Effect of CXCR4 on the Treatment Response and Prognosis of Carfilzomib in Multiple Myeloma / 中国实验血液学杂志

OBJECTIVE@#To explore the effect of CXCR4 on the treatment response and prognosis of Carfilzomib (CFZ) in multiple myeloma.@*METHODS@#Dataset GSE69078 based on microarray data from two CFZ-resistant MM cell lines and their corresponding parental cell lines (KMS11-KMS11/CFZ and KMS34-KMS34/CFZ) were downloaded from Gene Expression Omnibus (GEO). Differentially expressed genes (DEGs) were identified, and Protein-protein interaction (PPI) network was established to identify the key genes involved in CFZ resistance acquisition. Finally, the prognostic roles of the CFZ risistance key genes in MM using MMRF-CoMMpass data study was verified.@*RESULTS@#44 up-regulated and 46 down-regulated DEGs were identified. Top 10 hub genes (CCND1, CXCR4, HGF, PECAM1, ID1, HEY1, TCF4, HIST1H4J, HIST1H2BD and HIST1H2BH) were identified via Protein-protein interaction (PPI) network analysis. The CoMMpass data showed that high CXCR4 expression showed correlation to relative higher relapse and progress rates and the overall survival was significant decreased in high CXCR4 patients (P=0.013).@*CONCLUSION@#CXCR4 perhaps plays a crucial role in CFZ acquired resistance, which might help identifying potential CFZ-sensitive patients before treatment and providing a new therapeutic target in CFZ-resistant MM.

Análise de custo por desfecho das novas terapias de combinação tripla com lenalidomida para o mieloma múltiplo recidivado/refratário no Brasil / Cost by outcomes analysis of novel triplecombination therapies with lenalidomide for relapsed/refractory multiple myeloma in Brazil

Objetivo: Estimar o custo de tratamento das novas terapias de combinação tripla com lenalidomida no manejo dos pacientes com mieloma múltiplo recidivado/refratário (MMRR) sob a perspectiva do sistema de saúde privado brasileiro. Métodos: Os custos associados da combinação de lenalidomida + dexametasona com carfilzomibe (KRd), daratumumabe (DRd), elotuzumabe (ERd) e ixazomibe (IRd) foram comparados. Para cada terapia, a duração de tratamento foi estimada pela média do tempo de sobrevida livre de progressão (SLP) restrita a três anos a partir de dados de SLP dos estudos pivotais das respectivas terapias. Os custos de tratamento foram estimados para a duração de tratamento, considerando a posologia específica dos regimes terapêuticos. Os preços dos medicamentos foram baseados no preço fábrica de abril de 2020. Não foi considerado o compartilhamento de doses. O custo total do tratamento, o custo médio por ciclo e o custo por taxa de resposta objetiva (TRO) em três anos foram comparados. Resultados: A duração de tratamento no período de três anos foi de 23,3, 27,6, 20,3 e 20,9 meses para KRd, DRd, ERd e IRd, respectivamente. O custo médio total de tratamento foi estimado em 975.557 reais (BRL) para KRd, 1.507.544 BRL para DRd (+55% versus KRd), 1.207.899 BRL para ERd (+24% versus KRd) e 983.917 para IRd (+1% versus KRd). KRd teve o menor custo médio por mês de SLP (horizonte de três anos) entre as terapias, 41.957 BRL versus 54.709 BRL para DRd (+30% versus KRd), 59.635 BRL para ERd (+42% versus KRd) e 47.147 para IRd (+12% versus KRd). Similarmente, o custo por TRO foi 31% menor para KRd (1.119.770 BRL), comparado ao DRd (1.621.015 BRL), 27% menor, comparado ao ERd (1.528.986 BRL), e 11% menor, comparado ao IRd (1.256.064). Conclusões: Resultados da presente análise indicam que KRd está associado a um menor custo médio de tratamento, acompanhado de maior previsibilidade, menor custo por TRO e por mês de SLP, comparado ao DRd, ERd e IRd no horizonte de três anos sob a perspectiva do sistema de saúde privado brasileiro. Os resultados estão associados com alguma incerteza em razão das diferenças nas populações dos estudos, desenho dos estudos (duração fixa de carfilzomibe vs. tratamento até a progressão para daratumumabe, elotuzumabe e ixazomibe) e porque a duração de tratamento é tipicamente menor do que a SLP.

Objective: To estimate treatment costs for novel triple-combination therapies with lenalidomide in the management of relapsed/refractory multiple myeloma (RRMM) patients from the Brazilian private healthcare perspective. Methods: Treatment costs associated with lenalidomide + dexamethasone combinations with carfilzomib (KRd), daratumumab (DRd), elotuzumab (ERd) and ixazomib (IRd) were compared. For each therapy, treatment duration was estimated as the mean progression-free survival (PFS) time restricted to three years using published PFS data from pivotal trials available for these treatments. Treatment costs were estimated for the modeled treatment duration considering therapy-specific dosing schedules. Drug prices were based on April 2020 Brazilian list prices. No vial sharing was assumed. Total treatment costs, average cost per cycle, and cost per overall response rate (ORR) over the three-year period were compared. Results: Modeled treatment duration over the three-year period was 23.3, 27.6, 20.3 and 20.9 months for KRd, DRd, ERd and IRd respectively. Corresponding average total treatment costs were estimated to be 975,557 Brazilian Real (BRL) for KRd; 1,507,544 BRL for DRd (+55% versus KRd); 1,207,899 BRL for ERd (+24% versus KRd) and 983,917 for IRd (+1% versus KRd). KRd had the lowest average cost per month of restricted PFS (3-year time frame) among the therapies, 41,957 BRL versus 54,709 BRL for DRd (+30% versus KRd); 59,635 BRL for ERd (+42% versus KRd); and 47,147 for IRd (+12% versus KRd). Similarly, the cost per achieved ORR was lower for KRd (1,119,770 BRL) than that for DRd (1,621,015 BRL); ERd (1,528,986 BRL); and IRd (1,256,064) by 31%, 27% and 11%, respectively. Conclusions: Results of the present analysis indicate that KRd is associated with lower mean treatment costs and more predictable costs, lower cost per ORR and per month in PFS than DRd, ERd and IRd over a relevant three-year time horizon from the Brazilian private healthcare perspective. The results are associated with some uncertainty due to differences in trial populations, trial design (fixed duration for carfilzomib vs treatment till progression for daratumumab, elotuzumab and ixazomib) and because treatment duration is typically shorter than PFS.

Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm. There has been a lot of attention to applying these drugs for solid tumor treatment. Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib (CFZ), a second generation proteasome inhibitor. However, no insight has been gained regarding the mechanism. In this study, we have systematically investigated the CFZ functions in cell proliferation and growth, cell cycle arrest, and apoptosis in lung adenocarcinoma cells. Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma. MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells. All results were consistently correlated to the upregulation expression of Gadd45a, which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses. Here, upregulation of Gadd45a expression was observed after CFZ treatment. Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells, and reduced cytotoxicity of this drug. The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment. These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity, and shed light on novel preferable therapeutic strategy for lung adenocarcinoma. We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.

Carfilzomib inhibits the growth of lung adenocarcinoma via upregulation of Gadd45a expression / 浙江大学学报（英文版）（B辑：生物医学和生物技术）

Proteasome inhibitors have shown remarkable success in the treatment of hematologic neoplasm. There has been a lot of attention to applying these drugs for solid tumor treatment. Recent preclinical study has signified the effectiveness on cell proliferation inhibition in lung adenocarcinoma treated by carfilzomib (CFZ), a second generation proteasome inhibitor. However, no insight has been gained regarding the mechanism. In this study, we have systematically investigated the CFZ functions in cell proliferation and growth, cell cycle arrest, and apoptosis in lung adenocarcinoma cells. Flow cytometry experiments showed that CFZ significantly induced G2/M cell cycle arrest and apoptosis in lung adenocarcinoma. MTS and colony formation assays revealed that CFZ substantially inhibited survival of lung adenocarcinoma cells. All results were consistently correlated to the upregulation expression of Gadd45a, which is an important gene in modulating cell cycle arrest and apoptosis in response to physiologic and environmental stresses. Here, upregulation of Gadd45a expression was observed after CFZ treatment. Knocking down Gadd45a expression suppressed G2/M arrest and apoptosis in CFZ-treated cells, and reduced cytotoxicity of this drug. The protein expression analysis has further identified that the AKT/FOXO3a pathway is involved in Gadd45a upregulation after CFZ treatment. These findings unveil a novel mechanism of proteasome inhibitor in anti-solid tumor activity, and shed light on novel preferable therapeutic strategy for lung adenocarcinoma. We believe that Gadd45a expression can be a highly promising candidate predictor in evaluating the efficacy of proteasome inhibitors in solid tumor therapy.

New proteasome inhibitors in the treatment of multiple myeloma

Abstract The treatment of patients with relapsed and/or refractory multiple myeloma has improved considerably in the last 15 years, after the introduction of proteasome inhibitors and immunomodulatory drugs. The first clinical trials with new proteasome inhibitors have produced exciting results, particularly those comparing triplet regimens with standard doublet regimens, with a gain in progression-free survival accompanied by an acceptable safety profile and either similar or better health-related quality of life. New proteasome inhibitors hold the potential to fill unmet needs in multiple myeloma management regarding improvement of clinical outcomes, including delayed progression of disease in high-risk patients. This review summarizes the main pharmacological properties and clinical outcomes of these agents, and discusses their potential to change the whole multiple myeloma therapeutic landscape.

Cardiotoxicity evaluation of three novel proteasome inhibitors in zebrafish / 中国药科大学学报

@#To evaluate the cardiotoxicity of three novel proteasome inhibitors(NNU395, NNU458 and NNU459)in zebrafish, normal developmental zebrafish embryos at 6 hours post fertilization(hpf)were treated with different doses of NNU395 and NNU458 and NNU459 until 72 hpf, the zebrafish mortality was counted. Morphologic changes of the cardiovascular system were observed under a stereomicroscope, and the number of heart beats within 1 min was determined. The expression of cardiac development-related genes in zebrafish was detected by RT-qPCR(Quantitative Real-Time PCR). Results showed that NNU395, NNU458 and NNU459 increased the mortality of zebrafish in a concentration-dependent manner and the values of LC50(50% lethal concentration)were(179. 7±12. 2), (27. 5±1. 3)and(24. 4±2. 6)μmol/L, respectively. Moreover, the toxicity of our three compounds in zebrafish are less when compared with their modified precursors. Upon administration of NNU395 at the concentrations of 120- 200 μmol/L, and NNU458 or NNU459 at the concentration of 30 μmol/L, the zebrafish showed obvious pericardial edema cardiac malformation. 120- 200 μmol/L NNU395 and 0. 1- 30 μmol/L NNU458 or 10- 30 μmol/L NNU459 significantly reduced the heart rate of zebrafish. All of three compounds at the tested concentration had no significant effects on the expression of the heart development-related genes in zebrafish. Our results suggested that low concentrations of NNU395, NNU458 and NNU459 have no obvious toxicity on cardiac development of zebrafish. While, higher concentrations of them showed cardiovascular toxicity on zebrafish.

Carfilzomib ameliorates hepatic function in mice with cancer cachexia and its molecular mechanism / 中华内分泌外科杂志

Objective To study the role of CFZ in the amelioration of hepatic function in cancer cachexia and its associated mechanism.Methods Forty BALB/c mice were selected.BALB/c mice were divided into 4 groups randomly,including a healthy control group (HC),a CFZ prevention group (CP),a CFZ treatment group (CT) and a cancer cachexia group (CC).Cancer cachexia model was induced by injecting murine colon 26 adencarcinoma cells into male BALB/c mice intraperitoneally.Following administration of CFZ intraperitoneally twice a week to CP and CT groups on the days 5 and 12 after tumor cells injection,respectively,all mice were acrificed on day 19.hepatic function was detected by automatic biochemistry analyzer,The concentration of inflammatory cytokines and CRP were detected by ELISA.The mRNA and protein expression of IκBα and p65 were detected by real-time PCR and western blotting.Results Compared with HC group,CP group and CT group,the albumin in CC group was significantly decreased,and the concentration of glutamate transaminase,total bilirubin,direct bilirubin and triglyceride were significantly increased,(221.67±12.38)U/L、(315.53±13.60)U/L、(1.65±0.32)mmol/L、(0.88±0.21) mmol/L、(4.98±0.32)mmol/L respectively.Liver biochemical test of CP group [(108.27±16.55)U/L、(180.45±15.28)U/L、(1.15±0.27) mmol/L、(0.58±0.12) mmol/L、(2.93±0.18) mml/L) and CT group [(148.56± 18.16)U/L、(247.18±21.64)U/L、(1.34±0.19) mmol/L、(0.69±0.16) mml/L、(3.75±0.28) mmol/L] was improved after CFZ treatment,and CP group was better than that of CT group.The concentrations of TNFa,IL-1,IL-6 and CRP in CC group [(156±9.56)ng/L、(762±9.46)ng/L、(962±9.12) ng/L、(772±10.04 ng/L)] were significantly higher than those in HC group[(16.42±5.63ng/L、174±9.61 ng/L、206±8.27 ng/L、397±10.2 ng/L)],CP group[(71.25± 4.41 ng/L、398±9.72 ng/L、398±9.72 ng/L、483±9.71 ng/L)] and CT group [(113±8.01 ng/L、506±8.74 ng/L、703± 7.76ng/L、651±11.31 ng/L)].The expression of IκBα in HC group,CP group and CT group were higher than that in CC group,and the difference was statistically significant.The expression of IκBαwas was more obvious in CP group than that in CT group.Compared with HC group,the expression of p65 in CP group,CT group and CC group was significantly increased,respectively,and the difference was statistically significant.The expression of p65 in CP group was lower than that in CT group(P=0.000).Conclusion CFZ ameliorates hepatic function in cancer cachexia mice,which may be related to the inhibition of NF-κB resulting in liver function improvement,the inhibition of tumor growth and the consumption of skeletal muscle.

Custo-efetividade do esquema com daratumumabe, bortezomibe e dexametasona em comparação com terapias à base de carfilzomibe, elotuzumabe e ixazomibe para o tratamento de mieloma múltiplo recidivado e refratário na perspectiva de um pagador do sistema de saúde suplementar brasileiro / Cost-effectiveness analysis of daratumumab, bortezomib, and dexamethasone combination in comparison to carfilzomib, elotuzumab and ixazomib-based therapies for the treatment of patients with relapsed and refractory multiple myeloma from a Brazilian private payer perspective

Objetivo: O objetivo deste estudo é estimar a razão de custo-efetividade incremental da combinação de daratumumabe, bortezomibe e dexametasona (DVd) em comparação com carfilzomibe com dexametasona (Kd); carfilzomibe, lenalidomida e dexametasona (KRd); elotuzumabe, lenalidomida e dexametasona (ERd); e ixazomibe, lenalidomida e dexametasona (IRd) no tratamento do mieloma múltiplo refratário ou recidivado (MMRR) sob a perspectiva de um pagador privado no Brasil. Métodos: Foi utilizado um modelo de transição com três estados, baseado no método de área sob a curva, para simular a trajetória de uma coorte com MMRR: pré-progressão, pós-progressão e morte. Parâmetros clínicos foram obtidos por meio de uma metanálise e os custos incluídos foram aquisição e administração de medicamentos e serviços médicos. O horizonte de tempo adotado foi de 30 anos e descontos de 5% foram aplicados tanto a custos quanto a desfechos de efetividade. Análise de sensibilidade probabilística foi realizada. Resultados: Demonstrou-se que o esquema terapêutico DVd é dominante sobre Kd, KRd, ERd e IRd. DVd gerou 1,09 ano de vida incremental versus Kd com economia de R$ 174.227; 0,15 ano de vida incremental com redução de R$ 238.324 em comparação com KRd; incremento de 0,06 ano de vida com redução de R$ 641.021 comparado com ERd; e 0,59 ano de vida incremental com economia de R$ 254.367 comparado com IRd. A análise de sensibilidade probabilística confirmou a consistência e a robustez do modelo e demonstrou que DVd tem probabilidades de 92,9%, 89,1%, 99,9% e 94,2% de ser custo-efetivo em comparação com Kd, KRd, ERd e IRd, respectivamente, assumindo um limiar de disposição a pagar de 3 PIB per capita. Conclusão: DVd demonstrou ser superior aos comparadores tanto em desfechos clínicos quanto econômicos no tratamento do MMRR, dados a maior sobrevida e os menores custos.

Objective: To estimate the incremental cost-effectiveness ratio of daratumumab, bortezomib, and dexamethasone (DVd) combination in comparison to carfilzomib and dexamethasone (Kd); carfilzomib, lenalidomide and dexamethasone (KRd); elotuzumab, lenalidomide and dexamethasone (ERd); and ixazomib, lenalidomide and dexamethasone (IRd) for the treatment of patients with relapsed and refractory multiple myeloma (RRMM) from a Brazilian private payer perspective. Methods: It was used a three-health state transition model based on the area under the curve method to simulate the cohort trajectory: pre-progression, post-progression, and death. Clinical parameters were obtained in a meta-analysis and considered costs were: drugs acquisition and administration, and medical services. Time-horizon was 30 years, and discount rates applied to costs and outcomes were 5%. A probabilistic sensitivity analysis was performed to evaluate the impact of the uncertainty of the input values. Results: The analysis demonstrated that DVd treatment is dominant over Kd, KRd, ERd, and IRd, providing an increment of 1.09 life year with cost reduction of R$174.227 when compared to Kd, an increment of 0,15 life year with cost reduction of R$238.324 when compared to KRd, an increment of 0,06 life year with cost reduction of R$641.021 when compared to ERd, and an increment of 0,59 life year with cost reduction of R$254.367 when compared to IRd. The probabilistic sensitivity analysis confirms the robustness of the model and results consistency, demonstrating that DVd has 92.9%, 89.1%, 99.9%, and 94,2% probability of being cost-effective versus Kd, KRd, Erd, and IRd, respectively, when an ICER of 3 per-capita GDP is assumed. Conclusion: DVd combination demonstrated superior clinical and economic outcomes in RRMM patients when compared to Kd, KRd, Erd, and IRd, since the therapy provides longer survival to patients at a lower cost to payers.

Determination of Carfilzomib for Injection by HPLC / 中国药师

Objective:To establish an HPLC method to determine the content of carfilzomib for injection. Methods:The chroma-tographic column was a Waters symmetry C18(250 mm ×4.6 mm, 5 μm)column, the sample solvent was methanol, the mobile phase was 0. 05% trifluoroacetic acid-acetonitrile(57 ∶43) at a flow rate of 1. 0 ml · min-1 , the detection wavelength was 210 nm, the col-umn temperature was 25℃ and the injection volume was 10 ml. Results:The linear range of carfilzomib was 120-600 μg·ml-1 ( r=0. 999 7). The average recovery was 100. 4%( RSD=0. 24%,n=9). Conclusion:The method is rapid and effective, which can be used for the content determination of carfilzomib for injection.

Simultaneous Determination of 3 Optical Isomers in Carfilzomib by HPLC / 中国药师

Objective:To establish an HPLC method for the determination of optical isomers in carfilzomib .Methods:The sample was separated on a Chiralpak OX-H column.The mobile phase consisted of n-hexane∶isopropanol∶alcohol (89 ∶5 ∶6, v/v/v) with a flow rat of 1.0 ml· min-1 .The detection wavelength was 220 nm.Results:The linear rang of enantiomer , diastereomer Ⅰand di-astereomer Ⅱwas 0.54-2.14 μg· ml -1,0.11-1.80 μg· ml-1 and 0.11-1.81 μg· ml-1(r≥0.998), respectively.The lower limit of quantification was 0.07-0.27 μg· ml-1 .The recoveries of optical isomers were within the range of 99.6%-100.9% with RSD of 1.13%-1.59%(n=9).Conclusion:The method is sensitive, simple, fast, accurate and specific, and suitable for the study of opti-cal isomers in carfilzomib .

Carfilzomib en el tratamiento de mieloma múltiple: revisión sistemática de la literatura y experiencia colombiana basada en RIPS / Carfilzomib for the Treatment of Multiple Myeloma: Systematic Review of the Literature and Colombian Experience Based on RIPS / Carfilzomib no tratamento do mieloma múltiplo: revisão da literatura e da experiência colombiana baseada em RIPS

Introducción: El mieloma múltiple es un tumor maligno y progresivo de las células B asociado a lesiones osteolíticas, inmunodeficiencia y disfunción renal que ha sido tratado desde 2008 con bortezomib con el cual se logró un aumento del tiempo de sobrevida de los pacientes, sin embargo su uso se vio limitado por efectos adversos dependientes de la dosis, en especial la neuropatía periférica dolorosa. Recientemente ha entrado en uso carfilzomib (agente inhibidor de proteosoma de segunda generación) aprobado por la FDA en 2012 como agente único para tratamiento de enfermedad refractaria y recaídas de mieloma múltiple. Objetivo: Realizar una revisión de la literatura y determinar la experiencia colombiana con el medicamento carfilzomib teniendo en cuenta las estadísticas nacionales consignadas en los registros individuales de prestación de servicios de salud. Además se describe la situación de un caso clínico. Metodología: La revisión se hizo con base en literatura indexada en PubMed; como criterio de inclusión se tuvo en cuenta que los artículos a revisar fueran estudios clínicos de fase 2 y 3 de carfilzomib en manejo de mieloma múltiple Respecto a la experiencia colombiana se identificaron 37 pacientes colombianos con mieloma múltiple diagnosticado entre 2003 y 2012 y a quienes se hubiera prescrito carfilzomib, teniendo en cuenta información proporcionada por Biotoscana. Resultados: En total se localizaron 8 estudios clínicos con asignación al azar que evidencian efectos adversos no hematológicos como fatiga (367 de los 678 pacientes, 54%), y náusea (323 pacientes, 48%). En el caso de los RIPS, de los 37 pacientes, 22 pacientes recibieron de 1 a 8 ciclos de carfilzomib (promedio 3.0, mediana 3). Se evaluó la respuesta clínica en 9 de ellos, encontrándose 4 pacientes (22%) en respuesta parcial muy buena, 4 pacientes (22%) en respuesta parcial, 1 paciente (6%) con enfermedad estable. Conclusiones: Se encontró diferencia entre los efectos adversos que se reportan en Colombia y los que se han reportado globalmente, predominando en nuestros pacientes la fatiga; asimismo se concluye que la experiencia con nuevos medicamentos no ha sido suficientemente documentada. [Castañeda C, Pantoja MC, Montaño L, Rosselli D. Carfilzomib en el tratamiento de mieloma múltiple: revisión sistemática de la literatura y experiencia colombiana basada en RIPS. MedUNAB 2015; 17(2):99-106].

Introduction: Multiple myeloma is a B-cell malignant and progressive tumor, associated with osteolytic lesions, immunodeficiency and renal dysfunction, that has been treated since 2008 with Bortezomib, which achieved an increase in patients survival, however its use was limited due to dose dependent adverse effects, especially painful peripheral neuropathy, it has recently come into use Carfilzomib (a second generation proteasome inhibitor agent) approved by the FDA in 2012 as the only agent for treatment of refractory disease and relapsing of multiple myeloma. Objective: To conduct a literature review and determine the Colombian experience with the drug Carfilzomib, considering national statistics contained in the individual records of health service delivery, plus the status of a case is described. Methodology: for the review was considered literature indexed in PubMed, as an inclusion criterion was considered clinical studies Phase 2 and 3 that reviewed Carfilzomib in handling multiple myeloma. Regarding the Colombian experience, taking information provided by Biotoscana, 37 multiple myeloma Colombian patients diagnosed between 2003 and 2012 and who had been prescribed Carfilzomib were identified. Results: A total of eight randomized trials shown on hematologic adverse effects such as fatigue (367 of 678 patients, 54%), and nausea (323 patients, 48%). For the RIPS of 37 patients, 22 patients received 1 to 8 cycles Carfilzomib (3.0 average, median 3). Clinical response in 9 of them, 4 patients (22%) very good partial response, 4 patients (22%) partial response, 1 patient (6%) with stable disease was assessed. Conclusions: We found difference between the side effects reported in Colombia from the ones who have been reported globally, fatigue prevails in our patients, also experience with new drugs has not been sufficiently documented. [Castañeda C, Pantoja MC, Montaño L, Rosselli D. Carfilzomib for the Treatment of Multiple Myeloma: Systematic Review of the Literature and Colombian Experience Based on RIPS. MedUNAB 2015; 17(2):99-106].

Introdução: O mieloma múltiplo é um tumor maligno e progressivo das células B associado com lesões osteolíticas, imunodeficiência e disfunção renal que tem sido tratados desde 2008 com bortezomib com o qual se conseguiu um aumento no tempo de sobrevida dos pacientes, entretanto a seu uso foi limitado pelos efeitos colaterais dose dependente, especialmente a neuropatia periférica dolorosa. Recentemente se introduziu o uso Carfilzomib (agente inibidor do proteosoma de segunda geração), aprovado pelo FDA em 2012 como única droga para o tratamento da doença refratária e recidiva do mieloma múltiplo. Objetivo: Realizar revisão da literatura e determinar a experiência colombiana com a droga Carfilzomib considerando as estatísticas nacionais contidas nos prontuários individuais de prestação de serviços de saúde, além de descrever um caso clínico. Metodologia: Para a revisão foi levantada a literatura indexada no PubMed, sendo o critério de inclusão os estudos clínicos de fase 2 e 3 de Carfilzomib no tratamento do mieloma múltiplo. Em relação a experiência colombiana, foram identificados 37 pacientes colombianos com mieloma múltiplo diagnosticado entre 2003 e 2012 e que foram submetidos a prescrição de Carfilzomib, levando em conta as informações fornecidas pela BIOTOSCANA. Resultados: Foram localizados 8 estudos clínicos randomizados que evidenciaram efeitos colaterais não hematológicos tais como fadiga (367 de 678 pacientes, 54%) e náuseas (323 pacientes, 48%). Para os RIPS, 22 dos 37 pacientes receberam de 1 a 8 ciclos de Carfilzomib (média=3,0,mediana=3). Foi avaliada a resposta clínica em 9 pacientes, sendo 4(22%) com resposta parcial muito boa, 4(22%) resposta parcial e 1 (6%) com doença estável. Conclusões: Encontramos diferença entre os efeitos colaterais relatados na Colômbia em relação aos relatados mundialmente, com predominância da fadiga em nossos pacientes e se conclue que a experiência com novas drogas não foi suficientemente documentada. [Castañeda C, Pantoja MC, Montaño L, Rosselli D. Carfilzomib no tratamento do mieloma múltiplo: revisão da literatura e da experiência colombiana baseada em RIPS. MedUNAB 2015; 17(2):99-106].