Chee, Cheng Ean

PURPOSE This randomized, open-label trial compared the efficacy and safety of adjuvant nab-paclitaxel + gemcitabine with those of gemcitabine for resected pancreatic ductal adenocarcinoma (ClinicalTrials.gov identifier: NCT01964430 ). METHODS We assigned 866 treatment-naive patients with pancreatic ductal adenocarcinoma to nab-paclitaxel (125 mg/m 2 ) + gemcitabine (1,000 mg/m 2 ) or gemcitabine alone to one 30-40 infusion on days 1, 8, and 15 of six 28-day cycles. The primary end point was independently assessed disease-free survival (DFS). Additional end points included investigator-assessed DFS, overall survival (OS), and safety. RESULTS Two hundred eighty-seven of 432 patients and 310 of 434 patients completed nab-paclitaxel + gemcitabine and gemcitabine treatment, respectively. At primary data cutoff (December 31, 2018; median follow-up, 38.5 [interquartile range [IQR], 33.8-43 months), the median independently assessed DFS was 19.4 ( nab-paclitaxel + gemcitabine) versus 18.8 months (gemcitabine; hazard ratio [HR], 0.88; 95% CI, 0.729 to 1.063; P = .18). The median investigator-assessed DFS was 16.6 (IQR, 8.4-47.0) and 13.7 (IQR, 8.3-44.1) months, respectively (HR, 0.82; 95% CI, 0.694 to 0.965; P = .02). The median OS (427 events; 68% mature) was 40.5 (IQR, 20.7 to not reached) and 36.2 (IQR, 17.7-53.3) months, respectively (HR, 0.82; 95% CI, 0.680 to 0.996; P = .045). At a 16-month follow-up (cutoff, April 3, 2020; median follow-up, 51.4 months [IQR, 47.0-57.0]), the median OS (511 events; 81% mature) was 41.8 ( nab-paclitaxel + gemcitabine) versus 37.7 months (gemcitabine; HR, 0.82; 95% CI, 0.687 to 0.973; P = .0232). At the 5-year follow-up (cutoff, April 9, 2021; median follow-up, 63.2 months [IQR, 60.1-68.7]), the median OS (555 events; 88% mature) was 41.8 versus 37.7 months, respectively (HR, 0.80; 95% CI, 0.678 to 0.947; P = .0091). Eighty-six percent ( nab-paclitaxel + gemcitabine) and 68% (gemcitabine) of patients experienced grade ≥ 3 treatment-emergent adverse events. Two patients per study arm died of treatment-emergent adverse events. CONCLUSION The primary end point (independently assessed DFS) was not met despite favorable OS seen with nab-paclitaxel + gemcitabine.

Abstract Background: In multiple myeloma (MM), a complete response (CR) is defined by the European Group for Blood and Bone Marrow Transplantation (EBMT) and the International Myeloma Working Group (IMWG) Uniform Response Criteria as absence of monoclonal protein in serum and urine by immunofixation (IFE), and a bone marrow (BM) aspirate/biopsy containing <5% plasma cells (PC). This definition of CR is widely adopted in clinical trials, but there is a high degree of non-compliance with the BM requirement. As a result, differences in CR rates across trials can occur not just as a result of treatment efficacy, but also on how rigorously the BM requirement for CR is implemented. Moreover, requiring BM examinations merely to confirm CR is cumbersome in clinical practice. The goal of this study was to determine the added value of BM examinations in patients who can otherwise be considered to be in CR by virtue of a negative IFE in the serum and urine. Methods: For the purpose of the study, we included only patients with MM who had measurable monoclonal (M) protein levels at baseline (defined as >1 gm/dL in the serum and/or >200 mg/24 hour in the urine) on protein electrophoresis; patients with non-secretory and oligo-secretory MM were excluded. We then identified patients who since 1995 had a negative IFE in the serum and urine and a BM aspirate/biopsy, all done at the same time (within 30 days of each other). Baseline demographics and clinical characteristics; date of diagnosis, last follow up, and follow up status; serum and urine M protein levels at diagnosis; and results of serum and urine IFE, serum free light chain (FLC) ratio and BM aspirate/biopsy within 30 days of complete response were all collected from the existing databases. Results: Ninety-five patients met the criteria for the study, all of whom had measurable disease at baseline and subsequently achieved negative IFE in serum and urine (‘IF- CR’). Of these, only 83 patients (87%) met criteria for CR by the EBMT/IMWG criteria with less than 5% PC in the BM; 13% of patients had 5% or more PC despite the apparent IF-CR on serum and urine IFE. In fact, the BM showed 10% or more PC in 5% of IF-CR patients. We then assessed whether a normal serum FLC ratio in addition to negative serum and urine IFE would eliminate the need for a BM biopsy. The additional requirement of the serum FLC ratio to negative IFE was not fully adequate in eliminating false positive CR’s. Among 34 patients who had IF- CR plus a normal serum FLC ratio, only 88% of patients met CR definition with <5% BM PC; 12% had 5% or more PC, and one patient (3%) had 10% or more PC. We studied the survival (from time of diagnosis) of patients who had true CR’s (negative IFE and <5% PC) versus patients who had IF- CR’s but BM had 5% or more PC. Overall survival from diagnosis between the two groups was 10.7 years versus 5.6 years, respectively, P=0.001 (see Figure 1). Conclusions: BM examination is essential to accurately estimate CR. Up to 13% of patients with negative IFE in serum and urine fail to meet the BM requirement. The addition of a normal serum FLC ratio to negative IFE did not significantly reduce the proportion of patients who fail to meet the BM requirement. Based on this study, we recommend that the CR definition in the EBMT and IMWG criteria should not be revised to eliminate the need for BM examination. Moreover, the consistent collection of BM samples is essential for future strategies to evaluate immunophenotypic CR and molecular CR in MM. Figure 1: Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells. Figure 1:. Kaplan-Meier curve showing survival benefit (in years) of patients in complete response with less than 5% bone marrow plasma cells.

Abstract Background: Most experts agree that iron chelation therapy is unlikely to benefit myelodysplastic syndrome (MDS) patients with a bone marrow (BM) blast percentage of ≥ 5% because of the associated short life expectancy. In contrast, using a serum ferritin of 1,000 ng/mL as a surrogate for iron overload, a recent study suggested a negative impact of iron overload on overall survival in MDS patients with < 5% BM blasts including those with refractory anemia with ringed sideroblasts (RARS) (Malcovati et al. JCO2005:23:7594). In the current retrospective study, we examined the validity of this observation in a large group of RARS patients seen at a single institution. Methods: The diagnosis of RARS was based on the French-American-British cooperative group criteria. Serum ferritin levels obtained both at diagnosis and during follow-up as well as total number of packed red blood cells transfused were recorded. Standard statistical methods were used for survival and other analyses. Results: A total of 126 RARS patients (median age 73 years, range 44-90; 67% males) were seen at our institution over the last several years. At diagnosis, median (range) values were 9.4 g/dL (5.7-13.4) for hemoglobin (Hgb), 2.8 × 109/L (0.3-13.7) for absolute neutrophil count (ANC) and 214× 109/L (22-819) for platelet count; 38% of the patients had received red blood cell (RBC) transfusions at the time of initial diagnosis. International Prognostic Scoring System (IPSS) risk distributions in evaluable patients were 66% for low, 28% for intermediate-1 and 6% for intermediate-2 risk. Median follow-up was 36 months and during this time 83 patients (66%) had died and leukemic transformation was documented antemortem in 8 patients (6%). As expected, IPSS was highly predictive of survival outcome (p<0.0001). In addition, history of RBC transfusions at diagnosis (p=0.001) but not the total number of RBC transfusions received during the entire disease course (p=0.17) carried an independent prognostic value for inferior survival. There were no significant correlations between overall survival and serum ferritin level at either diagnosis (median 567 ng/mL, range 16-3,475; p=0.24) or the maximum value during follow-up (median 1,108 ng/mL; range 238-43,500; p=0.72). Similarly, Kaplan-Meier plots of 77 evaluable patients stratified by serum ferritin levels of < or ≥1000 ng/mL at diagnosis or 107 evaluable patients stratified by maximal serum ferritin levels of < 1000, 1000-5000, or > 5000 ng/mL during follow-up revealed similar curves (Figure). Conclusions: The current study suggests no significant association between transfusional hemosiderosis and survival even in good risk patients with MDS. The study also undermines the utility of serum ferritin as a surrogate for assessing the value of therapeutic iron chelation. Figure Figure Figure Figure

Abstract Abstract 4048 Background: The plasma cell labeling index (PCLI) is measured as the percentage of bone marrow plasma cells (PC) in the S phase of the cell cycle and provides an estimate of the proliferative capacity of malignant PC in multiple myeloma (MM). The International Myeloma Working Group (IMWG) uniform response criteria measure the monoclonal (M) protein and serum free light chain (FLC) assay to evaluate clinical response. An elevated PCLI is an established adverse prognostic risk factor for survival, however it is unknown if the PCLI response to therapy offers further prognostic value. Methods: Data from 176 newly diagnosed MM patients from 1985 to 2005 were collected from the Mayo Clinic dysproteinemia database. Inclusion criteria for the study required a minimum initial PCLI of 0.5% and a subsequent PCLI 4 months after initiation of therapy. Baseline and subsequent serum M-protein, progression date, and overall survival were recorded. Clinical responses were assessed by the IMWG uniform response criteria. The association of PCLI response and treatment response (CR, VGPR, or PR) was assessed univariately. Overall survival based on PCLI response, M-spike reduction, and treatment response by IMWG criteria was estimated using the Kaplan-Meier method. Results: The median overall survival (OS) was 47 months (range: 4 – 165). Ninety-four patients (53%) demonstrated a ≥60% reduction in PCLI after initial therapy (responders) and this conferred a significant OS advantage of 51 months vs. 34 months (P<0.01; Figure 1) compared to those who achieved <60% PCLI reduction (non-responders) after initial therapy. The median PCLI percent difference following 4 months of therapy was -67% (+/− 137%; range: -100 to 953%). When patients were stratified into high (PCLI of ≥3%), intermediate (PCLI ≥1%) and low (PCLI <1%) risk groups, OS was significantly improved in the high and intermediate PCLI groups if they achieved ≥60% reduction in PCLI after initial therapy, 31 vs. 7 months (P<0.0022; Figure 2) and 63 vs. 25 months (P<0.0005; Figure 3), respectively. As observed in prior studies, patients with PCLI of ≥3% at diagnosis had shorter overall survival (17 months) when compared to patients with an initial PCLI of <1% (61 months; P < 0.0001). Of the 94 responders, 39% (n=37) did not achieve a response to therapy as measured by M-protein. Thirteen patients (14%) had no measurable serum M-protein at baseline. Conversely, 35% (n=31) of patients that responded by M-protein criteria did not achieve a PCLI response. In patients who achieved CR/PR after 4 months of therapy, the median PCLI reduction was 83.7% vs. 22.5% (P <0.0004) compared to patients with stable disease (not meeting criteria for CR or PR) or progressive disease (as specified by IMWG response criteria). This reflects a significant reduction in disease burden and as expected, median OS was better in the CR/PR group (53 vs. 31 months, P <0.0016). Conclusion: Our study demonstrates that the degree of PCLI reduction after therapy is important in predicting overall survival and response to therapy. This is an important finding in the current setting of effective MM treatment options, whereby patients who do not achieve an adequate response as defined as ≥60% reduction in PCLI in our study, may require change in therapy. Our data confirm that reduction of M-protein is an important surrogate endpoint, as patients who achieved PR and CR lived significantly longer. A significant portion of individuals 39% had a measurable response by PCLI that was not detected by M-protein. Further studies are needed to evaluate the predictive value of the addition a criterion that looks at reduction in proliferative rate as measured by PCLI or other methods such as flow cytometry. Disclosures: Greipp: Mayo Clinic: Patents & Royalties.

Abstract Abstract 4990 Background: Although there have been improvements in 5-year overall survival (OS) rates among patients with AL amyloidosis over the past decades, OS is still poor, and death rates within the first 3–6 months after diagnosis have not changed significantly. This retrospective study was performed to identify risk factors for and causes of death during the first 90 days following diagnosis of AL amyloidosis. Method: From July 2002 to April 2009, 301 patients with a diagnosis of AL amyloidosis who were seen at Mayo Clinic within 30 days of diagnosis were identified from the dysproteinemia database. The 100 who died within 90 days were the focus of our study. The other 201 who were alive beyond 90 days were used as a comparator group. Outside physician offices were contacted to obtain further information pertaining to treatment and cause of death for our study group. Results: Of the 100 patients with early death, median age at diagnosis was 63.7 years (range: 34.7–89.4). 25 patients were diagnosed with concurrent multiple myeloma (MM) based on MM-specific end-organ damage. Overall, the number of patients with 2, 3 and 4 organs (cardiac, renal, nerve or liver) involved with amyloidosis was 37, 15 and 4, respectively. Using the cardiac biomarker staging system, 78% of 46 evaluable patients were stage III at diagnosis followed by 22% stage II and no stage I. Table 1 describes the characteristics of the studied population. Amyloid-related deaths were identified in 61 patients with the most common cause being cardiac arrest or sudden death (33%) followed by end-organ failure (24%). Treatment was started in 50% of patients; 34% received no treatment; and no treatment information was available for the remainder. OS was 54.5 days in patients who received treatment as compared to 7.5 days in those who received no treatment (p<0.0001); outcomes were similar in the group in whom no treatment information was available and those patients who were known to have received treatment. Melphalan with dexamethasone was the most common treatment (21%) and was associated with improved OS compared to other treatments including novel agents (57 vs. 26 days, p=0.003). Outcomes were no different if the patients had received novel therapies, but numbers were small. When compared to patients who lived for more than 90 days from their diagnosis, patients with early mortality had higher median intraventricular septum (IVS) (15 vs. 13 mm, p<0.0001), lower ejection fraction (EF) (50 vs. 64%, p<0.0001), and higher troponin-T (0.125 vs. 0.01 ng/ml, p<0.0001) and NT-proBNP (9020 vs. 1292 pg/ml, p<0.0001). We also found that patients who died within 90 days of their diagnosis had significantly higher plasma cell labeling index (PCLI), uric acid, beta-2 microglobulin, involved free light chain (FLC) and creatinine. Conclusion: This study highlights the characteristics of patients who died within 90 days of diagnosis of AL amyloidosis. The majority of patients died from arrhythmia and organ failure. This implies that other interventions aside from treatment of the underlying plasma cell (PC) disorder will likely be required to change the early outcomes of this disease. Disclosures: Lacy: Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Abstract 1893 Background: Recent data has shown that the level of immunoglobulin free light chain (FLC) is a prognostic factor for patients with AL amyloidosis. Approximately 25% of patients with AL amyloidosis have coexistent multiple myeloma (MM) with myeloma-related end-organ damage and patients may also present with 310% plasma cells (PC) in the bone marrow (BM) in the absence of any MM features. The goal of this study was to determine the effect of increased BM plasmacytosis in the absence of MM end-organ damage on early mortality. Methods: We performed a retrospective study of 263 consecutive patients with AL amyloidosis seen at Mayo Clinic within 30 days of diagnosis from July 2002 – April 2009, to compare the effect of PC burden among those who died within 90 days of diagnosis (n=88) and those who survived more than 90 days after diagnosis (n=175). Only those patients with documented BM PC were included in this study. MM end-organ damage was defined according to the CRAB criteria. Results: In those who died <90 days after diagnosis and patients who lived beyond 90 days, the proportion of patients with 310% BM PC were 57% and 55%, respectively. Overall survival (OS) was significantly shorter in the early mortality group when there was 310% BM PC present at diagnosis (25 vs. 54 days, p=0.006), but this was not observed in the group who survived beyond 90 days (Figure 1). In patients with 310% BM PC, troponin-T, ejection fraction (EF), and hemoglobin (Hgb) were significantly worse in the early mortality cohort but patients who survived beyond 90 days had significant increase in intraventricular septal (IVS) thickness and beta-2 microglobulin (Table 1). As expected, patients with 310% BM PC in both cohorts had significantly higher serum M-spike and involved FLC (Table). The same cohort of patients were analyzed substituting MM-related end-organ damage for 310% BM PC and similar results were observed with the exception of uric acid and calcium being significantly higher in the early mortality cohort with MM (results not shown). Conclusion: This study demonstrated that an excess of early—but not late—deaths occur in AL amyloidosis patients with 310% BM PC at diagnosis. In our cohort, this finding can be attributed to higher troponin-T levels, indicating more severe cardiac involvement as observed by worse cardiac function. These findings warrant additional investigation. Disclosures: Lacy: Celgene: Research Funding. Kumar:Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.

Abstract Autophagy is a homeostatic, catabolic degradation process whereby cellular proteins and organelles are engulfed by autophagosomes, digested in lysosomes, and recycled to sustain cellular metabolism. Autophagy has dual roles in cancer, acting as both a tumor suppressor by preventing the accumulation of damaged proteins and organelles and as a mechanism of cell survival that can promote the growth of established tumors. Tumor cells activate autophagy in response to cellular stress and/or increased metabolic demands related to rapid cell proliferation. Autophagy-related stress tolerance can enable cell survival by maintaining energy production that can lead to tumor growth and therapeutic resistance. As shown in preclinical models, inhibition of autophagy restored chemosensitivity and enhanced tumor cell death. These results established autophagy as a therapeutic target and led to multiple early phase clinical trials in humans to evaluate autophagy inhibition using hydroxychloroquine in combination with chemotherapy or targeted agents. Targeting autophagy in cancer will provide new opportunities for drug development, because more potent and specific inhibitors of autophagy are needed. The role of autophagy and its regulation in cancer cells continues to emerge, and studies aim to define optimal strategies to modulate autophagy for therapeutic advantage. Mol Cancer Ther; 10(9); 1533–41. ©2011 AACR.

AbstractStandard myeloma treatment response criteria are determined principally by changes in the monoclonal protein. Reduction in the size of the proliferative component of malignant plasma cells may be an additional metric of assessing response to therapy. We retrospectively analyzed 176 patients with newly diagnosed myeloma with a measurable plasma cell labeling index (PCLI) at diagnosis and repeat measurement 4 months after initiation of therapy. PCLI response was defined as a ≥ 60% reduction. Baseline PCLI is an independent prognostic factor; therefore, we categorized patients into 3 groups: PCLI ≥ 3% (high), ≥ 1% (intermediate), and < 1% (low). Patients achieving a greater PCLI response had improved median overall survival of 54 months compared with 29 months in nonresponders (P = .02). Improved median overall survival with PCLI response occurred in the high initial PCLI group (28 vs 7 months; P = .003) and intermediate group (64 vs 24 months; P = .002). The application of PCLI response and serum M-spike response together provided further prognostic information. On multivariate analysis, the prognostic value of PCLI response was independent of β2-microglobulin, elevated creatinine, serum M-spike response, and baseline PCLI. We conclude that a significant reduction in plasma cell proliferation in patients with newly diagnosed myeloma is an important predictor of survival.

Abstract The current definition of complete response in multiple myeloma includes a requirement for a bone marrow (BM) examination showing less than 5% plasma cells in addition to negative serum and urine immunofixation. There have been suggestions to eliminate the need for BM examinations when defining complete response. We evaluated 92 patients with multiple myeloma who achieved negative immunofixation in the serum and urine after therapy and found that 14% had BM plasma cells more than or equal to 5%. Adding a requirement for normalization of the serum-free light chain ratio to negative immunofixation studies did not negate the need for BM studies; 10% with a normal serum-free light chain ratio had BM plasma cells more than or equal to 5%. We also found that, on achieving immunofixation-negative status, patients with less than 5% plasma cells in the BM had improved overall survival compared with those with 5% or more BM plasma cells (6.2 years vs 2.3 years, respectively; P = .01).