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: 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 1968 Two previous studies have reported that multiple myeloma (MM) patients (pts) with t(4;14), identified by FISH cytogenetics, experience a median progression-free survival (PFS) of only 8–9 mos and median overall survival (OS) of 18 mos when treated with a single ASCT (Chang H, et al. Bone Marrow Transplant 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). On the other hand, the novel agent bortezomib is efficacious in relapsed myeloma pts with t(4;14). Based on these observations, we designed a phase II protocol for newly diagnosed MM pts with t(4;14) that consists of induction with pegylated liposomal doxorubicin, bortezomib and dexamethasone (DBD) × 4 cycles, followed by post-induction therapy with oral cyclophosphamide 300 mg/m2 days 1,8 15, 22 with bortezomib 1.5 mg/m2 days 1,8,15 and prednisone 100 mg q 2 days of a 28-day cycle (CyBor-P) × 8 additional cycles. Maintenance therapy with dexamethasone (dex) 40 mg/month was then administered until progression. Although elective stem cell collection was recommended after induction, routine ASCT was not performed in the absence of disease progression. Between February 2008-July 2010, the bone marrows of 201 newly diagnosed MM pts were screened for t(4;14) in 7 Canadian centers, and 31 (15.4%) were found to be positive by FISH. Five pts did not meet the criteria for symptomatic MM, 4 had received ≥ 2 mos of prior therapy, 1 refused treatment and 2 were ineligible due to peripheral neuropathy or renal failure. Nineteen pts have been entered onto study. One of these was later determined to have a variant abnormality of chromosome 4 but not t(4;14) and underwent ASCT after induction; this pt is included in the safety analysis only. The median age was 60 yrs (45-69) and 53% were male. The median percent nuclei positive for t(4;14) was 26% (3-44%), serum β2-microglobulin was 318 nmol/L (43-1695) and albumin was 36 g/L (28-48); 6 pts had ISS stage 1, 6 had stage 2 and 5 had stage 3 MM. Immunoglobulin subtype included IgGκ (5), IgGλ (4), IgAκ (3), IgAλ (4), λ LC (1) and nonsecretory (1). To date, 15 pts have commenced DBD induction (57 total cycles administered), 12 have started post-induction CyBor-P (67 total cycles) and 6 are on maintenance dex (35 total cycles). Using modified Uniform criteria, the best response in 15 evaluable pts includes: sCR in 3 (20%), CR in 3 (20%), VGPR in 6 (40%), PR in 1 (6.7%) and stable disease in 2 (13.3%). Four have progressed a median of 3 mos (1-11) after commencing induction; one who progressed through DBD remains in nCR 1.5 yrs after salvage D-PACE followed by ASCT and lenalidomide maintenance. Fourteen SAEs occurred, of which 11 were grade 3 and 0 were grade 4; 5 pts developed grade 2 peripheral neuropathy (numbness and tingling) during induction with DBD. Grade 3/4 neutropenia was seen in 2/0 pts, and grade 3/4 thrombocytopenia in 2/1 pts, respectively. Two pts have died, due to MM progression in 1 and complex medical problems including syringomyelia with progressive weakness/ruptured diverticuli/depression in another who withdrew consent despite achieving VGPR with induction. Median follow-up (F/U) is 9.4 mos (1-23). Actuarial PFS is 66% (95% CI 42–100%) and overall survival is 92% (95%CI 79–100%) at 1 year. We conclude: 1) the incidence of t(4;14) by FISH in newly diagnosed MM pts is 15.4% as expected; 2) 26% of newly diagnosed pts with this entity have asymptomatic MM; 3) this bortezomib-based regimen is well-tolerated; 4) the overall response rate (sCR + CR + VGPR + PR) is 87%; 5) preliminarily, the 1-year PFS and OS with this approach compare favorably with reports of single ASCT in t(4;14) positive MM, although longer follow-up is required. Disclosures: Reece: Ortho Biotech: Honoraria, Research Funding. Off Label Use: Bortezomib as first line therapy in myeloma. Chen:Ortho Biotech: Honoraria. Kukreti:Ortho Biotech: Honoraria. Anglin:Ortho Biotech: Honoraria. Trudel:Ortho Biotech: Honoraria.

Abstract: Abstract 39 Three randomized trials have previously reported a progression-free survival (PFS) advantage for patients receiving thalidomide (T) maintenance post ASCT in MM. Two trials reported an overall survival (OS) advantage but the largest trial reported shows no OS advantage and in very high risk MM the use of T was deleterious. Recent trial reports demonstrate a PFS but not yet an OS advantage for patients receiving maintenance lenalidomide. We report results of NCIC CTG MY.10 which compared treatment with T (200 mg daily) and prednisone (50 mg alternate days) (T/P) until progression versus observation alone when used as maintenance therapy following ASCT. Importantly, OS was the 1ry endpoint of this study, 2ry endpoints were PFS, quality of life (QoL), toxicity, and the incidence of venous thromboembolism events (VTE). Eligibility: Patients with MM who had ASCT within 1 year of beginning initial treatment for their disease. Patients were randomized 60–100 days post ASCT and had no other medical condition precluding long term use of T/P. Results: 332 patients were enrolled. Median age was 58 years and the arms were balanced. Patients were stratified by age ( 〈 60 or 〉 60), and CR status post transplant. Median follow up is 4 years. Only 14% of patients were in CR post transplant. 111 patients died (50 versus 61 in T/P vs. observation). The median OS was 5 years for observation, and has not yet been reached for T/P, however T/P maintenance therapy did not significantly prolong OS: p = 0.18, HR of maintenance vs. observation 0.77 (95% CI 0.53–1.13). The 4 year survival rate was 68% for T/P and 60% for observation. Age and response to transplant had no significant association with OS (p=0.21), while higher disease stage was associated with shorter OS (p=0.03). The median PFS was 28 months for T/P versus 17 months for observation: p 〈 0.0001, HR of T/P vs. observation 0.56 (95% CI 0.43 – 0.73). The 4 year PFS rate was 32% for T/P treated patients versus 14% for patients on observation. At relapse, treatment by arm (T/P vs observation) included lenalidomide (39 vs 34%), T (13 vs 22%) or bortezomib (50 versus 46%). Non hematologic toxicities were seen in more patients with treatment (Grade 3: 92% T/P vs 49% observation, grade 4: 16% vs 7%). Common toxicities of all grades that were significantly higher in T/P treated patients included hyperglycemia, edema, hypertension, fatigue, Cushingoid appearance, constipation, mouth dryness, dyspepsia, anxiety, memory loss, sensory neuropathy, tremor, blurred vision, depressed consciousness, cataracts, dyspnea and bruising. 7% of patients on maintenance T/P developed a VTE in the absence of prophylaxis versus 0% on observation. NCIC CTG standardized response analysis was use to compare QoL data between the 2 treatment arms. Overall, patients on T/P had worse QoL specifically in physical (p=0.07), role (p=0.08), cognitive (p = 0.01) and global (p=0.06) domains, and worse symptoms with dyspnea (p = 0.0007), constipation (p 〈 0.0001), thirst (p=0.003), swelling in leg (p=0.03), numbness (p=0.02), dry mouth (p 〈 0.0001), and balance problems (p 〈 0.0001). However, patients on T/P reported improvement in appetite (p 0.02), and sleep (p=0.04). Conclusions: T/P maintenance did not improve overall survival, the primary objective of this trial, although a trend in favor of T/P was seen. In contrast, PFS was significantly improved in the T/P arm while toxicity was demonstrably increased and quality of life diminished. Disclosures: Stewart: Millennium: Consultancy; Celgene: Honoraria. Trudel:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Research Funding, Speakers Bureau. White:Celgene: Honoraria, Research Funding. Meyer:Celgene: Honoraria.

Abstract: Introduction: The NCIC CTG previously reported the results of a dose-finding trial testing the combination of Melphalan (M) and Lenalidomide (L) in previously untreated patients with multiple myeloma who were ineligible for stem cell transplantation because of older age and/or comorbidity (White, Blood2007; 110: 63a). Using a 28-day schedule, M (dose indicated as mg/m2/day given on days 1–4) and L (dose indicated in mg/day given on days 1–21) was associated with excess toxicity with the regimens M9L10, M4L15 and M6L10. We concluded that phase II testing of M5L10 was warranted and now report the results of this testing. Methods: Previously untreated symptomatic and consenting patients with tissue-confirmed plasmacytosis and a measurable M-protein were eligible provided that they had acceptable hematologic and biochemical laboratory parameters and no precluding comorbidities. Planned treatment consisted of M 5 mg/m2 days 1–4 and L 10 mg days 1–21, given every 28 days for 12 cycles. As our intent was to determine dose levels that could be given independently of G-CSF, primary prophylaxis with G-CSF was not included but use of G-CSF for established neutropenia was permitted. A hematologic dose limiting toxicity (H-DLT) was defined as the need for 2 dose attenuations of L or 1 dose attenuation of M occurring within the first 3 treatment cycles. Responses to treatment were classified using 1998 EBMT criteria and assessed after 2 and 6 cycles of therapy. Results: The intended sample size was 41 patients; 35 patients (1 ineligible) were enrolled before the study was closed due to observing a frequency of DLTs that surpassed predefined boundaries. Of the 34 eligible patients, median age was 73.4 yrs and ISS was stage I = 13, stage II = 11 and stage III = 10. Prior to study closure, 27 patients were evaluable for DLT; 7 (26%) did not experience a DLT. Among the remaining 20 (74%) patients, non-hematologic (N=2) and hematologic (N=18) DLTs requiring dose attenuations were seen within the first 3 treatment cycles; the H-DLTs included severe or prolonged neutropenia (N=11), thrombocytopenia (N=2) or both (N=5). One fatal serious adverse event was observed, this was due to a stroke. The other non-hematologic DLT was a cranial nerve III palsy which subsequently resolved. Responses after 2 cycles were evaluable in 21 patients and included partial response (PR) = 11, minimal response = 6, no change = 2 and progressive disease (PD) = 2. For those patients without PD after 2 cycles, responses after 6 cycles were evaluable in 8 and included PR = 6, stable response = 1 and PD = 1. Conclusion: Although M + L is an active combination for previously untreated myeloma patients, the regimen is associated with considerable myelosuppression. Without the routine use of GCSF, the doses used in the MY.11 study were not tolerable. Inability to use planned doses may have compromised the efficacy of the combination.

Abstract: Abstract 3982 Newly diagnosed multiple myeloma (MM) patients (pts) with t(4;14) identified by FISH who undergo a single ASCT after older induction regimens have a median progression-free survival (PFS) of only 8–9 months (mos) and median overall survival (OS) of 18 mos (Chang H, et al. Bone Marrow Transplan t 2005; 36: 793; Gertz M, et al. Blood 2005; 106: 2837). Given the efficacy of bortezomib in t(4;14) disease, we designed a phase II study based on this agent in which ASCT was not performed as part of first-line therapy. Pts received induction therapy with four 21-day cycles of pegylated liposomal doxorubicin 30 mg/m2on day 4, bortezomib 1.3 mg/m2on days 1, 4, 8, 11 and dexamethasone 40 mg on days 1–4, 8–11, 15–18 of cycle 1 and on days 1–4 and 11–14 of cycles 2–4 (DBD), followed by post-induction therapy with eight 28-day cycles of oral cyclophosphamide 300 mg/m2on days 1, 8, 15, 22, bortezomib 1.5 mg/m2 on days 1,8,15 and prednisone 100 mg q 2 days (CyBor-P). Maintenance therapy with dexamethasone 40 mg/weekly was then administered until disease progression. Although elective stem cell collection was recommended after induction therapy, routine ASCT was not performed in the absence of disease progression. Between February 2008-May 2011, 383 newly diagnosed MM pts were screened for t(4;14) in 8 Canadian centers, and 43 (11.2%) were found to be positive by FISH. Five did not meet the CRAB criteria for symptomatic MM, 7 were ineligible, 3 declined participation and 28 were entered onto study. One of these was later determined to have a variant abnormality of chromosome 4, but not t(4;14), and underwent ASCT after induction therapy; this pt is included in the safety analysis only. The median age was 60 years (range 42–69) and 63% were male. The median percent of nuclei positive for t(4;14) by FISH in the initial bone marrow (unpurified) was 26% (range 2–62), serum β2-microglobulin 239 nmol/L (range 43–1695) and albumin 36 g/L (range 28–48); ten pts had ISS stage 1,10 had stage 2 and 7 had stage 3 MM. Immunoglobulin subtype included IgGκ in 7, IgAκ in 6, IgAλ in 6, IgGλ in 5 and IgMλ in 1. Using modified uniform criteria, the best response in 23 evaluable pts includes: sCR in 6 (26%), CR in 4 (17%), VGPR in 9 (39%), PR in 2 (9%) and SD in 2 (9%). Median F/U is 13.5 mos (range 1.2–35); 6 have progressed at median of 3 mos on study (range 1–11). Four pts have died (due to progression in 3 and complex medical problems/consent withdrawal in 1 in VGPR). SAEs were reported in 7 pts; only 6 pts (21%) developed grade 2 peripheral neuropathy, which necessitated dose reductions of bortezomib in 4. The actuarial 2-yr PFS is 47.7% (95%CI 25.9–87.9%), median PFS is 23. 2 months and 2-yr OS is 76.8% (95%CI 58.3–100%); the median OS has not yet been reached. We conclude: 1) the incidence of t(4;14) by FISH in newly-diagnosed MM pts is 11.2%; which appears to be lower than the 15% anticipated 2) 11.6% of these are asymptomatic; 3) this bortezomib-based regimen is well-tolerated; 4) the overall response rate (sCR + CR + VGPR + PR) is 91% with 82% achieving ≥ VGPR and 43% ≥ CR; 5) the PFS and OS with this approach compare favorably with those seen with older studies of single or double ASCT, and even with some recently reported trials using more modern induction regimens before ASCT, in pts with t(4;14); and 6) the use of more effective maintenance therapy, including agents targeting the aberrations associated with t(4;14), would be of interest in future trials. Disclosures: Reece: Millennium: Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Johnson & Johnson: Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Bristol, Meyers, Squibb: Honoraria, Research Funding; Amgen: Honoraria. Off Label Use: Bortezomib regimens other than VMP (boretzomib, melphalan and prednisone)for initial therapy of myeloma. Piza Rodriguez:Celgene: Unrestricted educational grant; Otsuka: Honoraria. Belch:Ortho/Janssen: Honoraria; Celgene: Honoraria. White:Celgene: Consultancy, Honoraria, Research Funding; Ortho/Janssen: Honoraria, Research Funding. Chen:Celgene: Research Funding. Kukreti:Celgene: Honoraria.

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.