ALBERT

Description: Carfilzomib is a selective proteasome inhibitor that binds irreversibly to its target. In phase 1 studies, carfilzomib elicited promising responses and an acceptable toxicity profile in patients with relapsed and/or refractory multiple myeloma (R/R MM). In the present phase 2, multicenter, open-label study, 129 bortezomib-naive patients with R/R MM (median of 2 prior therapies) were separated into Cohort 1, scheduled to receive intravenous carfilzomib 20 mg/m2 for all treatment cycles, and Cohort 2, scheduled to receive 20 mg/m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The primary end point was an overall response rate (≥ partial response) of 42.4% in Cohort 1 and 52.2% in Cohort 2. The clinical benefit response (overall response rate + minimal response) was 59.3% and 64.2% in Cohorts 1 and 2, respectively. Median duration of response was 13.1 months and not reached, and median time to progression was 8.3 months and not reached, respectively. The most common treatment-emergent adverse events were fatigue (62.0%) and nausea (48.8%). Single-agent carfilzomib elicited a low incidence of peripheral neuropathy—17.1% overall (1 grade 3; no grade 4)—in these pretreated bortezomib-naive patients. The results of the present study support the use of carfilzomib in R/R MM patients. This trial is registered at www.clinicaltrials.gov as NCT00530816.

Description: The precise role of the endogenous immune system in modulating cancer development remains unclear. Tumor cells are generally thought to be nonimmunogenic because they are of ‘self’ origin. However, tumor-reactive lymphocytes can be isolated from patients with many types of cancer. It is unclear what role these lymphocytes play and why they fail to protect the host. Using a murine B-cell leukemia/lymphoma (BCL1) model, we showed the development of a vigorous antitumor T-cell response in the tumor-susceptible host. Specific T-cell responses against BCL1 developed as early as day 4. However, the nature of this nonprotective response is different from the protective response produced in a major histocompatibility complex–matched tumor-resistant host. Susceptible hosts developed a T helper 2 (Th2)-dominant response, whereas resistant hosts developed a Th1-dominant response to BCL1. Cytolytic activity against BCL1 developed in both resistant and susceptible hosts, but in the susceptible host, this response was weaker and delayed compared with that in the resistant host. Thus, tumor susceptibility does not necessarily mean the absence of an antitumor immune response. Rather, the nature of the antitumor immune response is critical in determining clinical outcome.

Description: Abstract 813FN2 Introduction: Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition absent of off-target effects relative to bortezomib. Carfilzomib has demonstrated durable anti-tumor activity and an acceptable tolerability profile in patients with multiple myeloma (MM). Final results will be presented for the bortezomib-naïve group of PX-171-004, a phase 2 study of single-agent carfilzomib in patients with relapsed and/or refractory MM. Herein we report the most recent data analysis available at time of abstract submission. Updated final results for the bortezomib-naïve group of PX-171-004, including OS data, will be presented at the meeting. Methods: Patients received either 20 mg/m2 for all treatment cycles (Cohort 1) or a stepped-up dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter (Cohort 2). Carfilzomib was administered over 2–10 minutes on Days 1, 2, 8, 9, 15, and 16 of every 28-day cycle, for a maximum of 12 cycles. The primary endpoint was the best overall response rate (ORR; [CR + VGPR + PR]) determined according to the IMWG Uniform Response Criteria. Secondary endpoints included the clinical benefit response rate (CBR; [ORR + MR per EBMT criteria]), progression-free survival (PFS), time to progression (TTP), duration of response (DOR), OS, and safety. The result of efficacy analysis from disease assessment by the Independent Review Committee is presented in this abstract. Results: 127 of 129 enrolled bortezomib-naïve patients were evaluable for response. Prior therapies included thalidomide (59%), lenalidomide (59%), alkylating agents (81%), and stem cell transplant (73%). Patients had received a median of 2 prior regimens (1 in 54 patients, 2 in 40 patients, 3 in 28 patients, and ≥4 in 7 patients). 84 patients (65%) were disease refractory to their most recent therapy, defined as ≤25% response or progression during or within 60 days after completion of therapy. The median duration of carfilzomib treatment is 7 cycles (range 1−12) in Cohort 1; 8 patients were receiving drug as of February 2011 in Cohort 2 with a median treatment of 6.5 cycles (range 1−13) at that time. Best ORR was 42% in Cohort 1 and 52% in Cohort 2. Median TTP was 8.3 months and median DOR was 13.1 months in Cohort 1. The median TTP and DOR for Cohort 2 have not been reached at the time of this interim analysis; the lower bound of the 95% CI for the median TTP was 10.2 months, and 84% were estimated to have DOR ≥1 year at the time of data cutoff. Higher response rates for Cohort 2 compared with Cohort 1 do not appear to be associated with higher toxicities. Patients with unfavorable cytogenetic characteristics (≥1 abnormality) per mSMART criteria had an ORR of 37% and CBR of 42% compared with 50% and 65%, respectively, for patients with no abnormality. The most common treatment-emergent adverse events (AEs), regardless of relationship to carfilzomib in Cohorts 1 and 2, respectively, were fatigue (71%, 54%), nausea (54%, 43%), anemia (46%, 37%), and dyspnea (49%, 33%). These were primarily ≤Grade 2 in severity. The most common Grade 3/4 AEs were anemia (15%), lymphopenia (15%), thrombocytopenia (13%), pneumonia (12%) and neutropenia (12%). Treatment-emergent peripheral neuropathy (PN) was mild and infrequent (16%). Only 1 case of Grade 3 PN (0.8%) was observed. Overall, 38 patients (30%) completed 12 cycles and 22 of these patients continued to receive carfilzomib therapy under a safety extension protocol (PX-171-010), an ongoing, multicenter, open-label phase 2 study to monitor long-term use of single-agent carfilzomib. Conclusions: To date we have seen robust and durable single-agent activity for carfilzomib in bortezomib-naïve patients with relapsed and often refractory MM with an ORR of 42−52% and a CBR of 59−63% from 2 separate dose cohorts in a population wherein 92% received an immunomodulatry drug and 73% had undergone an autologous stem cell transplant previously. These data are suggestive of a dose–response relationship and are being further evaluated in the exploratory phase 1b/2 study PX-171-007. Carfilzomib was associated with minimal PN and excellent long-term tolerability, with nearly one-third of patients completing 12 cycles and 22 of these continuing treatment beyond 1 year in the extension protocol PX-171-010. Disclosures: Vij: Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau. Kaufman:Millenium: Consultancy; Onyx Pharmaceuticals: Consultancy; Novartis: Consultancy; Keryx: Consultancy; Merck: Research Funding; Celgene: Research Funding. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx Pharmaceuticals: Consultancy, 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; Exelixis: Consultancy, Honoraria. Wang:Onyx Pharmaceuticals: Research Funding. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; OrthoBiotec.Imedex: Membership on an entity's Board of Directors or advisory committees; Medicom World Wide: Membership on an entity's Board of Directors or advisory committees; Optum Health Education: Membership on an entity's Board of Directors or advisory committees; PER Group: Membership on an entity's Board of Directors or advisory committees. Kukreti:Celgene: Honoraria. Alsina:Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Allergan: Research Funding. Belch:Celgene: Research Funding; Onyx: Research Funding. Gabrail:Millennium: Research Funding. Matous:Celgene: Speakers Bureau; Millenium: Speakers Bureau; Cephalon: Speakers Bureau. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Kunkel:VLST biothech: Consultancy; Threshold: Consultancy; Onyx Pharmaceuticals: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. Stewart:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding.

Description: Chemerin is a potent chemoattractant for cells that express the serpentine receptor CMKLR1 (chemokine-like receptor 1), such as plasmacytoid dendritic cells and tissue macrophages. Chemerin circulates in the blood in a relatively inactive form (prochemerin). Its chemotactic activity is unleashed following proteolytic cleavage of carboxyl-terminal amino acids by serine proteases including plasmin, factor XIIa and VIIa. Recruitment of plasmacytoid dendritic cells and macrophages by chemerin may play a role in local tissue immune and inflammatory responses. The shortest bioactive chemerin peptide NH2-YFPGQFAFS-COOH (9mer) is present in the carboxyl-terminal domain. In this work, we show that plasma carboxypeptidase N (CPN) and B (CPB or activated thrombin-activatable fibrinolysis inhibitor (TAFIa)) (30 nM) remove the C-terminal lysine (K) from YFPGQFAFSK (10mer) (200nM) and enhance the migration of CMKLR1-transfected cells by ∼16-fold. To investigate if sequential proteolysis by plasmin and carboxypeptidases can modulate the activity of chemerin peptides, we generated the carboxyl-terminal 15mer of prochemerin, NH2-YFPGQFAFSKALPRS-COOH. Plasmin cleavage (1 μM) generated a 10mer, which was further processed to 9mer by CPN or CPB (30 nM) cleavage. These sequential cleavages were paralleled by corresponding increases in chemotactic activity. At concentrations as high as 1 μM the 15 mer did not induce chemotaxis; after plasmin cleavage and conversion to 10mer, however, significant chemotactic activity was demonstrated. Treatment with CPN or CPB further enhanced this chemotactic activity. We observed a similar enhancement in bioactivity following sequential plasmin/CPN-or-CPB cleavage of full-length prochemerin. Endogenous plasma CPN supports the activation (∼2.5 fold increase in bioactivity) of plasmin-cleaved prochemerin (0.2 nM). This activation was blocked by incubating plasma with MGTA (DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid), a specific CPN inhibitor. In addition, we show that platelets are a rich source of chemerin (20–30 ng of chemerin/5x108 platelets). Chemerin released from activated platelets triggers CMKLR1-transfectant chemotaxis, which was blocked by anti-chemerin antibodies. Thus, the circulating humoral factors reported here (platelets, serine proteases, and carboxypeptidases) may contribute to the regulation of chemerin bioactivity in vivo and therefore play a critical role in CMKLR1-mediated immune responses.

Description: In CML patients, lymphocyte subsets have been shown to be disturbed. NK cells as well as CD8+ T cells have been shown to be significantly lower in patients with relapse after BMT than without relapse (Jiang et al., 1996). After successful treatment (IFN- α and BMT/SCT), MHC-restricted CD8+ T cells as well as MHC-unrestricted cytotoxic NK and lymphokine activated killer (LAK) cells play an important role in controlling the disease (Meseri et al., 1993, de Castro et al., 2003, Molldrem et al., 2000), which can lead not only to hematological, but also cytogenetic responses. The development of imatinib mesylate, a selective inhibitor of the bcr/abl tyrosine kinase, as a first-line therapy enormously enhanced treatment options for CML patients, and has led to hematologic, and occasionally cytogenetic, responses at various stages of disease. To explore, if CML patients, who develop clinical responses with imatinib mesylate treatment, have normalization of their lymphocyte subsets with restoration of CD8+ and NK cells, we studied peripheral blood T cell, B cell, and NK cell subpopulations in patients in chronic or accelerated phase before and after treatment with imatinib mesylate. In 5 CML patients, 8-color flow cytometry was applied to investigate the lymphocyte subsets using anti-CD3, anti-CD4, anti-CD8, anti-CD19, anti-CD56, anti-CD25, anti-CD27, and anti-CD45RA antibodies. 5 healthy donors served as controls. There was no significant difference in CD19+ B cells or CD3+ T cells as well as its CD4+ and CD8+ subsets between CML patients and healthy controls. T regulatory cells (CD4+CD25+) were also similar in patients in comparison to the healthy controls (0.6% – 3% vs 2.3%). In contrast, CD3–CD56+ NK cells (4% vs 14%, p

Description: Abstract 1938 Background: Carfilzomib (CFZ), a selective, epoxyketone proteasome inhibitor, produces potent, sustained proteasome inhibition and lacks many of the off-target activities associated with bortezomib (BTZ). Durable single-agent activity with CFZ has been observed in patients (pts) with relapsed/refractory multiple myeloma (R/R MM) who have received multiple prior therapies as well as in pts with advanced stage disease or significant comorbidities (Jagannath et al. ASCO 2009 Meeting. Abstract 8504). PX-171-004, is an ongoing Phase 2 study of single-agent CFZ in pts with relapsed or refractory MM following 1–3 prior therapies. Here we present updated data on the BTZ-naïve pts and report on activity observed in pts with significant comorbidities or poor-risk cytogenetic or FISH markers for myeloma. Methods: Enrolled pts received either 20 mg/m2 for all treatment cycles, or a stepped-up, dose-escalating regimen of 20 mg/m2 for Cycle 1 and 27 mg/m2 for all treatment cycles thereafter. CFZ was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days (one cycle), for a maximum of 12 cycles. Dexamethasone, 4mg, was administered prior to CFZ in Cycle 1 only. For the present analyses, pts were stratified according to several baseline criteria including ECOG performance score, cytogenetic or FISH markers of high-risk disease per mSMART criteria [del17p, t(4;14), t(14;16), del13 by karyotype and hypodiploidy] and serum ß2-microglobulin. The primary endpoint was overall response rate (ORR) per International Uniform Response Criteria for Multiple Myeloma. Results: Data are available for 110 BTZ-naïve pts. Baseline pt characteristics included: 60% of ECOG PS ≥1; 53% baseline neuropathy Grade 1/2; 30% moderately impaired renal function (CrCl 5% of pts included lymphopenia, neutropenia, pneumonia, thrombocytopenia, anemia and fatigue. Of note, there were no discontinuations for peripheral neuropathy and only 1 pt with impaired renal function at baseline was discontinued for creatinine increases. Twenty-four pts remain on study and 23% have completed the protocol-specified 12 cycles of therapy. Seventeen pts (20%) elected to continue CFZ on an extended treatment protocol (PX-171-010); no cumulative toxicities have been noted. Conclusions: Single-agent CFZ achieves high response rates in BTZ-naïve pts with relapsed myeloma, with minimal neuropathy, even in the setting of high-risk disease. In addition, single-agent CFZ continues to demonstrate long-term tolerability even in pts with comorbid conditions, including renal insufficiency and diabetes, who may benefit from a steroid-sparing treatment regimen. The data from this ongoing trial show that CFZ is a promising new treatment for multiple myeloma in the relapsed or refractory setting. Disclosures: Vij: Onyx: Honoraria. Kaufman:Celgene: Consultancy, Research Funding; Millenium: Consultancy; Merck: Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria; Centocor Ortho Biotec: 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. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Alsina:Millenium: Consultancy, Research Funding; Celgene: Research Funding; Novartis: Consultancy. Gabrail:Millenium: Research Funding. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millenium: Speakers Bureau. Le:Onyx Pharmaceuticals: Employment. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding.

Description: Abstract 3959 Background: Entinostat (ENT) is an oral, class 1 isoform selective HDACi. In vitro in HL cell lines, ENT decreases proliferation and induces cell death in a dose dependent manner with an IC50 of 0.4 uM. As an epigenetic agent, ENT modulates immune pathways from a TH2 to a TH1 cytokine/chemokine profile and can upregulate the expression of cancer testis antigens, thus acting as an immunomodulator. This phase 2 study was initiated to define ENT single agent antitumor activity and safety and tolerability. Methods: The trial is a Simon 2-stage design that has completed enrollment in 2 dosing schedules with 24 evaluable patients at 6 sites, 6 patients remain active; enrollment is continuing in an alternate dosing schedule. ENT was administered at a dose of 10 mg every 14 days (d), in a 28 d cycle (C) for the first stage of the study, for the second stage the dose was escalated to 15 mg every 14 d beginning C1d15. Subjects ongoing from the first stage were also allowed to escalate. CT/PET scans are conducted every 2 cycles. Blood samples for correlative study analysis are obtained pre-treatment, C1D8, C1D15, and C3D15. Results: As of August 6, 2010, demographic data are available on 23 evaluable subjects, median age is 28 years (19-53), median prior regimens is 3 (2-10), 13 (56%) had prior autologous transplant, 3 (13%) had prior allogeneic and 3 (13%) had prior autologous and allogeneic transplant. 23 patients have 〉1 post baseline result available, 65% have disease control (CR+PR+SD), 35% had PD and 2 patients with SD discontinued due to AE (Pericarditis and thrombocytopenia). Two (9%) responses (PR) are reported with time on study 14.7 months and one 〉6 months. An additional 4 (17%) patients have tumor reduction (25-49%) for at least 4 cycles. Six (26%) patients completed ≥ 6 cycles. Common G1/2 AEs including all causalities were gastrointestinal, fatigue, and pyrexia. Of the 32 patients evaluated for safety, G 3/4 thrombocytopenia occurred in 19 (59.4%) patients, G 3/4 neutropenia in 9 (28.1%) patients, and G 3/4 anemia in 11 (34.4%) patients, including all causalities. Profiling of cytokine, chemokine and growth factor levels in patient serum samples provides support for the biological activity of entinostat as an immunomodulatory agent with ongoing evaluation demonstrating a reduction of IL-13 and TNFα levels within one week of therapy. Conclusions: ENT as a single agent in HL was well tolerated and demonstrated encouraging activity in this heavily pretreated patient population. Further dose intensity is currently being tested; updated results on the immunomodulatory effects will be presented. Disclosures: Off Label Use: Given the CD20 positivity of nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) rituximab has been evaluated previously for relapsed NLPHL and was shown to be efficacious. Rituximab however is not FDA approved for NLPHL. This is a retrospective study that evaluates the use of R-CHOP and other therapies for NLPHL. Current NCCN guidelines support consideration of R-CHOP for NLPHL treatment, and given the rarity of the disease there is no one defined preferred chemotherapy regimen. This information will be disclosed to the audience.

Description: Imatinib mesylate, a selective inhibitor of the bcr/abl tyrosine kinase, has revolutionized the treatment of CML and is the first-line therapy for most patients. Most CML patients in chronic phase achieve hematologic remission under treatment with imatinib, with up to 70% also achieving cytogenetic remission. However, imatinib therapy is not curative, as patients who discontinue the drug invariably relapse. Thus, the need to find alternate, potentially curative therapies remains. Low levels of CD8+ T cell responses to certain HLA restricted peptides have been detected in CML patients after successful treatment. To determine, if CML patients in remission on imatinib develop and sustain anti-leukemia CD4+ or CD8+ T cell responses, blood samples from patients before and several time points after treatment were collected and analyzed. Pre-treatment samples were utilized as sources of autologous leukemic cells to detect anti-leukemia T cell responses in post-treatment remission samples. Autologous leukemic samples alone and remission samples alone served as controls. In 7 of the 14 patients investigated, significant IFN-γ responses (p

Description: The precise role of the endogenous immune system in modulating cancer development remains unclear. Tumor cells are generally thought to be nonimmunogenic because they are of ‘self’ origin. However, tumor-reactive lymphocytes can be isolated from patients with many types of cancer. It is unclear what role these lymphocytes play and why they fail to protect the host. Using a murine B-cell leukemia/lymphoma (BCL1) model, we showed the development of a vigorous antitumor T-cell response in the tumor-susceptible host. Specific T-cell responses against BCL1 developed as early as day 4. However, the nature of this nonprotective response is different from the protective response produced in a major histocompatibility complex–matched tumor-resistant host. Susceptible hosts developed a T helper 2 (Th2)-dominant response, whereas resistant hosts developed a Th1-dominant response to BCL1. Cytolytic activity against BCL1 developed in both resistant and susceptible hosts, but in the susceptible host, this response was weaker and delayed compared with that in the resistant host. Thus, tumor susceptibility does not necessarily mean the absence of an antitumor immune response. Rather, the nature of the antitumor immune response is critical in determining clinical outcome.

Description: Abstract 2930 Background: Carfilzomib is a next-generation proteasome inhibitor that selectively and irreversibly binds to its target. In patients with multiple myeloma (MM), single-agent carfilzomib shows activity with an acceptable safety and tolerability profile when administered IV over a period of 2–10 minutes at doses up to 27 mg/m2. Based on preclinical safety data that a slower infusion was better tolerated than a 2- to 10- minute infusion, the Phase 1b/2 PX-171-007 was designed to evaluate a 30-minute infusion of carfilzomib using a modified stepped-up dosing regimen. Preliminary data of encouraging activity and an acceptable safety profile have been previously reported from the dose-escalation phase, where a maximum tolerated dose (MTD) of 56 mg/m2 was initially established. Here we report the updated results from this study, including interim efficacy and safety data of the complete 56 mg/m2 dose-expansion cohort. Methods: Carfilzomib was given as a 30-minute IV infusion on days (D) 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). C1 D1–2 doses were 20 mg/m2, followed by escalation to a higher dose of either 36, 45, 56, or 70 mg/m2. Dexamethasone as premedication to mitigate infusion-related reactions (4 mg for ≤45 mg/m2, 8 mg for 〉45 mg/m2) was given prior to infusion. Overall response rate (ORR; [sCR + CR + VGPR + PR]) was determined according to International Myeloma Working Group Uniform Response Criteria. Pharmacokinetic and pharmacodynamic analyses were performed on samples obtained at C1D1 and C2D1. Safety assessments included incidence, severity, and duration of adverse events (AEs). Subjects were evaluated for dose-limiting toxicity (DLT) according to the Common Terminology Criteria for Adverse Events v 3.0. Results: A total of 33 patients were enrolled (4 at 36 mg/m2; 3 at 45 mg/m2; 24 at 56 mg/m2; 2 at 70 mg/m2). Patients had received a median of 5 (range 1–9) prior treatment regimens. The median duration of carfilzomib treatment is 4 cycles (range 1–17); 5 patients went on to receive ≥10 cycles, reinforcing carfilzomib tolerability at higher doses. DLTs occurred in 2 patients treated at 70 mg/m2, with both patients able to continue carfilzomib at reduced doses (1 patient reduced to 56 mg/m2 achieved a PR, ongoing into cycle 12). Best response to carfilzomib is detailed in the table. The 56 mg/m2 cohort had an ORR of 60%, with 1 patient achieving sCR, 4 patients achieving VGPR, and 7 patients attaining PR, as assessed by the investigator. Three patients remain active at this dose, with best response of 1 VGPR, 1 PR, and 1 SD. The majority of the AEs in the 20/56 mg/m2 cohort were G1-2 in severity with the exception of anemia and thrombocytopenia. The most common AEs, irrespective of relationship to carfilzomib, in this cohort were dyspnea (54%), fatigue (54%), nausea (54%), pyrexia (54%), anemia (38%), chills (38%), hypertension (38%), and thrombocytopenia (38%). There was 1 report of G1 peripheral neuropathy (4%) in this cohort. Additionally, the most common ≥G3 AEs in this group were thrombocytopenia (38%), anemia (21%), and hypertension (13%). Five patients (21%) treated at 20/56 mg/m2 required dose reductions. Pharmacodynamic analysis demonstrated inhibition of proteasome chymotrypsin-like activity in peripheral blood mononuclear cells of 〉80% at 20 mg/m2 and ≥95% at ≥56 mg/m2. Carfilzomib at 56 mg/m2 inhibited all 3 subunits of the immunoproteasome, resulting in ∼78% inhibition in total activity. Conclusions: The 20/56 mg/m2 dose for carfilzomib administered as a 30-minute IV infusion was associated with 60% ORR, noteworthy for a late-line, heavily pretreated patient population. The dose group additionally reported an acceptable safety profile (with 1 patient reporting G1 neuropathy), supporting the pre-clinical finding that longer infusion time enables higher dose and achieves greater levels of proteasome inhibition. Disclosures: Papadopoulos: Proteolix: Consultancy, Research Funding; Onyx Pharmaceuticals: Research Funding. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau; Onyx Pharmaceuticals: Research Funding. Holahan:Onyx Pharmaceuticals: Consultancy, Research Funding. Vesole:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Speakers Bureau. Kunkel:VLST biothech: Consultancy; Threshold: Consultancy; Onyx Pharmaceuticals: Consultancy. Hannah:Onyx Pharmaceuticals: Consultancy. Siegel:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.