 and 14–18. This regimen is repeated every 5 weeks for 3 courses. Patients without evidence of progressive disease are scheduled to receive 9 additional courses of MDT (but without DT on days 14–18) every 5 weeks.
Results: As of July 2004, 43 patients have been enrolled. Their median age is 78 years (range: 75 to 85 years). Features of advanced myeloma are frequent and include International Staging System (ISS) 3 in 58%, hemoglobin <8.5g/dl in 13%, calcium >11.5 in 15%, creatinine > 2 mg/dl in 28% and elevated serum LDH in 11%. On an intent-to-treat basis, 72% of patients achieved at least a partial response (EBMT criteria) including 10% of patients who achieved a complete response with negative immunofixation. Median time to 50% reduction of monoclonal protein was 2 months (range 0.5 to 5.5). Grade 3 or 4 granylocytopenia and thrombocytopenia occurred in 15% and 10% of patients respectively. Twelve episodes of infections were noted one of which was fatal. Several patients developed thalidomide-related side effects, usually of mild or moderate degree, such as constipation (30%), somnolence (35%), tremor (25%), xerostomia (15%), headache (10%). Deep venous thromosis (DVT) and peripheral neuropathy occurred in 10% of patients each. With a mean follow-up of 15 months, 88% of patients remain alive.
Conclusions: This is one of few prospective studies designed for myeloma patients with advanced age (≥75 years) ie patients who are frequently excluded from trials. The pulsed MDT regimen appears to be a well tolerated and active primary treatment for elderly patients with multiple myeloma. The incidence of DVT and of peripheral neuropathy appears lower than that seen when thalidomide is administered continuously. Patient accrual and follow-up is ongoing in order to assess the impact of this regimen on response duration and survival.
Bortezomib Induced Paralytic Ileus: Are we Aware?
