RESUMEN
Melphalan plus prednisone (MP) has long been considered the gold-standard treatment for elderly patients with newly diagnosed myeloma, and it still forms the backbone for combinations based on novel agents. MP plus thalidomide (MPT), bortezomib (VMP), or lenalidomide (MPR), as induction plus maintenance, have proved to be superior to MP and are currently the treatment of choice for this population. Low-dose dexamethasone in combination with thalidomide and cyclophosphamide (CTDa) or with lenalidomide can be an alternative option for these patients. The benefit of these novel agents in terms of prolonged survival is accompanied by increases in treatment-related adverse events, however, which may be particularly pronounced in older individuals. In managing these patients, efficacy and toxicity should be balanced, and thus prophylactic measures to avoid adverse effects are mandatory. Moreover, reduced-intensity regimens are recommended for fragile or very elderly patients. Finally, the wide array of new treatment options will facilitate individualized treatment approaches, based on characteristics of the disease, patient comorbidities, and personal and social circumstances.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Ácidos Borónicos/administración & dosificación , Bortezomib , Ciclofosfamida/administración & dosificación , Dexametasona/administración & dosificación , Humanos , Lenalidomida , Melfalán/administración & dosificación , Mieloma Múltiple/diagnóstico , Prednisona/administración & dosificación , Pirazinas/administración & dosificación , Talidomida/administración & dosificación , Talidomida/análogos & derivados , Resultado del TratamientoRESUMEN
Multiple myeloma (MM) is an heterogeneous disease and this concept, together with the recent discovery of new drugs with novel mechanisms of action, will lead to the design of individualized treatments. The term "high-risk MM" includes those patients with at least one of the following features: deletion of 17p or t(4;14) or t(14;16), detected by fluorescence in situ hybridization analysis; deletion of 13q detected by conventional cytogenetics; or hypodiploidy or complex karyotype. In addition, patients with high proliferative activity of plasma cells (> or = 3%) measured by the PC labeling index or S-phase by flow cytometry as well as those with a poor response to induction therapy are also high risk. The definition of high-risk MM has been based on patients treated with conventional drugs with or without autologous transplant. However, current data suggest that novel agents can overcome the initial adverse prognosis of deletion 13q and t(4;14) but probably not that of 17p deletion, at least when using immunomodulatory drugs. Nevertheless, the number of patients analyzed is rather limited and, more important, time to progression is only available in a small number of studies. On the basis of these data, it is probably premature to mandate specific therapies on the basis of cytogenetic abnormalities. Moreover, it is possible that the more intensive therapies selected for high-risk patients may be of even greater benefit to standard-risk cases. Accordingly, at present, although we discourage treatment of high-risk patients with conventional schedules, we recommend to include them in large cooperative trials based on novel agents and performing a comprehensive genetic analysis up-front, so that the patients benefiting most from each treatment can subsequently be identified.
Asunto(s)
Mieloma Múltiple/tratamiento farmacológico , Inhibidores de la Angiogénesis/uso terapéutico , Antibióticos Antineoplásicos/uso terapéutico , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Ácidos Borónicos/uso terapéutico , Bortezomib , Doxorrubicina/uso terapéutico , Perfilación de la Expresión Génica , Humanos , Lenalidomida , Mieloma Múltiple/genética , Mieloma Múltiple/inmunología , Mieloma Múltiple/terapia , Pronóstico , Inhibidores de Proteasas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirazinas/uso terapéutico , Medición de Riesgo , Talidomida/análogos & derivados , Talidomida/uso terapéuticoRESUMEN
Despite recent progress in its treatment, multiple myeloma (MM) remains incurable, thus necessitating identification of novel anti-MM agents. We report that the marine-derived cyclodepsipeptide Aplidin exhibits, at clinically achievable concentrations, potent in vitro activity against primary MM tumor cells and a broad spectrum of human MM cell lines, including cells resistant to conventional (e.g., dexamethasone, alkylating agents, and anthracyclines) or novel (e.g., thalidomide and bortezomib) anti-MM agents. Aplidin is active against MM cells in the presence of proliferative/antiapoptotic cytokines or bone marrow stromal cells and has additive or synergistic effects with some of the established anti-MM agents. Mechanistically, a short in vitro exposure to Aplidin induces MM cell death, which involves activation of p38 and c-jun NH(2)-terminal kinase signaling, Fas/CD95 translocation to lipid rafts, and caspase activation. The anti-MM effect of Aplidin is associated with suppression of a constellation of proliferative/antiapoptotic genes (e.g., MYC, MYBL2, BUB1, MCM2, MCM4, MCM5, and survivin) and up-regulation of several potential regulators of apoptosis (including c-JUN, TRAIL, CASP9, and Smac). Aplidin exhibited in vivo anti-MM activity in a mouse xenograft model. The profile of the anti-MM activity of Aplidin in our preclinical models provided the framework for its clinical testing in MM, which has already provided favorable preliminary results.
Asunto(s)
Depsipéptidos/farmacología , Depsipéptidos/uso terapéutico , Mieloma Múltiple/tratamiento farmacológico , Animales , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/fisiología , Línea Celular Tumoral , Supervivencia Celular/efectos de los fármacos , Técnicas de Cocultivo , Depsipéptidos/administración & dosificación , Depsipéptidos/aislamiento & purificación , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Humanos , Factor I del Crecimiento Similar a la Insulina/farmacología , Interleucina-6/farmacología , Ratones , Ratones SCID , Mieloma Múltiple/genética , Mieloma Múltiple/patología , Análisis de Secuencia por Matrices de Oligonucleótidos , Péptidos Cíclicos , Agua de Mar , Células del Estroma/efectos de los fármacos , Células del Estroma/fisiología , Factores de Tiempo , Resultado del Tratamiento , Urocordados/química , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
BACKGROUND: In the United States, darbepoetin alfa (Aranesp) is often used to treat patients with chemotherapy-induced anemia using weekly or every-2-week administration schedules. In Europe, darbepoetin alfa is used either weekly or in every-3-week dosing. The every-3-week schedule can be synchronized with many chemotherapy regimens, resulting in fewer visits and reducing burden to patients, but the safety and efficacy of this regimen have not been clear. METHODS: A randomized, double-blind, double-dummy, active-controlled phase 3 trial was performed in 110 European centers. Eligible patients (age > or = 18 years) were anemic (hemoglobin level < 11 g/dL), had a nonmyeloid malignancy, and were to receive at least 12 weeks of chemotherapy. Patients were randomly assigned 1:1 to darbepoetin alfa treatment every 3 weeks (500-microg dose) or weekly (2.25-microg/kg) for 15 weeks. We compared red blood cell transfusion incidence among the two arms from week 5 to the end of the treatment phase using a noninferiority study design. Noninferiority was determined if the upper limit of the 95% confidence interval (CI) for the difference in blood transfusions between groups, calculated using Kaplan-Meier methods, did not exceed 12.5%, a margin based on previous placebo-controlled studies. RESULTS: A total of 705 patients were randomly assigned, and 672 remained in the study at week 5. Fewer patients in the every-3-week arm than in the weekly arm received blood transfusions from week 5 to the end of the treatment phase (unadjusted Kaplan-Meier estimates = 23% versus 30%, difference = -6.8%; 95% CI = -13.6 to 0.1). Percentages of patients achieving the target hemoglobin level (> or = 11 g/dL, consistent with evidence-based practice guidelines) were 84% (every 3 weeks) and 77% (weekly). The frequency of cardiovascular/thromboembolic adverse events was 8% in both groups, and safety was comparable. CONCLUSIONS: Patients with chemotherapy-induced anemia can safely and effectively be treated with 500 microg of darbepoetin alfa every 3 weeks.
Asunto(s)
Anemia Hipocrómica/inducido químicamente , Anemia Hipocrómica/tratamiento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Eritropoyesis/efectos de los fármacos , Eritropoyetina/análogos & derivados , Adulto , Darbepoetina alfa , Método Doble Ciego , Esquema de Medicación , Transfusión de Eritrocitos/estadística & datos numéricos , Eritropoyetina/administración & dosificación , Europa (Continente) , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
The aim of the present randomized trial was to compare high-dose therapy (HDT) with continued conventional chemotherapy in patients with multiple myeloma (MM) who responded to the initial treatment. From May 1994 to October 1999, 216 patients (122 men/94 women; stage II or III; Eastern Cooperative Oncology Group [ECOG] score less than 3) entered the study. Initial chemotherapy consisted of 4 cycles of alternating vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, Adriamycin, dexamethasone (VBMCP/VBAD). Responding patients were randomly assigned to receive 8 additional cycles of VBMCP/VBAD, intensification with melphalan 200 mg/m2, or melphalan 140 mg/m2 plus 12 Gy fractionated total body irradiation (TBI). One-hundred sixty-four patients were randomly assigned, 83 to continued chemotherapy and 81 to HDT. The complete remission (CR) rate was significantly higher with HDT (30% vs 11%; P = .002). However, progression-free survival (PFS) was not significantly different between HDT and conventional therapy (median, 42 vs 33 months; P = not significant [NS]), and overall survival (OS) was similar in both groups (median, 61 vs 66 months). Finally, survival after relapse was identical in the 2 arms (15.9 vs 16.4 months). In conclusion, these results show that HDT intensification, when given to myeloma patients who have responded to the initial chemotherapy, significantly increases the CR rate but has no significant impact on PFS or OS.