Thalidomide (HAL) Maintenance Following High-Dose Melphalan with Autologous Stem Cell Transplant (ASCT) for Myeloma.

Background: High-dose chemotherapy with ASCT has improved survival in myeloma, but remains a non-curative therapy. Recent experience with THAL maintenance after ASCT has shown improvement in progression-free and event-free survival (Attal 2006). The tolerability and efficacy of maintenance THAL following high-dose melphalan with ASCT was investigated in this single institution study.

Methods: From May 2001 to March 2005, 38 myeloma patients were enrolled and treated with melphalan 200 mg/m² followed by ASCT. THAL was started on day 60 post-ASCT after recovery of blood counts (neutrophils ≥750 mm³/mL, platelets ≥20 k/μL), and was continued for 1 year. THAL was started at 50 mg/day, and escalated in 50 mg increments every 2 weeks to a maximum dose of 200 mg/day. Patients did not receive prophylactic anticoagulants while on THAL.

Results: The median patient age was 60, and 92% of patients had Durie-Salmon stage II or III disease at diagnosis (26% stage II, 66% stage III). Nine patients (24%) had previously been treated with THAL. The median time from diagnosis to transplant was 7.3 months. Of the 38 enrolled patients, 7 patients never received THAL for reasons including early progression (n=1), early toxic death (n=1), and patient refusal (n=5). Thirty-one patients received maintenance THAL and are considered evaluable for tolerability and efficacy. Only 10/31 evaluable patients achieved a dose of 200 mg/day and just 5 were able to maintain this dose for ≥75% of the planned treatment course. In fact, only 16/31 patients were able to tolerate THAL at a dose of ≥100 mg/day for ≥75% of the planned treatment course. Fourteen patients received <1 year of thal. The primary reasons for early discontinuation were sensory neuropathy and fatigue, and the median duration of treatment in these 14 patients was 5.2 months. Sensory neuropathy was the most commonly reported toxicity and reason for dose modification (1 grade 3 event, 17 ≤grade 2 events). Other reasons for discontinuation or dose modification included constipation, depression, and recurrent infections. No patient required discontinuation of THAL for hematologic toxicities and no thromboembolic complications were observed. A complete (CR) or near complete response (nCR) was achieved in 60% and 58% of patients at 2 months and 1 year post-ASCT, respectively. THAL maintenance improved responses post-ASCT in 9 of 31 patients (29%). At a median follow-up of 34 months, median PFS was 31.4 months, and median OS was 50.2 months (survival from date of transplant).

Conclusion: THAL maintenance at a goal dose of 200 mg/day was not feasible post-ASCT. Just 10/38 (26%) even achieved the goal dose and only 5/38 (13%) were able to maintain the goal dose. The major reason for intolerance was peripheral neuropathy. Our data suggest that 100 mg is a more reasonable goal dose post-ASCT. Recent data in relapsed myeloma show similar survival with high-dose (400 mg/day) vs. low-dose (100 mg/day) THAL (Yakoub-Agha 2006), and support the concept of a lower maintenance dose post-ASCT.