Thalidomide Maintenance after Tandem Transplants Improves Survival in Myeloma
Thalidomide Maintenance after Tandem Transplants Improves Survival in Myeloma
Abstract & Commentary
By Andrew S. Artz, MD, MS, Section of Hematology/Oncology, University of Chicago. Dr. Artz reports no financial relationship to this field of study.
Synopsis: An increasing number of active therapies have become available for multiple myeloma in addition to high dose chemotherapy followed by autologous transplant (ASCT). This three-arm randomized trial compared, to pamidronate, to thalidomide and pamidronate, against no therapy as maintenance after a second ASCT. In the 597 randomized patients, all younger than 65 years of age, responses (CR + VGPR) were better in the thalidomide maintenance arm at 67% (P= 0.03) compared to 55 to 57% in the other cohorts. OS was also better at 87%, compared to 74 to 77% in the other groups (P < 0.04). Pamidronate did not reduce skeletal events. Thalidomide maintenance improved responses and survival in younger patients after tandem autologous transplant.
Source: Michel Attal, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294.
The therapeutic landscape for multiple myeloma has changed dramatically over the past decade from limited choices to an "embarrassment or riches." High-dose chemotherapy followed by autologous stem cell rescue (ASCT) plays a central role in eligible patients. It has a clear survival benefit, although the timing of ASCT, the need for single or double ASCT, and the value of maintenance treatment remain clinical challenges.1,2 Further, new agents such as thalidomide, lenalidomide, and bortezomib have considerable activity and the combination of various agents may enhance responses. Despite these advances, relapses eventually occur in most patients, even after ASCT. Maintenance therapy after ASCT is one strategy to prolong responses or even eradicate the malignant clone. Prior studies on maintenance have been hampered by agents exhibiting modest activity, such as interferon or corticosteroids.
In this trial, Attal and colleagues evaluated maintenance thalidomide therapy after tandem ASCT. Between 2000 and 2003, the French intergroup enrolled 1019 patients younger than 65 years of age from 74 centers on two consecutive myeloma trials. Inclusion required at least one of two adverse prognostic factors of elevated Beta-2-microglobulin or deletion of chromosome 13. Induction therapy consisted of continuous infusion VAD (vincristine, doxorubicin and dexamethasone) every 3 weeks for 3 to 4 cycles. Patients with a preserved performance status underwent tandem ASCT after high dose melphalan chemotherapy using 140 mg/m2 before the first ASCT and 200 mg/m2 before the second ASCT.
Two months after the second ASCT, the 597 (77%) patients without progressive disease were randomized to one of three arms: no maintenance (group A), pamidronate monthly (group B), pamidronate monthly and thalidomide at 400 mg daily (group C) without thromboembolic prophylaxis. Thalidomide was discontinued due to toxicity in 39% at a median of 8 months. Thrombosis was rare and did not differ among groups.
At randomization (after tandem ASCT), the response rates prior to maintenance were similar across study arms at 47% to 50% CR/VGPR (very good partial response) and 39% to 42% PR. The thalidomide arm showed the best improvement in CR, enabling 67% to achieve a CR/VGPR compared to 55% in arm A and 57% in arm B (P = 0.03). The thalidomide cohort also experienced improved relapse-free survival (P = 0.003) and overall survival (P = 0.04). The actuarial four year survival was 75% (70%-82%) without thalidomide and 87% (80%-93%) with thalidomide after randomization. Salvage therapies and survival after relapse were fairly similar at about 73% to 78% at one year after relapse. Although the survival benefit persisted in most subgroups, thalidomide did not appear to afford a survival benefit for baseline deletion of chromosome 13 (P = 0.2) and those in CR at randomization. Skeletal events appeared similar in all arms at 24% in group A, 21%, in Group B, and 18% in Group C (P = 0.4).
Commentary
This well-designed trial demonstrates a benefit in responses and overall survival for thalidomide maintenance after tandem ASCT. The results contrast with another recently published study by Barlogie and colleagues using thalidomide and tandem ASCT. In that randomized study, active treatment entailed thalidomide not only for maintenance but also during the entire period before and after ASCT. Thalidomide was continued until toxicity or disease progression. Thalidomide improved response rates and event free-survival but did not benefit overall survival.3 The difference may relate to increased toxicity of administering thalidomide during chemotherapy.
Thalidomide tolerance is a major issue as the drug may lead to somnolence, fatigue, constipation, peripheral neuropathy and venous thrombosis. It was reassuring that using thalidomide, the thrombosis risks was low, even without prophylaxis. Presumably, this relates to administering it as monotherapy as opposed to during other chemotherapy and/or corticosteroids, where the risk may be higher. Nevertheless, 39% discontinued the drug due to peripheral neuropathy and the mean dose used was 200 mg/day for a mean of 15 months, indicating the 400 mg starting dose frequently required reduction.
Several additional limitations must be considered. First, induction therapy consisted of VAD. Whether the use of other more active agents for induction will mitigate the benefit of thalidomide maintenance after ASCT can not be determined. Second, a tandem ASCT is often reserved for incomplete responses or progression after the first ASCT. Should thalidomide maintenance have a role after a first ASCT when the second ASCT is not immediately planned? Finally, the results, albeit positive, also underscore limitations in efficacy of this approach. The survival curve did not "plateau," implying tumor control, rather than complete eradication, and the subset harboring a deletion of chromosome 13 did not appear to benefit.
The results clearly point to alternative strategies of testing agents that have a better toxicity profile and activity against deletion of chromosome 13 such as lenalidomide and bortezomib.4 The promising findings also suggest it is a viable strategy to incorporate active agents and high-dose chemotherapy with autologous transplant to improve outcome.
References
1. Attal M, et al. A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. N Engl J Med. 1996;335:91-97.
2. Blade J, et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood. 2005;106:3755-3759.
3. Barlogie B, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-1030.
4. Richardson PG, et al. A phase 2 study of bortezomib in relapsed, refractory myeloma. N Engl J Med. 2003;348:2609-2617.
An increasing number of active therapies have become available for multiple myeloma in addition to high dose chemotherapy followed by autologous transplant (ASCT).Subscribe Now for Access
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