The role of maintenance treatment with immunomodulatory drugs in multiple myeloma

Szpiczak plazmocytowy jest uważany za chorobę niewyleczalną. Nowoczesne leczenie indukujące w sekwencji z autologiczną transplantacją komórek krwiotwórczych pozwoliło jednak na znaczące wydłużenie przeżycia. Szansy na dalszy postęp w tym zakresie upatruje się w stosowaniu leczenia podtrzymującego z użyciem leków immunomodulujących. W badaniach nad długotrwałym stosowaniem talidomidu wykazano istotne wydłużenie czasu wolnego od progresji. Leczenie to obarczone jest jednak dużą częstością występowania działań niepożądanych, a zwłaszcza polineuropatii. W ostatnich miesiącach opublikowano wyniki trzech prospektywnych badań dotyczących stosowania lenalidomidu, spośród których w jednym wykazano korzystny wpływ na całkowite przeżycie, a we wszystkich – na przeżycie wolne od progresji. Dalsze analizy powinny być ukierunkowane na zdefiniowanie grup chorych, u których leczenie podtrzymujące może przenieść największą korzyść.Multiple myleoma is considered an incurable disease. However, the introduction of novel induction regimens followed by autologous hematopoietic stem cell transplantation significantly prolonged survival. Further improvement is expected with the introduction of maintenance treatment including the use of immunomodulatory agents. Studies on long-term use of thalidomide demonstrated its beneficial effect on progression-free survival. Unfortunately, the treatment was associated with increased risk of adverse events, in particular peripheral neuropathy. More recently, results of three trials regarding the use of lenalidomide have been published. One of them demonstrated advantage with regard to the overall survival, all three – prolongation of progression-free survival. Further efforts are needed to define subgroup of patients who benefit most strongly from the maintenance treatment

Chromosome 7 monosomy and deletions in myeloproliferative diseases

We studied deletion and monosomy of chromosome 7 in 150 patients with myeloproliferative diseases. We found 8/150 patients with monosomy 7 by cytogenetics and 4/150 with deletions of the long arm of chromosome 7 by restriction fragment length polymorphism (RFLP) analysis performed with Southern and polymerase chain reaction. To overcome limitation of RFLP analysis, we restricted loss of heterozygosity study with microsatellites to 45 patients, observing deletion 7q31.1 in 7/45 patients. In all patients with molecular alterations the deletion was observed only in myeloid cells, while the monosomy was detected in both myeloid precursor and lymphocytes. This finding suggests a CD34-totipotent stem cell origin for the monosomy and a colony forming unit - granulocyte, erythrocyte, monocyte, megakaryocytes (CFU-GEMM) stem cell origin for the deletions

The maintenance therapy in multiple myeloma

Multiple myeloma (MM) remains the incurable disease despite considerable progress in chemotherapy. Optimal way of maintenance treatment is still searching, which it would be maximally effective near acceptable toxicity. The hypothesis about possible successful maintenance therapy, which may improve survival of MM patients became more actual in the face of the incorporate to the studies with maintenance of a new drugs as: thalidomide, lenalidomide and bortesomib. The expectations on the essential progress to establish the optimal bortesomib-based regimen of the maintenance treatment in MM cause the results of the studies with its subcutaneous administration, which proved comparable efficacy with advantage in toxicity profile, especially neurological in comparison to classic intravenous way. The standard of the maintenance treatment for multiple myeloma patients is not established. Individual therapeutic approach after induction-consolidation phase using the most effective drugs is recommended in every case

Estudio epidemiológico para determinar la incidencia del mieloma y del mieloma quiescente, en el área norte de la provincia de Santa Cruz de Tenerife

El mieloma múltiple (MM) es el segundo cáncer hematológico más frecuente tras los linfomas, representando aproximadamente el 10% de las neoplasias sanguíneas y el 1% de todas las neoplasias1. La incidencia se sitúa en 5,8 casos por 100.000 habitantes/año2. La información sobre la epidemiología en España es escasa y hasta la fecha no se había analizado en nuestra provincia. Pacientes y métodos: Realizamos un estudio de todos los pacientes diagnosticados de MM en nuestra área de referencia, que incluye el norte de la isla de Tenerife y la totalidad de la isla de La Palma, con una residencia de al menos 2 años en dicha zona, entre 1990 y 2009. Recogimos variables demográficas, analíticas, de tratamiento y respuesta, diferenciándolos por municipios y tipo de mieloma, tanto sintomático como asintomático, y año de diagnóstico. Utilizamos el padrón anual de cada municipio para el cálculo de la incidencia. Resultados: Del total de 409 pacientes (203 hombres y 206 mujeres), 313 fueron sintomáticos y 96 fueron quiescentes (MQ) (29 de bajo riesgo y 49 de alto riesgo con 18 casos sin clasificar). La edad media fue de 68,4 años (± 0,568), con un rango comprendido entre 32 y 92 años. La mediana de la supervivencia global desde el diagnóstico (SV) fue de 44,97 meses ± 4,43 meses (IC 95% 36,28-53,65 meses) y desde el inicio de tratamiento (SV_T) de 33,39 meses ± 3,46 meses (IC 95% 26,6-40,17 meses). La mediana de la supervivencia libre de progresión desde el diagnóstico (SLP) fue de 22,47 meses ± 2,11 meses (IC 95% 18,32-26,61 meses) mientras que desde el tratamiento (SLP_T) fue de 16,15 meses ± 1,25 meses (IC 95% 13,70-18,60 meses). La mediana del tiempo de progresión a MM sintomático para los quiescentes de bajo riesgo fue de 48,29 meses ±8,13 meses (IC 95% 32,34-64,23 meses) mientras que para los de alto riesgo fue de 14,5 meses ±3,02 meses (IC 95% 8,58-20,43 meses) (p = 0,003).La SG del MQ de alto riesgo a partir del tratamiento no fue diferente a la del MM de novo (p = 0,267). La incidencia del área total en los 15 últimos años (datos más consistentes) es de 5,6 casos por 100.000 habitantes/año. La incidencia de la isla de La Palma es de 7,53 y la de Tenerife es de 5,14 (p = 0,0012). Teniendo los picos máximos en el año 2008 Tenerife (8,29) y en el año 2002 La Palma (15,99) aunque en ambas islas la tendencia de la incidencia agrupada por lustros es siempre ascendente. Dentro de la isla de Tenerife, el municipio de Tegueste y La Laguna presentan las incidencias más altas (8,64 y 5,10 respectivamente) mientras que en la isla de La Palma lo son Barlovento (12,05), Villa de Mazo (10,37) y Garafía (10,21). La última incidencia disponible obtenida del último lustro analizado es de 6,36 (5,89 en Tenerife y 8,39 en La Palma). (p= ) Conclusiones: El MQ de alto riesgo evoluciona mucho más rápido a sintomático y la supervivencia, una vez tratado, es similar al sintomático. Este hallazgo sugiriere que el mieloma quiescente de alto riesgo debiera ser asimilado, en términos pronósticos, al mieloma sintomático. La incidencia de MM en nuestra área es elevada, especialmente en la isla de La Palma. Las causas de esta incidencia tan elevada en algunos municipios de la provincia deberían ser estudiadas con más detalle

Trial efficacy vs real world effectiveness in first line treatment of multiple myeloma

Background: Large randomized clinical trials (RCT) are the foundation of the registration of newly developed drugs. A potential problem with RCTs is that the inclusion/exclusion criteria will make the population different from the actual population treated in real life. Hence, it is important to understand how the results from the RCT can be generalized to a general population. Aims: The primary aim of the present study was to assess the generalizability of the large 1st line RCTs in Multiple Myeloma (MM) to the Nordic setting and to understand potential difference and magnitude in outcomes between RCTs and patients treated in standard care in the Nordics. Methods: A retrospective analysis was performed on an incident cohort of 2960 MM-patients from 24 hospitals in Denmark, Finland, Norway and Sweden. The database contained information on patient baseline characteristics, treatments and outcomes. Data from relevant 1st line MM RCTs was selected from the treatment MP (Waage, A., et al., Blood. 2010], MPT (Waage, A., et al., Blood. 2010) and VMP (San Miguel, J.F., et al., N Engl J Med, 2008) and baseline characteristics were compared to newly diagnosed Nordic MM treated patients. Potential difference in response and overall survival (OS) was estimated by adjusting the RWE population to the RCT population using matching adjusted indirect comparisons. Patients were matched on age (median approximated to mean), gender, calcium, beta2-microglobulin and ISS score 3. These variables were selected because they were reported in all trials and have previously been identified as having prognostic value. Results: Patients in the Nordic database treated with MP (n=880) had a response rate of (PD, NR, PR, VGPR, ≥nCR) of (13%, 39%, 38%, 6%, 4%). After matching (n=347), the response rate was slightly worse (12%, 43%, 36%, 6%, 3%). This can be compared to the response rate from the RCT of (7%, 53%, 33%, 3%, 4%). OS for Nordic MP treated patients was 2.67 years (2.25-3.17). After matching the OS was 3.37 years (2.86-3.96) and this can be compared to the trial with OS 2.40 years (2.23-2.66). Patients treated with MPT (n=283) in the Nordic countries had a response rate of (5%, 14%, 52%, 20%, 9%). After matching (n=179) the response rate was slightly changed to (6%, 20%, 50%, 13% 11%). The corresponding RCT response results were 14%, 29%, 34%, 10%, and 13% respectively. OS for Nordic MPT treated patients was 4.15 years (3.73- 4.74). After matching the OS was 4.28 years (3.98-NA) years and compared to 2.42 years (2.08-3.17) OS observed in the corresponding trial. Patients treated with VMP (n=59) in the Nordic countries had a response rate of (4%, 5%, 40%, 18%, 33%). After matching (n=31) the response rate was improved to (8%, 11%, 28%, 8%, 45%). This corresponding response rates shown in the trial are 1%, 23%, 33%, 8%, and 33% respectively. OS for Nordic MP treated patients was 4.86 years (3.79-NA). After matching the OS was 4.86 years (4.86-NA) and this can be compared to the trial with OS 4.70 years. Summary and Conclusions: Surprisingly Nordic treated MM patients do very well compared to, and even better than, patients treated in RCTs. Since the OS for all tested treatments improves after matching to the RCT baseline characteristics, patients recruited to the RCTs seems to be a bit better than ordinary Nordic patents. The database used in the present study, and the used method, can be valuable for generalizing the results to the Nordic setting and estimating potential difference for future RCTs and Nordic MM treated patients. Future research should include different data cuts to see whether the analyses are biased by differences subsequent treatments applied in RCTs and clinical practice

Micro-costing study of rituximab subcutaneous injection versus intravenous infusion in dutch setting

Background: Rituximab for subcutaneous (SC) administration has recently been approved for use in common forms of diffuse large B-cell lymphoma (DLBCL). This form of rituximab is supplied in ready-to-use vials that do not require individual dose adjustment. It is expected that SC-injection will shorten the treatment time per administration of rituximab in comparison with currently available intravenous (IV) infusion. Aims: The goal of this study is to identify and compare all direct costs of IV and SC rituximab given to the DLBCL patients in the Netherlands. Methods: Using a prospective, observational, bottom up, micro-costing study we collected primary data on the direct medical costs of the preparation, administration and acquisition of rituximab. Drug costs and spillage, labor costs, material costs and remaining daycare costs were identified using standardized forms, structured using guideline prices and compared for the IV and SC forms of rituximab. Results: Measurements were done on 53 administrations (33 IV and 20 SC). The mean total costs of the IV infusion were €2174, and €1907 for the SC injection. The estimated difference of €267 per administration was mainly due to spillage costs and differences in chair time, related daycare costs and drug costs. Summary and Conclusions: Rituximab administered in the form of SC injection is less costly than its IV form. Taking into account their equal effectiveness, favorable pharmacoeconomic profile of SC rituximab can result in significant savings when transferred to the total DLBCL population in the Netherlands

90y-ibritumomab tiuxetan as consolidation therapy after autologous stem cell trasplantation in aggressive non-Hodgkin lymphoma

Targeted radioimmunotherapy with 90Y-labeled ibritumomab tiuxetan is a novel therapeutic approach for CD20-positive relapsed or refractory non-Hodgkin lymphoma (NHL). Methods: Seven consecutive patients with CD20-positive aggressive NHL who did not fully respond to prior myeloablative chemotherapy were enrolled. A 14.8 MBq (0.4 mCi)/kg dose of 90Y-ibritumomab tiuxetan was administered to all patients, and approximately 100 d afterward 18F-FDG PET/CT was performed to assess response. Results: PET/CT showed a complete response in 5 of 7 patients. Of the 2 nonresponsive patients, 1 showed persistent disease and the other progression. Toxicity included thrombocytopenia in all 7 patients and grade IV neutropenic fever in 1 patient. Conclusion: Despite the small series studied, we suggest that radioimmunotherapy is safe for consolidation in patients treated with high-dose chemotherapy for aggressive NHL and may provide clinical benefit in extensively pretreated patients