Stadtmauer, Edward A.

Abstract Introduction: The impact of transplanted CD34+ cell dose on clinical outcomes remains controversial. The purpose of this study was to examine the relationship between CD34+ cell dose transplanted and platelet, neutrophil, and lymphocyte counts at 100 days, 6, and 12 months following autologous transplantation in patients with non-Hodgkin’s lymphoma (NHL) and multiple myeloma (MM). Methods: Data were obtained from two phase 3 clinical studies that compared the safety and efficacy of plerixafor and G-CSF with placebo and G-CSF in mobilization of hematopoietic blood stem cells for autologous transplantation in NHL patients and in MM patients. The details of the study designs and preliminary safety and efficacy outcomes have been reported (DiPersio, ASH 2007). The following data were obtained from the two clinical study databases: number of CD34+ cells transplanted (first transplant only) as determined by a central laboratory, absolute neutrophil, platelet, red blood cell, and lymphocyte counts at 100 days, 6, and 12 months post-transplant. The proportions of patients who had platelet ≥150 x 109/L or neutrophil ≥2.5 x 109/L or lymphocyte ≥0.5 x 109/L at 100 days, 6, and 12 months were compared among these transplanted CD34+ cell dose categories regardless of mobilization treatment: 2–4 x 106 cells/kg, >4–6 x 106 cells/ kg, and > 6 x 106 cells/kg. Two separate analyses were performed, one for NHL patients and one for MM patients. Results: For the NHL study, 135/150 (90.0%) patients in the plerixafor group underwent transplantation after initial mobilization compared with 82/148 (55.4%) patients in the placebo group, p<0.001. The mean number of CD34+ cells transplanted was 6.06 ± 2.98 x 106 (median 5.41, range 1.79–17.6) for the plerixafor-treated patients and 4.09 ± 1.56 x 106 (median 3.85, range 1.98–8.7) for the placebo-treated patients, p<0.001. For the MM study, 142/148 (95.9%) patients in the plerixafor group and 136/154 (88.3%) patients in the placebo group underwent transplantation. The mean number of CD34+ cells transplanted was 5.84 ± 2.64 x 106 (median 5.34, range 1.9 to 16.7) for the plerixafor-treated patients and 4.37 ± 2.01 x 106 (median 3.98, range 1.8 to 16.9) CD34+ cells/kg for the placebo- treated patients. A significant linear trend with increasing proportion of patients with platelet count ≥150 x 109/L with increasing transplanted cell dose categories was observed at 100 days, 6, and 12 months for NHL patients and at 100 days for MM patients (Table 1). There were no apparent significant relationships between transplanted cell dose categories and other hematopoietic parameters. Table 1: Analysis of percentage of patients reaching a platelet count of ≥ 150 x 109/L by transplanted cell dose categories Transplant Cell Dose (CD34+ cells/kg) 2–4 x 106 ≥ 4–6 x 106 ≥ 6 x 106 P value* NHL Patients N=76 N=75 N=66 100 days 28 (48.3%) 42 (66.7%) 45 (81.8%) <0.001 6 months 31 (56.4%) 36 (66.7%) 42 (76.4%) 0.026 12 months 18 (56.3%) 21 (80.8%) 24 (82.8%) 0.020 MM Patients N=75 N=82 N=64 100 days 41 (68.3%) 57 (90.5%) 47 (88.7%) 0.004 6 months 48 (78.7%) 61 (89.7%) 51 (87.9%) 0.147 12 months 25 (73.5%) 33 (82.5%) 26 (81.3%) 0.435 For all transplanted cell dose categories, the proportions of patients are based on the number of patients with available data at each time point.*p-value for testing linear trend using Mantel-Haenszel Chi-square test Conclusions: Results from these ad hoc analyses confirm previous reports that transplanted cell dose may be associated with better long-term platelet recovery. Due to the small sample size in each transplanted cell dose category and the nature of ad hoc analyses, further studies are warranted to determine if the introduction of plerixafor will allow the mobilization and transplantation of higher quantity of CD34+ cells, which may positively influence long-term hematopoietic recovery.

Introduction Renal dysfunction is a recognized risk factor for mortality after HCT, as it is included in the comorbidity index (HCT CI). Yet, further understanding on outcomes in patients with different level of renal dysfunction or undergoing hemodialysis (HD) at time of transplant remains scant. This study explores the impact of different levels renal dysfunction on major HCT outcomes in a large population using data reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Methods The study population included 8,102 patients age 40 years and older who received HCT for treatment of malignancies from 2008 to 2016, with available pre-transplant creatinine measurement. eGFR, calculated using CKD-EPI (CKD-epidemiology collaboration) method, was used to assigned patients in four categories: eGFR ≥ 90ml/min (eGFR≥ 90, N=4,237, reference), eGFR 60-90ml/min (eGFR 60-90, N=3,158), eGFR 45-59ml/min (eGFR 45-59, N=538) and eGFR <45ml/min(eGFR<45, N=169). A separate cohort of patients on HD at time of HCT (N=46) was analyzed independently. Multivariate analysis models were built for assessment of overall mortality, transplant-related mortality (TRM), disease relapse or progression, graft-versus-host disease (GVHD), hepatic sinusoidal obstructive syndrome (SOS), thrombotic microangiopathy (TMA), idiopathic pneumonia syndrome (IPS) and need of HD post-transplant. Common patient-, disease- and transplant-related covariates were tested on all models and HCT CI was computed without reported renal dysfunction comorbidity to avoid collinearity. Results Patient characteristics are shown in table 1. The groups were comparable on disease risk index, graft and donor source, but patients with eGFR>90 were younger and received myeloablative conditioning more frequently. The cohort of eGFR <45 had a higher proportion of patients with HCT CI ≥3. TRM and overall survival according to eGFR groups are shown in Figure. In the multivariate analysis models eGFR as the main effect was associated with TRM (p<0.0001), overall mortality (p<0.0001), and requirement of HD post HCT (p<0.0001), but not for relapse/progression (p=0.98), GVHD (grades II-IV, p=0.34; III-IV, p=0.70; and chronic, p=0.20), TMA (p=0.46), SOS (p=0.02) or IPS (p=0.06). Compared to eGFR ≥90, the hazard ratio (HR) for TRM for eGFR 60-89 was 1.12 (p=0.07), for eGFR 45-59 was 1.46 (p<0.001) and for eGFR<45 was 1.74 (p=0.004). Corresponding HRs for overall mortality were 1.0 (p=0.9), 1.17 (p=0.03) and 1.63 (p<0.0001), respectively. Similarly, for the need of HD post HCT, HR for eGFR60-89 was 1.29 (p=0.03), eGFR45-59 was 2.45 (p<0.001) and for eGFR<45 was 3.09 (p<0.0001). Only eGFR<45 was associated with higher risk of SOS (HR2.66, p=0.03). Among 46 patients on HD prior to HCT, one-year probability of overall survival was 20% (95% Confidence Interval [CI] 10-32%) and cumulative incidence of TRM at one year was 67% (95% CI, 50-81%). Conclusion These findings indicate that degree of renal dysfunction is an independent predictor of OS, TRM, probability of receiving HD and SOS when adjusted for other risk factors. The impact of eGFR on the need of HD, a complication that increases morbidity post HCT is an important finding. Additionally, the outcomes of a subset of patients on HD at time of transplants are dismal. These results can further assist the prognostic assessment of candidates for an allogeneic HCT. Disclosures Stadtmauer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy, Research Funding; Tmunity: Research Funding; Abbvie: Research Funding. Wingard:Ansun: Consultancy; Pluristem: Consultancy; Celgene: Consultancy; Merck: Consultancy; Shire: Consultancy. Ganguly:Seattle Genetics: Speakers Bureau; Daiichi Sankyo: Research Funding; Kite Pharma: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board. Pasquini:Pfizer: Other: Advisory Board; Amgen: Consultancy; Medigene: Consultancy; BMS: Research Funding; Novartis: Research Funding; Kit Pharma: Research Funding.

Abstract Introduction: Venetoclax (Ven), an oral agent that targets the antiapoptotic protein, BCL-2, has demonstrated efficacy, as monotherapy and combined with proteasome inhibitor (PI) bortezomib, in relapsed/refractory (R/R) multiple myeloma (MM). We report preliminary safety and efficacy data for Ven combined with the second generation PI carfilzomib (K) and dexamethasone (VenKd) in R/R MM. Methods: In this ongoing phase 2, dose escalation study (NCT02899052), patients with R/R MM and no prior K exposure received VenKd on 28-d cycles in 4 dose finding and one expansion cohorts: Ven 400 mg/day + K 27 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 8, 15, 22 (Cohort 1), same regimen but with Ven 800 mg/day (Cohort 2), Ven 800 mg/day + K 70 mg/m2 Day 1, 8, 15 + dex 40 mg Day 1, 8, 15, 22 (Cohort 3/expansion cohort), or Ven 800 mg + K 56 mg/m2 Day 1, 2, 8, 9, 15, 16 + dex 40 mg Day 1, 2, 8, 9, 15, 16, 22, 23 (Cohort 4). Treatment continued until progressive disease (PD) or unacceptable toxicity. Results: As of June 11, 2018, 42 patients were enrolled. The median age was 66.5 years (min, max: 37, 79), 63% had ISS II/III disease, and 8 patients (19%) had t(11;14). Patients received a median of 2 prior therapies (range: 1 - 3), 93% had received prior PI (50% refractory), 62% were refractory to immunomodulatory therapies, and 33% double refractory. At the data cut off, 29 patients were still active and had completed ≥2 cycles and 13 patients discontinued with the primary reason being disease progression (n=4), death (n=3), physician decision (n=2), withdrawal of consent (n=2), lack of efficacy (n=1), and AE (n=1). All patients experienced at least one AE, and grade 3/4 AEs experienced by >10% of subjects included: decreased lymphocyte count (26%), decreased neutrophil count (14%), and hypertension (12%). Thirteen subjects experienced at least one serious AE. Maximum tolerated dose was not reached and Ven 800 mg/day + K 70 mg/m2 was selected for expansion. Ven mean (% coefficient of variation) maximum plasma concentration (Cmax) and area under the plasma concentration-time curve over 24 hours (AUC24) on Cycle 1 Day 15 were 2.7 (57) mg/mL and 33.1 (54) mg×h/mL, respectively, at 400 mg venetoclax (n=4); and were 2.42 (53) mg/mL and 38.7 (51) mg×h/mL, respectively, at 800 mg venetoclax (n=13) in the dose escalation cohorts. The overall response rate (ORR) was 78% and the very good partial response (VGPR) or better rate was 56% (Table). Median time from first dose to the data cut or discontinuation was 5.7 months (range: 0.9 - 16.3) and the median time to first response was 1.9 months (95% CI: 0.9, 9.2). ORRs for subgroups of interest are reported in the Table. Conclusions: The combination of VenKd appears tolerable with no new safety signals or changes in Ven pharmacokinetics. VenKd shows promising preliminary efficacy in R/R MM patient subgroups. Response rates were comparable in all high risk subgroups and overall population. However, the subset of patients with t(11;14) had the highest response. Overall, these results demonstrate that VenKd is a safe and efficacious regimen in R/R MM and support the continued study of VenKd. Disclosures Costa: Abbvie: Research Funding; BMS: Research Funding; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Research Funding. Stadtmauer:Celgene: Consultancy; AbbVie, Inc: Research Funding; Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy. Morgan:Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding. Kovacsovics:Amgen: Honoraria, Research Funding; Abbvie: Research Funding. Jakubowiak:Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; SkylineDx: Consultancy, Honoraria; Adaptive Biotechnologies: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Kaufman:Roche: Consultancy; BMS: Consultancy; Karyopharm: Other: data monitoring committee; Janssen: Consultancy; Abbvie: Consultancy. Mobasher:Genentech Inc: Employment; F. Hoffmann-La Roche Ltd: Other: Ownership interests non-PLC. Freise:AbbVie, Inc: Employment, Equity Ownership. Ross:AbbVie, Inc: Employment, Equity Ownership. Pesko:AbbVie, Inc: Employment, Equity Ownership. Munasinghe:AbbVie, Inc: Employment, Equity Ownership. Gudipati:AbbVie, Inc: Employment, Equity Ownership. Mudd:AbbVie, Inc: Employment, Equity Ownership. Bueno:AbbVie, Inc: Employment, Equity Ownership. Kumar:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract Background: The phase 3 double-blind, CALGB/Alliance 100104 study assessed the efficacy and safety of lenalidomide (LEN) or placebo maintenance therapy until relapse in post-autologous stem cell transplantation (ASCT) patients with newly-diagnosed multiple myeloma (NDMM). Interim analyses demonstrated superiority for LEN versus placebo for time to progression (TTP), thus meeting the primary TTP endpoint of the trial. The study was unblinded in December 2009 and, based on the TTP and overall survival (OS) benefit observed with LEN, patients in the placebo arm (who had not yet progressed) at the time of unblinding were given the option of crossing over to receive LEN. Data have been reported for a follow-up of 91 months based on the planned intention to treat (ITT) analysis, yielding a TTP hazard ratio (HR) 0.57 and an OS difference of HR 0.61 (Holstein SA, et al. Lancet Haematol. 2017;4:e431-42). Crossover to active treatment enabled patients to benefit from LEN maintenance and collection of additional efficacy and safety data; however, crossover can confound the estimates of OS for longer follow-up. We report the results of an analysis adjusted for crossover, thus aiming to provide a more accurate estimate of the survival benefit achieved with LEN maintenance therapy. Methods: Results are reported for an analysis based on an updated data cutoff, post-October 2016. The rank-preserving structural failure time model (RPSFTM) was considered the most appropriate method to adjust for crossover (Robins JM, Tsiatis AA. Commun Stat Theory Methods. 1991;20:2609-31). This method requires that the assumption that the treatment effect is the same for patients who receive LEN at randomization as those who receive LEN as crossover treatment is not violated; a landmark analysis was performed to explore this. The iterative parameter estimation (IPE; Branson M, Whitehead J. Stat Med. 2002;21:2449-63) algorithm was used as validation. Both the RPSFTM and IPE analyses assume a residual LEN effect after discontinuation (base case). Results: A total of 76 NDMM patients who had not progressed, as determined by central adjudication, crossed over from placebo to LEN and were included in the analysis. The landmark analysis of OS from the date of unblinding indicated that the treatment effect for the crossover versus the non-crossover placebo group was HR 0.57 (95% confidence interval [CI] 0.29-1.15) (Figure). This also provided a measure of the benefit of LEN maintenance in patients who started maintenance therapy after the trial-specified 90-100 day window post-ASCT (median 11.5 months post-randomization; range 3.2-51.0 months). Adjustment for crossover using the RPSFTM or IPE resulted in an increase in the relative treatment effect of LEN maintenance (vs placebo) on OS from 30.8 months for the ITT analysis (HR 0.61; 95% CI 0.47-0.81) to 40.1 months (HR 0.52; 95% CI 0.36-0.73) for the RPSFTM analysis and 38.8 months (HR 0.52; 95% CI 0.37-0.74) for the IPE analysis (Table). Results were consistent across the two methods. Discussion: This analysis was performed on an updated version of the data set reported in the Holstein article. Once we adjusted for crossover, depending on the methodology used, there was an additional gain of ~40 months of OS. Previously, a pre-planned, pooled meta-analysis of 3 studies that included CALGB/Alliance (McCarthy PL, et al J Clin Oncol. 2017;35:3279-89) indicated that the OS gain was 2.5 years; however, our analysis from the CALGB study alone shows that LEN maintenance may provide a survival benefit of > 3 years. In diseases where prolonged follow-up is required to demonstrate survival benefits, allowing patients to crossover to active treatment may be important to facilitate this. However, the results should be analyzed appropriately to enable assessment of the value of the therapy. As this analysis indicates, the value of active treatment may be underestimated if adjustment for crossover is not performed. In conclusion, the data reported here provide further insight into the survival benefits of LEN maintenance therapy post-ASCT and support guideline recommendations to offer LEN maintenance therapy to all patients post-ASCT. Support: U10CA180821, U10CA180882, U10CA180820; ClinicalTrials.gov Identifier: NCT00114101. Disclosures McCarthy: Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Richardson:Amgen: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Cooper:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Saunders:Celgene: Consultancy; BresMed Health Solutions Ltd: Employment. Dhanasiri:Celgene: Employment, Equity Ownership. Anderson:Bristol Myers Squibb: Consultancy; Millennium Takeda: Consultancy; C4 Therapeutics: Equity Ownership, Other: Scientific founder; Celgene: Consultancy; OncoPep: Equity Ownership, Other: Scientific founder; Gilead: Membership on an entity's Board of Directors or advisory committees. Stadtmauer:Celgene: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Takeda: Consultancy. Holstein:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Abstract Introduction: We previously reported that plerixafor + G-CSF was as safe as and more effective than placebo + G-CSF in mobilizing hematopoietic stem cell for autologous transplant in patients with multiple myeloma (MM) through 100 days follow-up (DiPersio ASH 2007). We report herein the 12 months data. Methods: This is a phase 3, multi-center, randomized (1:1), double-blind, placebocontrolled study. Multiple myeloma patients requiring an autologous hematopoietic stem cell transplant, in first or second complete or partial remission were eligible. Patients received G-CSF (10μg/kg/day) subcutaneously for up to 8 days. Beginning on evening of Day 4 and continuing daily for up to 4 days, patients received either plerixafor (240μg/kg) or placebo subcutaneously. Starting on Day 5, patients began daily apheresis for up to 4 days or until ≥ 6 x 106 CD34+cells/kg were collected. We report herein the 12 months graft durability and hematology data. Results: As reported previously, the primary endpoint of collecting ≥ 6 x 106 CD34+ cells/kg in ≤ 2 days of apheresis was met in 106/148 (71.6%) patients in the plerixafor group and 53/154 (34.4%) patients in the placebo group, p<0.001. 142 (96%) patients in plerixafor group and 136 (88%) patients in placebo group underwent transplantation. Median time to PMN and PLT engraftment was similar in both groups. Through 12 months follow-up, there were no differences in graft durability and hematology profiles between groups (Table 1). Over the 12 months, 6/142 (4.2%) patients in the plerixafor group and 5/136 (3.7%) patients in the placebo group died. Of the patients who died, 2 patients in the plerixafor group and 2 patients in the placebo grouped died due to disease progression. Plerixafor + G-CSF Placebo + G-CSF Hematology data presented as mean ± SD and n=number of patients with available data P values were NS for all variables at all time points between groups aAll patients who underwent transplantation bAll patients who underwent transplantation and had laboratory data at the study visit Graft durability (n, %) 100 daysa 140/142 (98.6%) 133/136 (97.8%) 6 monthsb 133/135 (98.5%) 125/127 (98.4%) 12 monthsb 127/128 (99.2%) 119/120 (99.2%) Platelet (x 109/L) 100 days 226 ± 80 (n=90) 210 ± 88 (n=87) 6 months 218 ± 67 (n=95) 209 ± 89 (n=93) 12 months 204 ± 69 (n=53) 205 ± 80 (n=54) Neutrophils (x 109/L) 100 days 3.3 ± 2.3 (n=88) 3.0 ± 1.7 (n=80) 6 months 3.4 ± 1.6 (n=90) 3.5 ± 1.8 (n=88) 12 months 3.1 ± 1.1 (n=52) 3.6 ± 2.1 (n=52) Hemoglobin (mg/dL) 100 days 12.5 ± 1.5 (n=89) 12.6 ± 1.3 (n=86) 6 months 12.7 ± 1.4 (n=94) 12.7 ± 1.6 (n=92) 12 months 12.9 ± 1.8 (n=53) 13.1 ± 1.5 (n=54) Conclusions: The addition of plerixafor to G-CSF resulted in higher CD34+ cell collection in fewer days of apheresis than G-CSF alone. Importantly, this 12 months report showed that transplants with cells collected with plerixafor resulted in graft durability rates that were similar to cells collected with G-CSF alone.

Abstract Abstract 2877 FLC assay measures circulating unbound k and l light chains and is of diagnostic and prognostic value in plasma cell disorders. Normalization of FLC ratio is considered a higher level of complete response (CR) in MM but this has not been well validated prospectively. HLC is a novel antibody based assay that targets the unique junctional epitopes between the heavy chain and light chain constant regions of intact immunoglobulin (Ig) molecules. It separately measures in pairs the light chain types of each immunoglobulin class generating ratios of monoclonal Ig/background polyclonal Ig concentrations (i.e IgGκ/IgGλ, IgAκ/IgAλ and IgMκ/IgMλ); potentially simplifying assessment of monoclonal protein response. To assess the prognostic impact of these assays and to correlate them with electrophoretic/immunofixation (SPE/IFE) assessment, we analyzed 497 stored serum samples from patients enrolled in the Blood and Marrow Transplant Clinical Trials Network (BMT CTN) 0102 clinical trial, sponsored by the NHLBI and NCI, of tandem autologous (autoHCT) vs. tandem autoHCT- allogeneic (alloHCT). Samples were collected prior to the first autoHCT and analyzed for FLC (Freelite™) and HLC (Hevylite™) at The Binding Site, UK. Corresponding disease status determination was centrally performed by an expert data review committee using uniform response criteria and correlated with FLC and HLC results. HLC remission was defined as normalization of composite heavy and light chain ratios across all 3 measured heavy/light chain pairs or the normalization of clonal isotype with normal ratios of uninvolved pairs. The demographics of 497 patients with HLC/FLC samples at baseline were concordant with the main study and showed similar patient proportions from the 2 study arms. Of the 211 pts with baseline SPE response better than or equal to a very good partial response (>VGPR), 188 also had an HLC remission (Sensitivity=89%). Comparison of the HLC remission with the >VGPR disease state also identified a specificity of 52%, positive predictive value (PPV) of 58% and a negative predictive value (NPV) of 87%. Similarly, all 56 patients in complete remission (CR) by SPE/IFE were in HLC remission. Compared with conventional CR assessment, sensitivity of HLC remission was 100%, specificity 39%, PPV and NPV values of 17% and 100% respectively. FLC remission correlated with >VGPR disease state had a sensitivity of 47%, specificity of 81% and a PPV and NPV of 64% and 67% respectively. Multivariate models for post transplant progression free survival (PFS) indicated that baseline disease response (>VGPR vs. partial remission (PR) or<PR) was associated with longer PFS. Adjusted models including baseline response, myeloma stage and study arm were used to compare the predictive utility of HLC and FLC assays. There was a lower risk of treatment failure (HR 0.74, p=0.02) and superior PFS for patients who achieved an HLC remission. When stratified by baseline disease response states, there was no additional prognostic impact for HLC remissions on PFS. Normalization of FLC ratio among patients with >VGPR disease state did not impact PFS (HR 0.96, p=0.83). Abnormal HLC after induction therapy has a high negative predictive value (100%) for identifying patients not achieving CR by uniform response criteria and is also associated with shorter PFS after transplant. FLC ratio normalization had no impact suggesting that stringent CR criteria may need further validation. Disclosures: Krishnan: Celgene: Speakers Bureau; Millenium: Speakers Bureau. Alvi:the binding site: Employment. Harding:The Binding Site Group Ltd: Employment. Maloney:Cellgene: Consultancy.

Abstract Introduction: Multiple myeloma (MM) accounts for about 20% of deaths from hematological cancers and remains incurable despite conventional and high-dose chemotherapy. Two phase III trials in patients with relapsed or refractory MM (MM-009 and MM-010) showed that lenalidomide combined with dexamethasone resulted in significantly improved response rates and significantly prolonged median time to progression (TTP) and overall survival (OS) compared with dexamethasone alone. This current sub-analysis of lenalidomide plus dexamethasone therapy assessed whether there was a survival benefit in maintaining patients on therapy after achieving their best response and what the impact of early discontinuation on TTP and OS was. Methods: Of the 353 patients from MM-009 and MM-010 treated with lenalidomide plus dexamethasone, 32 did not respond. Of the remaining 321 responding patients, 214 had a partial response (PR) or better and 107 patients had stable disease (SD). In this post-hoc sub-analysis, we first assessed the outcome of continuing treatment for ≤10 months vs. >10 months in all 321 patients who achieved SD or better, after they achieved their best response. In this landmark analysis, OS was measured from the time of achieving best response to death from any cause or to last contact. In a second analysis, we assessed the impact of early discontinuation due to adverse events or withdrawn consent on OS and TTP in all patients who achieved SD or better. Therefore, we excluded patients who discontinued treatment due to disease progression, death, or lack of efficacy. Patients who achieved SD or better and who continued on therapy were compared with those who discontinued. OS and TTP were assessed from time of randomization. Results: In the landmark analysis, of the 321 responding patients (≥PR, n=214; SD, n=107), 223 patients received treatment for ≤10 months after achieving their best response and 98 patients for >10 months after achieving their best response. Patients who continued therapy for >10 months after achieving their first best response had significantly longer OS vs. those who received therapy for ≤10 months (not reached vs. 23.4 months; p<0.0001). At 24 months after achieving their best response, significantly more patients were alive if they continued therapy >10 months vs. ≤10 months (93.8% vs. 48.4%, p<0.0001). In the second analysis, in order to evaluate the impact of discontinuation in patients achieving SD or better, we excluded 134 patients due to disease progression, death, or lack of efficacy. Of the remaining 187 responding patients, 72 discontinued treatment for AE (n=42) or withdrew consent (n=30), while the remaining 115 patients continued treatment. Median OS and TTP were significantly longer for patients who continued vs. those who discontinued treatment (median OS: not reached vs. 29.5 months, p<0.0001; median TTP: not reached vs. 13.6 months, p<0.0001). Conclusions: In patients achieving SD or better, prolonged duration of treatment was associated with significantly longer OS and TTP. In contrast, early discontinuation of treatment led to reduced OS and TTP. Therefore, efforts should be made to manage adverse events while maintaining patients on therapy. Furthermore, maintaining treatment with lenalidomide and dexamethasone after achieving the optimal response ensures a significant improvement in OS for patients with relapsed or refractory MM.

Abstract Background: Obesity is increasing in prevalence worldwide and has potential implications on chemotherapy dosing and selection of patients for therapy. Auto HCT improves outcomes for patients with MM, but optimal chemotherapy dosing for obese patients is poorly defined. Methods: We identified 1087 patients reported to the CIBMTR between 1995 and 2003 who underwent auto HCT for MM as part of initial therapy, defined as within 18 months of diagnosis, and received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal (18.5– 24.9), overweight (25–29.9), obese (30–34.9), or severely obese (≥35). Underweight patients (BMI <18.5, N=9) were excluded from analysis. We analyzed overall survival (OS) and progression-free survival (PFS) from date of transplant, using Kaplan-Meier curves and the log-rank test for univariate analyses and using Cox proportional hazards models for multivariate analyses. Results: Cases were reported from 114 centers in 10 countries. There were 292 patients of normal weight (27%); 472 were overweight (43%), 198 were obese (18%), and 125 severely obese (11%). Median follow-up of survivors was 63, 61, 60 and 59 months, respectively. Significant baseline differences among BMI groups indicate that obese patients selected for transplant were younger (median age 58, 58, 56, and 55 years, respectively, p=0.005) and had less severe disease at diagnosis, with lower bone marrow plasmacytosis and less frequent renal failure, hypercalcemia, and severe anemia. Obese patients received higher total melphalan doses but lower doses per square meter of body surface area (calculated based on actual body weight). Univariate analyses show no significant effect of BMI category on either OS or PFS. However, among patients who received TBI as part of conditioning, multivariable analyses show a significant effect of BMI on PFS (p-value for interaction 0.006). In this subgroup, a higher BMI was associated with longer PFS (p=0.006, Figure 1). Among patients who received melphalan alone, no effect of BMI was apparent (Figure 2). The difference in PFS for patients receiving melphalan/TBI was due to a decreased risk of relapse among obese patients. Pairwise comparisons of conditioning regimen (TBI vs. no TBI) within BMI categories showed significant reduction in risk of treatment failure for obese (HR=0.54, p=0.04) and severely obese (HR=0.32, p=0.001) patients who received TBI. No differences in OS were apparent in multivariate analyses. Relative risks (RR) for PFS from a multivariable model adjusting for possible confounders are shown below: TBI No TBI n RR (95% CI) P n RR (95% CI) P Normal 44 1.00 Poverall=0.006 248 1.00 Poverall=0.18 Overweight 62 0.92 (0.60–1.40) 0.69 405 0.90 (0.75–1.08) 0.24 Obese 21 0.49 (0.27–0.90) 0.021 177 0.85 (0.68–1.07) 0.16 Severely obese 22 0.39 (0.20–0.76) 0.005 100 1.12 (0.86–1.45) 0.42 Conclusion: Obesity, when measured by BMI, has no statistically significant effect on OS among patients with myeloma receiving high-dose melphalan. Among patients receiving melphalan with TBI, a higher BMI is associated with improved PFS. The reason for the restriction of this effect to TBI-containing conditioning regimens requires further investigation. The current common strategy of reducing melphalan doses (i.e. calculating based on ideal or adjusted body weight) does not appear to impair outcomes for obese patients. Obesity should not exclude patients from consideration of autologous transplantation. Figure Figure

Abstract Abstract 985 Introduction: CFZ is a novel and highly selective epoxyketone proteasome inhibitor currently in clinical development for the treatment of multiple myeloma (MM). Ph 1 and 2 studies with CFZ have demonstrated durable single-agent antitumor activity in pts with relapsed or refractory (R/R) MM. The present study, PX-171-003-A1, was an open-label, single-arm Ph 2b trial and enrolled patients with multiply relapsed MM whose disease was refractory (defined as <25% response on, or progression during or <60 days after completion of, therapy) to their last treatment regimen. Patients must have received ≥2 prior therapies including: 1) bortezomib (BTZ) and either thalidomide (THAL) or lenalidomide (LEN), and 2) an alkylating agent. Materials and Methods: Pts received CFZ at 20 mg/m2 on a QDx2 schedule (Days 1, 2, 8, 9, 15, and 16 every 28 days) in cycle (C) 1 and were dose escalated to 27 mg/m2 on the same schedule thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study (PX-171-010). The primary endpoint was overall response rate (ORR) (≥ partial response [PR]). Secondary endpoints included: clinical benefit response (CBR) (ORR + Minimal response [MR]), duration of response for ≥PR (DOR), overall survival (OS), time to progression (TTP), progression free survival (PFS), and safety. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed and confirmed by an Independent Response Committee (IRC). Results: 266 pts were enrolled with a median duration of MM of 5.4 years including 83% whose disease had progressed on or within 60 d of last therapy and 17% whose disease had achieved <25 % response to the regimen immediately preceding study entry. Of the 266 pts enrolled pts, 257 were evaluable for response; 9 patients were considered not evaluable based on missing baseline or lacking at least one post-baseline M-protein. An ORR (≥PR) of 24% with a median DOR of 7.4 mo (range 6.2–10.3) was determined. Responses are detailed in the table. The CBR (ORR + MR) was 36%. Median DOR of pts with MRs was 6.3 months, indicating that long-term MRs were observed. An additional 32% (83 pts) achieved SD for at least 6 wks. To date, 79 pts (30%) completed ≥6 C and >11% of pts have completed all 12 C of protocol specified therapy and most have entered the extension protocol; 15 pts remain on study (all >10 C). OS and TTP data for the overall population will also be reported. The enrolled pts in this study were heavily pretreated having received a median of 5 prior lines of therapy (range 1–20, median of 13 anti-myeloma agents). 85% of pts had received at least 2 and 37% had received at least 3 drugs in the regimen just prior to entering the study. Prior anti-myeloma agents included 99.6% (265/266 pts) BTZ (median 2 prior regimens containing BTZ), 99.6% either THAL (74%) or LEN (94%), 98% corticosteroids, 91% alkylating agents, and 74% stem cell transplant; 65% of pts were refractory to BTZ at any point in time prior to study entry. The most common treatment-emergent adverse events ≥ Grade (G) 3 regardless of relationship to study drug were predominantly hematologic and included thrombocytopenia (22%), anemia (20%), lymphopenia (10%), pneumonia (8%), neutropenia (8%), fatigue (7%), hyponatremia (5%), and hypercalcemia (5%). Although 206 pts (77%) had G1/2 peripheral neuropathy (PN) at baseline, new onset PN was infrequent and G ≥3 PN occurred in <1%. Interestingly, in this subset of patients, efficacy response was nearly identical to that seen in the full study population with an ORR (≥PR) of 24%. Conclusions: Single-agent CFZ achieved durable responses in pts with R/R MM whose disease had relapsed after all available therapies including BTZ and immunomodulatory agents. The CBR and median DOR achieved with this steroid-sparing regimen establish that CFZ has the potential to offer substantial clinical benefit to patients with relapsed or refractory disease. CFZ was well-tolerated and side effects were clinically manageable with no new or unexpected toxicities observed. Importantly, exacerbation of pre-existing PN was uncommon. Cumulative side effects were not observed, allowing prolonged single-agent dosing for chronic disease control. Disclosures: Siegel: Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Vij:Onyx: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Stewart:Millennium: Consultancy; Celgene: Honoraria. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx : Research Funding.

Abstract Abstract 3031 Background: Treatment-induced peripheral neuropathy (TIPN) can be a debilitating side-effect as well as a therapy-limiting complication in multiple myeloma (MM). Thalidomide (THAL) and bortezomib (BTZ) are two therapies frequently associated with TIPN in MM. Carfilzomib (CFZ) is a novel and highly selective epoxyketone proteasome inhibitor that differs from BTZ both structurally and mechanistically. CFZ overcomes BTZ-resistance in vitro, lacks the off-target activities of BTZ in preclinical studies, and does not cause neurotoxicity in long-term (6–9 month) chronic animal toxicology studies (Kirk et al. Blood, 2008). Single-agent CFZ produces durable responses in relapsed or refractory (R/R) MM without dose-limiting PN. Here we report on the clinical experience with single-agent CFZ in the Ph 2b PX-171-003-A1 trial in patients (pts) with R/R MM and Grade (G) 1/2 PN at study entry. Methods: Pts received CFZ at 20 mg/m2 IV, on Days 1, 2, 8, 9, 15, and 16 in a 28-day cycle (C) for the first C followed by 27 mg/m2 thereafter for up to 12 C. Pts completing 12 C were eligible to enter an extension study. Responses and progression were determined according to the International Myeloma Working Group (IMWG) criteria and were assessed by an Independent Review Committee (IRC). PN data were collected for all pts on study and included neuropathy history, neurological physical exam and PN-related quality of life data (FACT-GOG/NTx v 4.0 scores) collected at screening. Prospective neurological exams and subjective reporting of PN occurred every 2 cycles until study discontinuation to proactively assess for PN. Adverse event (AE) data were also collected, with AEs reported as ‘neuropathy peripheral', ‘neuropathic pain', ‘neuropathy', and ‘peripheral sensory neuropathy' included as PN. AE reports of ‘paraesthesias' and ‘dysesthesias' were counted separately. Results: Of the 266 pts with R/R MM in PX-171-003-A1, 237 (89%) had a history of PN which was attributable to prior anti-myeloma therapy, including THAL (108 pts/41%), BTZ (134 pts/50%), or both BTZ and THAL (17 pts/6.4%). 206 of the 266 (77%) had G1/2 PN at baseline and a median disease duration of 5.9 years. This subset with active PN at baseline had received a median of 5 prior lines of therapy (range 1–20), with a median 13 anti-myeloma agents, and a median of 2 prior BTZ- and 1 prior THAL- containing regimens. Prior therapies included 100% BTZ, and 100% either THAL (77%) or prior lenalidomide (95%). Responses in the subset of pts with baseline PN were nearly identical to those seen in the full study population with an overall response rate (ORR; ≥ partial response [PR]) of 24% and a clinical benefit response rate (CBR; ≥ minimal response [MR]) of 36%. The median duration of response (≥PR) was 7.4 mo (95% CI 5.6–not reached) and median duration of MR was 6.3 months in both the overall and PN-baseline cohorts. OS and TTP data will also be reported. The most common treatment-emergent ≥G3 adverse events regardless of relationship to study drug were primarily hematologic and were as follows: thrombocytopenia (24%), anemia (21%), lymphopenia (11%), pneumonia (9%), neutropenia (9%), fatigue (7%), hypercalcemia (7%), and hyponatremia (6%). Although 77% of pts had G1/2 PN at baseline, new onset PN was infrequent with PN AEs of any grade reported in 31 (15%) pts and G3 PN reported in only 1 (0.4%) pt. New onset or worsening of paraesthesias (6.8%) and dysesthesias (0%) was also infrequent. Conclusions: Analysis of the subset of pts (77%) with active PN (G1/2) in this single-agent Ph 2 trial of CFZ in pts with R/R MM demonstrated that PN has no impact on depth or durability of responses, or on the tolerability of CFZ, in heavily pretreated pts with multiply relapsed and refractory MM. Reports of new or worsening PN were very uncommon, and paraesthesias and dysesthesia were generally infrequent and mild. CFZ can be given to pts with baseline PN with little risk of exacerbation; prolonged therapy is possible in this population. Disclosures: Martin: Celgene: Honoraria; Onyx: Consultancy. Singhal:Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Vij:Onyx: Honoraria. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Stewart:Millennium: Consultancy; Celgene: Honoraria. Jagannath:Millenium, OrthoBiotec, Celgene, Merck, Onyx: Honoraria; Imedex, Medicom World Wide, Optum Health Education, PER Group: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Lonial:Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Chang:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.