ALBERT

Description: This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow–derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.

Description: Background Light chain (AL) amyloidosis is typically a systemic disease resulting from the malignant production and deposition of immunoglobulin light chain fragments in various tissues. Pulmonary AL amyloidosis is uncommon but can be seen concomitantly with non-Hodgkin lymphoma (NHL) as one of two distinct syndromes. In the more common presentation, a NHL, typically lymphoplasmacytic lymphoma or extranodal marginal zone lymphoma, produces a measurable serum/urine M-protein or light chain resulting in a systemic AL amyloidosis. There have also been sporadic reports of a less common, nodular form of pulmonary AL amyloidosis due to peritumoral amyloid deposition in patients with pulmonary extranodal marginal zone lymphoma of MALT type. This latter association is probably under-recognized. Here we present two cases from our institution with important diagnostic and therapeutic implications. Case 1 A 60 year old male was found to have bilateral pulmonary nodules. A percutaneous biopsy of the largest lesion in the left perihilar region revealed a MALT lymphoma. He was treated with eight cycles of R-CVP with a partial response. Significant residual disease led to further treatment with radioimmunotherapy using ibritumomab tiuxetan but without additional radiographic improvement. Due to concerns about the persistence of multiple pulmonary nodules, the original diagnostic biopsy was stained with Congo red to reveal amyloid deposition. No measurable monoclonal protein was present in the serum or urine. He has been observed now for an additional 4 years without evidence of progression. This patient has pulmonary amyloidosis in a nodular pattern in conjunction with a pulmonary MALT lymphoma. Pathologic review has shown the individual pulmonary nodules to be composed of both lymphoma and amyloid. The decrease in the size of the nodules with initial chemotherapy indicates a response to therapy, likely of the lymphoma component. The lack of response to typically effective additional therapy and the stability of the nodules over an extended period of time lead us to conclude that the residual nodules are likely to be primarily composed of amyloid. The initial lack of recognition of the amyloid component was disadvantageous and made determination of treatment response difficult. Case 2 A 37 year old male with HIV was found to have multiple pulmonary nodules. Pulmonary wedge resection revealed an extranodal marginal zone lymphoma of MALT type and amyloidosis that was confirmed as AL type by laser dissection and mass spectroscopy. Initial PET/CT demonstrated widespread FDG-avid lymphadenopathy and non-FDG-avid pulmonary nodules. There was no other evidence of systemic amyloidosis. The patient has been treated with three cycles of bendamustine and rituximab. Restaging PET/CT has shown a decrease in FDG-avid lymphadenopathy but no significant improvement in the size or number of pulmonary nodules. His chemotherapy is being continued. This patient has pulmonary AL amyloidosis in association with a stage IV extranodal marginal zone lymphoma. At first glance, the patient appears to have had a discordant response to initial treatment. However, the diagnosis of amyloidosis allows us to determine that his lymphoma has responded to therapy and the lack of response seen in the lungs is likely due to the presence of persistent amyloid. If the diagnosis of pulmonary amyloidosis was not made or known, this may have been mistakenly considered as refractory disease resulting in an unnecessary change in therapy. Conclusion The association between pulmonary amyloidosis and extranodal marginal zone lymphoma of MALT type may be more prevalent than previously recognized. All cases of pulmonary MALT lymphoma should be carefully examined for evidence of amyloid deposition. If proven, imaging studies, serum/urine electrophoresis and serum free light chain studies and organ assessments will help to determine whether the amyloid is a nodular form due to local deposition of light chain fragments or a systemic amyloidosis secondary to NHL. The former has a better prognosis than its systemic counterpart since the amyloidosis is typically localized to the lungs, has a more indolent course and is unlikely to involve other organs. As the above cases highlight, assessment of lymphoma response is greatly complicated by the concurrent presence of amyloid and PET/CT may be particularly useful in this scenario. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting 〉 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

Description: Abstract 449 Background ARRY-520 is a kinesin spindle protein (KSP) inhibitor that arrests cells in mitosis and induces apoptosis due to degradation of the BCL2 family survival protein MCL-1. As previously reported, ARRY-520 has demonstrated single-agent activity in relapsed and refractory multiple myeloma (RRMM). In preclinical myeloma models, the addition of dexamethasone (Dex) increases the activity of ARRY-520, supporting clinical investigation of ARRY-520 combined with low-dose Dex (LoDex). Here, the efficacy and safety of ARRY-520 is compared in 2 Phase 2 cohorts in RRMM: as a single agent (Cohort 1) and in combination with LoDex (Cohort 2). Methods Both cohorts were designed as 2-stage single-arm Phase 2 studies. Cohort 1 evaluated the efficacy and safety of 1.5 mg/m2/d ARRY-520 administered intravenously on Days 1 and 2 every 2 weeks with prophylactic granulocyte colony-stimulating factor (G-CSF) support. Eligible patients had RRMM with 2 prior lines of therapy that included both bortezomib (BTZ) and an immunomodulatory agent (IMiD), unless refusing or ineligible for this therapy. Cohort 2 is evaluating the efficacy and safety of the same dose and schedule of ARRY-520 and G-CSF with LoDex (40 mg PO weekly). Eligible patients had RRMM with 2 prior lines of therapy, and had disease refractory to (progressed on or ≤ 60 days of treatment) their last line of therapy and that was refractory to BTZ, lenalidomide (Len) and dexamethasone. Data from Cohort 1 and the first stage of Cohort 2 are reported. Results At the time of data cutoff, a total of 32 patients were enrolled into Cohort 1 with a median age of 65 years (range 51–82) and a median of 6 prior regimens (range 2–19). All patients received prior IMiD, 90% received prior BTZ and 78% had prior autologous stem cell transplant (ASCT). The defined first stage of Cohort 2 has been enrolled with 18 evaluable patients. These patients had a median age of 67 years (range 53–78) and were more heavily pretreated, with a median of 10 prior therapies (range 5–13). Safety was similar for both cohorts. A possible trend for more infections in Cohort 2 was noted. The most commonly reported (20% of patients) treatment-related adverse events (AEs) in both cohorts included thrombocytopenia, anemia, neutropenia and fatigue. No treatment-related events of neuropathy were observed in either cohort. The most common Gr 3/4 AEs (in Cohort 1, Cohort 2) included neutropenia (38%, 33%), thrombocytopenia (44%, 44%) anemia (28%, 50%), pneumonia (3%, 17%) and fatigue (16%, 11%). Treatment discontinuations due to AEs were infrequent (9%, 11%). Of 32 patients in Cohort 1, confirmed responses (≥ Minor Response (MR)) were observed in 6 patients (19%) with 5 Partial responses (PR) (16%) per International Melanoma Working Group (IMWG) and European Group for Blood and Marrow Transplantation (EBMT) criteria. The median treatment time was 2.1 months. In the subset of patients with disease refractory to both BTZ and Len, a 15% overall response rate (ORR ≥ MR) was observed. Among the 18 evaluable patients in Cohort 2, the ORR (≥ MR) was 28% (5/18), with 4 patients ≥ PR (22%). At the time of data cutoff, the median treatment time was 3.9 months. Summary Patients with RRMM refractory to both IMiD and proteasome inhibitor therapy have a poor prognosis with median survival of as little as 6 months1. New drugs with clinically meaningful activity in this population are needed. ARRY-520 is a novel agent with a distinct mechanism of action relative to other myeloma drugs and shows promising clinical activity both alone and combined with Dex in RRMM. Notably, in patients with triple-refractory MM, ARRY-520 + LoDex has shown a preliminary 28% ORR (≥ MR), with a manageable safety profile. These data are comparable to those reported for pomalidomide or carfilzomib in less heavily pretreated patients. Both the median time on study and ORR in Cohort 2 were greater than the activity seen for Cohort 1, despite the more advanced stage of these patients and the fact that they were heavily pretreated with Dex, suggesting that LoDex may enhance ARRY-520 activity. Based on this evidence of activity, further development of ARRY-520 + LoDex is warranted in patients who have exhausted other therapeutic options. Disclosures: Shah: Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau. Off Label Use: ARRY-520. Zonder:Millenium: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Kaufman:Onyx: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millenium: Consultancy. Orlowski:Array BioPharma: Honoraria, Membership on an entity's Board of Directors or advisory committees. Walker:Array BioPharma: Employment. Hilder:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Consultancy. Lonial:Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 815FN2 INTRODUCTION: Perifosine, an orally-bioavailable, novel signal transduction modulator has multiple pathway effects including inhibition of Akt, NFkB and activation of JNK. We conducted a phase I/II study of perifosine + bortezomib (Vel) +/− dexamethasone (Dex) which demonstrated encouraging safety and preliminary clinical activity in relapsed and refractory multiple myeloma (MM) patients (pts) (ASH 2009 # 1869). We report final results, including overall response rate (ORR), progression-free survival (PFS) and overall survival (OS) for the treatment of MM pts previously relapsed from and/or refractory to Vel. METHODS: The phase I stage of the study enrolled a total of 18 pts with a selected phase II dose of perifosine 50 mg qd + Vel 1.3 mg/m2 (d 1, 4, 8, 11) in 21-d cycles, which enrolled 66 pts. Dex 20mg (on day of and after each Vel dose) could be added in pts with progressive disease (PD). NCI CTCAE v3.0 was used for toxicity assessment. Response was assessed by modified EBMT and Uniform Criteria. RESULTS: A total of 84 pts were enrolled comprised of 51 men and 33 women, median age 63 y (range 35–89): 88% of pts had relapsed and refractory MM (73% Vel refractory), with a median of 5 lines of prior treatment (range 1–13). Prior therapy included Vel (100%), dex (98%), lenalidomide (76%), thalidomide (75%) and SCT (58%), with pts receiving a median of 2 prior Vel-based treatments. Median interval between diagnosis and inclusion was 4.5 years. Seventy three pts were evaluable for response (having completed at least two or more cycles of therapy), and all 84 were assessed for safety. Most common grade 1/2 events included nausea, diarrhea, fatigue and musculoskeletal pain, which were manageable with supportive care and dose reductions. Grade 3/4 adverse events included thrombocytopenia, neutropenia, anemia, pneumonia and musculoskeletal pain. Two pts had grade 3 peripheral neuropathy (PN), which was reversible with Vel dose reduction and/or treatment discontinuation. No grade 4 PN was observed. Overall 26 (31%) pts had treatment-related PN of any grade. Two pts had perifosine reduced to 50 mg (for GI related toxicity) in the phase 1 portion of the study, and 8 pts reduced to qod dosing in the phase II: 23 pts had Vel dose reductions primarily due to hematologic toxicity. No treatment-related mortality was seen. Eleven pts were inevaluable for response due to unrelated toxicity (n=5), rapid disease progression (〈 1 cycle received; n=3), or withdrawal of consent (n=3). For 73 response-evaluable pts, the ORR was 41%, including 4% CR, 18% PR and 19% MR. Prior best response (≥ PR) to last Vel-based regimen was 43% (36/84 pts), of which most were triple drug combinations (eg RVD). Of 53 pts who were refractory to prior Vel, ORR to perifosine, Vel +/− Dex was 32%, including 2% CR, 11% PR and 19% MR. ORR for 20 Vel-relapsed pts was 65%; 10% achieved a CR and 35% a PR. Median PFS was 6.4 mos with a range of 5 wks to over 3 yrs (95% CI: 5.3, 7.1), and 8.0 mos (95% CI: 6.4, 9.8) for the 30 evaluable pts who achieved ≥ MR. Median PFS for the 53 Vel-refractory pts was 5.7 mos (95% CI: 4.3, 6.4), with 40% of pts achieving PFS of 〉 6 mos. For the 20 Vel-relapsed pts, median PFS was 8.8 mos (95% CI: 6.3, 11.2), with 70% of pts achieving PFS of 〉 6 mos. Importantly, median PFS for all pts receiving prior Vel-based regimens prior to study entry was 5.3 mos. As of August 2011, median OS for all evaluable study pts was 25 mos (95% CI: 16.3, 31.1), 22.5 mos (95% CI: 14.2, 31.1) for the Vel-refractory pts and 30.4 mos (95% CI: 17.8, NR) for Vel-relapsed pts. Median OS for those pts who achieved PR + CR was 37 mos (95% CI: 13.8, NR) and for those pts who achieved SD + MR was 29 months (95% CI: 18, 32.4). CONCLUSIONS: Perifosine in combination with Vel (+/− dex) demonstrated impressive and durable activity in both heavily pre-treated, Vel-refractory pts (with an ORR of 32% and median OS of 22.5 mos), and in Vel-relapsed pts (with an ORR of 65%, median PFS of 8.8 mos and OS of 30.4 mos), with manageable toxicity. Survival data were encouraging, even in pts exposed to and refractory to Vel, as well as prior IMiDs, so providing another example of a rational combination strategy integrating novel therapies to further improve patient outcome. An international phase III randomized trial evaluating perifosine vs. placebo when combined with Vel and Dex in Vel-exposed pts with relapsed and refractory MM has been granted special protocol assessment (SPA) status and is currently underway to confirm the efficacy of this approach. Disclosures: Richardson: Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: 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; Keryx Biopharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Wolf:Millennium: Honoraria, Speakers Bureau. Jakubowiak:Millennium: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Onyx: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Honoraria; Exelixis: Consultancy, Honoraria. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Amgen: Consultancy; Medtronic: Consultancy; Celgene: Speakers Bureau. Lonial:Millennium: Consultancy; Novartis: Consultancy; Celgene: Consultancy; BMS: Consultancy; Onyx: Consultancy; Merck: Consultancy. Krishnan:Millennium: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Raje:Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Astra Zeneca: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Acetylon: Research Funding. Ghobrial:Noxxon: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Research Funding; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Munshi:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees. Allerton:Keryx Biopharmaceuticals: Consultancy. Hideshima:Acetylon: Consultancy. Sportelli:Keryx Biopharmaceuticals: Employment, Equity Ownership. Gardner:Keryx Biopharmaceuticals: Employment, Equity Ownership. Anderson:Celgene: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Merck: 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; Novartis: Membership on an entity's Board of Directors or advisory committees; Acetylon: Membership on an entity's Board of Directors or advisory committees.

Description: Abstract 860 Background: PD 0332991, the only known selective inhibitor of cyclin-dependent kinase (CDK) 4/6, is reversible and orally bioavailable. Inhibition of CDK4/6 phosphorylation of retinoblastoma (Rb) induces prolonged early G1 cell cycle arrest and synchronous progression to S phase upon withdrawal, which sensitizes human multiple myeloma (MM) cells to killing by bortezomib (B) or dexamethasone (D) in vitro and in animal models. This multicenter phase I trial is investigating the combination of PD 0332991 with these agents in MM during prolonged G1 arrest alone (Schedule A) or together with synchronization into S phase (Schedule B). The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D) of PD 0332991 and the schedule for combination. Methods: Adults with Rb protein-positive, symptomatic, relapsed and/or refractory MM (International Myeloma Working Group [IMWG] definition) after ≥1 prior treatment were eligible. Patients (pts) received oral PD 0332991 once daily on Days 1–21 of a 28-day cycle (Schedule A) or Days 1–12 of a 21-day cycle (Schedule B) for a maximum of 10 cycles. The starting dose of PD 0332991 was 100 mg, with planned escalation to 125 mg or de-escalation to 75 mg. Intravenous B 1.0 mg/m2 (with planned escalation to 1.3 mg/m2) and oral D 20 mg were administered on Days 8, 11, 15, and 18 on both schedules. A 3+3 dose-escalation scheme was used. The MTD was defined as the dose level at which ≤1/6 pts experienced dose-limiting toxicity (DLT), with the next higher dose level having ≥2/3 or ≥2/6 pts with DLTs. The RP2D was determined based on the MTD and overall safety and tolerability. The primary endpoint was first-cycle DLTs; tumor response (per IMWGURC) and PD 0332991-mediated inhibition of CDK4/6 activity and cell proliferation by immunohistochemistry (IHC) of CDK4/6-specific phosphorylation of Rb (pSRb) and Ki67, respectively, in bone marrow MM cells were secondary endpoints. The effects of B and D on PD 0332991 pharmacokinetics were also evaluated. Results: Twenty-one pts were enrolled: 9 on Schedule A (3 on PD 0332991 100 mg and 6 on 75 mg); 12 on Schedule B (7 on 100 mg and 5 on 125 mg). Sixty-seven percent of pts had an Eastern Cooperative Oncology Group performance status of 1. At baseline, median β2 microglobulin was 3.9 (range 1.6–14.8), median hemoglobin was 10.9 (7.3–13.4), and median calcium was 9.1 (6.6–11.5). The median number of prior therapies was 4 (range 1–9); 86% had received prior B. Eighteen pts have discontinued (14 due to progressive disease; 4 due to an adverse event [AE]). On Schedule A, 2/3 pts on PD 0332991 100 mg and 2/6 pts on 75 mg experienced DLTs (inability to receive ≥80% of PD 0332991 or B doses due to treatment-related toxicity), thus the MTD was not determined. On Schedule B, 1/6 DLT-evaluable pts on 100 mg and 2/4 on 125 mg experienced DLTs, and the MTD was determined to be PD 0332991 100 mg plus B 1.0 mg/m2 and D 20 mg. The most common treatment-related AEs were grade ≥3 thrombocytopenia (n=13) and neutropenia (n=7). There were no pts with QTc intervals 〉500 msec observed on study. The mean plasma AUC(0–12) of PD 0332991 was 539 ng · h/mL in the absence and 555 ng · h/mL in the presence of B and D (n=6). IHC showed preferential and complete (13/16 pts) or 〉80% (3/16 pts) inhibition of both pSRb and Ki67 in bone marrow MM cells before initiation of B and D treatment on Day 8, and cell cycle progression following PD 0332991 withdrawal on Day 18 of Schedule B (7/7 pts). One pt achieved a very good partial response (VGPR), 1 achieved a PR, and 3 had stable disease ≥3 months. Conclusions: In this first phase I trial of PD 0332991 in combination therapy, the MTD and RP2D have been determined to be PD 0332991 100 mg plus B 1.0 mg/m2 and D 20 mg on Schedule B in MM. The most commonly reported AEs were cytopenias, consistent with the known safety profiles of PD 0332991 and B. B and D had no apparent impact on the plasma AUC(0–12) of PD 0332991. Regardless of treatment history, PD 0332991 preferentially and completely inhibited CDK4/6 and cell cycle progression in MM cells, and this was reversible. Encouraging antitumor activity was observed in this heavily pretreated MM population, including VGPR in a pt with t(4:14) who had relapsed on lenalidomide, bortezomib, and carfilzomib therapies and a stem cell transplant. The phase II portion of the trial to evaluate the antitumor activity of targeting CDK4/6 with PD 0332991 using the Schedule B combination is underway. Disclosures: 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. Lentzsch:Celgene Corp: Research Funding. Singhal:Takeda/Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Onyx: Research Funding; Celgene: Speakers Bureau. Zonder:Millennium: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Consultancy, Research Funding; Celgene: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event; Novartis: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event; Proteolix: 10/16/2010 Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event. Courtney:Pfizer: Employment, Equity Ownership. Shaik:Pfizer Inc: Employment, Equity Ownership. Kim:Pfizer Inc.: Employment, Equity Ownership. Randolph:Pfizer: Employment, Equity Ownership.

Description: Abstract 303 Introduction: Elotuzumab is a humanized monoclonal IgG1 antibody directed against the cell surface glycoprotein CS1, which is highly expressed on tumor cells from 〉95% of multiple myeloma (MM) patients. The mechanism of action of elotuzumab is primarily natural killer cell-mediated antibody-dependent cellular cytotoxicity against myeloma cells. A Phase 1 study of elotuzumab (at doses of 5, 10, and 20 mg/kg) in combination with lenalidomide and low-dose dexamethasone (N=28) in relapsed/refractory MM patients demonstrated an 82% objective response rate (ORR). Median PFS was not yet reached after a median of 16.4 months follow-up in patients who were treated until progression (only the 20 mg/kg cohort). Of the 13 Phase 1 patients without premedication, 12 (92%) experienced infusion reactions (IR), including 2 with Grade 3/4 IR adverse events (AE). Phase 3 trials of lenalidomide/dexamethasone with or without elotuzumab are ongoing. Methods: In the ongoing Phase 2 study, patients with relapsed/refractory MM and 1 to 3 prior therapies were randomized to elotuzumab 10 or 20 mg/kg IV (days 1, 8, 15, and 22 every 28 days in the first 2 cycles and days 1 and 15 of subsequent cycles), lenalidomide 25 mg PO (days 1–21) and dexamethasone 40 mg PO weekly or 28 mg PO plus 8 mg IV on elotuzumab dosing days. Patients treated with prior lenalidomide were excluded. All patients received a premedication regimen, which consisted of either methylprednisolone (50 mg IV) or in a later amendment dexamethasone (8 mg IV), diphenhydramine (25–50 mg PO or IV) or equivalent, ranitidine (50 mg IV) or equivalent, and acetaminophen (650–1000 mg PO). Treatment continued until disease progression or unacceptable toxicity. The primary objective was to assess efficacy (ORR; 'partial response [PR]) according to the International Myeloma Working Group criteria. The incidence of IRs were analyzed by 1) AEs, regardless of investigator attribution, and that potentially could be an IR by virtue of their onset on the day of, or day after, elotuzumab infusion, and 2) investigator attribution of an AE as an IR. Results: Among 73 enrolled and treated patients (median age 63 years; range 39–82), 55% had ≥2 prior therapies, 62% received prior thalidomide, 60% received prior bortezomib, and 47% had β2 microglobulin ≥3.5 mg/L at screening (N=71). ORR was 82% in the combined treatment group (10 mg/kg, n=36; 20 mg/kg, n=37), including 44% ≥ very good PR (VGPR). Of these patients, 12% had a stringent complete response (CR) or a CR, and 32% had a VGPR. In the 10 mg/kg group (Phase 3 dose), the ORR was 92%. ORRs for patients who received 10 mg/kg by subgroup were: 1 prior therapy (n=16), 100%; ≥2 prior therapies (n=20), 85%; prior thalidomide (n=21), 91%; prior bortezomib (n=22), 86%. Median time to objective response was 1.0 months (range, 0.7–4.3). After a median follow-up of 11.4 months, 22% of patients had progressed in the 10 mg/kg group and 30% of patients in the 20 mg/kg group. For all treated patients, the most common Grade 3/4 treatment-emergent AEs were lymphopenia (16%), thrombocytopenia (16%), neutropenia (15%), and anemia (11%). Forty-six patients (63%) experienced a study sponsor-defined IR (all grades).The most common IR AEs (mostly Grade 1/2; 1 Grade 3 nausea) were nausea (18%), headache (14%), pyrexia (14%), and dizziness (12%). Among the pre-specified IR AEs, Grade 3 rash and Grade 3 nausea were identified in 2 patients, respectively. However, the incidence of investigator-identified IR AEs was 16% (all grades) including the Grade 3 rash. No Grade 4 or 5 IR AEs were reported. Of the 73 patients, 40 patients are still on treatment. Conclusions: Elotuzumab 10 mg/kg in combination with lenalidomide and low-dose dexamethasone was generally well tolerated and exhibited a 92% ORR in relapsed/refractory MM patients; 10 mg/kg is the Phase 3 dose. Twenty-two percent of patients progressed after a median of 11.4 months follow-up. Elotuzumab-associated AEs were primarily Grade 1 and 2 infusion-related reactions, with the incidence and severity mitigated by the defined premedication regimen. Phase 3 clinical trials of this combination are ongoing in relapsed/refractory MM (ELOQUENT2; CA204-004) and front-line MM (ELOQUENT1; CA204-006); the latter is based on the Phase 2 study ORR of 100% in patients who had received only 1 prior therapy. Updated results will be presented at the meeting. Disclosures: Lonial: Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Onyx: Consultancy; Merck: Consultancy. Off Label Use: Elotuzumab. Jakubowiak:Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Jagannath:Millennium: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Facon:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Vij:Washington University School of Medicine: Honoraria, Research Funding, Speakers Bureau; Multiple Myeloma Consortium: Membership on an entity's Board of Directors or advisory committees. Reece:Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Otsuka: Honoraria, Research Funding; Merck: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Princess Margaret Hospital: Honoraria, Research Funding; Johnson&Johnson: Research Funding. White:Celgene: Consultancy, Honoraria, Research Funding. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Rossi:Pierre Fabre Medicaments: Consultancy; LFB: Consultancy. Tsao:Abbott Biotherapeutics Corp.: Employment. Parli:Abbott Biotherapeutics: Employment. Kroog:Bristol-Myers Squibb: Employment. Singhal:Abbott: Employment. Richardson:Millennium Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; Novartis Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: 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.

Description: Introduction African-American ethnicity, male sex, older age and obesity are accepted risk factors for multiple myeloma (MM). Obesity early in life is a risk factor for many cancers, including MM; most studies have focused on populations of European origin. African-Americans have a higher prevalence of obesity than other populations, and may have a distinct genetic contribution to this condition. We established a multi-center collaborative study to investigate possible explanations for the excess risk of MM among African-Americans. The aim of the present case-case analysis was to determine whether body mass index (BMI) was associated with risk factors and clinical characteristics at presentation in African-American MM patients. Methods Patients diagnosed with active MM since January 1, 2009 were recruited from nine outpatient centers and three Surveillance, Epidemiology, End-Results Program (SEER) population-based cancer registries. Information on weight and height at 20 years of age and at 5 years prior to diagnosis was obtained from questionnaires. Clinical information collected included age at diagnosis, stage, percent plasmacytosis on bone marrow biopsy, β2 microglobulin level, Ig serotype, light vs. heavy chain disease, and presence of lytic bone lesions. BMI (ht/wt2) was categorized into 3 levels (normal 30) according to World Health Organization standard. The Pearson chi-square test was used to test the association between BMI category, and risk factors and clinical characteristics. Mean ages at diagnosis across BMI categories were compared using linear regression and a t-test for trend calculated. Results To date, 1,044 African-American MM patients have been enrolled and of those, 1,014 provided a DNA sample. At present, 970 patients have completed a questionnaire, clinical records have been abstracted for 823 patients, and 509 patients have some information on gender, age at diagnosis, weight, height and clinical characteristics.The mean age at diagnosis was 59. Increasing BMI at age 20 was associated with younger age at diagnosis (p= 0.0004), whereas BMI at 5 years prior to diagnosis was not associated with age at diagnosis (p=0.9477). Among men, mean age at diagnosis decreased with increasing BMI at age 20 (p= 0.0125) (Table 1a) and at 5 years prior to diagnosis (p=0.0252) (Table 1b). Among women, the trend was signficant at age 20 (p=0.0018) (Table 1a) but not at 5 years prior to diagnosis (p= 0.7094) (Table 1b). Increasing BMI was not significantly associated with any other clinical characteristics. Conclusion/Discussion In a large collection of African-American MM patients, we observed a strong association between increasing BMI at age 20 and younger age at diagnosis. A similar trend was observed in men only at 5 years prior to diagnosis, consistent with previous reports. Obesity is one of the few known potentially modifiable risk factors for MM. Younger age at diagnosis reflects an earlier accumulation of either or both genetic and environmental risk factors. Obesity at an early age may influence MM risk through shared biological pathways such as interleukin-6 and insulin-like growth factor, by contributing to chronic B-cell activation, thereby increasing susceptibilty for MM later in life. The significance of the gender difference for the association closer to diagnosis is unclear and requires additional study. Disclosures: Terebelo: Amgen: Honoraria; Millennium: Honoraria. Mehta:Celgene: Speakers Bureau; Millennium: Speakers Bureau. Zonder:Skyline: Consultancy. Orlowski:Bristol-Myers Squibb: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Millennium: The Takeda Oncology Company: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Resverlogix: Research Funding; Array Biopharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Genentech: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Membership on an entity’s Board of Directors or advisory committees. Lonial:Celgene Corporation: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Bristol Myers Squibb: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Description: Abstract 304 Background: Bendamustine is a bifunctional alkylating agent that is approved for the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin's lymphoma. This first multicenter, phase I/II trial investigated the combination of bendamustine, lenalidomide and dexamethasone (BLD) as a potentially effective treatment option for multiple myeloma (MM) patients, particularly for those with pre-existing or bortezomib-induced neuropathy. Our primary objective was to determine the maximum tolerated dose (MTD) and safety profile of bendamustine and lenalidomide when administered with dexamethasone for patients with relapsed or refractory MM. Methods: We conducted an open-label, dose escalation study (Table 1). Patients were enrolled from June 2008 through February 2011. Eligible patients were aged ≥ 18 years with confirmed, measurable stage II or III MM that was refractory to or progressed after 1 or more prior therapies including lenalidomide. Patients were assigned to their dose levels in a classical 3+3 cohort design. Phase I was to assess the safety and to establish the MTD of the combination treatment. The phase II portion of the study was to assess the overall response rate (ORR) at the MTD. Intravenous bendamustine was given on days 1 and 2, oral lenalidomide on days 1–21, and oral dexamethasone on days 1, 8, 15, and 22 of the 28-day cycle. Treatment was given until plateau of best response as determined by the International Myeloma Working Group uniform response criteria for a maximum of 8 cycles. The study doses were escalated through 3 levels, in a 3+3 dose escalation scheme. The MTD was defined as the dose level at which ≤1 of 6 patients experienced dose-limiting toxicity (DLT) during the first cycle of therapy when the next higher dose level was associated with DLTs in ≥ 2 patients. Primary endpoint was the MTD. After determining the MTD, up to 12 additional patients were enrolled in an MTD expansion arm to better evaluate toxicity and clinical activity. Secondary endpoints included preliminary efficacy, as evidenced by objective response, time to disease progression, and overall survival. Results: 36 patients with a median age of 63 years (range 38 to 80) were enrolled. The median number of prior therapies was 3 with a range of from 2–9; 79% of the patients had prior lenalidomide, 48% had prior thalidomide, and 34% had both. 69% of the patients had a prior autologous stem cell transplant. The MTD was 75 mg/m2 for bendamustine and 10 mg for lenalidomide. DLTs included at dose level 2: 1 grade 4 neutropenia; at dose level 3: 2 grade 4 neutropenias and 1 delayed platelet recovery from grade 3 thrombocytopenia. 25 received at least 2 cycles and were included into the response assessment. A partial response or better was observed in 52% (n=13) of the patients, including 24% (n=6) VGPR. MR was observed in 24% (n=6), SD 16% (n=4), and PD 8% (n=2). BLD induced fast responses with a time to best response of 1.6 months (range 0.7–7.4). The response was independent of prior exposure to lenalidomide evidenced by the fact that 84% of patients with VGPR/PR had prior treatment with lenalidomide. The median follow up for patients at risk of progression is 8 months (range 4–13). The estimated median progression free survival (PFS) is 4.4 months (95% CI (3.4, 9.2). 4 patients have died and the median follow up for patients who are still alive is 13 months (range 6–33). The median OS survival has not been reached yet. We did not observe any unanticipated DLTs. The only grade 4 adverse events for all patients for all cycles included 24.1% neutropenia and 7% thrombocytopenia. No infection was associated with the neutropenia and all AE resolved successfully. Conclusions: This is the first phase I/II trial testing bendamustine, lenalidomide and dexamethasone in combination for relapsed and refractory MM. This regimen is safe and well tolerated even in older patients up to 80 years. Based on the mainly myelosuppressive side effects, concomitant treatment with filgastrim is recommended. This regimen induced fast responses and high response rates even in heavily pretreated MM patients. The high responses were also achieved in patients with prior exposure to lenalidomide suggesting that BLD overcomes resistance to lenalidomide and is a highly active regimen. Disclosures: Lentzsch: Celgene Corp: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; prIME Oncology: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria. Burt:Celgene Corp: Honoraria, Speakers Bureau; Cephalon: Honoraria, Speakers Bureau. Roodman:Amgen: Consultancy; Millennium Pharmaceuticals: Consultancy. Agha:Novartis: Consultancy. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy.

Description: Abstract 1876 Carfilzomib (CFZ), 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, is being evaluated in MM patients. The selectivity of CFZ for the proteasome may explain the low rates of peripheral neuropathy (PN) relative to historical data for bortezomib (BTZ). Safety data have been compiled for 〉700 patients who received CFZ in 9 Phase (Ph) 1 or 2 trials, 4 of which are completed. The majority of patients had relapsed and refractory (R/R) MM, and many had comorbidities including baseline PN and renal insufficiency. This abstract updates and summarizes mature safety data for single-agent CFZ in 526 patients with R/R MM who took part in 1 of 3 Ph 2 studies and is a follow-up with more mature data compared with those presented at ASH 2010. Patients enrolled and treated with CFZ in the following trials are included in this analysis: PX-171-003 (conducted in 2 parts, a pilot study, PX-171-003-A0 [R/R MM], followed by 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, CFZ was dosed on Days 1, 2, 8, 9, 15, and 16 of a 28-day cycle (C). Doses were 20 mg/m2 in C1, escalating to 27 mg/m2 in C2 for all studies with the exception of 005 (15 mg/m2 in C1, 20 mg/m2 in C2, and 27 mg/m2 in C3). Overall, CFZ had a favorable safety profile in these studies. The most frequently reported adverse events (AEs) occurring in ≥30% of patients included fatigue (55%), anemia (47%), nausea (45%), thrombocytopenia (36%), dyspnea (35%), diarrhea (33%), and pyrexia (30%). The most common (≥10% of patients overall) ≥G3 AEs were thrombocytopenia (23%), anemia (22%), lymphopenia (18%), pneumonia (11%), and neutropenia (10%). The assessment of PN was based on a pooled aggregate of PN preferred terms, including neuropathy peripheral, neuropathy, peripheral sensory neuropathy, and peripheral motor neuropathy. PN was reported infrequently (14% overall) across all studies. Although 378 (72%) patients had baseline PN (≤G 2), only 13% reported treatment-emergent symptoms during the study. PN was generally mild to moderate in severity (1.3% G3 PN with no G4 PN), and only 5 patients (1%) required dose modification or discontinuation due to PN. Renal AEs (mainly ≤G2) were reported in 174 (33%) patients, and CFZ was discontinued because of a renal AE in only 21 patients (4%). A summary of CFZ exposure and discontinuation rates is reported in the table. There were a total of 37 (7%) deaths on study, including within 30 days of the last dose of study drug. The primary cause of death was due to disease progression in 22/37 patients (4.2%); however, AEs, including in order of frequency, cardiac events, hepatic failure, and infection, contributed to 14 of these deaths.No. of Patients (%) in Ph 2 MM Studies Who Received Carfilzomib003-A0 (N = 46)003-A1 (N = 266)004 (N = 164)005 (N = 50)All Patients (N = 526)Cycles, mean, n (SD)4.4 (3.4)5.3 (4.1)7.0 (4.4)5.5 (3.7)5.7 (4.2)Completed ≥12 cycles4 (8.7)40 (15.0)47 (28.7)3 (6.0)94 (17.9)Reason for not completing 12 cycles    Progressive Disease23 (50.0)157 (59.0)64 (39.0)24 (48.0)268 (51.0)    Adverse Event13 (28.3)33 (12.4)26 (15.9)6 (12.0)78 (14.8)    Withdrew Consent2 (4.3)22 (8.3)9 (5.5)4 (8.0)37 (7.0)    Other4 (8.7)14 (5.3)10 (6.1)028 (5.3) Of the 526 patients included in these analyses, 〉50% were treated on the 003-A1 dose and schedule (20/27 mg/m2), and fewer than 10% required dose reduction. 18% of patients completed ≥12 cycles (∼1 y) and were eligible to participate in an ongoing, multicenter, open-label Ph 2 study (PX-171-010) to monitor long-term single-agent CFZ safety. To date, patients in this extension trial have not shown evidence of cumulative toxicity. In summary, these data confirm and extend results that were previously presented, namely that single-agent CFZ has an acceptable safety profile in heavily pretreated patients with R/R MM, including those with pre-existing renal dysfunction and PN. Disclosures: Singhal: Onyx Pharmaceuticals: Research Funding, Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. 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. Martin:Celgene: Honoraria; Onyx Pharmaceuticals: Consultancy. Vij:Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Research Funding, Speakers Bureau; Millennium: Speakers Bureau. Wang:Onyx Pharmaceuticals: Research Funding. Jakubowiak:Ortho Biotech: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Speakers Bureau; Millennium: 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. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx Pharmaceuticals: Consultancy; Merck: Consultancy. Kukreti:Celgene: Honoraria. Zonder:Millennium: Consultancy, Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Medtronics: Honoraria; Amgen: Consultancy. Wong:Onyx Pharmaceuticals: Employment, Equity Ownership. McCulloch:Onyx Pharmaceuticals: Employment. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium Pharmaceuticals, Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Research Funding; Seattle Genetics Inc: Research Funding, Speakers Bureau. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Stewart:Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Kotlovker:Onyx Pharmaceuticals: Employment. 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.