Jagannath, Sundar

Abstract 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 <60 mL/min), and 17% diabetes. Approximately 13% of pts had cytogenetic or FISH markers of poor prognosis. The ORR for the entire BTZ-naïve population was 48%; the ORR for BTZ-naïve pts receiving 20–27 mg/m2 was 54%. The ORRs stratified according to dose and baseline measurements are detailed in the following table. The most common treatment-emergent AEs, regardless of relationship to study drug, were fatigue (61%), nausea (43%), anemia (39%), dyspnea (36%), cough (34%), headache (31%), thrombocytopenia and upper respiratory infections (30% each) and were primarily ≤ Grade 2 in severity. Grade 3/4 AEs occurring in >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.

Abstract Abstract 1942 Background: The impact of cytogenetic abnormalities on the response to therapies and survival in patients (pts) with multiple myeloma (MM) has been well established in the literature. Bortezomib (BTZ), either alone or in combination with other agents, has been shown to overcome the adverse impact of several common unfavorable cytogenetic features. In addition, responses with lenalidomide (LEN)/dexamethasone and pomalidomide have also been reported in patients with unfavorable cytogenetic profiles. Carfilzomib (CFZ) is a novel and highly selective epoxyketone proteasome inhibitor which produces durable single-agent activity in pts with R/R MM. The objective of this analysis was to evaluate the influence of cytogenetics in a large Ph 2b study (PX-171-003-A1), with single-agent CFZ in pts with R/R MM. Methods: Of the 266 pts enrolled in the 003-A1 study, 229 pts (86%) were response evaluable and had available metaphase cytogenetics and/or fluorescence in situ hybridization (FISH) analyses for hypodiploidy, chromosome 13 deletions, del 17p13, t(4:14), and t(14;16) chromosomal abnormalities. Metaphase cytogenetic analyses were available for 200 pts (75%) and FISH results were available for 205 pts (77%). All pts received CFZ at 20 mg/m2 IV on days 1, 2, 8, 9, 15, and 16 in a 28-day cycle (C) in C1 followed by 27 mg/m2 in each C thereafter for up to 12 C. Pts who completed 12 C of therapy were eligible to continue CFZ on an extension study. For the analysis, overall response rate was defined as ≥PR by International Myeloma Working Group (IMWG) criteria. Clinical benefit response (CBR; ORR + MR as defined by EBMT criteria) was also assessed. All responses were assessed and confirmed by an Independent Response Review Committee (IRC). Results: The median age in this subpopulation was 64 yrs. Pts must have had disease that was relapsed after ≥2 regimens including BTZ and either thalidomide (THAL) or LEN, and must have been refractory to their most recent regimen. In this heavily pre-treated pt population, pts had received median of 13 prior anti-myeloma drugs and a median of 5 prior regimens. 99.6% of pts had previously received treatment with BTZ, 74% received prior thalidomide, 94% prior lenalidomide, and 74% prior stem cell transplantation. The ORR (≥PR) for the pts with available metaphase cytogenetics and/or FISH analyses was 25% and the CBR (≥MR) was 38%. 71 of 229 pts (31%) had at least one cytogenetic abnormality. Of these, 27/71 (38%) pts had abnormalities detected via metaphase cytogenetics, 24 (34%) pts were detected by FISH and 20 (28%) pts had abnormalities by both methods. The presence of deletion 13 or hypodiploidy by cytogenetics or del17p13, t(4;14), or t(14;16) by FISH did not significantly impact the ORR. Specifically, 30% of pts with ≥1 abnormality responded compared to 23% with none. The CBR was also unaffected at 34% vs. 39% for pts with ≥1 and no abnormalities, respectively. For all pts in this analysis, the median duration of response (DOR) was 8 months (95% CI 6–10). For pts with ≥1 abnormality, the DOR was 7 months (95% CI 4–10) and did not differ significantly from the DOR of 8 months (95% CI 6–not reached) in pts with no abnormalities. A complete breakdown of response categories and time-to-progression (TTP) will also be presented. Conclusions: CFZ demonstrated durable and comparable activity in pts with R/R MM in both the absence or presence of one or more cytogenetic abnormalities including hypodiploidy, chromosome 13 deletions, del 17p13, t(4:14), or t(14;16). Notably, these results are consistent with data obtained in another Ph2 study with CFZ in pts with relapsed MM following 1–3 prior therapies and who had abnormal cytogenetics (PX-171-004). The results of the present study suggest that durable responses to CFZ can be achieved in heavily pretreated patients and responses are not impacted by poor prognostic cytogenetic features. Disclosures: 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. 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. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Vij:Onyx: 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. Kukreti:Celgene: Honoraria; Roche: Honoraria; Ortho Biotech: Honoraria. Bray:Onyx Pharmaceuticals: Employment. Vallone:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

Abstract Abstract 1954 Background: Carfilzomib (CFZ) is a novel, highly selective epoxyketone proteasome inhibitor that produces potent and sustained proteasome inhibition both in vitro and in vivo. CFZ appears to lack many of the off-target activities frequently associated with bortezomib (BTZ). This lack of off-target activity may account for observed differences in tolerability seen with CFZ including lack of significant neuropathy and minimal neutropenia and diarrhea. To date, single agent CFZ has been evaluated in Ph 1 and 2 studies in >600 patients, and the vast majority of patients treated had relapsed and/or refractory (R/R) MM. In these settings, CFZ has demonstrated durable single-agent activity and was well-tolerated in patients with advanced stage disease with co-morbidities including baseline neuropathy or renal insufficiency. Here we present the results of parallel safety analyses of patients from four Ph 1 and 2 studies with CFZ. Materials and Methods: The present safety analyses were based on data accumulated from patients enrolled in the following trials: PX-171-003 A0 (R/R MM), PX-171-003 A1 (R/R MM), PX-171-004 (relapsed MM), and PX-171-005 (R/R MM with varying degrees of renal function). In all studies, the treatment schedule was based on a 28-day cycle, dosing CFZ QDx2 each week for 3 weeks (Days 1, 2, 8, 9, 15, 16) with 12 days of rest. Doses of CFZ ranged from 15–20 mg/m2 in cycle 1 (005 [15 mg/m2], 003 A0 and A1, 004 [20 mg/m2]). In three studies CFZ was escalated to 27 mg/m2 after the first cycle, as tolerated (003- A1, 004-BTZ naïve subset and 005). In PX-171-005, low-dose dexamethasone was added in the majority of patients. Results: CFZ was well-tolerated by patients across the 4 studies analyzed. The most common treatment-emergent adverse events (AEs) included fatigue, anemia, nausea, dyspnea, and thrombocytopenia. Detailed descriptions of the incidence of treatment-related AEs (all Grades (G) in ≥25% of pts; ≥G3 in ≥5% of pts) across studies are presented in the table. Peripheral neuropathy (PN) occurred infrequently across all 4 studies (N= 517), with only 20 patients (3.9%) experiencing PN of any G and only 2 patients (0.4%) with G3 PN. Febrile neutropenia was likewise uncommon, occurring in only 3 patients (0.6%). Serious treatment emergent AEs (SAEs) occurring in ≥1% of patients and considered possibly/probably related to study drug across all 4 studies included: pneumonia (3.5%), congestive cardiac failure (2.5%), acute renal failure (1.7%), pyrexia (1.2%), and dyspnea (1%). Conclusions: Despite a substantial disease burden present in the patient populations described here, CFZ was well-tolerated by patients with MM across all studies examined. The excellent safety/tolerability profile of CFZ has permitted prolonged administration (in some cases over 24 mos of continuous therapy including extension study) with minimal dose modifications or discontinuations due to toxicity. The low levels of neuropathy seen with CFZ make this agent a potentially important treatment option for patients with pre-existing neuropathy from either underlying disease or prior neuropathic anti-myeloma therapy. Disclosures: Singhal: Celgene: Speakers Bureau; Takeda/Millenium: Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding. Siegel:Millenium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Martin:Celgene: Honoraria; Onyx: Consultancy. Vij:Onyx: Honoraria. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: 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. 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. Zonder:Millenium: Consultancy, Honoraria, Research Funding; Cephalon: Research Funding; Celgene: Honoraria. Wong:Onyx Pharmaceuticals: Employment. McCulloch:Onyx Pharmaceuticals: Employment. Kauffman:Onyx Pharmaceuticals: Employment. Niesvizky:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, 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.

Abstract Abstract 303 Background: Carfilzomib (CFZ) is a novel proteasome inhibitor that binds its target selectively and irreversibly, resulting in greater and more sustained proteasomal inhibition compared to BTZ (Demo et al, Cancer Res 2007). CFZ overcomes BTZ-resistance in vitro (Kuhn et al, Blood 2007) and in a previous Phase 2 study (PX-171-003), single-agent CFZ achieved durable responses and maintained disease control [e.g. ≥ Stable Disease (SD)] in patients with progressive multiple myeloma (MM) despite treatment with essentially all available agents. PX-171-004 is an ongoing Phase 2 study of CFZ monotherapy in MM patients with relapsed or refractory disease following 1–3 prior therapies. Here we report updated data for the BTZ-treated cohort. Methods: Patients with relapsed or refractory (defined as < 25% response or disease progression during therapy) MM were enrolled and stratified based on prior BTZ exposure (e.g. BTZ-naïve and BTZ-treated). For the BTZ-treated cohort, tolerability and response to prior BTZ [≥ Minor Response (MR)] was not required. CFZ 20 mg/m2 IV was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. The primary endpoint was Overall Response Rate (ORR) [≥ Partial Response (PR)] by IMWG criteria. Secondary endpoints included Clinical Benefit Response (CBR = ORR + MR) and safety. Results: Thirty-five BTZ-treated patients were enrolled. Six (17%) patients had previously received BTZ exclusively as a single agent, 15 (43%) received BTZ as part of a chemotherapy combination and 10 (29%) received BTZ as part of a stem cell transplant (SCT) regimen. An additional 4 (11%) received BTZ in a chemotherapy combination as well as part of a separate transplant regimen. Other prior therapies included alkylators (89%), SCT (81%), thalidomide (69%), lenalidomide (37%), and anthracyclines (31%). Six (17%) patients had disease refractory to BTZ and 9 (26%) additional patients had discontinued BTZ due to toxicities. At baseline, 19 (54 %) patients had an ECOG score ≥ 1, 17 (49%) patients had neuropathy of Grade ≥ 1, 9 (26%) patients had impaired renal function (CrCl <60 mL/min) and 9 (26%) had diabetes. The median time since diagnosis was 3.6 years (range 1.2–13.2). To date, the mean number of CFZ doses administered was 29.3 (∼5 four-week cycles; range 4–72 doses, 0.7–12 cycles). Thirty-three patients who initiated therapy were evaluable for response per protocol. The ORR was 18% (6/33), including 1 CR and 5 PRs. An additional 4 (12%) patients had MR (CBR= 30%) and 13 (39%) had SD for ≥ 6 weeks. For evaluable patients who were either refractory or intolerant to their prior BTZ therapy, responses to CFZ included 1 PR and 1 MR and 8 SDs. The most common adverse events (AEs) (≥ 30% patients) were primarily Grades 1/2 and included fatigue (57%), nausea (54%), vomiting (37%), dyspnea (34%), diarrhea (34%), anemia (31%), increased creatinine (31%) and upper respiratory tract infection (31%). Grade 3/4 AEs occurring in ≥ 10% of patients were anemia (14.3%) and neutropenia (11.4%). There were no reports of febrile neutropenia. Dose modifications were rarely required. Peripheral neuropathy (PN) was uncommon (4 patients, 11%); only 1 patient had a Grade 3 event that lasted < 36 hours and did not result in missed doses or dose modification. None of the 9 patients with baseline renal impairment were discontinued for renal AEs. To date, 6 (17%) patients have completed the full 12-cycle protocol at the initial dose and schedule, 6 (17%) remain on study and 1 patient has received > 19 cycles on a recently initiated extended treatment protocol. Conclusions: In a BTZ-exposed population that includes BTZ treatment failures and significant comorbidities (e.g. diabetes, renal insufficiency, etc), the 18% ORR (CBR 30%) is notable for this steroid- and anthracycline-sparing regimen. Single-agent CFZ is well tolerated, even in patients with renal insufficiency, and both myelosuppression and PN are uncommon. These data support the continuing evaluation of CFZ as a safe and effective treatment option in MM. Disclosures: Siegel: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Proteolix, Inc.: Research Funding. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Kukreti:Celgene: Honoraria. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. McDonagh:Proteolix: Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Le:Proteolix, Inc.: Employment. Kunkel:Proteolix: Consultancy, Employment. Bennett:Proteolix: Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix, Inc.: Consultancy, Research Funding.

Abstract Abstract 2878 Poster Board II-854 Background: Significant advances have been made in the treatment of myeloma with the introduction of thalidomide, its analogue, lenalidomide, and the proteasome inhibitor bortezomib. While these new drugs have improved the outcome of patients with myeloma, the disease still remains incurable. Effectiveness of upcoming new therapies will need to be assessed in the context of anticipated outcome with the currently available therapies. However, given the rapid pace of development over the past decade, outcome of patients who have relapsed on the new therapies remain unclear. Methods: In order to further study this group of patients, we undertook a study of patients who have relapsed on or are refractory to one of the IMiDs (thalidomide or lenalidomide) as well as bortezomib. A total of 300 cases from 8 sites in the US, 5 sites in Europe and one site in Asia were identified for this study. Enrolled patients had relapsed and refractory multiple myeloma, per the EBMT or IMWG response criteria, after at least 2 prior treatments. Patients were refractory to bortezomib, defined as having no response on a prior bortezomib-containing regimen or experiencing disease progression within 60 days of a bortezomib-containing regimen. Patients also should have relapsed, refractory, intolerant, and/or ineligible in the opinion of the investigator, to other therapies, including an IMiD (thalidomide or lenalidomide). Clinical and laboratory data pertaining to the time of diagnosis and from the time of individual relapses were obtained from the clinical records. The date patients satisfied the above entry criteria was defined as time zero. Results: The current analysis includes the first 119 patients with complete data available. The median age at initial diagnosis was 59 years (range, 31-86 yr); 71% were males. The ISS stage distribution at diagnosis was 33%, 39% and 28% for stages 1, 2, and 3 respectively. 19 patients (37%) had high risk disease by FISH [t(4;14), t(14;16), del17p] or by cytogenetics [del 13, hypodiploidy]. The median time from diagnosis to time zero was 3.8 yrs (range 0.2-18.7 yr) and the median reported lines of therapy before time zero was 2. 74% patients had at least 1 autologous stem cell transplant prior to becoming eligible for the study. Following time zero, 77 (65%) pts had a treatment recorded, including an autologous SCT in 21 (18%), with the treatment regimen starting at a median of 1 month after time zero. A variety of treatment regimens were utilized beyond time zero (median=1; range 0-7). Thirty-two (27%) patients had a response any time following time zero, and only 8 had a subsequent response. Response to the first treatment, or supportive care for patients not treated, recorded following time zero included minor response or stable disease (n=14; 12%), PR (n=17, 14%), and VGPR or better (n=6, 5%). Patients treated with SCT had a higher rate of PR or better compared to patients receiving other treatments (85%; 17/20 vs. 26%; 15/57). In a multivariate analysis, the only significant predictor of a PR or better after time zero was younger age (<60 yrs). The median overall survival (OS) and event free survival (EFS) were 6 mos (95% CI, 4-7 mos) and 1 month (95% CI,1-2 mos) respectively. In a multivariate analysis normal creatinine predicted for a better overall survival and having an IgG M protein type predicted for better EFS. A complete analysis from all 300 patients will be presented at the meeting. Conclusions: This study confirms the poor outcome of patients once they become relapsed and refractory to agents that have become the mainstay of myeloma therapy. The findings highlight the incurable nature of the disease and urgent need to develop newer effective therapeutic agents for this group of patients, who currently do not have effective treatment options. Disclosures: Kumar: CELGENE: Research Funding; MILLENNIUM: Research Funding; BAYER: Research Funding; GENZYME: Research Funding; NOVARTIS: Research Funding. Jagannath:Merck: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Laubach:Novartis: . Palumbo:Ortho Biotech, Janssen-Cilag: Honoraria; Celgene: Honoraria, Speakers Bureau. Richardson:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Johnson and Johnson: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Keryx: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. San Miguel:Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Sonneveld:Janssen-Cilag: Honoraria. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

Abstract Abstract 2865 Poster Board II-841 BACKGROUND: The ubiquitin-proteasome pathway, which has been shown to be an essential cellular degradative system in myeloma cells, can also regulate bone formation through its effects on osteoblast differentiation. Retrospective analysis of variation of ALP during treatment with bortezomib indicates a close correlation between myeloma response and serum ALP levels which multiple studies have shown to be of bone origin. To determine if this effect is a class effect of proteasome inhibitors (PIs), this retrospective study analyzed variation of ALP in relationship to myeloma response during treatment with carfilzomib, the first in a new class of selective epoxyketone PIs that has demonstrated encouraging safety and efficacy in two phase 2 studies of relapsed or refractory myeloma patients. METHODS: Retrospective analysis of serum ALP was performed on relapsed or refractory myeloma patients enrolled on two phase 2 studies (PX-171-003 and PX- 171-004) evaluating the safety and efficacy of single agent carfilzomib. We analyzed data from 38 patients in the first cohort of the PX-171-003 study, a relapsed and refractory myeloma trial for patients who have received ≥ 3 prior therapies including bortezomib and an IMiD and 29 patients in PX-171-004, a relapsed or refractory myeloma trial that included bortezomib naïve patients. All patients received 20 mg/m2 of carfilzomib on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. RESULTS: Seventy-seven patients were enrolled. The median age was 63 years with a median time since diagnosis of 4.6 years, 52% were male, 84.% had relapsed after autologous transplants, 82.% were previously exposed to bortezomib, and 92% were previously exposed to an IMiD. Sixty seven patients with ALP data were evaluable for response. In PX-171-003 the ORR (≥PR) was 18% and the clinical benefit response (CBR; ≥MR) was 26%, while in PX-171-004 the ORR was 35.5% overall and 57% in bortezomib naive patients. ALP increment from baseline, which was most evident during the second cycle of treatment, was statistically different in patients who achieved ≥VGPR compared to all others on Days 1 (P=0.0049) and 8 (P=0.006) of Cycle 2. In all patients achieving a VGPR or better, ALP increased more than 15 units per liter at Cycle 2 Day 1 over baseline An ALP increase over the same period of time was seen in 26 %, 13%, and 11% of patients achieving PR, MR, and SD, respectively. None of the patients with progressive disease exhibited a similar increase. Our study indicates that response first assessed on Day 15 of Cycle 1 parallels the ALP elevation which returned to baseline levels at the end of Cycle 3. CONCLUSIONS: This retrospective analysis on a subset of patients in these ongoing phase 2 studies of single agent carfilzomib in relapsed or refractory multiple myeloma suggests that elevation in ALP may be associated with best response. Taken with previous publications describing bortezomib treatment, these results suggest that this specific anabolic bone phenomenon could be a class effect of proteasome inhibitors. These phase 2 studies are ongoing with a higher dose of carfilzomib (27 mg/m2) being evaluated. The data from this small subset analysis suggests that further exploration of this relationship is warranted. Disclosures: Zangari: Milllennium: Honoraria, Research Funding; Novartis: Research Funding; Celgene: Honoraria; OrthoBiotech: Honoraria; Optum Health: Honoraria; Educational Concepts Group, LLC: Membership on an entity's Board of Directors or advisory committees. Vij:Proteolix: Consultancy, Research Funding. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Merck: Honoraria. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Stewart:Millennium: Consultancy, Research Funding; Proteolix: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Celgene: Honoraria. Wang:Proteolix: Honoraria, Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Trudel:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Singhal:Celgene: Speakers Bureau; Millennium: Speakers Bureau.

Abstract Background: Treatment of multiple myeloma has evolved considerably in the past few years with availability of several news drugs as well as increasing use of multidrug combinations. These changes have no doubt led to the improved survival seen among patients with MM. We have previously shown that outcomes of patients intolerant or refractory to one of the IMiDs and bortezomib had a poor outcome. Since that time, other drugs of the same class as well as new classes of drugs have been introduced for the treatment of MM. We designed this retrospective study to estimate the outcomes in patients with relapsed myeloma, who have become refractory to the current generation IMiDs and proteasome inhibitors. Patients and Methods: Patients with relapsed multiple myeloma who have received at least 3 prior lines of therapy, is refractory to both an IMiD (lenalidomide or pomalidomide) AND a proteasome inhibitor (bortezomib or carfilzomib), and has been exposed to an alkylating agent were identified from multiple centers. The time patients met the above criteria was defined as T0, and details of all treatment regimens before and after T0 were collected using electronic CRFs. The study was approved by the IRB at the respective centers. Results: 543 patients were enrolled in this study; median age was 62 years (31-87) and 61% were males. Patients were enrolled from centers in North America (n=181), Europe (n=318), and Asia Pacific (n=44). Patients were diagnosed between 2006 and 2014, the median duration between diagnosis of myeloma and study entry (T0) was 3.1 years (0.3 to 9). The median (95% CI) estimated follow up from diagnosis and from T0 were 61 (57, 66) months and 13 (11, 15) months respectively. The median number of lines of therapy prior to T0 was 4 (3-13), 48% had a prior transplant. The median OS from T0 for the entire cohort was 13 (11, 15) months. For these 462 patients, the median number of recorded regimens was 2 (1-9). The overall response and the depth of response to each line of treatment following T0 are as shown in the table. The median (95% CI) PFS and OS from T0 was 5 (4, 6), and 15.2 (13, 17), respectively. The overall survival for the 81 patients with no treatment post T0 was only 2.1 months. In a multivariate analysis, duration from diagnosis to T0, ISS stage III and number of lines of therapy were all associated with inferior PFS, as well as OS, and in addition, serum creatinine>2 mg/dL at T0 also predicted inferior OS. Conclusions: The study provides the expected outcome following development of myeloma that is refractory to a PI and an IMiD. The outcomes of these patients appear to be better than we had seen historically in patients refractory/ intolerant to bortezomib and IMiDs, highlighting the increased treatment options available for these patients. However, there is decreasing response rate to sequential regimens highlighting the development of drug resistance. The data provides a bench mark for comparison of new therapies that are being evaluated in this disease. Table Table. Disclosures Dimopoulos: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: 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; Genesis: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Kastritis:Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Terpos:BMS: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Celgene: Honoraria; Takeda: Consultancy, Honoraria; Genesis: Consultancy, Honoraria, Other: Travel expenses; Amgen: Consultancy, Honoraria, Other: Travel expenses, Research Funding; Novartis: Honoraria. Hillengass:Sanofi: Research Funding; Novartis: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria. Leleu:TEVA: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; LeoPharma: Honoraria; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Pierre Fabre: Honoraria; Celgene: Honoraria; Novartis: Honoraria; Takeda: Honoraria. Oriol:Janssen: Honoraria, Other: Expert board committee; Amgen: Honoraria, Other: Expert board committee. Cavo:Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Janssen-Cilag: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Mateos:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Vij:Shire: Consultancy; Takeda: Consultancy, Research Funding; Jazz: Consultancy; Karyopharma: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Amgen: Consultancy, Research Funding. Lokhorst:Genmab: Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. van de Donk:Amgen: Research Funding; Janssen: Research Funding; BMS: Research Funding; Celgene: Research Funding. Mark:Onyx: Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Ludwig:Amgen: Research Funding, Speakers Bureau; Takeda: Research Funding, Speakers Bureau; BMS: Speakers Bureau; Janssen: Speakers Bureau. Jagannath:Novartis: Consultancy; Janssen: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Merck: Consultancy. Usmani:Array: Research Funding; Britsol-Myers Squibb: Consultancy, Research Funding; Skyline: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BioPharma: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharmacyclics: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Research Funding, Speakers Bureau; Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Speakers Bureau. Dytfeld:Janssen Poland: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Moreau:Novartis: Honoraria; Amgen: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Janssen: Honoraria, Speakers Bureau. Lee:Amgen: Membership on an entity's Board of Directors or advisory committees. Shustik:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millenium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. de la Rubia:Celgene: Consultancy; Bristol Myers: Consultancy; Amgen,: Consultancy; Janssen: Consultancy. Durie:Takeda: Consultancy; Amgen: Consultancy; Janssen: Consultancy.

Abstract Background: p38a mitogen-activated protein kinase (MAPK) mediates production of proinflammatory cytokines and other factors including PGE-2 induced RANKL and IL-1 induced IL-6. SCIO-469 inhibits p38a MAPK blocking synthesis of Il-1ß, PGE2, VEGF, MIP-1α and TNFα thus reducing in vitro MM tumor growth and survival, and drug resistance. Objectives: Assess efficacy, safety, tolerability of SCIO-469 as M or MB in patients (pts) with relapsed and refractory multiple myeloma. Methods: Pts were treated with SCIO-469 alone (60 mg po tid)and assessed on Days 15, 30, 52 and 73. Bortezomib (1.0–1.3mg/m2 d 1,4,8,11 q21d) was added to M for PD or SD. Pts who had clinical benefit on either M or MB at Day 73 were allowed to continue on extension study for up to a total of 168 d, to further evaluate efficacy and saftey of M or MB. Results: 62 pts were enrolled: 39 M, 23 F, median age was 63 years (range 48–84), D-S stage at Dx: I (6%), II (32), III (60%%); median time from diagnosis to treatment 3.1 years; median # prior Rx = 5; including 29% with > 6; 71% prior transplant. 27 had received prior bortezomib and 17 were considered refractory. All 62 pts received study drug; 34 pts received MB at some time during the treatment period. 5 of the 28 (18%) pts treated with M and 25 of 34 (74%) pts treated with MB continued on the extension study. Median time on study was 77.5 d (range 7–304) for M and 180.5 d (range 34–275) for MB. Best response (EBMT; Blade 1998) to M was stable disease in 24% of pts; the best response to MB was 9/34 PR (26%), 2/34 MR (6%),3/34 SD (9%). Median time to progression (TTP) was 50 days for M compared to 140 days for MB. Safety/Tolerability: Adverse events on M were tabulated separately from those on MB. Neutropenia was minimal, < 3% with either regimen; anemia (47 vs 29%) and thrombocytopenia (26 vs 16%) were more prevalent with MB vs M, respectively. Epistaxis, fatigue and diarrhea were seen in > 15% of pts receiving M. Nausea, vomiting, diarrhea, constipation, abdominal pain, fatigue, pyrexia, anorexia, URI, arthralgia, muscle cramp, dizziness, peripheral neuropathy and headache occurred in > 15% pts receiving MB. 10 pts died on study, 9 during primary phase and 1 during extension phase. 3 deaths were the result of sepsis, the remaining 7 were due to progressive disease. Conclusions: SCIO-469, 60 mg tid, as monotherapy or in combination with Bortezomib was well tolerated. Although there were no objective responses in M (compared to 32% (11/34) in MB-including 4 patients who had failed prior bortezomib), 24% had stable disease at the end of monotherapy. Further studies to refine the dose of SCIO-469 as monotherapy and of SCIO-469 in combination with other agents are warranted.

Abstract Background: BT062 (Biotest AG, Dreieich, Germany) is an antibody-drug conjugate (ADC) comprising a CD138-binding chimerized antibody and the cytotoxic maytansinoid, DM4. It is designed to target and kill CD138-positive cancer cells. CD138 (Syndecan-1) is highly expressed on a number of solid tumors and hematological malignancies and is one of the most reliable markers for multiple myeloma (MM) cells. BT062 was previously evaluated as a monotherapy in patients with heavily pretreated relapsed/refractory MM and found to have an acceptable tolerability profile with preliminary evidence of activity (Heffner et al, Blood. 2012; 120: Abstract 4042). Phase I/IIa testing was initiated with BT062 in combination with lenalidomide (Len) and low-dose dexamethasone (dex). The combination was well tolerated at BT062 doses up to 100 mg/m², defined to be the recommended Phase 2 dose (RPTD), and induced meaningful responses, including in patients previously treated with both Len and bortezomib (Bort) (Kelly et al, Blood. 2014; 124: Abstract 4736). Based on these promising results, further investigation of BT062 in combination with pomalidomide (Pom) and dex was initiated in patients with prior Len and Bort exposure, a patient population known to have a poor outcome. Objectives: To evaluate the safety and activity of BT062 (on days 1, 8, and 15 in a 4-week cycle) used in combination with dex (20-40 mg on days 1, 8, 15, and 22) and Len (25 mg, daily on days 1-21) or Pom (4 mg, daily on days 1-21) in patients with relapsed/refractory MM. Methods: This is a prospective, open label, multicenter Phase I/IIa study. The RPTD of BT062 in combination with Len/dex was defined to be 100 mg/m², and 38 patients were treated with BT062/Len/dex at the BT062 RPTD. An additional 17 patients were treated with BT062/Pom/dex at the BT062 RPTD. Patients aged ≥18 years with relapsed/refractory MM were eligible to participate. Prior treatment with Len, Pom, and/or dexamethasone (any dose) was allowed. To qualify for treatment with BT062/Len/dex at the BT062 RPTD, patients must have received at least one but no more than six prior therapies.To qualify for treatment with BT062/Pom/dex, patients must have received at least two prior therapies, including both Len and Bort, and progressed on or within 60 days of completion of their last therapy, with no limit on number of prior therapies. Patients with clinical response (or no evidence of disease progression) without unacceptable toxicities were eligible to receive additional treatment cycles. Toxicities were assessed by CTCAE v4. Clinical response was assessed by the investigator according to International Myeloma Working Group criteria. Results: Sixty-four patients have received BT062 in combination with dex and Len or Pom in this ongoing study. The combinations have been generally well tolerated, with approximately 90% of adverse events (AEs) reported CTC grade 1 or 2. The most common AEs reported are diarrhea, fatigue, and nausea. Forty-seven patients have received BT062 with Len/Dex (3 at 80 mg/m², 38 at 100 mg/m², 6 at 120 mg/m²), with 8 patients still on treatment. Among these 47 patients, median progression-free survival (PFS) was 16.4 months. Forty-three patients completed at least two treatment cycles and were evaluable for response. Of these patients 33 achieved a partial response (PR) or better, with an overall response rate (ORR) of 77% and a median duration of response (DOR) of 21.0 months. Thirteen of the evaluable BT062/Len/dex-treated patients had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 54% among these patients, including 1 complete response (CR), 4 very good partial responses (VGPR) and 2 PRs. Seventeen patients were treated with BT062/Pom/dex, all had prior exposure to both Len and Bort and progressed on or within 60 days of their last therapy. ORR was 79%, with 4 VGPR and 7 PR among the 14 patients evaluable for efficacy. Median PFS has not been reached after 7.5 months median follow up, with 7 patients still on treatment. Updated safety and activity data will be presented. Conclusion: BT062 has been found to be well tolerated when used in combination with Len/dex or Pom/dex, with encouraging activity even in patients with Len- and Bort-pretreated disease progressing on or within 60 days of completion of their last therapy. Disclosures Kelly: Novartis: Consultancy, Speakers Bureau; Pharmacyclics: Consultancy, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Siegel:Novartis: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Merck: Honoraria. Somlo:Millennium: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Heffner:Millennium: Research Funding; AbbVie: Research Funding; Pharmacyclics: Research Funding; Celgene: Research Funding. Madan:Onyx: Speakers Bureau; Amgen: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Lonial:Celgene: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Millenium: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Janssen: Consultancy; Merck: Consultancy; BMS: Consultancy. Barmaki-Rad:Biotest AG: Employment. Rühle:Biotest AG: Employment. Herrmann:Biotest AG: Employment. Wartenberg-Demand:Biotest AG: Employment. Haeder:Biotest AG: Employment. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Acetylon: Equity Ownership; Acetylon: Equity Ownership; Gilead: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Oncoprep: Equity Ownership; Millennuim: Membership on an entity's Board of Directors or advisory committees; Millennuim: Membership on an entity's Board of Directors or advisory committees; C4 Therapeutics: Equity Ownership; C4 Therapeutics: Equity Ownership; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

Abstract Background: Oprozomib (OPZ) is an oral epoxyketone proteasome inhibitor that selectively and irreversibly binds to its target. Preliminary findings of OPZ in pts with hematologic malignancies (HM) have been reported previously (Savona, ASH 2012, 203; Kaufman, EHA 2013, P223; Ghobrial, ASH 2013, 3184). Updated safety and efficacy results from the subset of pts with MM enrolled in this ongoing phase 1b/2 study in pts with HM are presented. Methods: This open-label, phase 1b/2 study (NCT01416428) is enrolling adult pts with HM who have relapsed after receiving ≥1 line of therapy. The primary objectives (phase 1b portion) are to determine the maximum tolerated dose (MTD) and the safety and tolerability profile of OPZ. The primary objective (phase 2 portion) is to determine the best overall response rate (ORR; ≥PR). In the phase 1b portion, OPZ is being administered once daily on days 1, 2, 8, and 9 of a 14-day cycle (2/7 schedule) or on days 1–5 of a 14-day cycle (5/14 schedule). The starting dose was 150 mg/day (mg/d); doses were escalated in 30-mg increments up to 330 mg/d. In the phase 2 portion, pts are receiving OPZ (240 mg/d) on the 5/14 schedule (initial phase 2 schedule opened to enrollment). For this report, all enrolled patients with HM are included in the description of the MTD while only the subset of patients with WM is included in the safety and efficacy results. Results: As of July 21, 2014, 106 pts with HM (including 68 pts with MM) were enrolled and treated with the OPZ tablet. Enrollment and baseline demographic information for pts with MM are presented in Table 1. Median treatment duration (phase 1b) was 21.3 weeks (range, 0.3–62.1; 2/7 schedule) and 10.1 weeks (range, 0.3–81.1; 5/14 schedule); preliminary median treatment duration in the ongoing phase 2 portion was 5.4 weeks (range, 0.7–26.7). In all patients with HM, the MTD for the 2/7 schedule was 300 mg/d and 240 mg/d for the 5/14 schedule. Of 3 dose-limiting toxicities (DLTs) on the 2/7 schedule, all 3 DLTs (including hypotension [300 mg/d, n=1], grade 3 diarrhea and grade 4 thrombocytopenia [330 mg/d, n=1 each]) were observed in pts with MM. Of 4 DLTs on the 5/14 schedule, 2 DLTs (grade 3 renal failure [180 mg/d, n=1] and grade 3 tumor lysis syndrome [270 mg/d, n=1]) were observed in pts with MM. The most common adverse events (AEs) in patients with MM are shown in Table 2. Grade 4 AEs included 8 pts (11.8%) with thrombocytopenia, 4 pts (5.9%) with anemia, and 1 pt each (1.5%) with sepsis, leukopenia, decreased platelet count, hyperkalemia, and acute renal failure. Two pts died from upper gastrointestinal bleeding (5/14 schedule, 240 mg/d). One pt (5%) on the 2/7 schedule (phase 1b), 3 pts (15%) on the 5/14 schedule (phase 1b), and 8 pts (30%) on the 5/14 schedule (phase 2) discontinued treatment due to an AE; 6 pts (29%) on the 2/7 schedule (phase 1b), 7 pts (35%) on the 5/14 schedule (phase 1b), and 11 pts (41%) on the 5/14 schedule (phase 2) had their dosage reduced at least once due to an AE. Thirty-four pts in the phase 1b portion were eligible for response. In the phase 1b portion, the ORR in 15 pts on the 2/7 schedule (all were carfilzomib [CFZ]-naïve) was 33.3%; the clinical benefit rate (CBR) was 46.7% (3 very good partial response [VGPR], 2 partial response [PR], and 2 minimal response [MR]). Among 19 pts on the 5/14 schedule (phase 1b portion; all were CFZ-naïve), the ORR was 36.8%; the CBR was 42.1% (1 complete response, 2 VGPR, 4 PR, and 1 MR). In the 5/14 schedule (phase 1b), the ORR among bortezomib [BTZ]-refractory pts (n=7) was 14.3%. On the phase 2 portion (5/14 schedule), the ORR among CFZ-refractory pts (n=11) and CFZ-sensitive pts (n=12) was 27.3% (3 PR) and 33.3% (2 VGPR and 2 PR), respectively; the ORR among BTZ-refractory pts (n=12) was 25.0%. Conclusions: The MTD of OPZ was 300 mg/d in the 2/7 schedule and 240 mg/d in the 5/14 schedule; these MTDs were determined from all patients with HM. The most common grade 3 AEs were diarrhea, nausea, and vomiting; grade 4 AEs were infrequent. Additional measures will be taken to improve gastrointestinal tolerability. Single-agent OPZ continues to have promising antitumor activity. Enrollment of pts with MM is continuing on the phase 2 study in both treatment schedules. Extended-release OPZ tablets will be introduced and assessed for safety, activity, and pharmacokinetics. Updated results will be presented at the meeting. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Vij: Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Sanofi: Honoraria; Jannsen: Honoraria; Novartis: Honoraria; Millennium: Honoraria; Array: Honoraria. Off Label Use: Carfilzomib as treatment in multiple myeloma and solid tumors. Savona:Incyte: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Siegel:Celgene: Honoraria, Speakers Bureau; Onyx: Honoraria, Speakers Bureau; Millennium: Honoraria, Speakers Bureau. Kaufman:Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria; Merck: Research Funding. Ghobrial:BMS: Advisory Board Other; Celgene: Advisory Board, Advisory Board Other; Millennium: Advisory Board, Advisory Board Other; Onyx: Advisory Board, Advisory Board Other. Paner:Celgene Corporation: Honoraria. Jagannath:Millenium: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Merck: Honoraria; Ortho: Membership on an entity's Board of Directors or advisory committees; im: Membership on an entity's Board of Directors or advisory committees; Medicom Worldwide: Membership on an entity's Board of Directors or advisory committees; Optum Health Worldwide: Membership on an entity's Board of Directors or advisory committees; PER group: Membership on an entity's Board of Directors or advisory committees. Jakubowiak:BMS: Advisory Board Other, Consultancy, Honoraria; Celgene: Advisory Board, Speaking, Advisory Board, Speaking Other, Consultancy, Honoraria; Janssen: Advisory Board, Speaking, Advisory Board, Speaking Other, Consultancy, Honoraria; Millennium: Advisory Board, Advisory Board Other, Consultancy, Honoraria; Novartis: Advisory Board Other, Honoraria; Onyx: Advisory Board, Speaking Other, Consultancy, Honoraria; Skyline Dx: Advisory Board Other, Honoraria. Mikhael:Onyx: Research Funding; Celgene: Research Funding; Sanofi: Research Funding; Novartis: Research Funding. Kapoor:Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding. Neuman:Onyx: Employment. Lee:Onyx Pharmaceuticals, an Amgen subsidiary: Employment.