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High-dose melphalan with autologous stem cell support improves survival for patients with myeloma. For selected patients, we have been using a protocol of short hospitalization, discharging patients to home with careful outpatient monitoring in the office, which we hypothesized would reduce complications and utilization of inpatient beds.We reviewed 301 initial autologous transplants for myeloma, categorized as brief stay (≤ 4 days, 82 patients) or prolonged stay (≥ 5 days, 219 patients). Selection for a brief stay was determined by clinical characteristics, availability of caregivers at home, distance from our medical center, and patient preference.Within the brief stay population, 67% required readmission before day + 100, but this group still had fewer cumulative hospital days (9 vs. 18, P.0001). There were fewer documented infections among brief stay patients (22% vs. 46% P.001) and fewer admissions to intensive care units (0% vs. 5.9%, P = .02). The groups had similar rates of bleeding (1.2% vs. 1.4% P = 1.0) and thrombosis (3.7% vs. 4.6% P = 1.0). No patients in the brief stay group died within 100 days, compared with mortality of 1.8% (P = .6) in the prolonged stay group.Carefully selected patients receiving an autologous stem cell transplant for treatment of myeloma can be managed with a brief initial hospitalization and outpatient follow-up, with low morbidity and mortality.

The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.

This article attempts to examine the integration and efficiency of the pacific country Fiji’s stock and foreign exchange markets. The study employed, Unit Root test, Cointegration and Error correction models, and the VEC Grangers causality test, using the daily data of FJ$/USD $, and Fiji’s market capitalization index (stock market), from 3 rd August 2010 to 10 th July 2012. The level form data follows the unit root time series process , and the difference form, and return form data follow stationary process .This broadly supports the ‘weak form efficient market’ hypothesis. However, the market capitalization index, and FJ$/US$ rates are cointegrated. The cointegrating coefficient of the FJ dollar is positively related to the market capitalization index, and therefore, the FJ dollar appreciation stimulates the Fiji market capitalization index. This is perhaps the first scientific research which shows that for the small open Pacific economy of Fiji, a strong currency supports the stock market by encouraging a low inflation environment and therefore there may be some merit in the argument for aligning to strong neighboring currency of Australian dollar. The changes in the market capitalization index is related to the long run trend factors in FJ dollar index as revealed in the error correction model. The return data of FJ dollar, do not Granger cause the return data of the Fiji stock market return in the short run with out an error correcting factor equation and vice versa as well. This supports the semi strong form of efficient market hypothesis, though more studies on markets integration are recommended by us, and we recommend more policy intervention to create more liquidity and depth in Fiji stock markets.

Capital Asset Pricing model (CAPM) is widely researched, tested, and paradoxically both generally accepted and rejected model of asset pricing. From its beginning (1964) it has occupied the pride of place among the financial economist’s research, and still part of the text books on finance in the leading business schools all over the world. The study covered monthly data of Indian companies’ from the ‘National Stock Exchange’ (NSE) for the period 2005 to 2009. In our first model, betas are estimated where the risk free rate is the intercept term. The results show that for the State Bank Of India(SBIN), HDFC bank, and Tata Motors, the betas are more than one and significant, and for the Reliance,it is near one, and for Infosystch, it is less than one and statistically significant . The second model of ‘ Jen’s alphas’ results show that for only SBIN, and Reliance group, ‘Jensen’s alpha ‘ is positive, and for other three companies, it is negative. For positive values of ‘ Jensen’s alpha, the conclusion is that those companies ear ned return more than the companies of similar betas, and for negative values, those companies earned less than the companies of similar betas. Over the sample period, for SBIN, HDFC, and Reliance companies, the actual return is are greater than the required returns, and for Tata Motors,, and Infosystch, the actual return is less than the required returns .There is an equity risk premium for many of the Indian securities during the sample period. On the whole, the CAPM model could satisfactorily explain the risk-return relationship in the Indian Stock market.

s from the 2012 BMT Tandem Meetings. Poster presentation in San Diego, CA. This paper is posted at ScholarlyCommons. http://repository.upenn.edu/dental_papers/34 For more information, please contact repository@pobox.upenn.edu. Recommended Citation Vogl, D. T., Mick, R., Stoopler, E. T., Davis, L. E., Paul, T. M., Salazar, G., Raguza-Lopez, M., Porter, D. L., Luger, S. M., & Stadtmauer, E. A. (2012). Effect of Body Composition and Renal Function on the Pharmacokinetics of High-Dose Melphalan for Multiple Myeloma. Biology of Blood and Marrow Transplantation, 18 (2), S248-. http://dx.doi.org/10.1016/j.bbmt.2011.12.131 Effect of Body Composition and Renal Function on the Pharmacokinetics of High-Dose Melphalan for Multiple Myeloma Disciplines Biological Factors | Other Pharmacy and Pharmaceutical Sciences | Pharmaceutical Preparations | Surgical Procedures, Operative Comments Abstracts from the 2012 BMT Tandem Meetings. Poster presentation in San Diego, CA. Author(s) Dan T. Vogl, Rosemarie Mick, Eric T. Stoopler, Lisa E. Davis, Thomas M. Paul, German Salazar, Maria Raguza-Lopez, David L. Porter, Selina M. Luger, and Edward A. Stadtmauer This other is available at ScholarlyCommons: http://repository.upenn.edu/dental_papers/34

Abstract 1869 BACKGROUND: The aggresome/autophagy pathway is the primary mechanism for disposal of ubiquitinated proteins for cells exposed to proteasome inhibition. Preclinical evidence shows that combining inhibition of the proteasome with bortezomib (Bz) and inhibition of autophagy with the anti-malarial drug hydroxychloroquine (HCQ) leads to enhanced cytotoxicity in myeloma cells. METHODS: Patients with relapsed or refractory myeloma enrolled on a standard 3+3 dose escalation design. Patients received 2-weeks of single-agent oral HCQ, followed by the addition of Bz on days 1, 4, 8, and 11 of 21-day cycles. HCQ and Bz doses were determined by dose level: (1) 200 mg qod / 1.0 mg/m2, (2) 200 qod / 1.3, (3) 200 qd / 1.3, (4) 200 bid / 1.3, (5) 400 bid / 1.3, (6) 600 bid / 1.3. Dose-limiting toxicity (DLT) was defined as grade ≥3 toxicity probably related to study therapy and occurring during the first 5 weeks, with the exception of any anemia or lymphopenia, neutropenia responsive to growth factor, platelets >10,000/mm3 not associated with bleeding, or gastrointestinal complaints relieved by symptomatic therapy. We used electron microscopy to characterize changes in autophagic vesicles in serial samples of peripheral blood mononuclear cells and CD138-selected bone marrow plasma cells. RESULTS: We enrolled 25 patients between 1/2008 and 2/2011, of which 21 patients completed at least 1 cycle of combined therapy and were evaluable for toxicity. The median duration of study participation was 14 weeks (range 1–77). Reasons for study discontinuation were side effects of therapy (6), lack of response (7), disease progression (11), and non-compliance (1). No protocol-defined dose limiting toxicities occurred, and the maximum tolerated dose was determined to be the top dose level of Bz 1.3 mg/m2 and HCQ 600 mg twice daily. Hematologic abnormalities were generally more attributable to disease progression than to treatment toxicity, but at the top dose level one patient had grade 3 thrombocytopenia and neutropenia after starting with a normal platelet count and ANC, without evidence of progression through therapy. At the top dose level, gastrointestinal toxicities predominated, including 5 out of 6 evaluable patients with some form of grade 3 GI toxicity. Treatment emergent neuropathy occurred in 7 patients but was restricted to grade 1 or 2 and was easily managed with dose reduction of the Velcade. Three patients came off study before receiving the combined regimen and were not evaluable for response. The best responses for the remaining 22 patients included 3 near complete responses (nCR), 3 minor responses (MR), 9 stable disease (SD), and 7 progression (PD). The 3 nCRs occurred in Bz-naïve patients receiving HCQ at 400 mg/d (1 pt) and 1200 mg/d (2 pts). Two patients who had previously progressed while receiving weekly maintenance Bz had MRs on study, including one who maintained a MR for over 7 months. Three additional Bz-refractory patients initially achieved stable disease during study treatment, with on study TTP of 8 weeks (at HCQ 1200 mg/d), 15 weeks (100 mg/d), and 17 weeks (200 mg/d). Preliminary analyses of vesicle counts at HCQ doses up to 800 mg/d identify individual patients with increases in autophagic vesicles in either peripheral blood or bone marrow plasma cells, but these are not consistent, nor is there any evident correlation with response. CONCLUSION: Combined Bz and HCQ is tolerable, with a phase 2 dose of Bz 1.3 mg/m2 and HCQ 1200 mg/d and likely hematologic and gastrointestinal DLTs. There is a suggestion of improved efficacy over Bz alone, with minor responses and long periods of stable disease in Bz-refractory patients. Final analysis of autophagy inhibition in correlative specimens, including the top dose cohort, will be available for the meeting. Disclosures: Vogl: Millennium Pharmaceuticals: Honoraria, Research Funding. Off Label Use: Hydroxychloroquine is FDA approved for treatment of malaria and rheumatoid arthritis. This paper discusses its use in treatment of myeloma. Carroll:Agios Pharmaceuticals: Research Funding; TetraLogic Pharmaceuticals: Research Funding; Sanofi Aventis Corporation: Research Funding; Glaxo Smith Kline, Inc.: Research Funding. Amaravadi:Millennium Pharmaceuticals: Honoraria, Research Funding.

Abstract 1349 Background: High dose melphalan is the most common conditioning regimen for patients undergoing autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma (MM). However, toxicity and efficacy of this treatment are variable, with the sources of variability poorly understood. We hypothesized that variation in melphalan pharmacokinetics would explain differences in outcomes after transplant. Methods: We evaluated 41 patients with MM undergoing ASCT with high-dose melphalan conditioning. Patients received melphalan on day -2 at a dose of 200 mg/m2 (one patient with poor renal function received 180 mg/m2) and ASCT on day 0. Melphalan dose was calculated using ideal body weight (IBW), with adjusted IBW used for patients weighing >120% of IBW. We assessed toxicity on day +7 using the Oral Mucositis Assessment Scale (OMAS), a physician evaluated measurement of erythema and ulceration (on a scale of 0–5, with higher scores indicating more severe mucositis). Patients reported the severity of mouth soreness on a scale of 0–10 using the Mucositis Daily Questionnaire (MDQ) on days 0, +3, +7, +11, +19, and +28. Melphalan concentrations were measured using HPLC/tandem mass spectrometry in plasma samples obtained during infusion and 2, 4, 8, 15, and 30 minutes, and 1, 2, 3.5, 8, and 14 hours after its completion, as well as immediately prior to stem cell infusion. Melphalan area under the curve (AUC) was estimated by non-compartmental analysis. Results: Patients' median age was 57 years (range 39–72); 59% were male. We observed significant variation in melphalan exposure, with a range of 7.6–26.6 mg*h/L (median 13.5). Severity of oral mucositis was directly related to AUC (with an increase of 0.1 on the OMAS score for every 1 unit increase in AUC, p=0.003). The most severe mucositis was seen in the 4 patients with an AUC ≥17.5 (75% had OMAS scores >1), while severe mucositis was rarely seen in the 18 patients with AUC ≤12.5 (only 1 of 18 had an OMAS score >1). The association between AUC and maximum reported mouth soreness was not statistically significant (an increase of 0.2 on the MDQ scale for every 1 unit increase in AUC, p=0.17), but there was a trend toward higher maximum reported mouth soreness in the 4 patients with AUC≥17.5 (mean 7.5 vs. 4 for other patients, p=0.07). Eight patients had detectable melphalan concentrations at the time of stem cell infusion (mean 3.8 ng/mL, range 1.8–7.1), though time to neutrophil and platelet recovery did not differ for these patients compared with those with undetectable melphalan levels. Of 19 patients with measurable disease at the time of transplant, 8 had stable disease (SD), 9 partial response (PR), and 2 complete response (CR) at day +100. The 2 patients with CR had higher melphalan exposure than patients without a CR (mean AUC 19 vs 11.6, p= 0.002), but there was no discernable difference in melphalan levels between patients with a PR or SD. Conclusion: Using standard dosing calculations in a representative sample of patients with myeloma, melphalan drug exposure was highly varied. Drug exposure was correlated with severity of oral mucositis, and complete responses were seen only in patients with high drug exposure. Further analyses are planned into the effect of obesity and renal dysfunction on pharmacokinetics. Exploration of the appropriate target AUC and strategies for reducing variability in drug exposure have the potential to improve both efficacy and toxicity of this effective and commonly used therapy. Disclosures: No relevant conflicts of interest to declare.

Abstract 1177 Poster Board I-199 BACKGROUND: High dose melphalan followed by an autologous peripheral blood stem cell transplant (ASCT) is standard initial therapy for multiple myeloma (MM). However, toxicity and efficacy of this treatment are variable, with the sources of variability being poorly understood. We hypothesized that obesity and renal insufficiency modulate the pharmacokinetics of melphalan and therefore impact treatment toxicity. METHODS: We evaluated 39 patients with MM undergoing high-dose melphalan followed by ASCT. Patients received melphalan on day -2 at a dose of 200 mg/m2 (one patient with poor renal function received 180 mg/m2) and ASCT on day 0. We assessed body composition using dual energy x-ray absorptiometry (DEXA) and renal function using 24 hour urine creatinine clearance. We assessed toxicity on day +7 using the Oral Mucositis Assessment Scale (OMAS), a physician evaluated measurement of erythema and ulceration (on a scale of 0-5, with higher scores indicating worse mucositis). We also assessed patient reported symptom scores for mouth and throat soreness using the Mucositis Daily Questionnaire (MDQ) periodically during the first month (on a scale of 0-10, with higher scores indicating worse soreness). RESULTS: The median age was 55 years (range 37-70). 59% were male. The median weight was 83 kg (48-128), with median percentage body fat as measured by DEXA of 31% (range 15–53), and the median glomerular filtration rate (GFR) was 105 ml/min (range 28-194). Results from univariate and multivariate analyses are shown in the table below. In univariate analyses, we observed a weak and statistically insignificant direct correlation between percent body fat and toxicity (as measured by OMAS score or peak soreness), and a weak and statistically significant indirect correlation between GFR and OMAS score. In a multi-variable linear regression model including percent body fat, weight, GFR, and actual melphalan dose, we observed a correlation between OMAS score and percent body fat, with an increase in body fat percentage of 0.10 associated with a 0.65 unit increase in OMAS score (p=0.01). In a similar multi-variable model, we observed a correlation between MDQ soreness score and percent body fat, with an increase in body fat percentage of 0.10 associated with a 2.07 increase in MDQ soreness score (p=0.05). CONCLUSION: More obese patients, as measured by percent body fat, have more severe oral mucositis after high dose melphalan, independent of melphalan dose, weight, and renal function. We are measuring melphalan pharmacokinetics in this group of patients, and further research should help guide rational chemotherapy dosing for this highly effective treatment. Disclosures: No relevant conflicts of interest to declare.

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