Mıkhael, Joseph

Abstract Background Patients with cancer may face a significant knowledge deficit as they battle their illness. We developed a first of its kind comprehensive patient symposia (Living with Cancer (LWC): A Mayo Clinic Symposia for Patients and Loved Ones) with 8 hours of general sessions (covering nutrition, exercise, cancer inheritance, financial and legal challenges, communication, survivorship, and cancer therapy) and a 4-hour disease specific breakout (myeloid diseases, myeloma, lymphoma, chronic lymphocytic leukemia, breast cancer, lung cancer, cutaneous malignancy, colorectal cancer, and prostate cancer). Through voluntary questionnaires, we studied the impact of this cancer symposium on quality of life, cancer specific knowledge, and symptom management among cancer patients. Methods LWC meeting attendees were provided surveys prior to and 3 months following the convention. Surveys included 1) EORTC-QLQ-C30; 2) new disease understanding tool developed specifically for this conference; 3) distress thermometer and problems checklist; 4) validated disease-specific questionnaires. Changes over time were assessed using McNemar’s tests and paired t-tests for categorical and continuous variables, respectively. Results Patients:158 attendees completed the pre-convention survey. The median age was 67.5 (range 30-86), 49% males, 76% over 1 year from diagnosis. Cancer type included 37% hematologic malignancies, 23% breast cancer, 23% prostate cancer, and 17% other. The hematologic malignancies were comprised of 34% leukemia, 31% CLL/lymphoma, 25% amyloid/multiple myeloma, and 9.3% myeloproliferative neoplasms. Baseline Disease Understanding, Symptoms, QOL: Most attendees endorsed understanding their disease quite a bit (54%) or very much (29%). Most respondents reported at least “quite a bit” of understanding regarding treatment options (84%), screening modalities (83%), symptomatology (74%), and cancer-related side effects (71%). Attendees endorsed the least understanding of disease-related stress (49%), risk factors (49%), management of disease related fatigue (41%), and legal issues related to disease/treatment (27%) Mean QLQ-C30 scores were 84.4 for physical functioning, 83 for role functioning, 80.7 for social functioning, and 72.7 for global health status. The symptoms with highest mean scores were insomnia, fatigue, and pain. Knowledge Improvement Durable at 3 Months: 115 (73%) patients completed the post-symposium survey. There was improvement in 12 of 14 areas of self-reported knowledge (Table 1) especially in areas of nutrition, and management of disease related stress and fatigue (all p<0.001). Symptomatic Changes at 3 Months: There was no significant change in QLQ-C30 physical/role/emotional functioning, fatigue, pain, or insomnia. Conclusions This first evaluation of a patient centered cancer symposium as an education intervention suggests patients selecting to participate in such an event seek to improve an already solid knowledge base regarding their malignant disease. Participating in the event improved disease specific knowledge in numerous areas. However, as a single intervention, function and symptoms tended not to improve with participation. Future efforts on 1) improving participation with disease knowledge “naïve” patients and 2) targeted efforts aimed at specific symptom management (i.e. insomnia, stress) are planned. This study serves as an avenue to empower patients and inform physicians to improve the experience of living with cancer. Disclosures: No relevant conflicts of interest to declare.

Abstract Background SAR650984 (SAR) is a naked humanized IgG1 monoclonal antibody (mAb) that binds selectively to the human surface antigen CD38 highly expressed in multiple myeloma cells and other hematological malignancies. SAR kills tumor cells via 3 different biological mechanisms: Antibody-dependent cellular-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and Induction of apoptosis (pro-apoptosis). Here we present preliminary data from the ongoing first in human, Phase I dose escalation study of SAR in patients with selected CD38+ hematological malignancies. (clinicaltrials.gov: NCT01084252) Objectives The primary objective is to determine the maximum tolerated dose (MTD). Secondary objectives include characterization of safety, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity and disease response. Methods SAR is administered as a single agent IV infusion every week (QW) or every 2 weeks (Q2W) to adult patients with selected CD38+ hematological malignancies who have progressed on or after standard therapy or for whom no effective standard therapy exists. An accelerated dose escalation schedule was used for the first 5 dose levels (DL) (0.0001 mg/kg to 0.1 mg/kg Q2W), with one evaluable patient per DL unless DLT was experienced. All subsequent DL (0.3 mg/kg, 1 mg/kg, 3 mg/kg, 5mg/kg, 10 mg/kg, 20 mg/kg Q2W and 10 mg/kg QW), followed the classic 3+3 design for dose escalation based on DLT. Results 32 patients have been treated across all DLs including 3 patients with NHL, 2 with CLL, and 27 with MM. The 20 mg/kg Q2W and 10 mg/kg QW DLs are currently being evaluated and the MTD has not been reached. DLTs have been limited to Grade (G) 2 infusion reactions during cycle 1 with 1 at DL 0.3 mg/kg and 1 at DL 3.0 mg/kg. This was mitigated by the implementation of routine pretreatment with methylprednisone, diphenhydramine, ranitidine and acetaminophen. The most frequent occurring adverse events (≥ 10%) all DL, regardless of causality, are fatigue (46.9%), nausea (31.3%), pyrexia (28.1%), cough (25%), vomiting (21.9%), hypercalcemia (18.8%), with headache, constipation, bone pain, chills and diarrhea each occurring in 15.6% of patients. In addition, pneumonia, anemia, dysgeusia and hypokalemia each occurred in 12.5% of patients. Serious adverse events considered related to therapy include G 3 pneumonia (6.3%) associated with fever (3.1%), hyperglycemia (3.1%) and one Grade 2 infusion reaction (3.1%). Of the 19 patients treated at DL 1.0 mg/kg to 10 mg/kg Q2W, 1 had CLL, 1 had NHL and 17 had MM. The 17 MM patients were older and heavily pretreated patients; median age of 64 years (range: 55-74); and median of seven prior regimens (range: 2-14). All MM patients had received prior lenalidomide and bortezomib. The median time from diagnosis to first SAR650984 dosing was 6. 8 years (range 1.8 – 16.8 years). Responses in this group (fig 1), according to EBMT MM criteria, included 1 PR at 1 mg/kg (n = 3) and 5 mg/kg (n=3), and 1 MR at DL 3 mg/kg (n = 6). The 10 mg/kg DL demonstrated 3 PR and 2 SD among 6 MM patients treated. For the 19 patients treated at or above the 1 mg/kg DL the median time on treatment is 8 weeks (range 2-50 weeks). Immunogenicity studies show no anti-SAR antibodies. Receptor Occupancy could be detected from DL 1 mg/kg and reached a range of 84.1 to 97.7 % at 10 mg/kg. PK analysis show a more than dose proportional increase of exposure over the 0.03 to 10 mg/kg dose range with clearance in a similar range between 5 mg/kg and 10 mg/kg. No accumulation was observed based on Cmax at cycle 2 over the 0.03 to 3 mg/kg dose range. Tumor growth inhibition threshold was reached at Cmax for 1 patient at DL 5 mg/kg and 5 patients at DL 10 mg/kg. Conclusion The safety profile of SAR is predictable and manageable and the MTD has not been reached. SAR demonstrates encouraging single agent activity in patients with heavily pretreated RRMM and warrants further evaluation in this patient population. Disclosures: Zheng: sanofi: Employment. Daskalakis:sanofi: Employment.

Abstract Abstract 445 Background: Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has a favorable toxicity profile that has shown significant activity in relapsed multiple myeloma (MM), leading to recent FDA accelerated approval. To achieve rapid and deep response in patients eligible for stem cell transplant, we combined carfilzomib with the regimen of cyclophosphamide-thalidomide-dexamethasone (CTD). We recently reported the results of the Phase I component of the trial (in which no MTD was reached) followed by the initial Phase II trial; however, with increasing evidence for the safe and effective use of higher doses of carfilzomib, we now report results from dose escalation extension of the Phase II trial. Methods: Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with Carfilzomib IV Days 1,2,8,9,15,16 (see Table 1 below for dosing per cohort) along with Cyclophosphamide 300 mg/m2 PO Days 1,8,15, Thalidomide 100 mg PO Days 1–28 and Dexamethasone 40 mg PO Days 1,8,15,22. We initially conducted a Phase I run in trial of 6 patients with no DLT observed before expanding to the Phase II portion of the study. The initial phase II regimen is shown below – as no DLTs were observed, we have now fully accrued to the Phase II dose level +1. Treatment was for 4 cycles with expected SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results: A total of 38 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II, and the remaining at dose escalated cohorts. We are reporting the 27 patients who have completed therapy and will update with the dose escalated cohorts. Median age was 65 (range 27–74) and 52% were female. ISS Stage was advanced (II-III) in 56%. Best overall response rate during 4 cycles of CYCLONE at dose level 0 is 96%: CR 29%, VGPR 46%, PR 21% (1 pt achieved MR). Adverse events of grade 3 or higher at least possibly related to CYCLONE occurred in 12 (44%). Most commonly reported non hematological toxicities (all grades) included fatigue (67%), constipation (56%), lethargy (41%) somnolence (37%), malaise (30%) depressed level of consciousness (22%); however, grade 3/4 toxicities occurring in >5% were uncommon: thromboembolic event 11%) and muscle weakness (7%). Two cases of pneumonia required hospitalization. Eight patients (30%) developed grade 1 sensory neuropathy; no higher grade or painful neuropathy was evident. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included neutropenia (15%) and lymphopenia (7%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. Conclusion: The 4 drug CYCLONE regimen is highly efficaceous with a response rate after only 4 cycles of 96% (75% ≥VGPR, 29% CR) at the current dosing level of carfilzomib IV 20/27 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. Increasing the dose of carfilzomib is feasible and updated results of dose escalated cohorts will be reported at 20/36 and 20/45 mg/m2. Disclosures: Bergsagel: onyx: Membership on an entity's Board of Directors or advisory committees. Stewart:Millennium Pharmaceuticals: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Celgene: Consultancy.

Introduction With the introduction of novel agents, survival in multiple myeloma has successively increased in the past decade. This improved survival increases the risk for late complications. Patients continue to receive melphalan therapy as a standard induction for those over the age of 65. Lenalidomide is considered a standard component of induction therapy in the United States for patients who are transplant candidates. Stem cell transplantation remains the standard of care for patients eligible to receive it. As a consequence of exposure to lenalidomide, stem cell transplant, and melphalan, the risk of late myelodysplasia and acute leukemia remains significant. We reviewed the Mayo Clinic experience with therapy-induced myelodysplasia beginning with the advent of novel agents. Patients and Methods All patients that carry the diagnosis of multiple myeloma between January 1, 2000, and September 1, 2011, were included. Patients with a synchronous diagnosis of a myeloproliferative or a myelodysplastic disorder or those who developed the myelodysplastic disorder within 15 months of first chemotherapy exposure were excluded. The date of diagnosis for the purpose of this abstract was based on first exposure to chemotherapy and not first detection of a monoclonal protein or smoldering multiple myeloma. All patients had to have morphologic verification in the bone marrow of dysplastic change consistent with therapy-related myelodysplasia. Results Of 3111 patients who had a myeloma diagnosis and first treatment after January 1, 2000, through September 1, 2011, 22 patients were identified to fulfill the criteria of myelodysplasia. There were 13 men and 9 women with a median age of 67 (46 to 82). At the time of this report, 17 have died. Prior to the development of myelodysplasia, exposure to an alkylating agent, lenalidomide, or an auto stem cell transplant was seen in 13, 15, and 10, respectively. Only one patient had been exposed to lenalidomide alone. Eighteen patients were classified as myelodysplasia. Four had acute non-lymphocytic leukemia. Metaphase cytogenetics was available in 19 and only one was normal. Twelve were hypodiploid. Trisomy 8 or abnormalities of chromosome 5 and 7 were present in 13. Seven patients received a hypomethylating agent with no clear evidence of response in any. Four patients had an allotransplant to manage the MDS/AML and only one survives 487 days after a matched-related donor allogeneic transplant. The median time from initial therapy of multiple myeloma to recognition of MDS or AML was 50.9 months (range: 15.2-146.5 months) fig 1. The median overall survival of the 22 patients is 6.5 months. Fig 2 Six of the 22 had active myeloma at the diagnosis of MDS/AML. Conclusion Myelodysplasia during the era of novel agents is a devastating complication of therapy with a very short survival and low response rate. As a time-dependent complication, the overall risk cannot be accurately estimated but has occurred in <1% of our patient population to date. Hypomethylating agents were ineffective in the seven that received it. One of four allotransplant patients remains alive. Ongoing surveillance for MDS/AML in this population is warranted and more effective therapies are needed. Disclosures: Kumar: Onyx: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Abstract Background Carfilzomib is a proteasome inhibitor that irreversibly binds its target and has been validated as both relapse and upfront therapies for multiple myeloma. To optimize pre transplant response, we combined carfilzomib with the widely accessible backbone of cyclophosphamide-thalidomide-dexamethasone (CTD). We previously reported results of the Phase I component of the trial (in which no MTD was reached); we now report results for the MTD and fully accrued expansion cohorts at the MTD of the CYCLONE trial NCT01057225. Methods Newly diagnosed myeloma patients intended for stem cell transplant were eligible. All patients were treated on a 28 day cycle with carfilzomib IV Days 1,2,8,9,15,16 (see Table below for dosing per cohort) along with cyclophosphamide 300 mg/m2 PO Days 1,8,15, thalidomide 100 mg PO Days 1-28 and dexamethasone 40 mg PO Days 1,8,15,22. The initial phase I/ II regimen is shown below – as no DLTs were observed, we increased dosing of carfilzomib to 36 and then 45mg/m2 and have now nearly fully accrued to the Phase II dose level +1 (27mg/m2) and expansion MTD (36mg/m2). Treatment was for 4 cycles with planned SCT post induction. The primary endpoint of the trial is the proportion of patients who have ≥very good partial response (VGPR) to treatment. All patients received herpes zoster prophylaxis and ASA daily. Results A total of 54 patients have been accrued to the trial, 6 in the initial Phase 1, 21 in the initial Phase II (CFZ 27mg/m2), and 27 at CFZ 36-45mg/m2. Median age was 63 (range 27-77) and 52% were male. ISS Stage was advanced (II-III) in 57% The overall partial response rate or better following 4 cycles of CYCLONE at dose level 0 or greater is 91%: CR 18%, VGPR 58%, PR 16%, MR 2%, SD 4%. One patient withdrew from the trial after cycle 1. At dose level 2, 3/7 patients experienced dose-limiting toxicity in cycle 1 including: grade 3 alanine aminotransferase increase (possibly related); grade 3 infusion reaction (probably related); and grade 4 heart failure with grade 3 dyspnea, atrial fibrillation, and fatigue (all possibly related). No dose-limiting toxicity was observed in 6 patients at dose level 1 and thus DL1 was deemed the MTD. Across dose levels, adverse events are fully evaluable in 48 patients. AEs of grade 3 or higher at least possibly related to CYCLONE occurred in 26 (54%) – 35% non hematological and 33% hematological. Most commonly reported non hematological toxicities (all grades) included fatigue (63%), constipation (46%), elevated creatinine (27%), hyperglycemia (27%), lethargy (25%) peripheral sensory neuropathy (25% - all grade 1), and somnolence (21%); however, grade 3/4 toxicities occurring in >5% were uncommon: hypertension (8%), thromboembolic event (6%) and hyperglycemia (6%). Three cases of pneumonia required hospitalization. There were no cardiac events seen in greater than 5% of patients. Grade 3/4 hematological toxicities included lymphopenia (23%) and neutropenia (17%). All patients advancing to SCT successfully collected stem cells. One patient died on study from pneumonia. 90% completed at least 4 cycles. With median follow-up of 16 months (range 0-64), 1-year PFS was 90% and 1-year OS was 98%. Conclusion The 4 drug CYCLONE regimen is highly efficacious with an overall response rate after only 4 cycles of 91% (76% ≥VGPR) at the dosing level of carfilzomib IV 20/27-36 mg/m2 in newly diagnosed myeloma. Toxicities are manageable, with only grade 1 neuropathy and minimal cardiac or pulmonary toxicity. CYCLONE is a combination that results in rapid and deep responses with minimal neuropathy prior to stem cell transplant. Comparative studies of this regimen with longer duration of therapy (as induction or consolidation) at the defined MTD should be considered. Disclosures: Mikhael: Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding. Reeder:Millenium: Research Funding; Celgene: Research Funding; Novartis: Research Funding. Costa:Otsuka: Research Funding. Stewart:Celgene: Honoraria; Millenium: Honoraria, Research Funding; Onyx: Research Funding.

Abstract 5079 Introduction: IgD monoclonal proteins are rare. They are not seen as a MGUS and are present in 1% to 2% of patients with myeloma. In light chain amyloidosis (AL), IgD monoclonal proteins are rare. When an IgD protein is found, amyloidosis is often omitted from the differential diagnosis. An IgD protein in amyloidosis has been reported in single cases but never as a patient series. We report IgD AL in 53. Patients & Methods: Clinical and demographic data for patients were retrieved from the patient records. Factors of interest were compared between patients who did and did not have an IgD protein. Results: Among 3,955 patients with AL amyloidosis seen, 53 patients (1.3%) had a serum IgD monoclonal protein. (Table 1) A serum monoclonal protein peak was visible on SPE in only 14, and only 5 had an M spike greater than 1 g/dL. On immunofixation of the serum, the IgD light chain was k in 11, λ in 35, and uncertain in 6; 1 patient had a biclonal D λ and G k protein. A urine monoclonal protein was detected in 43 of 51 patients; urinary immunofixation detected a λ light chain in 33 and a k light chain in 10. Biopsy of tissues showed amyloid deposits in the bone marrow in 47% and in the fat aspirate in 73%. Six patients (age 47–63 years) underwent autologous SCT. Four had renal & two had cardiac AL. All 6 had hematologic PR, 4 CR, and 4 had organ response. One patient had relapse of disease and is now on dialysis, and another had relapse and is alive with salvage chemotherapy. One patient had disease relapse and died of progressive GI amyloidosis at 22 months. The other 5 are alive at a median of 68 months (range, 7.5–83.5 months). We compared the 53 patients with IgD amyloidosis with 144 patients with non-IgD amyloidosis. (Table 2) Findings that were significantly different between groups included a lower frequency of renal amyloidosis (P=.005) and a lower prevalence of cardiac amyloidosis (P=.047). There was a higher serum albumin level (P=.04) related to the lower level of proteinuria. No difference in survival was seen between the groups. (Figure). Variables that might affect survival—liver size, performance status, septal thickness, serum creatinine level, and β2-microglobulin level—were not different between groups. Conclusions: IgD AL patients have a lower frequency of renal involvement and possibly also of cardiac involvement. The overall survival of these patients does not appear to be different from that of patients who have AL associated with another monoclonal protein. IgD monoclonal proteins are so closely linked to the diagnosis of multiple myeloma in the mind of a clinician that the possibility of amyloidosis may be overlooked. Disclosures: No relevant conflicts of interest to declare.

Abstract Background Multiple myeloma (MM) is the second most common hematologic malignancy in the U.S. and is characterized by increased immunoglobulin production and infiltration of the bone marrow by malignant plasma cells. Myeloma cell growth is supported by both the elements present in the bone marrow microenvironment as well as deregulation of internal cellular systems associated with proliferation and apoptosis. Defective programmed cell death by BCL2 or MCL1 upregulation is observed in >80% of myeloma cases and is associated with an aggressive clinical course. Remarkably, there is no approved drug with the ability to target BCL2 or MCL1. Various strategies to mitigate the effects of increased BCL2 functionality, via small molecule inhibitors or BCL2-specific antisense oligonucleotides have been previously examined in MM. These studies revealed that 1) apart from BCL2, additional anti-apoptotic members belonging to the BCL2 family (i.e. MCL1, BCL-xL) play integral roles in maintenance of the myeloma cell phenotype, 2) drugs, which target only BCL2 offer limited therapeutic advantage and 3) given that survival factors engaged in MM are multifactorial, perhaps isolated targeting of the BCL2 pathways may not be sufficient. We therefore hypothesized that the clinical development of drugs that target various antiapoptotic BCL2 family members will require a partnership with established anti-MM regimens whose activity can potentially be further enhanced with correction of the apoptotic response system. Aim Since lenalidomide and dexamethasone (LD) is an established therapy for plasma cell cancers, we investigated if the pan-BCL2 inhibitor AT-101 (BH3 mimetic), which has high binding specificity for BCL2, MCL1 and BCL-xL, can be an effective therapeutic partner to enhance anti-MM effects of LD. Methods Human MM (KMS11, U266, OPM2) and WM (BCWM.1) cell lines along with their corresponding bortezomib resistant (BR) clones, (KMS11/BR, U266/BR, OPM2/BR and BCWM.1/BR) which were developed in our laboratory were used in this study. For gene expression profiling, the Illumina HumanHT-12 v3 whole-genome gene expression array and Nanostring nCounter mRNA quantification assays (NanoString, Seattle, WA) were utilized. Statistical analysis was conducted using R-based packages and the MeV software (TIGR). Apoptosis was measured by annexin-v/PI staining, and mitochondrial membrane permeability (MOMP) was assessed using TMRM followed by flow cytometry. Protein profiles were ascertained by western blot. Results Gene expression and immunoblot analysis of six plasma cell cancer models showed upregulation of various BCL2 family members, notably MCL1 and BCL-xL. In a dose-dependent manner, AT-101 was able to downregulate BCL2 and MCL1 and induced apoptotic cell death in MM and WM cells in a dose dependent manner. Tumor cell death was associated with caspase and PARP-1 cleavage accompanied by an increase in MOMP. This cytotoxic effect and BCL2 downregulation were further potentiated when AT-101 was combined with lenalidomide/dexamethasone (LDA). Nanostring nCounter mRNA quantification and IPA analysis revealed differential changes in the CCNA, FRZB, FYN, IRF1, PTPN11 genes in LDA treated cells. IPA canonical pathway analysis demonstrated the p53 signaling and the cyclins and cell cycle regulation pathways to be the most significantly activated by LDA therapy. Summary In summary, we describe for the first time the cellular and molecular events associated with the use of AT-101 in combination with lenalidomide/dexamethasone in preclinical models of plasma cell malignancy. This study lays the rationale for engaging and handicapping the intrinsic apoptotic system through the pan-BCL2 targeting capabilities of AT-101; thus enhancing the anti-MM effects of lenalidomide/dexamethasone. Disclosures: Foran: Celgene: Research Funding.

Abstract Abstract 2992 Background: Patients with myeloma receiving initial therapy with lenalidomide-based regimens can have difficulty collecting adequate stem cells for an autologous transplant. Stem cell collection in these patients can be significantly enhanced by addition of the CXCR-4 antagonist plerixafor to the mobilization regimen. Plerixafor is typically given subcutaneously (SQ), with collection approximately 11 hours after injection to obtain maximum yield. Intravenous administration can potentially allow more rapid and predictable mobilization compared to the SQ route. We designed this trial to prospectively assess the efficacy of intravenous plerixafor administration in patients undergoing lenalidomide therapy. Patients and methods: Patients who were receiving initial therapy with a lenalidomide-based regimen and were undergoing stem cell collection within 12 months of their myeloma diagnosis were enrolled. Patients received GCSF at 10 μg/kg/day for 4 days followed by addition of plerixafor at 0.24 mg/kg/dose starting on day 5. Plerixafor was administered intravenously early morning (6–7 am) followed by apheresis beginning 4–5 hours later. Plerixafor was administered for a maximum of 4 days; but patients could continue apheresis beyond the 4th day at treating physician discretion. The aims of the study were to determine the proportion of patients reaching a stem cell yield of at least 3 million CD34 cells/kg by second day of apheresis, the safety and tolerability of intravenously administered plerixafor, and the overall rate of failure to mobilize (defined as less than 2.5 million CD34 cells/kg in 4 collections). Results: Thirty-seven patients were accrued between December 2009 – April 2011, and 36 were eligible for analysis. The median age was 61 years (range; 28–73); 61% were male. The median time from start of initial therapy to enrollment was 4.6 months (range; 2.6 to 11.1) and the median cycles of lenalidomide were 4 (range; 3–11). Thirty-four (94%) of the patients achieved at least 3 million CD34 cells/kg within 2 days of apheresis. The median CD34 cells/kg after 1 day of collection was 3.9 million (range; 0.7 to 9.2) and after two days of collection was 7.02 million (range: 1.1–16.5). Two patients failed the mobilization (<2.5 million CD34 cells/kg). There were no grade 3 or 4 non-hematological adverse events and one patient experienced grade 4 thrombocytopenia. The most common grade 1 or 2 adverse events seen were gastrointestinal, namely nausea, diarrhea and abdominal pain or bloating. Grade 1 dizziness was reported in 8 patients. Overall, the infusion was well tolerated. Conclusion: Intravenously administered plerixafor is an effective strategy for mobilization in this patient group with low rate of failure to mobilize. It is well tolerated with toxicity comparable to the SQ administration. It also offers flexibility in patient scheduling with a convenient schedule for early morning infusion followed by apheresis later in the day. Disclosures: Kumar: Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals, Inc.: Research Funding; Genzyme: Research Funding; Novartis: Research Funding. Off Label Use: Use of the investigational agent MLN9708 for the treatment of previously untreated multiple myeloma. Lacy:Celgene: Research Funding.

Abstract Background Pomalidomide (POM) is the newest Immunomodulatory agent (IMiDs) that has shown clinical efficacy in relapsed multiple myeloma (MM) refractory to lenalidomide (LEN) and thalidomide (THAL). Studies of MM cell microenvironment suggest that tumor subclones compete for dominance during changes in drug therapy. It was previously observed that a minor clonal population increased in prominence of MM cells after 1 year of treatment with LEN. We examined whether the patients having THAL or LEN as the most recent prior-line therapy affects response to POM. Methods We studied 208 patients enrolled in a phase II trial of POM / dexamethasone between November 2007 and March 2012 at Mayo Clinic, Rochester. We reviewed the immediate prior-line therapy before enrollment in our trial. Comparison of treatment duration of POM and response rates were conducted between patients who had either THAL or LEN as latest prior-line therapy, and patients who were treated with non-IMiDs immediate before enrollment in POM trial. Treatment duration of POM was estimated using Kaplan Meier method and the survival curves were compared using log-rank test. We used univariate Cox proportional hazard models to estimate the prognostic impact of different variables. Results The median age of patients was 63 (range from 32 to 88). 68 % were males. 80 patients (38.5%) had THAL or LEN immediate prior to POM. Median prior-line therapies were 3. Patients who received THAL or LEN immediately prior to POM had a lower response rate than those who had non-IMiDs as latest therapy (29% vs 44%, p 0.04) and shorter median duration of POM treatment (5.7 months vs 7.3 months, p 0.02). In 190 (91%) patients who were previously treated with LEN and THAL at any time, median time between the end of LEN or THAL treatment and the initiation of POM was higher for POM responders than non-responders (10 months vs 3 months, p 0.0008). Patients responded to POM had a shorter duration of prior LEN or THAL treatment compared to non-responders (9 months vs 15 months, p 0.001). Conclusion THAL or LEN as an immediate prior-line therapy to POM is associated with a lower response rate and shorter effective treatment duration. Longer interval between prior immunomodulatory compounds and POM, and shorter exposure to previous immunomodulatory compounds are associated with better POM treatment response. Disclosures: Gertz: Celgene: Honoraria. Kumar:Merck: Consultancy, Honoraria; Celgene: Consultancy, Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Novartis: Research Funding; Genzyme: Research Funding. Lacy:Celgene Corporation: Research Funding.

Abstract Abstract 2942 Background: Pomalidomide (pom) is a distinct immunomodulatory (IMid) drug with high response rates in relapsed MM, including patients previously treated with thalidomide, bortezomib and lenalidomide. However, its duration of response and long term outcome is unknown. We evaluated the long term outcomes of the first Mayo Clinic cohort of pts treated with Pom. Methods: Pts with relapsed/refractory myeloma with 1–3 prior therapies were enrolled. Pom 2 mg/d was given orally continuously on 28 day cycle with weekly dexamethasone 40 mg. All pts received DVT prophylaxis with aspirin, heparin or warfarin. Results: 60 pts with relapsed MM were enrolled from Nov 2007-Aug 2008. Median age was 65.5; 36 were male. Median time from diagnosis was 45.6 mo (9.–-192.5). Nineteen (32%) were high-risk according to mSMART (msmart.org), and 78% were ISS Stage 2/3. Prior therapies included transplant (65%), bortezomib (33%), thalidomide (47%), lenalidomide (35%) [previous IMiD 60%] and radiation (38%). Toxicities at least possibly attributed to Pom included G3/4 anemia (5/0%), leukopenia (17/3%) and thrombocytopenia (3/0%). G3/4/5 non-hematological toxicities occurred in 30 (50%) and included fatigue (18/0/0%), pneumonia (8/2/2%), hyperglycemia (5/0/0%) and constipation (5/0/0%). Only one pt had grade 3 neuropathy. Treatment adjustment for occurred in 30 pts (50%) for pom (mostly for neutropenia) and 35 pts (58%) for dex. A median of 11.5 cycles were administered. With median follow up of 30.1 months (mo), overall response was seen in 39 (65%) [4 sCR, 5 CR, 16 VGPR, 14 PR]. Median time to first reponse (≥PR) was 1.7 mo (0.8–14.8). Median duration of response (in responders of ≥PR) was 21.3 mo. Median PFS was 13 mo and the 2 year OS rate was 76%. Standard risk pts had median PFS of 18.4 mo and 2 year OS rate was 85%; high risk pts had median PFS of 9.2 mo and 2 year OS rate was 57%. (Figure 1) Conclusions: Pom/dex is highly effective and well tolerated in relapsed MM, with a response rate of 65% even in pts with multiple prior therapies, including other IMiDs, bortezomib and transplant. The response is also durable, with median duration in excess of 21 months. Pom/dex provides long term benefit with median PFS 13 months and 2 year OS rate of 76%. Disclosures: Kumar: Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees. Stewart:Celgene Corporation: Consultancy, Research Funding; Millenium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Fonseca:Consulting :Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding. Lacy:Celgene: Research Funding.