Background: preclinical data suggest that autophagy can serve as an adaptive mechanism facilitating tumor cell survival and resistance to therapy-induced apoptosis. Subsequently, inhibitors of autophagy are thought to enhance the efficacy of therapeutic strategies designed to induce tumor cell apoptosis. Based upon our preclinical results, we hypothesized that the addition of chloroquine, an autophagy inhibitor, to the combination of a proteasome inhibitor, and cyclophosphamide might result in a synergistic effect. Patients and Methods: We designed a phase II trial of bortezomib, cyclophosphamide and chloroquine in patients with refractory myeloma (defined by > 25% increase in M-protein) who progressed on a combination of bortezomib and cyclophosphamide. Treatment consisted of 42 day cycles repeated until disease progression with bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11, 22, 25, 29 and 32; cyclophosphamide 50 mg orally twice a day; and chloroquine at 500 mg orally daily on days 1-14 and 22-35. The primary endpoint was to estimate clinical benefit (CR+VGPR+PR+SD) after 2 cycles. Results: Between October 2011 and April 2013, 11 patients including 7 men and 4 women were enrolled and treated. The median age was 62 years (range 53-80). All patients were ISS stage II and III. Prior therapies for most patients included transplant, bortezomib, cyclophosphamide and lenalidomide. One patient withdrew after C1D1 and two patients progressed prior to completion of cycle 1. Of the 8 evaluable patients who completed at least 2 cycles, 3/8 achieved a partial response, 1/8 showed stable disease and 4/8 progressed with a clinical benefit rate of 4/10 (40%). Among the 3 patients who achieved a partial response, median duration of response was 4 months (250, 131 and 117 days respectively). The most common non-hematological adverse events (AEs) observed in >25% of patients (any Gr/Gr >3) and felt to be at least possibly related to the study drug were: fatigue (91%/18%); constipation (72%); myalgia, nausea (64% each); cough (55%), diarrhea, neuropathy (45% each); congestion (36%/9%); anorexia and dyspnea (27% each). The most commonly observed hematological AEs were neutropenia (45%/36%) and thrombocytopenia (55%/45%). Data from LC3 and beclin1 assays used to measure correlations of clinical response with in vitro autophagy inhibition will be presented. Conclusions: this study suggests that the addition of chloroquine to bortezomib and cyclophosphamide is effective in overcoming proteasome inhibitor resistance in a significant fraction of heavily pretreated patients, with an acceptable toxicity profile. Disclosures No relevant conflicts of interest to declare.

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Kratak sadr`aj: Oksidativni stres dovodi se u vezu sa pojedina~nim komponentama metaboli~kog sindroma i povezan je sa razvojem komplikacija u metaboli~kim poreme}ajima. U ovoj studiji upore|eni su nivoi oksidativnog stresa kod gojaznih Indijaca (populaciji sa visokim rizikom za razvoj dijabetesa i kardiovaskularnih poreme}aja) sa i bez metaboli~kog sindroma. Trideset odraslih normotenzivnih, normoglikemi~nih gojaznih ispitanika i 35 odraslih osoba sa metaboli~kim sindromom oba pola sa ITM >23 kg/m 2 pore|eno je sa 30 odraslih zdravih dobrovoljaca sa ITM <23 kg/m 2 . Ispitivani su antropometrijski parametri, krvni pritisak, biohemijski parametri, nivoi hidroperoksida i ukupni antioksidantni kapacitet. U gojaznim grupama sa i bez metaboli~kog sindroma antropometrijski parametri kao {to su obim struka i indeks centralne gojaznosti i aqueous phase hidroperoksidi bili su zna~ajno povi{eni u pore|enju sa kontrolnim subjektima. Grupa sa metaboli~kim sindromom tako|e je imala zna~ajno povi{ene nivoe {e}era u krvi, lipidni profil i nivoe hidroperoksida u pore|enju sa gojaznom ili kontrolnom grupom. Ni u jednoj grupi nije bilo promena u ukupnom antioksidantnom kapacitetu. Odnos trigliceridi/HDL holesterol (>3), kao surogat marker insulinske rezistencije, ukazuje na rezistenciju na insulin u grupi sa metaboli~kim sindromom. Antropometrijski profil, insulinska rezistencija i oksidativni stres prisutni u gojaznosti dalje se razvijaju u metaboli~kom sindromu. Otud rana iden tifikacija osoba sa visokim rizikom na osnovu antro pometrijskih parametara, lipidnog profila, insulinske rezistencije i indeksa oksidativnog stresa mo`e doprineti spre~a -vanju razvoja komplikacija metaboli~kog sindroma.

Although the metabolic syndrome is a known predictor of coronary heart disease and type-2 diabetes mellitus, it has no agreed definition. The concordance of its various definitions has been studied for a limited number of populations and there are few studies on the rural populations in India. The present study was done to determine the prevalence of metabolic syndrome in a rural population of South India and to evaluate the concordance of the modified National Cholesterol Education Programme-Adult Treatment Panel III definition and International Diabetes Federation definition for the diagnosis of Metabolic Syndrome. Anthropometric and biochemical parameters (fasting blood glucose and lipid profile) and blood pressure were measured using standard procedures. The prevalence of metabolic syndrome was calculated using the two sets of criteria and compared for their concordance. Descriptive statistics was used to analyze age and risk factors of metabolic syndrome. The chi-square test was applied to compare the prevalence of metabolic syndrome obtained from the two criteria (significant if p<0.05). An inter-rater reliability analysis using the kappa statistic was performed to determine consistency between the two sets of criteria in diagnosing the metabolic syndrome. The modified National Cholesterol Education Programme-Adult Treatment Panel III definition and International Diabetes Federation definition for metabolic syndrome identified overall age-adjusted prevalence of 17.8% and 20.5% respectively, which were not significantly different. Kappa statistics revealed only moderate agreement of 0.44 between the two sets of criteria. The impact of economic development and preponderance of genetic factors is increasing the prevalence of metabolic syndrome in rural India. It is important to determine which definition of the metabolic syndrome best predicts coronary heart disease and type 2 diabetes in this population in order to formulate effective public health policy.