Improving access to care and community health in Haiti with optimized community health worker placement.

The national deployment of polyvalent community health workers (CHWs) is a constitutive part of the strategy initiated by the Ministry of Health to accelerate efforts towards universal health coverage in Haiti. Its implementation requires the planning of future recruitment and deployment activities for which mathematical modelling tools can provide useful support by exploring optimised placement scenarios based on access to care and population distribution. We combined existing gridded estimates of population and travel times with optimisation methods to derive theoretical CHW geographical placement scenarios including constraints on walking time and the number of people served per CHW. Four national-scale scenarios that align with total numbers of existing CHWs and that ensure that the walking time for each CHW does not exceed a predefined threshold are compared. The first scenario accounts for population distribution in rural and urban areas only, while the other three also incorporate in different ways the proximity of existing health centres. Comparing these scenarios to the current distribution, insufficient number of CHWs is systematically identified in several departments and gaps in access to health care are identified within all departments. These results highlight current suboptimal distribution of CHWs and emphasize the need to consider an optimal (re-)allocation.

A Journey Through Myeloma Evolution: From the Normal Plasma Cell to Disease Complexity.

The knowledge of cancer origin and the subsequent tracking of disease evolution represent unmet needs that will soon be within clinical reach. This will provide the opportunity to improve patient's stratification and to personalize treatments based on cancer biology along its life history. In this review, we focus on the molecular pathogenesis of multiple myeloma (MM), a hematologic malignancy with a well-known multi-stage disease course, where such approach can sooner translate into a clinical benefit. We describe novel insights into modes and timing of disease initiation. We dissect the biology of the preclinical and pre-malignant phases, elucidating how knowledge of the genomics of the disease and the composition of the microenvironment allow stratification of patients based on risk of disease progression. Then, we explore cell-intrinsic and cell-extrinsic drivers of MM evolution to symptomatic disease. Finally, we discuss how this may relate to the development of refractory disease after treatment. By integrating an evolutionary view of myeloma biology with the recent acquisitions on its clonal heterogeneity, we envision a way to drive the clinical management of the disease based on its detailed biological features more than surrogates of disease burden.

Monitoring the sustainable development goals through human rights accountability reviews.

The Universal Periodic Review is a comprehensive, state-to-state peer-review mechanism of the United Nations (UN) Human Rights Council. Created in 2006, the mechanism scrutinizes the human rights record of all UN Member States, including their efforts to realize the right to health. However, the mechanism is relatively under-used in global health governance compared to treaty-based procedures, such as those overseen by the Committee on the Rights of Persons with Disabilities or the Committee on the Elimination of Discrimination against Women. We suggest that the Universal Periodic Review could be used to support the monitoring and review processes of the sustainable development goals (SDGs). The review could offer a unique perspective for other actors on how to ensure accountability for the complex and intertwined SDGs, including their commitments for health. This article provides an overview of how health-related rights have been addressed in the Universal Periodic Review process and how the review can contribute to advancing global commitments to health, including those embodied in the SDGs. We present some of the current limitations in the way health is addressed in the Universal Periodic Review. We also consider what role specialized UN agencies, such as the World Health Organization, might play during the Universal Periodic Review process and how this involvement can contribute towards the comprehensive realization of health and wellbeing for all.

L'Examen périodique universel est un mécanisme complet d'évaluation entre États du Conseil des droits de l'homme des Nations Unies (ONU). Créé en 2006, ce mécanisme passe en revue les réalisations de l'ensemble des États membres de l'ONU dans le domaine des droits de l'homme, et notamment leurs efforts en faveur de l'application du droit à la santé. Ce mécanisme est néanmoins relativement sous-utilisé dans la gouvernance de la santé mondiale par rapport aux procédures fondées sur des traités comme celles supervisées par le Comité des droits des personnes handicapées ou le Comité pour l'élimination de la discrimination à l'égard des femmes. Nous suggérons d'utiliser l'Examen périodique universel pour soutenir les processus de suivi et d'examen des objectifs de développement durable (ODD). L'examen pourrait offrir une perspective unique à d'autres acteurs sur la façon de garantir le principe de responsabilité pour les ODD, complexes et interdépendants, et notamment leurs engagements en matière de santé. Cet article fournit un aperçu de la façon dont les droits liés à la santé sont traités dans le cadre de l'Examen périodique universel et de la façon dont l'examen peut contribuer à faire avancer les engagements mondiaux en faveur de la santé, et notamment ceux inclus dans les ODD. Nous présentons quelques-unes des limites actuelles de l'Examen périodique universel concernant la façon dont il traite de la santé. Nous avons également étudié le rôle que peuvent jouer certaines institutions spécialisées des Nations Unies, telles que l'Organisation mondiale de la Santé, dans le cadre de l'Examen périodique universel, et en quoi ce rôle peut contribuer à l'atteinte de l'objectif de la santé et du bien-être pour tous.

La Revisión periódica universal es un mecanismo integral de revisión entre pares de estado a estado del Consejo de Derechos Humanos de las Naciones Unidas (ONU). Creado en 2006, el mecanismo examina el historial relativo a los derechos humanos de todos los Estados Miembros de las Naciones Unidas, incluidos sus esfuerzos por cumplir el derecho a la salud. Sin embargo, el mecanismo está relativamente infrautilizado en la gobernanza de la salud mundial en comparación con los procedimientos basados en tratados, como los supervisados por el Comité sobre los Derechos de las Personas con Discapacidad o el Comité para la Eliminación de la Discriminación contra la Mujer. Se sugiere que la Revisión periódica universal se utilice para apoyar los procesos de seguimiento y revisión de los objetivos de desarrollo sostenible (ODS). La revisión podría ofrecer una perspectiva única para otros participantes sobre cómo asegurar la responsabilidad de los complejos y vinculados ODS, incluyendo sus compromisos con la salud. Este artículo ofrece una visión general de cómo se han abordado los derechos relacionados con la salud en el proceso de la Revisión periódica universal y cómo la misma puede contribuir al avance de los compromisos mundiales con la salud, incluidos los incorporados en los ODS. Se presentan algunas de las limitaciones actuales en la forma en que se aborda la salud en la Revisión periódica universal. También se valora qué papel podrían desempeñar los organismos especializados de las Naciones Unidas, como la Organización Mundial de la Salud, durante el proceso de la Revisión periódica universal y cómo esta participación puede contribuir a la realización integral de la salud y el bienestar para todos.

HIF-1α inhibition blocks the cross talk between multiple myeloma plasma cells and tumor microenvironment.

Multiple myeloma (MM) is a malignant disorder of post-germinal center B cells, characterized by the clonal proliferation of malignant plasma cells (PCs) within the bone marrow (BM). The reciprocal and complex interactions that take place between the different compartments of BM and the MM cells result in tumor growth, angiogenesis, bone disease, and drug resistance. Given the importance of the BM microenvironment in MM pathogenesis, we investigated the possible involvement of Hypoxia-Inducible transcription Factor-1 alpha (HIF-1α) in the PCs-bone marrow stromal cells interplay. To test this hypothesis, we used EZN-2968, a 3rd generation antisense oligonucleotide against HIF-1α, to inhibit HIF-1α functions. Herein, we provide evidence that the interaction between MM cells and BM stromal cells is drastically reduced upon HIF-1α down-modulation. Notably, we showed that upon exposure to HIF-1α inhibitor, neither the incubation with IL-6 nor the co-culture with BM stromal cells were able to revert the anti-proliferative effect induced by EZN-2968. Moreover, we observed a down-modulation of cytokine-induced signaling cascades and a reduction of MM cells adhesion capability to the extracellular matrix proteins in EZN-2968-treated samples. Taken together, these results strongly support the concept that HIF-1α plays a critical role in the interactions between bone BM cells and PCs in Multiple Myeloma.

Autoimmune diseases during treatment with immunomodulatory drugs in multiple myeloma: selective occurrence after lenalidomide.

Immunomodulatory drugs (IMiDs) may favor autoimmune disease (AD) occurrence. We conducted a retrospective study to evaluate AD occurrence among IMiD-treated patients with myeloma. Patients were grouped into three classes depending on the type of IMiD engaged. The first group included patients treated with thalidomide (Thal) (n = 474), the second group with lenalidomide (Len) (n = 140) and patients in the third group were first treated with Thal followed by Len (Thal-Len) (n = 94). Absolute risk of AD was 0.4% for patients treated with Thal, 4.3% for Len and 1.1% for Thal-Len. ADs manifested prevalently as autoimmune cytopenias (55%), although we observed one vasculitis, one optic neuritis, one Graves' disease and one polymyositis. ADs occurred preferentially in the first months of IMiD treatment. A previous autologous transplant was shown to be a significant risk factor. All ADs were managed with IMiD discontinuation and steroids, resolving in a few weeks, except for Graves' disease and polymyositis.

Hypoxia inducible factor-1 alpha as a therapeutic target in multiple myeloma.

The increasing importance of hypoxia-inducible factor-1α (HIF-1α) in tumorigenesis raises the possibility that agents which specifically inhibit this transcription factor, would provide significant therapeutic benefit. The constitutive expression of HIF-1α in about 35% of Multiple Myeloma (MM) patients suggests HIF-1α suppression might be part of a therapeutic strategy. Accordingly, we explored the effect of EZN-2968, a small 3rd generation antisense oligonucleotide against HIF-1α, in a panel of MM cell lines and primary patients samples. Here, we demonstrated that EZN-2968 is highly specific for HIF-1α mRNA and that exposure of MM cells to EZN-2968 resulted in an efficient and homogeneous loading of the cells showing a long lasting low HIF-1α protein level. In MM cells, HIF-1α suppression induced a permanent cell cycle arrest by prolonging S-phase through cyclin A modulation and in addition it induced a mild apoptotic cell death. Moreover, HIF-1α suppression caused a metabolic shift that leaded to increased production of ATP by oxidative phosphorylation (i.e. Warburg effect reversion), that was confirmed by the observed mitochondrial membrane potential decrease. These results show that HIF-1α is an important player in MM homeostasis and that its inhibition by small antisense oligonucleotides provides a rationale for novel therapeutic strategy to improving MM treatment.

Autologous stem cell transplantation for T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of T-cell malignancies characterized by a very poor outcome. The optimal treatment for PTCLs remains controversial. The role of stem cell transplantation in PTCLs has been investigated; however, no randomized control studies specifically dedicated to PTCLs are currently available. Several retrospective and prospective studies have suggested that high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) may improve the survival in patients with chemosensitive T-cell lymphoma, either upfront or as salvage treatment. This review provides a summary of the current literature with the intent to explore the role of ASCT in various clinical scenarios.

Bortezomib and dexamethasone as salvage therapy in patients with relapsed/refractory multiple myeloma: analysis of long-term clinical outcomes.

Bortezomib (bort)-dexamethasone (dex) is an effective therapy for relapsed/refractory (R/R) multiple myeloma (MM). This retrospective study investigated the combination of bort (1.3 mg/m(2) on days 1, 4, 8, and 11 every 3 weeks) and dex (20 mg on the day of and the day after bort) as salvage treatment in 85 patients with R/R MM after prior autologous stem cell transplantation or conventional chemotherapy. The median number of prior lines of therapy was 2. Eighty-seven percent of the patients had received immunomodulatory drugs included in some line of therapy before bort-dex. The median number of bort-dex cycles was 6, up to a maximum of 12 cycles. On an intention-to-treat basis, 55 % of the patients achieved at least partial response, including 19 % CR and 35 % achieved at least very good partial response. Median durations of response, time to next therapy and treatment-free interval were 8, 11.2, and 5.1 months, respectively. The most relevant adverse event was peripheral neuropathy, which occurred in 78 % of the patients (grade II, 38 %; grade III, 21 %) and led to treatment discontinuation in 6 %. With a median follow up of 22 months, median time to progression, progression-free survival (PFS) and overall survival (OS) were 8.9, 8.7, and 22 months, respectively. Prolonged PFS and OS were observed in patients achieving CR and receiving bort-dex a single line of prior therapy. Bort-dex was an effective salvage treatment for MM patients, particularly for those in first relapse.

Current state of art for transplantation paradigms in peripheral T-cell lymphomas.

Peripheral T-cell lymphomas (PTCLs) are a rare and aggressive lymphoproliferative disorder characterized, with few exception, by poor prognosis. A correct diagnosis is still hampered by the heterogeneity and rarity of disease. Historically, PTCLs were treated like aggressive B-cell lymphoma with anthracycline-based combination chemotherapy with disappointing results. Neither dose intensification nor dose escalation of chemotherapy has been successful in prolonging the survival of PTCL patients. Due to this discouraging scenario, new therapeutic strategies have been tested. A therapeutic program including hematopoietic stem-cell transplantation (SCT) may represent an interesting strategy for high-risk patients. Although no randomized trials are available, autologous SCT may offer a chance of cure in chemosensitive disease. Nonmyeloablative allogeneic SCT has shown a curative potential with limited toxicity, and it is actively being investigated. We will review the role of the current therapeutic approach to PTCL focusing on the most recent advances in SCT.

The value of 18F-FDG PET/CT after autologous stem cell transplantation (ASCT) in patients affected by multiple myeloma (MM): experience with 77 patients.

AIM: The objective of this study was to analyze the prognostic value of (18)F-FDG PET/CT after therapy in patients with multiple myeloma (MM). PATIENTS AND METHODS: One hundred seven patients prospectively recruited with MM had FDG PET/CT at staging 3 months after therapy (autologous stem cell transplantation) and every 6 to 12 months during the follow-up (mean 41 months). Patients were divided into group 1 (relapsed) and group 2 (nonrelapsed). In group 1, PET results and SUV(max) were compared to the time to relapse (TTR). In group 2, the presence of PET finding changes during follow-up was analyzed to identify typical patterns of disease behavior (ie, late responders or stabilized disease). Patients with a negative PET at staging were excluded from further evaluation. RESULTS: Forty-seven out of 107 (44%) patients relapsed: 10 were excluded because of a negative PET at staging. In group 1, 22 patients had a negative posttherapy PET (59%, mean TTR = 27.6 months) and 15 had a positive posttherapy PET (41%, mean TTR = 18 months). There was a significant difference between the TTR of the two subgroups (t test P = 0.05). In patients with a positive posttherapy PET, the SUV(max) was inversely correlated to the TTR (correlation coefficient = -0.7; P < 0.01).Sixty out of 107 (56%) patients did not relapse. Twenty patients were excluded because of a negative PET at staging. In group 2, 27 patients had a negative posttherapy PET (68%) and 13 had a positive posttherapy PET (32%). None of nonrelapsed patients showed a progressive increase in SUV(max) during the follow-up. There was no significant difference between relapsed and nonrelapsed patients in terms of SUV(max) at posttherapy PET/CT (t test P = 0.7). CONCLUSION: In our series of MM patients, a negative posttherapy PET was predictive for nonrelapse or a long disease-free survival. In contrast, a persistent significantly increased SUV(max) after therapy was correlated to a short TTR.

Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma.

In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, and consolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.

Long-term results of thalidomide and dexamethasone (thal-dex) as therapy of first relapse in multiple myeloma.

Thal-dex (TD) is an effective therapy for advanced MM. We evaluated TD as salvage treatment of MM patients at first relapse. Thal was given at a daily dose of 100 or 200 mg until progression. Dex was administered 160 mg/month. One hundred patients were enrolled. First line therapy included ASCT (72%) and conventional CHT (28%). Fifty-nine percent received a fixed thal dose of 100 mg/day. The most frequent adverse events were constipation (42%), peripheral neuropathy (58%, 5% grade 3), bradycardia (20%), skin rash (11%), and VTE (7%). Discontinuation of thal due to adverse events was recorded in eight patients. On ITT, 46% of patients achieved at least a PR. Median DOR was 28 months, median time to next therapy was 15.5 months. Median OS, TTP, and PFS were 43, 22, and 21 months, respectively. TTP and PFS were significantly longer for patients with at least PR to TD. TD was an effective salvage treatment for MM patients at first relapse, as demonstrated by durable disease control and prolonged OS. TD was well tolerated, as reflected by the long stay on treatment without disease progression (median 25 months) and a low discontinuation rate due to toxicity (8%).

Prognostic relevance of 18-F FDG PET/CT in newly diagnosed multiple myeloma patients treated with up-front autologous transplantation.

We prospectively analyzed the prognostic relevance of positron emission tomography-computed tomography (PET/CT) at diagnosis, after thalidomide-dexamethasone (TD) induction therapy and double autotransplantation (ASCT) in 192 newly diagnosed multiple myeloma (MM) patients. Presence at baseline of at least 3 focal lesions (FLs; 44% of cases), a standardized uptake value (SUV) > 4.2 (46%), and extramedullary disease (EMD; 6%) adversely affected 4-year estimates of progression-free survival (PFS; ≥ 3 FLs: 50%; SUV > 4.2: 43%; presence of EMD: 28%). SUV > 4.2 and EMD were also correlated with shorter overall survival (OS; 4-year rates: 77% and 66%, respectively). Persistence of SUV > 4.2 after TD induction was an early predictor for shorter PFS. Three months after ASCT, PET/CT was negative in 65% of patients whose 4-year rates of PFS and OS were superior to those of PET-positive patients (PFS: 66% and OS: 89%). In a multivariate analysis, both EMD and SUV > 4.2 at baseline and persistence of fluorodeoxyglucose (FDG) uptake after ASCT were independent variables adversely affecting PFS. PET/CT involvement at diagnosis, after novel agent-based induction and subsequent ASCT is a reliable predictor of prognosis in MM patients. This study is registered at www.clinicaltrials.gov as NTC01341262.

Immunomodulatory effects of lenalidomide and pomalidomide on interaction of tumor and bone marrow accessory cells in multiple myeloma.

The bone marrow (BM) microenvironment consists of extracellular-matrix and the cellular compartment including immune cells. Multiple myeloma (MM) cell and BM accessory cell interaction promotes MM survival via both cell-cell contact and cytokines. Immunomodulatory agents (IMiDs) target not only MM cells, but also MM cell-immune cell interactions and cytokine signaling. Here we examined the in vitro effects of IMiDs on cytokine signaling triggered by interaction of effector cells with MM cells and BM stroma cells. IMiDs diminished interleukin-2, interferonγ, and IL-6 regulator suppressor of cytokine signaling (SOCS)1 expression in immune (CD4T, CD8T, natural-killer T, natural-killer) cells from both BM and PB of MM patients. In addition, coculture of MM cells with healthy PBMCs induced SOCS1 expression in effector cells; conversely, treatment with IMiDs down-regulated the SOCS1 expression. SOCS1 negatively regulates IL-6 signaling and is silenced by hypermethylation in MM cells. To define the mechanism of inhibitory-cytokine signaling in effector cells and MM cells, we next analyzed the interaction of immune cells with MM cells that were epigenetically modified to re-express SOCS1; IMiDs induced more potent CTL responses against SOCS1 re-expressing-MM cells than unmodified MM cells. These data therefore demonstrate that modulation of SOCS1 may enhance immune response and efficacy of IMiDs in MM.

PI3K/p110{delta} is a novel therapeutic target in multiple myeloma.

In this study, we demonstrate expression and examined the biologic sequelae of PI3K/p110delta signaling in multiple myeloma (MM). Knockdown of p110delta by small interfering RNA caused significant inhibition of MM cell growth. Similarly, p110delta specific small molecule inhibitor CAL-101 triggered cytotoxicity against LB and INA-6 MM cell lines and patient MM cells, associated with inhibition of Akt phosphorylation. In contrast, CAL-101 did not inhibit survival of normal peripheral blood mononuclear cells. CAL-101 overcame MM cell growth conferred by interleukin-6, insulin-like growth factor-1, and bone marrow stromal cell coculture. Interestingly, inhibition of p110delta potently induced autophagy. The in vivo inhibition of p110delta with IC488743 was evaluated in 2 murine xenograft models of human MM: SCID mice bearing human MM cells subcutaneously and the SCID-hu model, in which human MM cells are injected within a human bone chip implanted subcutaneously in SCID mice. IC488743 significantly inhibited tumor growth and prolonged host survival in both models. Finally, combined CAL-101 with bortezomib induced synergistic cytotoxicity against MM cells. Our studies therefore show that PI3K/p110delta is a novel therapeutic target in MM and provide the basis for clinical evaluation of CAL-101 to improve patient outcome in MM.

A novel Aurora-A kinase inhibitor MLN8237 induces cytotoxicity and cell-cycle arrest in multiple myeloma.

Aurora-A is a mitotic kinase that regulates mitotic spindle formation and segregation. In multiple myeloma (MM), high Aurora-A gene expression has been correlated with centrosome amplification and proliferation; thus, inhibition of Aurora-A in MM may prove to be therapeutically beneficial. Here we assess the in vitro and in vivo anti-MM activity of MLN8237, a small-molecule Aurora-A kinase inhibitor. Treatment of cultured MM cells with MLN8237 results in mitotic spindle abnormalities, mitotic accumulation, as well as inhibition of cell proliferation through apoptosis and senescence. In addition, MLN8237 up-regulates p53 and tumor suppressor genes p21 and p27. Combining MLN8237 with dexamethasone, doxorubicin, or bortezomib induces synergistic/additive anti-MM activity in vitro. In vivo anti-MM activity of MLN8237 was confirmed using a xenograft-murine model of human-MM. Tumor burden was significantly reduced (P = .007) and overall survival was significantly increased (P < .005) in animals treated with 30 mg/kg MLN8237 for 21 days. Induction of apoptosis and cell death by MLN8237 were confirmed in tumor cells excised from treated animals by TdT-mediated dUTP nick end labeling assay. MLN8237 is currently in phase 1 and phase 2 clinical trials in patients with advanced malignancies, and our preclinical results suggest that MLN8237 may be a promising novel targeted therapy in MM.

Dual inhibition of akt/mammalian target of rapamycin pathway by nanoparticle albumin-bound-rapamycin and perifosine induces antitumor activity in multiple myeloma.

The phosphoinositide 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway mediates multiple myeloma (MM) cell proliferation, survival, and development of drug resistance, underscoring the role of mTOR inhibitors, such as rapamycin, with potential anti-MM activity. However, recent data show a positive feedback loop from mTOR/S6K1 to Akt, whereby Akt activation confers resistance to mTOR inhibitors. We confirmed that suppression of mTOR signaling in MM cells by rapamycin was associated with upregulation of Akt phosphorylation. We hypothesized that inhibiting this positive feedback by a potent Akt inhibitor perifosine would augment rapamycin-induced cytotoxicity in MM cells. Perifosine inhibited rapamycin-induced phosphorylated Akt, resulting in enhanced cytotoxicity in MM.1S cells even in the presence of interleukin-6, insulin-like growth factor-I, or bone marrow stromal cells. Moreover, rapamycin-induced autophagy in MM.1S MM cells, as evidenced by electron microscopy and immunocytochemistry, was augmented by perifosine. Combination therapy increased apoptosis detected by Annexin V/propidium iodide analysis and caspase/poly(ADP-ribose) polymerase cleavage. Importantly, in vivo antitumor activity and prolongation of survival in a MM mouse xenograft model after treatment was enhanced with combination of nanoparticle albumin-bound-rapamycin and perifosine. Utilizing the in silico predictive analysis, we confirmed our experimental findings of this drug combination on PI3K, Akt, mTOR kinases, and the caspases. Our data suggest that mutual suppression of the PI3K/Akt/mTOR pathway by rapamycin and perifosine combination induces synergistic MM cell cytotoxicity, providing the rationale for clinical trials in patients with relapsed/refractory MM. Mol Cancer Ther; 9(4); 963-75. (c)2010 AACR.

Thalidomide-dexamethasone as induction therapy before autologous stem cell transplantation in patients with newly diagnosed multiple myeloma and renal insufficiency.

The aim of this study was to evaluate the efficacy and the toxicity of thalidomide-dexamethasone (Thal-Dex) as induction therapy before autologous peripheral blood stem cell (PBSC) transplantation in patients with newly diagnosed multiple myeloma (MM) with renal insufficiency. The study included 31 patients with a baseline creatinine clearance value 4 x 10(6) CD34(+) cells/kg were collected. Double autologous transplantation was performed in 15 patients, and a single autologous transplantation was performed in 7 patients. After a median of 32 months of follow-up, median event-free survival was 30 months, and median survival was not determined. According to our data, Thal-Dex is effective and safe in patients with newly diagnosed MM and renal insufficiency. Given the relationship between recovery of renal function and response to induction treatment, more intensive Thal + bortezomib regimens could be explored to rescue higher numbers of patients.

Short-term thalidomide incorporated into double autologous stem-cell transplantation improves outcomes in comparison with double autotransplantation for multiple myeloma.

PURPOSE: To assess potential benefits with thalidomide incorporated into double autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS: One hundred thirty-five patients who received thalidomide from induction until the second ASCT were retrospectively analyzed in comparison with an equal number of pair mates treated with double ASCT not including thalidomide. RESULTS: On an intention-to-treat basis, the addition of thalidomide to double ASCT effected a significant improvement in the rate (68% v 49%; P = .001) and duration (62% v 33% at 4 years; P < .001) of at least very good partial response (VGPR), time to progression (TTP; 61% v 41% at 4 years; P < .001) and progression-free survival (PFS; 51% v 31% at 4 years; P = .001). A trend was also noted for extended overall survival (OS) among thalidomide-treated patients (69% at 5 years v 53% for the control group), although the difference between the two groups was not statistically significant (P = .07). Benefits with thalidomide in increasing the rate of VGPR or better response, TTP, and PFS were confirmed in a multivariate analysis. Median OS after relapse was 24 months for patients receiving thalidomide added to double ASCT and 25 months for the control group. Overall, 17% of patients discontinued thalidomide, including 8% because of drug-related adverse events. CONCLUSION: In comparison with double ASCT, the addition of first-line thalidomide to double ASCT improved clinical outcomes. Short-term thalidomide was generally well tolerated and had no adverse impact on postrelapse survival.