Timing of Second Autologous Transplantations in Multiple Myeloma: Results of a Multicenter Sequential Randomized Clinical Trial.

Background: Autologous stem cell transplantation (ASCT) is now considered standard therapy in young patients (<65 years) with multiple myeloma (MM). The Intergroupe Francophone du Myelome conducted a randomized trial of the treatment of MM with high-dose chemotherapy followed by either one or two successive ASCTs. The probabilities of event-free-survival and overall survival were doubled with a double transplant. However, no randomized trial has compared tandem transplant up-front with a strategy including planned second ASCT at relapse or progression. Therefore, we performed a multicenter, sequential, randomized trial designed to assess the optimal timing of a second ASCT.

Methods: From May 2003 to April 2006, 140 patients with symptomatic MM (de novo) and less than 60 years of age, were randomly assigned to receive either tandem transplantation up-front (within 6 months of the first transplantation) [Arm A, n=69] or one ASCT followed by a consolidation therapy with thalidomide (day +90, 100 mg/per day during 5 months) [Arm B, n=71]. Patients included in the arm B received a second transplant in case of disease progression on consolidation therapy, or in case of relapse in responders. Clinical characteristics of each group were similar. In both arms of the study, ASCT was preceded by first-line therapy with thalidomide-dexamethasone and subsequent collection of peripheral blood stem cells with high-dose cyclophosphamide (4 g/m²) and G-CSF. Data were analyzed on an intent-to-treat basis.

Results: With a median follow-up of 23 months (range: 6–34), the 2-year overall survival was 55% in the arm A and 75% in the arm B. Survival curves were not different (P=0.28, log-rank test). The 2-year event-free survival was 41% in the arm A and 60% in the arm B (P=0.4, log-rank-test). In the arm B, relapse-free survival of ≥ 16 months following the first transplantation was an important predictor of overall survival (p< 0.001).

Conclusion: Data from the present study suggest that up-front single ASCT followed by a consolidation therapy with thalidomide and a second ASCT after relapse or progression is a safe and effective global strategy to treat MM patients. Longer follow-up is needed before definite conclusions can be given concerning the optimal timing of second autologous transplantations in patients with MM.