ALBERT

Description: Background: GvHD following allogeneic hematopoietic stem cell transplantation (allo-HSCT) increases morbidity and mortality and is difficult to predict for. We explored the use of a novel immune function assay to determine whether an immunologic response to changes in immunosuppressive therapy for GvHD could predict clinical response. Methods: The FDA-approved Cylex ® Immune Cell Function assay (ICF) measures the response of whole blood CD4+ lymphocytes to stimulation with phytohemagglutinin (PHA) with as read-out ATP production. The assay is quick and results are available on the same day. Use of this test in solid-organ transplant recipients demonstrated its utility in monitoring changes in immunosuppressive therapy. A retrospective analysis of the ICF assay results from allo-HSCT patients treated at our center for acute or chronic GvHD was conducted. Results: 13 GvHD events (11 chronic, 2 acute) occurring in 8 patients between 35 and 2118 days post-transplant (682 +/− 556 d) were analyzed. At diagnosis of GvHD, the average ICF value was 425 +/− 111 ng/mL ATP. Same day white blood cell (WBC) and absolute neutrophil count (ANC) values were 10.6 +/− 3.2 x 103 cells/μL and 9.2 +/− 3.3 x 103 cells/μL, respectively. Treatment for GvHD consisted of increasing calcineurin inhibitor dose and addition of prednisone and/or other immunosuppressants. Ten GvHD events responded to therapy within 10 +/−7 days with a corresponding significant decrease of ICF values from 430 +/− 109 ng/mL to 239 +/− 130 ng/mL (p=0.002) and a decrease of WBC from 11.2 to 8.0 x103 cells/μL (p=0.027). ANC and C - reactive protein values were not statistically different (p=0.09 and p〉0.5 respectively). In contrast, no significant decrease in the ICF values before and after therapy (406 to 465 ng/mL ATP) was observed for the 3 GvHD events that failed to respond to therapy. Conclusion: These preliminary data suggest that the ICF assay is a good predictor of response of GvHD to immunosuppressive therapy and could be used to intensify immunosuppression early in non-responders.

Description: Abstract 988 Background: Dexamethasone remains a key component of myeloma therapy. We previously showed that expression levels of the nuclear glucocorticoid receptor NR3C1 were associated with OS and PFS in patients treated on Total Therapy 3 (TT3). Post relapse survival (PRS) is an important component of OS following initial PFS. In this study we investigate the effect of NR3C1 expression levels at baseline (BL) and at relapse (RL) on OS, PFS and PRS for patients treated on Total Therapy 2 (TT2). Methods: TT2 was a randomized phase-III trial evaluating the impact of the up-front addition of thalidomide (T) to a multi-agent chemotherapy and high-dose melphalan program supported by tandem autotransplants. Between October 1998 and February 2004, 668 patients with newly diagnosed progressive or symptomatic multiple myeloma up to age 75 were enrolled. 351 patients had gene expression profiling (GEP) obtained at BL and 121 had GEP data obtained at RL. There was no significant difference in OS, PFS or PRS between patients with or without GEP data at BL or at RL. This analysis is based on the cohort of patients with GEP data with a cut-off date of April 22, 2011. OS and PFS were measured from the time of initiation of protocol-based therapy while PRS was measured from the initiation of salvage therapy. Results: Among patients randomized to the control arm (-T), OS improved progressively with the transition from lower to middle to upper NR3C1 tertiles. No such difference was noted in the experimental group with T (+T). Examining treatment arms within NR3C1 expression tertiles showed significant benefit from T in both OS and PFS among patients presenting with lower tertile expression; in the mid tertile, this effect was limited to PFS while such benefit was absent in the top-tertile subgroup. Multivariate analysis accounting for the interaction between NR3C1 expression and T showed that randomization to T and lower tertile NR3C1 expression reduced the hazard of death, while high risk designation by GEP, elevated B2M, elevated LDH, cytogenetic abnormalities and MS subgroup designation all conveyed a higher HR for death. With an overall median PRS of 3.0 years, there was no difference related to the initial treatment randomization or between baseline NR3C1 expression levels. In the context of treatment arms in patients randomized to -T, high- and mid-tertile NR3C1 levels at baseline dramatically improved PRS; such an effect was not observed in +T. We next investigated the implications of NR3C1 levels at relapse on PRS, revealing a significant shortening of PRS with transition from top- to mid- to low-tertile expression. Patients maintaining low NR3C1 levels also at relapse had the shortest PRS, followed by those who lost mid to high expression levels of NR3C1 at relapse, while those with higher than low-tertile levels at relapse enjoyed the longest PRS regardless of NR3C1 expression levels at baseline. Multivariate analysis including data from baseline and relapse as well as accounting for interaction between NR3C1 and T identified GEP high risk status at relapse as the only feature linked to inferior PRS whereas upper tertile expression of NR3C1 conveyed improved PRS. Conclusion: Low expression of NR3C1 at baseline is associated with poor PFS and OS in patients treated on the control arm of TT2. This confirms our previously reported findings in TT3. Addition of T overcomes the poor OS in patients with low NR3C1 expression. Low expression of NR3C1 at relapse correlated with poor PRS. This study indicates that patients with low NR3C1 expression levels at baseline benefit from the addition of T and offers a scientific rationale for NR3C1 gene expression level testing. Future trials, that include thalidomide or lenalidomide in their treatment regimen, will have to take NR3C1 expression levels into account. Disclosures: Shaughnessy: Myeloma Health, Celgene, Genzyme, Novartis: Consultancy, Employment, Equity Ownership, Honoraria, Patents & Royalties. Barlogie:Celgene: Consultancy, Honoraria, Research Funding; IMF: Consultancy, Honoraria; MMRF: Consultancy; Millennium: Consultancy, Honoraria, Research Funding; Genzyme: Consultancy; Novartis: Research Funding; NCI: Research Funding; Johnson & Johnson: Research Funding; Centocor: Research Funding; Onyx: Research Funding; Icon: Research Funding.

Description: Background: The importance of MEL dose intensity for patients (pts) with MM is supported by a survival benefit when MEL-ASCT is utilized. This survival advantage is further enhanced when tandem ASCT are applied, suggesting that higher MEL doses would be desirable if gastrointestinal mucositis, the dose limiting toxicity of MEL is not excessive. Objective: To identify the predictors of severe mucositis in MM pts undergoing MEL - ASCT. Patients and methods: 382 consecutive MM pts enrolled in our Total Therapy 2 protocol, who received their first MEL - ASCT between 10/1998 and 12/2002. A MEL dose of 200 mg/m2 BSA was utilized when serum creatinine was 〈 3 mg/dl (reduced to 140 mg/m2 if 〉 3 mg/dl). BSA was based on actual weight if 〈 60 kg or calculated weight if 〉 60 kg. Mucositis peak was graded 0–4 (NCI Common Toxicity Criteria). Potential covariates included among others age, sex, MM remission status, time period between last chemotherapy and MEL-ASCT, MEL dose in mg/kg, CMV serostatus, DLCO, creatinine clearance (CrCl). Results: BSA dosing of MEL resulted in a wide range of MEL,when calculated based on actual weight (2.5–6.4 mg/kg). Mucositis developed in 83 % of pts and was severe (Grades 3 & 4) in 23 %. By univariate analysis, the following pre-ASCT risk factors for mucositis were identified: lower BSA (OR 0.31/m2; 95% CI 0.111 – 0.881; p=0.027), lower platelet counts (OR 0.998/1000 platelets / mL; 95% CI 0.996 – 1; p=0.025), lower CrCl (OR 0.991/ml/min; 95% CI 0.985 – 0.998; p= 0.011), higher LDH (OR 1.007U/L, 95% CI 1.002 – 1.011; p=0.005), lower DLCO (OR 0.989/unit; 95% CI 0.978 – 1; p= 0.04) and CMV seropositivity (OR 1.51; 95% CI 1.002 – 2.29; p= 0.04). Multivariate analysis identified higher mg/kg MEL dose as the most important risk factor for mucositis (OR=1.58/mg/Kg; 95% CI 1.148 – 2.177; p= 0.005). Additional pre-ASCT risk factors included higher LDH (OR 1.006; 95% CI 1.001 – 1.012; p= 0.007), lower CrCl (OR= 0.991/ml/mn; 95% CI 0.984 – 0.999; p= 0.02), and lower DLCO (OR 0.989; 95% CI 0.978 – 1; p = 0.04). Using the intended mg/kg MEL dose, pre-ASCT CrCl, LDH and DLCO a predictive model for severe mucositis (grade 3 and 4) was developed based on ordinal logistic regression analysis: p= exp(−2.1527−0.00248*PLT−0.00894* CrCl + 0.00646*LDH−0.0114*DLCO + 0.4578* Mel) / [1+exp (−2.1527−0.00248*PLT−0.00894*CrCl + 0.00646*LDH − 0.0114* DLCO + 0.4578* Mel)] This model will be prospectively validated. Conclusions: Dosing MEL on the basis of BSA results in widely variable MEL exposure and risk for severe mucositis following MEL-ASCT. MM pts scheduled to receive MEL-ASCT using a high mg/kg MEL dose and whose pre-ASCT variables include low CrCl, high LDH and /or low DLCO should be considered at greater risk for severe mucositis following ASCT.

Description: We have previously reported on the remarkable activity of the TT3 program that incorporated both bortezomib (V) and thalidomide (T) into the up-front management of 303 patients. TT3 consisted of 2 cycles each of induction prior to and of dose-reduced consolidation therapy with VTD-PACE (cisplatin, doxorubicin, cyclophosphamide, etoposide) after melphalan 200mg/m2 (M200)-based tandem transplants, followed by maintenance therapy for 3 years with VTD and, in later stages, VRD (substituting T for lenalidomide, R). Characteristics included a median age of 59yr (range, 33–75yr), B2M 〉=4mg/L in 37%, albumin

Description: Background: Among IA pts receiving antifungal therapy, a strong relationship exists between outcome of IA and resolution of immunosuppression. Determining the respective contributions of immune reconstitution and antifungal therapy to response has not been attempted. Yet, treatment strategies for IA have focused almost exclusively on antifungal agents to the detriment of immune therapies. Galactomannan (GM) is an Aspergillus-specific polysaccharide released during aspergillosis and detected by the serum GM test. This FDA-approved test is an accepted diagnostic marker for aspergillosis and preliminary data suggest a correlation between GM index (GMI) and outcome. Purpose: using GMI, to describe the contribution of immune recovery to outcome of IA in pts with hematological cancer (Hem-Ca). Patients and Methods: From 11/03–2/06, pts at risk for IA underwent GMI screening during periods at risk. The clinical and radiological findings of pts with ≥ 2 positive (+) GMI (optical density ≥ 0.5) were reviewed. Results: 30 pts had GMI (+) aspergillosis of the respiratory tract [myeloma 92%; median age: 59 years (27–75); 15 males]. Aspergillosis developed following stem cell transplant (SCT) [autologous (11), allogeneic (1)], or conventional chemotherapy (18). 25 pts were neutropenic (

Description: Background: CRP is an acute-phase reactant that increases rapidly in response to inflammation (including infection). Objective: to assess the value of daily CRP level as a predictor of severe complications [pneumonia, bacteremia or severe mucositis (Grades 3–4, NCI Common Toxicity Criteria)] after MEL-ASCT for MM. Patients and Methods: 199 MM patients (pts) who received a MEL-ASCT and had daily CRP levels on days 0–21 after ASCT. Results: Median age was 58 years (32 – 77) and 60% were males. Mucositis was present in 89% of pts and was severe in 20%; bacteremia and pneumonia developed in 23 % and 13 % of pts respectively.Daily CRP levels (days 0-21): All pts with severe complications had higher daily CRP levels vs. those with mild or no complications (p〈 0.0001). Higher CRP levels were observed among pts with pneumonia (p〈 0.0001 vs. no pneumonia), bacteremia (p〈 0.0001 vs. no bacteremia) and severe mucositis (p=0.002 vs. mild (grades 1–2) and no mucositis). When present among pts with mild mucositis, infection was associated with a higher CRP level (p〈 0.0001 vs. no infection). CRP peak levels: Comparable CRP peak levels were observed among pts with various complications: pneumonia (n=27), bacteremia (n=46) or severe mucositis (n=41) [Mean and range in mg/dl: 16.6 (3.63 – 35.3); 17.18 (1.29 – 36.9); 17.81 (4.8 – 36.01) respectively; p= 0.95]. The presence of infection among pts with mild mucositis significantly increased CRP peak [mean and range 15.73 (1.29 – 36.9) vs. 11.59 (1.31 – 35.06) respectively, p= 0.0028].Rate of CRP increase: A significantly faster rate of CRP increase was observed among pts with severe complication vs. those with mild or no complications: mean and range of increase: 2.39 mg/dl/day (0.30 – 9.86) vs. 1.9 mg/dl/day (0.15 – 7.83). A model predictive of severe complications based on rate of CRP increase per day was developed based on the following formula: p = exp(−0.6630 + 0.1837 * CRP slope (mg /dl/day)) 1+ exp (−0.6630 + 0.1873 * CRP slope (mg/dl/day)) This model will now be prospectively validated. Conclusions: Daily CRP levels provide an early identification of MM pts with severe complications after MEL-ASCT. Higher CRP levels correlate with severe mucositis and/or infection. Among pts with mild mucositis, a rapidly increasing and/or a high CRP level suggest the presence of severe infection.

Description: Background: MEL-ASCT is standard therapy for multiple myeloma (MM) but is associated with severe infections, at times life-threatening. Objective: To determine the risk factors for severe infection (bacteremia, septic shock, colitis, pneumonia) following MEL - ASCT for MM. Materials and Methods: 382 consecutive MM patients (pts) enrolled in our Total Therapy 2 protocol and who received their first MEL - ASCT between 10/1998 and 12/2002 were included. Variables evaluated included age, sex and MM remission status, severity of mucositis and others. Because of the known association between increased body iron stores and infection, pre-ASCT bone marrow (BM) iron stores were also evaluated. The AUC for severe neutropenia (

Description: Abstract 4800 Background: Despite availability of novel agents, many MM patients still relapse and require salvage interventions. In the Arkansas program, we have attempted to procure initially sufficient hematopoietic precursor cells, for use in high-dose therapy salvage regimens once phase I-II trials have been exhausted. We are reporting on the efficacy in terms of response rate, EFS and OS of ARMM patients receiving S-BEAM. Patients and Methods: S-BEAM comprised standard BEAM (carmustine 300 mg/m2 on day 1, etoposide 200 mg/m2 days 1–4, cytarabine 400 mg/m2 days 1–4, melphalan 140 mg/m2 on day 5) with the addition of cisplatin (10-12.5mg/m2/d CI × 5d), bortezomib (1.3-1.5mg/m2 on days 1 + 4), thalidomide (100-200mg/d for 5 days) or lenalidomide (25-100mg/d for 5 days), DEX (40-100mg/d for 5 days) plus rapamycin (3mg d1, 1mg d2-5). Statistical methods included Cox regression modeling using significance level 0.05 and Kaplan-Meier methodology for all figures. Comparisons within figures were made using the log-rank test. Results: The characteristics of 147 patients treated included prior transplant (Tx) in 67% (2Tx, 29%; =〉3Tx, 11%), and prior exposure and resistance in virtually all patients (92%) to bortezomib, thalidomide, lenalidomide applied in VTD, VRD or with chemotherapy VTD-PACE. Pre-S-BEAM high-risk features included low albumin (=3.5mg/L; 32%), high LDH (〉=ULN; 44%), and presence of cytogenetic abnormalities (CA) in 70%. Clinical outcomes included at least PR in 62% including 48% with n-CR and 29% with CR. Two-year estimates of EFS and OS were 29% and 33%; TRM within 60 days was 3%. At 4 years, 23% remain alive and 15% event-free. Independently significant variables affecting both OS and EFS adversely included, in a model without GEP, high B2M (〉5.5mg/L), high LDH (〉=ULN), low hemoglobin (=10 in 42%. When GEP data were included in a subset of 103 patients, high-risk designation, high LDH and age 〉=65 were identified on the basis of highest R2 values (49% for OS, 41% for EFS). Among 28 patients lacking any of these 3 features, 1-year OS/EFS was 83%/67%, with 1 variable (n=36) 53%/38%, with 2 (n=31) 22%/6% and with 3 (n=8) 0%/0% (both P

Description: Abstract 1969 Background: High-risk MM remains a very difficult clinical challenge despite advances in therapy for the majority of patients who have benefited from the use of high-dose therapies and novel agents. Recognizing that MM from the outset represents a genomically highly complex malignancy with even further accelerated acquisition of mutations with every further relapse, we have tried to develop multi-agent combinations employing drugs with efficacy in other high-grade tumors such as large cell lymphomas and incorporated novel agents as well. Patients and Methods: Eighty-four patients with AHRMM were given PACMED comprising cisplatin (15-25mg/m2 CI × 3d), cytarabine (1.0-1.5g/m2/d × 3), cyclophosphamide (1.0-1.5g/m2/d CI × 3), mesna (1.0-1.5g/m2/d CI × 3), etoposide (0.3-0.5g/m2/d × 3) and DEX (40-100mg/d × 3); additional agents included bortezomib (1.0-1.6mg/m2 on days 1 + 4), thalidomide (100-200mg/d × 4d) or lenalidomide (25-100mg/d × 4) and rapamycin (3mg d 1, 1mg d 2–4) with or without HPC boost. Statistical methods included Cox regression modeling for OS and EFS, along with Kaplan-Meier methodology for survival and cumulative incidence plots. Survival comparisons were made using the logrank test. Results: Baseline characteristics included age 〉=65 in 18%, B2M 〉=3.5mg/L in 68% and 〉5.5mg/L in 38%, CRP 〉=8mg/L in 60%, LDH 〉=ULN in 57%, and cytogenetic abnormalities (CA) in 62%. Gene expression profiling (GEP)-defined high-risk (70 genes, R70; 80 genes, R80) was present in 80% and 71%; PR (Proliferation), MF and MS subtypes were present in 44%, 27% and 14%. Prior transplants (Tx) had been given to 96%, including 40% who received 2Tx, 25% with 3Tx and 14% with 〉3Tx. PR was achieved by 29%, including 14% n-CR and 8% CR. 1-year estimates of OS and EFS were low at 13% and 8%, and median durations were 5 and 3 months. Increased age and high LDH were the only baseline characteristics adversely affecting both OS and EFS. The 29 patients with neither of these risk factors experienced 1-yr OS/EFS rates of 31%/17%; the corresponding values with 1 risk factor (n=47) were 5%/4% and with both risk factors (n=8) 0%/0%. Conclusion: Single cycle PACMED provides only transient tumor control in this heavily pretreated population with 80% displaying GEP-defined high-risk and 62% CA, as a manifestation of end-stage MM. We are currently evaluating repeated cycles of PACMED earlier in the disease course in high-risk MM, in the context of a Super-BEAM transplant regimen. Disclosures: No relevant conflicts of interest to declare.

Description: Background: The Durie-Salmon (DS) staging system represented the first clinically useful classification of MM. While distinguishing patients with differing event-free (EFS) and overall survival (OS), considerable outcome heterogeneity persisted. Patients and Methods: As part of a high-dose melphalan-based tandem transplant trial, Total Therapy 2 (TT2), 611 patients had both MBS and MRI performed at baseline, along with standard prognostic factors and cytogenetics. Results: In a comparison of all areas imaged by both techniques, at least one focal lesion (FL) was detected in 451 (74%) patients by MRI and 344 (56%) by MBS; 128 (21%) had no FL by either technique; 312 (51%) showed FL by both MBS and MRI; of 267 patients without FL on MBS, 139 (52%) had FL on MRI; of 160 without FL on MRI, 32 (20%) had FL on MBS. Mean FL number among those with FL was 13.4 by MRI and 7.8 by MBS. Significantly higher proportions of patients had FL on MRI than MBS in spine (78% vs. 16% p