ALBERT

Description: 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.

Description: 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.

Description: 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.