Multiple Myeloma Treatment in Real-world Clinical Practice : Results of a Prospective, Multinational, Noninterventional Study

Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: The authors would like to thank all patients and their families and all the EMMOS investigators for their valuable contributions to the study. The authors would like to acknowledge Robert Olie for his significant contribution to the EMMOS study. Writing support during the development of our report was provided by Laura Mulcahy and Catherine Crookes of FireKite, an Ashfield company, a part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals, Inc, and Janssen Global Services, LLC. The EMMOS study was supported by research funding from Janssen Pharmaceutical NV and Millennium Pharmaceuticals, Inc. Funding Information: M.M. has received personal fees from Janssen, Celgene, Amgen, Bristol-Myers Squibb, Sanofi, Novartis, and Takeda and grants from Janssen and Sanofi during the conduct of the study. E.T. has received grants from Janssen and personal fees from Janssen and Takeda during the conduct of the study, and grants from Amgen, Celgene/Genesis, personal fees from Amgen, Celgene/Genesis, Bristol-Myers Squibb, Novartis, and Glaxo-Smith Kline outside the submitted work. M.V.M. has received personal fees from Janssen, Celgene, Amgen, and Takeda outside the submitted work. M.C. reports honoraria from Janssen, outside the submitted work. M. B. reports grants from Janssen Cilag during the conduct of the study. M.D. has received honoraria for participation on advisory boards for Janssen, Celgene, Takeda, Amgen, and Novartis. H.S. has received honoraria from Janssen-Cilag, Celgene, Amgen, Bristol-Myers Squibb, Novartis, and Takeda outside the submitted work. V.P. reports personal fees from Janssen during the conduct of the study and grants, personal fees, and nonfinancial support from Amgen, grants and personal fees from Sanofi, and personal fees from Takeda outside the submitted work. W.W. has received personal fees and grants from Amgen, Celgene, Novartis, Roche, Takeda, Gilead, and Janssen and nonfinancial support from Roche outside the submitted work. J.S. reports grants and nonfinancial support from Janssen Pharmaceutical during the conduct of the study. V.L. reports funding from Janssen Global Services LLC during the conduct of the study and study support from Janssen-Cilag and Pharmion outside the submitted work. A.P. reports employment and shareholding of Janssen (Johnson & Johnson) during the conduct of the study. C.C. reports employment at Janssen-Cilag during the conduct of the study. C.F. reports employment at Janssen Research and Development during the conduct of the study. F.T.B. reports employment at Janssen-Cilag during the conduct of the study. The remaining authors have stated that they have no conflicts of interest. Publisher Copyright: © 2018 The AuthorsMultiple myeloma (MM) remains an incurable disease, with little information available on its management in real-world clinical practice. The results of the present prospective, noninterventional observational study revealed great diversity in the treatment regimens used to treat MM. Our results also provide data to inform health economic, pharmacoepidemiologic, and outcomes research, providing a framework for the design of protocols to improve the outcomes of patients with MM. Background: The present prospective, multinational, noninterventional study aimed to document and describe real-world treatment regimens and disease progression in multiple myeloma (MM) patients. Patients and Methods: Adult patients initiating any new MM therapy from October 2010 to October 2012 were eligible. A multistage patient/site recruitment model was applied to minimize the selection bias; enrollment was stratified by country, region, and practice type. The patient medical and disease features, treatment history, and remission status were recorded at baseline, and prospective data on treatment, efficacy, and safety were collected electronically every 3 months. Results: A total of 2358 patients were enrolled. Of these patients, 775 and 1583 did and did not undergo stem cell transplantation (SCT) at any time during treatment, respectively. Of the patients in the SCT and non-SCT groups, 49%, 21%, 14%, and 15% and 57%, 20%, 12% and 10% were enrolled at treatment line 1, 2, 3, and ≥ 4, respectively. In the SCT and non-SCT groups, 45% and 54% of the patients had received bortezomib-based therapy without thalidomide/lenalidomide, 12% and 18% had received thalidomide/lenalidomide-based therapy without bortezomib, and 30% and 4% had received bortezomib plus thalidomide/lenalidomide-based therapy as frontline treatment, respectively. The corresponding proportions of SCT and non-SCT patients in lines 2, 3, and ≥ 4 were 45% and 37%, 30% and 37%, and 12% and 3%, 33% and 27%, 35% and 32%, and 8% and 2%, and 27% and 27%, 27% and 23%, and 6% and 4%, respectively. In the SCT and non-SCT patients, the overall response rate was 86% to 97% and 64% to 85% in line 1, 74% to 78% and 59% to 68% in line 2, 55% to 83% and 48% to 60% in line 3, and 49% to 65% and 36% and 45% in line 4, respectively, for regimens that included bortezomib and/or thalidomide/lenalidomide. Conclusion: The results of our prospective study have revealed great diversity in the treatment regimens used to manage MM in real-life practice. This diversity was linked to factors such as novel agent accessibility and evolving treatment recommendations. Our results provide insight into associated clinical benefits.publishersversionPeer reviewe

Synergistic Antitumor Effect of Doxorubicin and Tacrolimus (FK506) on Hepatocellular Carcinoma Cell Lines

Hepatocellular carcinoma is the fifth most common cancer worldwide and shows a complex clinical course, poor response to pharmacological treatment, and a severe prognosis. Thus, the aim of this study was to investigate whether tacrolimus (FK506) has synergistic antitumor effects with doxorubicin on two human hepatocellular carcinoma cell lines, Huh7 and HepG2. Cell viability was analyzed by Sulforhodamine B assay and synergic effect was evaluated by the software CalcuSyn. Cell apoptosis was evaluated using Annexin V and Dead Cell assay. Apoptosis-related protein PARP-1 cleaved and autophagy-related protein expressions (Beclin-1 and LC3B) were measured by western blotting analysis. Cytokines concentration in cellular supernatants after treatments was studied by Bio-Plex assay. Interestingly the formulation with doxorubicin and tacrolimus induced higher cytotoxicity level on tumor cells than single treatment. Moreover, our results showed that the mechanisms involved were (i) a strong cell apoptosis induction, (ii) contemporaneous decrease of autophagy activation, understood as prosurvival process, and (iii) downregulation of proinflammatory cytokines. In conclusion, future studies could relate to the doxorubicin/tacrolimus combination effects in mice models bearing HCC in order to see if this formulation could be useful in HCC treatment

Comparison of quantitative HCMV DNAemia in whole blood and leukocytes, and Real-Time PCR in a BMT patient

Background. HCMV is the most opportunistic viral agent in the transplantation of bone marrow and solid organ. Early therapy based on the detection of HCMV pp65 antigen in peripheral blood leukocytes, has led to a significant reduction in the incidence of related HCMV diseases.The pp65 antigenemia is difficult to standardize, while the quantification of HCMV DNA by Real-Time PCR is an alternative diagnostic approach with greater sensitivity and reproducibility, providing important information in the management of infected patients. Objectives. The aim of this study was the comparative analysis of quantitative HCMV DNAemia in leukocytes and in whole blood, with Real-time PCR, in a BMT patient with HCMV post-transplant reactivation, in order to analyze the relationship between levels of viral DNA at different time-points obtained in the two biological matrices. Study Design. The presence of HCMV DNA was detected in whole blood and peripheral blood leukocytes in a patient who underwent allogeneic marrow transplant for Ph1 + acute lymphoblastic leukemia in molecular remission. After 5-6 months, the patient has increased molecular Bcr-Abl (Philadelphia chromosome). It was activated immune reaction by means of tapering (lowering the dose of cyclosporine) that uses the GvL effect to turn negative the Philadelphia chromosome positivity (Bcr/Abl negativity). Later, the patient develops GvHD and cortisone is administered. The persistence of grafts treated with immunosuppressants periodically reactivates HCMV infection. The DNA extraction from whole-blood was performed by automatic extractor QIACUBE (Qiagen), while extraction from leucocytes was performed on a standard number of leukocytes (EXTRAcell- Nanogen).The extracted DNA was amplified by Real-Time Alert Q-PCR (Nanogen).The samples were analyzed weekly for about 5 months from 1 year after transplantation. Results. The patient at 1 year after transplantation, has three HCMV reactivation at 56th, 62th and 67th week. In all reactivations a good overlap values of viraemia in both whole blood leukocytes is shown. Conclusions. Our data confirm that the whole blood is a biological matrix with diagnostic similar performance not only to pp65 antigenaemia, as supported by extensive scientific literature, but also to the DNAemia in leukocytes that has been for a long time considered the elective matrix for evaluating the post-transplant HCMV infection, for pre-emptive therapy particularly in BMT patients

Vitamin C effect on mitoxantrone-induced cytotoxicity in human breast cancer cell lines.

In recent years the use of natural dietary antioxidants to minimize the cytotoxicity and the damage induced in normal tissues by antitumor agents is gaining consideration. In literature, it is reported that vitamin C exhibits some degree of antineoplastic activity whereas Mitoxantrone (MTZ) is a synthetic anti-cancer drug with significant clinical effectiveness in the treatment of human malignancies but with severe side effects. Therefore, we have investigated the effect of vitamin C alone or combined with MTZ on MDA-MB231 and MCF7 human breast cancer cell lines to analyze their dose-effect on the tumor cellular growth, cellular death, cell cycle and cell signaling. Our results have evidenced that there is a dose-dependence on the inhibition of the breast carcinoma cell lines, MCF7 and MDA-MB231, treated with vitamin C and MTZ. Moreover, their combination induces: i) a cytotoxic effect by apoptotic death, ii) a mild G2/M elongation and iii) H2AX and mild PI3K activation. Hence, the formulation of vitamin C with MTZ induces a higher cytotoxicity level on tumor cells compared to a disjointed treatment. We have also found that the vitamin C enhances the MTZ effect allowing the utilization of lower chemotherapic concentrations in comparison to the single treatments

Resilience, quality of life and symptoms of depression among elderlies receiving outpatient care

Objetivo: analizar la relación entre la resiliencia y variables sociodemográficas, calidad de vida y síntomas depresivos de los ancianos atendidos en un ambulatorio geriátrico. Método: estudio transversal y analítico en que participaron 148 ancianos y que utilizó un cuestionario de caracterización sociodemográfica y de salud, la Escala de Resiliencia, el World Health Organization Quality of Life Bref, el World Health Organization Quality of Life Old y la Center for Epidemiologic Survey - Depression. Para el análisis de datos, se utilizaron estadística descriptiva, la prueba t-Student y la correlación de Pearson. Resultados: hubo una correlación positiva entre resiliencia y escolaridad (r=0,208; p=0,010), ingresos (r=0,194; p=0,017), el World Health Organization Quality of Life Bref (r=0,242; p=0,003) y el World Health Organization Quality of Life Old (r=0,522; p<0,001), y una correlación negativa con síntomas depresivos (r=-0,270; p=0,001). Conclusión: la resiliencia se relacionó con el nivel de escolaridad, ingresos, calidad de vida y síntomas depresivos de los ancianos. Se espera que estos resultados puedan ayudar al equipo multidisciplinario a planificar acciones destinadas a impulsar la resiliencia, con el propósito de promover la salud y la buena calidad de vida en la vejez.Objetivo: analisar a relação entre a resiliência e as variáveis sociodemográficas, a qualidade de vida e os sintomas depressivos dos idosos atendidos em um Ambulatório de Geriatria. Método: estudo transversal e analítico, realizado com 148 idosos, utilizando-se um questionário de caracterização sociodemográfica e de saúde, a Escala de Resiliência, o World Health Organization Quality of Life Bref, o World Health Organization Quality of Life Old e a Center for Epidemiologic Survey - Depression. Para a análise dos dados, utilizaram-se a estatística descritiva, o teste t-Student e a correlação de Pearson. Resultados: houve correlação positiva entre a resiliência e a escolaridade (r=0,208; p=0,010), a renda (r=0,194; p=0,017), o World Health Organization Quality of Life Bref (r=0,242; p=0,003) e o World Health Organization Quality of Life Old (r=0,522; p<0,001) e negativa com sintomas depressivos (r=-0,270; p=0,001). Conclusão: a resiliência apresentou relação com a escolaridade, a renda, a qualidade de vida e os sintomas depressivos dos idosos. Espera-se que esses resultados possam auxiliar a equipe multidisciplinar no planejamento de ações que visem à promoção da resiliência, com finalidade de promoção da saúde e boa qualidade de vida na velhice.Objective: to analyze the relation between resilience and demographic variables, quality of life and symptoms of depression in elderlies attended at a Geriatric Outpatient Clinic. Method: analytical cross-sectional study, conducted with 148 elderlies, with a questionnaire of sociodemographic and health characterization, the Resilience Scale, the World Health Organization Quality of Life Bref, the World Health Organization Quality of Life Old, and the Center for Epidemiologic Survey - Depression Scale. Descriptive statistics, Student’s t-test and Pearson correlation were used for data analysis. Results: there was a positive correlation between resilience and schooling (r = 0.208; p = 0.010), income (r = 0.194; p = 0.017), the World Health Organization Quality of Life Bref (r = 0.242; p = 0.003), and the World Health Organization Quality of Life Old (r = 0.522; p <0.001), and negative correlation regarding symptoms of depression (r = -0.270; p = 0.001). Conclusion: Resilience presented relation to schooling, income, quality of life and symptoms of depression in the elderly. These results are expected to help the multidisciplinary team plan actions aimed at developing resilience towards the promotion of health and good quality of life in old age

Suspected chromosomally integrated human herpes virus 6 in hematopoietic stem cell transplantation

Background and aims: We report a case of a 27-year-old male affected by acute myeloid leukaemia MLL-PTD positive. After autologous stem cell transplantation, he was monitored based on cytomegalovirus, Epstein-Barr virus and human herpes virus 6 (HHV-6) DNA quantification in blood. Relapse occurred one year after transplantation; then the patient underwent to allogenic bone marrow transplantation using genotypically HLA-identical donor (sister). HHV-6 DNAemia was positive and persistently elevated, either after autologous either after allogenic transplant suggesting the occurrence of HHV-6 chromosomally integration. The work aim is to prove the occurrence of chromosomally integrated-HHV-6 (ci-HHV-6). Materials and Methods: HHV-6 DNA extraction was performed by automated extractor and DNA was amplified-quantified by Real Time polymerase chain reaction. Species identification was performed by sequencing HHV6-U100 glycoprotein using automated sequencer and sequencing products were analysed using the Blast program. Results: After autologous transplantation HHV6-DNAemia was 5.4 log copies/mL setting to 3.9 log copies/mL for a long period post allogenic transplantation. The patient’s hair follicles were tested for HHV- 6 DNA having positive results. Sequences of both strains of HHV6 extracts from blood and hair follicles resulted species B. HHV6 viral load decreased significantly after Lymphocyte Infusion by ci-HHV6 negative donor (sister), having steady viral load during the following six months of monitoring. One year later, patient is in complete haematological remission. Conclusions: Detection of HHV-6 in hair follicles and HHV-6 DNAemia persistently elevated before allogenic transplant, confirm the occurrence of ci-HHV-6. The observed important decreasing viral load is potentially due to the successful engraftment of ci-HHV-6-negative donor marrow after allogeneic transplant

Role of 1q21 in Multiple Myeloma: From Pathogenesis to Possible Therapeutic Targets

Multiple myeloma (MM) is characterized by an accumulation of malignant plasma cells (PCs) in the bone marrow (BM). The amplification of 1q21 is one of the most common cytogenetic abnormalities occurring in around 40% of de novo patients and 70% of relapsed/refractory MM. Patients with this unfavorable cytogenetic abnormality are considered to be high risk with a poor response to standard therapies. The gene(s) driving amplification of the 1q21 amplicon has not been fully studied. A number of clear candidates are under investigation, and some of them (IL6R, ILF2, MCL-1, CKS1B and BCL9) have been recently proposed to be potential drivers of this region. However, much remains to be learned about the biology of the genes driving the disease progression in MM patients with 1q21 amp. Understanding the mechanisms of these genes is important for the development of effective targeted therapeutic approaches to treat these patients for whom effective therapies are currently lacking. In this paper, we review the current knowledge about the pathological features, the mechanism of 1q21 amplification, and the signal pathway of the most relevant candidate genes that have been suggested as possible therapeutic targets for the 1q21 amplicon

Cell viability %.

<p>The histograms show how changes the viability in MCF7 cell lines after MTZ, vit C, and their combination treatment for 48 h. Experiments were in triplicate. On the x-axis are showed the different drugs concentrations (DC): 1 (MTZ: 0.07 µM; vit C: 0.09 mM), 2 (MTZ: 0.15 µM; vit C: 0.19 mM), 3 (MTZ: 0.29 µM; vit C: 0.38 mM), 4 (MTZ: 0.58 µM; vit C: 0.75 mM), 5 (MTZ: 1.17 µM; vit C: 1.5 mM), 6 (MTZ: 2.34 µM; vit C: 3 mM), 7 (MTZ: 4.68; vit C: 6 mM), 8 (MTZ: 9.36; vit C: 12 mM) for MCF7 and 1(MTZ: 0.04 µM; vit C: 0.03 mM), 2 (MTZ: 0.75 µM; vit C: 0.06 mM), 3 (MTZ: 0.15 µM; vit C: 0.13 mM), 4 (MTZ: 0.3 µM; vit C: 0.25 mM), 5 (MTZ: 0,6 µM; vit C: 0.5 mM), and 6 (MTZ: 1,2 µM; vit C: 1 mM), 7 (MTZ:2,4; vit C: 2 mM), 8 (MTZ: 4,8; vit C: 4 mM) for MDA-MB231; on the y-axis: the viability percentage is presented as means ± standard deviation. Moreover, we indicate with “a” or “b” if the difference between cell viability after co-treatment and vit c or MTZ is statistically significant (with p-value<0.05).</p