1 Oncology Research Unit and 2 Department of Hematology, Oncology Hospital National Medical Center, México, D.F. Mexico
* Correspondence to: Dr A. Avilés, Plaza Luis Cabrera 5-502, Colonia Roma, 06700, México, D.F. Mexico. Tel: +52-55-5627-6959; Fax: +52-55-5761-0952; Email: agaviles{at}avantel.net
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Abstract |
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Patients and methods: Thirty-six patients, previously untreated with diagnosis of multiple myeloma were enrolled to received the DAI regimen (dexamethasone 30 mg/m2, i.v., days 14, all-trans-retinoic acid 45 mg/m2, p.o., days 514 and interferon alpha 2a, 4.5 MU s.c., days 514) administered every 28 days for six cycles before high-dose chemotherapy (melphalan 200 g/m2) and autologous stem cell transplantation.
Results: Overall response was observed in 29 cases (80%), complete response in 19 and partial response in 10 patients. Five patients were >65 years old and were treated with dexamethasone/thalidomide. Twenty-four patients underwent transplants. At a median follow-up of 31.6 months, no relapse or disease progression was observed, thus actuarial curves at 3-years showed that event-free survival was 86% and overall survival was 94%. Toxicity was mild.
Conclusions: This regimen appears to be an excellent alternative as cytoreductive treatment before high-dose chemotherapy and autologous stem cell transplantation with excellent overall response and minimal toxicity. Controlled clinical trials are warranted to define the role of this new therapeutic approach.
Key words: all-trans-retinoic acid, dexamethasone, interferon, multiple myeloma
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Introduction |
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Biological modifiers, such as interferon, have proven to be useful as maintenance therapy, offering improvement in relapse free-survival, but not in overall survival. Retinoids that have a different mechanism of action have been employed in a small number of studies. However, when interferon has been employed with retinoids, the combination has been shown to be active against myeloma cells in vitro, with different and most cases synergy between mechanism of action [38
]. However, the use of these drugs in combination are limited and results are not definitive [9
11
]. Dexamethasone is one of the most useful drugs in the treatment of patients with multiple myeloma and, in combination with interferon and retinoids, can offer a new therapeutic schedule, because the combination shows a low toxicity profile. For this reason we developed a regimen that combined retinoids, interferon and dexamethasone in an attempt to maintain clinical effect while reducing acute and late toxicity. In patients with refractory multiple myeloma this combination showed an excellent clinical profile, with >75% of patients achieving a response [12
] and 14% of patients alive and in remission >5 years after therapy was administered (data not shown). Toxicity of this drug combination was mild, all patients received the planned dose and no delay was observed, thus we started a phase II study in naïve patients as cytoreductive regimen before transplant procedures.
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Patients and methods |
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Patients were scheduled to received six monthly cycles of the following DAI program: dexamethasone, 30 mg/m2, i.v., days 14; all-trans-retinoic acid, 45 mg/m2, p.o., days 514; interferon alpha 2a, 4.5 MU, s.c., days 514. For response criteria we adopted the criteria suggested by the Subcommittee of the European Group for Blood and Marrow Transplant [14]. Patients received support (radiotherapy, pain management, hypercalcemia) according to each case. Patients with complete and partial responses and <65 years old proceeded to blood stem cell mobilization with cyclophosphamide 2 g/m2 and granulocyte colony-stimulating factor. High dose chemotherapy, melphalan 200 mg/m2, was employed as myeloablative regimen. No further treatment was employed.
Statistical analysis
The EFS estimated from complete response was documented until relapse, progression of disease or death due to tumor progression or treatment; overall survival was considered from diagnosis to death due to any cause. No attempt was made to evaluate prognostic factors because the population was uniform.
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Results |
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Discussion |
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In this study we confirm that the DAI regimen can achieve an excellent response with minimal toxicity even in older patients (>65 years old). We agree that the VAD regimen appears to be the most common cytoreductive therapy; however, acute hematological toxicity and late neurological and cardiac toxicity limit the use of VAD in multiple myeloma. Other cytotoxic regimens have been reported and all showed different grades of toxicity that required hospitalization, use of antibiotics and affected quality of life [2, 15
]. The DAI regimen was well tolerated, with no hematological, cardiac or neurological toxicity observed >3 years after treatment. Moreover, the number of cells collected for transplant was excellent and complete hematological recovery was observed between 18 and 30 days (median 21 days). We conclude that the DAI regimen is a good option for the treatment of patients with multiple myeloma and that controlled clinical trials comparing this regimen with other cytoreductive therapies are necessary. Our institution has already begun a controlled clinical trial comparing the DAI regimen with VAD chemotherapy.
Received for publication February 29, 2004. Revision received June 20, 2004. Accepted for publication September 16, 2004.
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References |
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