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Percentage Change from Baseline (PCB) for B-cells (CD19+) and Immunoglobulins (Ig)at 20-day time intervals post-baseline.

Percentage Change from Baseline (PCB) for B-cells (CD19+) and Immunoglobulins (Ig)at 20-day time intervals post-baseline.

Bortezomib pharmacokinetic parameters following a single intravenous 1.3 mg/m2 bolus dose and varying single intravenous doses of tabalumab

Bortezomib pharmacokinetic parameters following a single intravenous 1.3 mg/m2 bolus dose in the presence or absence of tabalumab and dexamethasone

Purpose: Tabalumab, a human mAb that neutralizes B-cell–activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib.Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter.Results: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months.Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation. Clin Cancer Res; 22(23); 5688–95. ©2016 AACR.

Pharmacokinetic parameters of tabalumab in multiple myeloma patients

Patients with multiple myeloma can now be treated with chimeric antigen receptor T-cell (CAR-T) therapy. We studied how CAR-T therapy is used for multiple myeloma. We also studied things that could help make this therapy easier for doctors to use. The CAR-T process takes 13 steps and 177 days. It begins with the choice to use the therapy and ends about 100 days after it is used. The process uses 46 different healthcare professionals and ten different locations. We found several possible changes that can improve this process. Of these changes, three stand out. First, improved teamwork between members of the care team can help them prepare for and resolve possible problems. Second, reducing insurance red tape will make it easier to provide CAR-T therapy to patients. Third, allowing use of CAR-T therapy in places other than hospitals can help more patients receive this therapy. If applied, these three things may lower the time needed to treat patients by 14.4% and may reduce costs by 13.2%.

The maximum tolerated dose of the panobinostat and carfilzomib combination in patients with relapsed/refractory multiple myeloma (RRMM) was not reached in our previous dose-escalation study. We report additional dose levels in the phase I/II, single-arm, multicenter, standard 3+3 dose-escalation expansion-cohort study (NCT01496118). Patients with RRMM were treated with panobinostat 30 mg, carfilzomib 20/56 mg/m2 (N = 3), or panobinostat 20 mg, carfilzomib 20/56 mg/m2 (N = 33). Treatment cycles lasted 28 days; panobinostat: days 1, 3, 5, 15, 17, 19; carfilzomib: days 1, 2, 8, 9, 15, 16. For dose level 6 (DL 6), median age was 63 years (range, 49-91 years), 60.6% were male, 42.4% were high risk. Patients received a median of two prior therapies (range 1-7); proteasome inhibitors (PI; 100%), immunomodulatory imide drugs (IMiD; 78.8%), and stem cell transplant (36.4%); 48.5%, 51.1% , and 24.2% were refractory to prior PI or prior IMiD treatment or both, respectively. Patients completed a median of seven (range 1-40) treatment cycles. Overall response rate (primary endpoint) of evaluable patients in the expansion cohort (N = 32): 84.4%; clinical benefit rate: 90.6%. With a median follow-up of 26.1 months (range, 0-72.5 months), median (95% CI) progression-free survival, time-to-progression and overall survival of patients was 10.3 (6.1, 13.9), 11.7 (5.6, 14.5), and 44.6 (20.8, N/A) months, respectively. Common adverse events (AEs) included thrombocytopenia (78.8%), nausea (63.6%), fatigue (63.6%), diarrhea (51.5%), and vomiting (51.5%). Seven patients had serious treatment-related AEs. There was one treatment-related death. In conclusion, panobinostat plus carfilzomib is an effective steroid-sparing regimen for RRMM. This article is protected by copyright. All rights reserved.

Summary Background Bortezomib, lenalidomide, and dexamethasone (VRd) is a standard therapy for newly diagnosed multiple myeloma. Carfilzomib, a next-generation proteasome inhibitor, in combination with lenalidomide and dexamethasone (KRd), has shown promising efficacy in phase 2 trials and might improve outcomes compared with VRd. We aimed to assess whether the KRd regimen is superior to the VRd regimen in the treatment of newly diagnosed multiple myeloma in patients who were not being considered for immediate autologous stem-cell transplantation (ASCT). Methods In this multicentre, open-label, phase 3, randomised controlled trial (the ENDURANCE trial; E1A11), we recruited patients aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for, or did not intend to have, immediate ASCT. Participants were recruited from 272 community oncology practices or academic medical centres in the USA. Key inclusion criteria were the absence of high-risk multiple myeloma and an Eastern Cooperative Oncology Group performance status of 0–2. Enrolled patients were randomly assigned (1:1) centrally by use of permuted blocks to receive induction therapy with either the VRd regimen or the KRd regimen for 36 weeks. Patients who completed induction therapy were then randomly assigned (1:1) a second time to either indefinite maintenance or 2 years of maintenance with lenalidomide. Randomisation was stratified by intent for ASCT at disease progression for the first randomisation and by the induction therapy received for the second randomisation. Allocation was not masked to investigators or patients. For 12 cycles of 3 weeks, patients in the VRd group received 1·3 mg/m2 of bortezomib subcutaneously or intravenously on days 1, 4, 8, and 11 of cycles 1–8, and day 1 and day 8 of cycles nine to twelve, 25 mg of oral lenalidomide on days 1–14, and 20 mg of oral dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. For nine cycles of 4 weeks, patients in the KRd group received 36 mg/m2 of intravenous carfilzomib on days 1, 2, 8, 9, 15, and 16, 25 mg of oral lenalidomide on days 1–21, and 40 mg of oral dexamethasone on days 1, 8, 15, and 22. The coprimary endpoints were progression-free survival in the induction phase, and overall survival in the maintenance phase. The primary analysis was done in the intention-to-treat population and safety was assessed in patients who received at least one dose of their assigned treatment. The trial is registered with ClinicalTrials.gov, NCT01863550. Study recruitment is complete, and follow-up of the maintenance phase is ongoing. Findings Between Dec 6, 2013, and Feb 6, 2019, 1087 patients were enrolled and randomly assigned to either the VRd regimen (n=542) or the KRd regimen (n=545). At a median follow-up of 9 months (IQR 5–23), at a second planned interim analysis, the median progression-free survival was 34·6 months (95% CI 28·8–37·8) in the KRd group and 34·4 months (30·1–not estimable) in the VRd group (hazard ratio [HR] 1·04, 95% CI 0·83–1·31; p=0·74). Median overall survival has not been reached in either group. The most common grade 3–4 treatment-related non-haematological adverse events included fatigue (34 [6%] of 527 patients in the VRd group vs 29 [6%] of 526 in the KRd group), hyperglycaemia (23 [4%] vs 34 [6%]), diarrhoea (23 [5%] vs 16 [3%]), peripheral neuropathy (44 [8%] vs four [ Interpretation The KRd regimen did not improve progression-free survival compared with the VRd regimen in patients with newly diagnosed multiple myeloma, and had more toxicity. The VRd triplet regimen remains the standard of care for induction therapy for patients with standard-risk and intermediate-risk newly diagnosed multiple myeloma, and is a suitable treatment backbone for the development of combinations of four drugs. Funding US National Institutes of Health, National Cancer Institute, and Amgen.

Proteasome inhibitors (PIs) have markedly improved response rates as well as the survival of multiple myeloma (MM) patients over the past decade and have become an important foundation in the treatment of MM patients. Unfortunately, the majority of patients either relapses or becomes refractory to proteasome inhibition. This report describes that both PI sensitive and resistant MM cells display enhanced sensitivity to PI in the presence of synthetic amphiphilic block copolymers, Pluronics (SP1017). SP1017 effectively overcomes both acquired resistance and tumor microenvironment-mediated resistance to PIs. The combination of bortezomib and SP1017 augments accumulation of ubiquitinated proteins, increases markers of proteotoxic and ER stress, and ultimately induces both the intrinsic and extrinsic drug-induced apoptotic pathways in MM cells. Notably, co-treatment of bortezomib and SP1017 intensifies SP1017-induced disorganization of the Golgi complex and significantly reduces secretion of paraproteins. Using a human MM/SCID mice model, the combination of bortezomib and SP1017 exerted enhanced antitumor efficacy as compared to bortezomib alone, delaying disease progression, but without additional toxicity. Collectively, these findings provide proof of concept for the utility of combining PI with SP1017 and present a new approach to enhance the efficacy of current treatment options for MM patients.

Summary This United States community study evaluated the combination of daratumumab, bortezomib, cyclophosphamide and dexamethasone (D‐VCd) in newly diagnosed multiple myeloma (NDMM) and relapsed multiple myeloma (RMM). Patients received 4–8 induction cycles of bortezomib 1·5 mg/m2, cyclophosphamide 300 mg/m2 and dexamethasone 40 mg weekly. Intravenous daratumumab 16 mg/kg was administered as approved except for a split‐first dose in Cycle 1. Eligible patients underwent autologous stem cell transplantation. All patients received ≤12 daratumumab maintenance doses monthly. Eighty‐six NDMM and 14 RMM patients received ≥1 treatment dose. In NDMM patients, very good partial response or better (≥VGPR) and overall response rates after 4 induction cycles were 44% (primary endpoint) and 79%, respectively, and 56% and 81% at end of induction. The 12‐month progression‐free survival (PFS) rate was 87%. Efficacy was also observed in RMM patients. Fatigue (59%) and neutropenia (13%) were the most frequent treatment‐emergent adverse event (TEAE) and grade 3/4 TEAE, respectively. Infusion reactions occurred in 54% of patients, primarily during the first dose, and were mild (2% grade 3). The first 2 daratumumab infusions were 4·5 and 3·8 h (median). Overall, D‐VCd was well tolerated, split‐first daratumumab dosing was feasible, the ≥VGPR rate after 4 cycles was 44% and the 1‐year PFS rate was 87%.

CAR-T therapies represent a novel advance in oncology, albeit at list prices that exceed $373,000 (and that does not capture their total cost to the healthcare system). Since initial product approval in 2017, stakeholders and observers have attempted to investigate clinical and financial impacts of CAR-T therapies, and potential approaches to optimizing access and use by eligible patients. Most existing research is from a single stakeholder perspective - patients, providers, or payers - limiting the ability to draw broader conclusions on trends and offer prospective recommendations. To address this knowledge gap, we sought to identify and describe critical success factors for optimal delivery of CAR-T therapies. We undertook a qualitative study based on interviews with multiple US-based stakeholders including clinicians, financial and operations staff, and payer-insurers. Interviewees--which included oncologists (n=6), facility financial and operational personnel (n=4), and coverage and reimbursement decision-makers from US health plans (n=3)--completed structured, live, hour-long, interviews covering clinical, administrative, and general topics on patient access to CAR-T therapies. All clinicians had experience with ≥1 FDA-approved CAR-T therapies in both registered clinical trials and clinical practice; financial and operational personnel were affiliated with the same facilities as the clinicians, and also had real-world experience with these therapies; payer representatives were directors from a large national commercial plan, regional integrated delivery network, and a Medicare administrative contractor, respectively. Consensus facility feedback (i.e., clinicians, operational personnel) was that CAR-T is effective, and that their administrative processes had been optimized through care team coordination and experience-based efficiencies; in contrast, 2 of 3 payer interviewees expressed that, while CAR-T therapies have shown efficacy, their real-world benefits and applicability are less well-defined. Facility interviewees noted that: (1) reimbursement from commercial insurers is higher than from Medicare, with the latter associated with per-patient net-neutral or negative margins; (2) when possible, differential reimbursement between inpatient and outpatient settings may drive patient management towards outpatient care; and (3) negative-margin cases are currently deemed acceptable due to nonclinical factors (i.e., competitive pressure within a geographic region, anticipated branding/marketing value) and relatively small treated populations. From payer interviewees, CAR-T cost and perceived cost-to-value have made health plans more receptive to considering outcomes-based contracting, capitated provider payments, or other mitigation methods. Left unoptimized, these factors may adversely impact patient access to, and long-term provider attractiveness of, CAR-T therapies. All interviewees agreed that as the CAR-T marketplace grows, a strong preference exists for manufacturers to develop and communicate for their therapies durable outcomes data, clear and comprehensive reimbursement information, and competitive pricing. With the potential for many approved products in a single indication, and/or a single approval for indications with relatively large eligible patient populations, interviewees also conveyed interest in compelling health economic data. Facility interviewees also acknowledged that if it remains an overall net-negative margin service, new providers will be less able to start CAR-T programs and smaller programs may encounter sustainability issues, collectively jeopardizing patient access to these life-changing therapies. Overall, findings from this study suggest that during the continued maturation of the landscape, stakeholders will need to be proactive to ensure that CAR T-cell therapies can be maintained amidst financial and operational pressures. Several CAR-T therapy options for multiple myeloma are on the immediate horizon, likely increasing demand among eligible patients. Accordingly, the need to link real-world evidence of the clinical value and institutional investment burden of these therapies to reimbursement is imperative, both to insulate payers and enable clinicians to provide innovative therapies. Figure 1 Figure 1. Disclosures Faber: Amgen: Honoraria; Adaptive: Honoraria; Cardinal Health: Honoraria; Celgene: Honoraria; Astra Zeneca: Honoraria; GlaxoSmith Kline: Honoraria; Janssen: Honoraria; Juno: Honoraria; Karyopharm: Honoraria; Kite: Honoraria; Takeda: Honoraria; Sanofi Genzyme: Honoraria. Hunter: BMS: Consultancy, Honoraria; Kite: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria. Deol: Kite, a Gilead Company: Consultancy. Crivera: Johnson & Johnson: Current Employment, Current equity holder in publicly-traded company. Riccobono: Legend Biotech: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Garrett: Legend Biotech USA: Current Employment. Jackson: Memorial Sloan Kettering Cancer Center: Consultancy; Janssen: Current Employment. Fowler: Amgen: Ended employment in the past 24 months; Janssen: Current Employment. Berger: Janssen Scientific Affairs: Consultancy, Research Funding. Lorden: Janssen Scientific Affairs: Consultancy, Research Funding. Stewart: Janssen Scientific Affairs: Consultancy, Research Funding.

8035 Background: LYRA is a community practice-based, phase 2, single-arm study (NCT02951819) evaluating DARA + CyBorD as an immunomodulatory drug-sparing regimen in MM. The primary analysis demonstrated the safety and efficacy of DARA + CyBorD in newly diagnosed MM (NDMM) and relapsed MM (RMM), and an update showed that DARA maintenance therapy deepened responses. We present the final end-of-study analysis of LYRA. Methods: US pts aged ≥18 years with MM per IMWG criteria and ≤1 prior line of therapy received 4-8 induction cycles of DARA + CyBorD (cyclophosphamide 300 mg/m2 PO weekly [QW]; bortezomib 1.5 mg/m2 SC on Days [D] 1, 8, and 15; dexamethasone 40 mg PO or IV QW every 28 days; DARA IV 8 mg/kg on D1 and D2 of cycle [C]1, 16 mg/kg QW C1D8-C2, 16 mg/kg Q2W C3-6, and 16 mg/kg Q4W C7-8). After induction, eligible pts could receive autologous stem cell transplantation (ASCT). Pts received up to 12 maintenance cycles with DARA 16 mg/kg IV Q4W and were followed for up to 36 months after induction. Results: In total, 101 (NDMM, n = 87; RMM, n = 14) pts were enrolled; 36% of pts had high-risk cytogenetics. NDMM and RMM pts received a median of 6 and 8 induction cycles, respectively. Among NDMM pts, 44.8% (39/87) underwent ASCT and 72.4% (63/87) completed 12 months of maintenance. Rates of ≥VGPR and ≥CR were 82.1% and 48.7% in NDMM pts who underwent ASCT, and 70.2% and 29.8% in NDMM pts who did not (Table). With a median follow-up of 35.7 months, median progression-free survival (PFS) and overall survival (OS) were not reached for NDMM pts. Estimated 36-month PFS rates were 69.3% and 72.6% for NDMM pts who did and did not receive ASCT, respectively; estimated 36-month OS rates were 94.9% and 84.3% (Table). Among RMM pts, 7.1% (1/14) underwent ASCT and 50.0% (7/14) completed 12 months of maintenance; efficacy outcomes are shown in the Table. Grade 3/4 treatment-emergent adverse events (TEAEs) occurred in 62.0% of all pts, with the most common (≥10%) being neutropenia (14.0%). Serious TEAEs occurred in 33.0% of pts, the most common being pneumonia (4.0%) and pulmonary embolism (3.0%). TEAEs led to death in 2.0% of pts, all unrelated to study treatment. Infusion-related reactions occurred in 56.0% of pts; the majority were mild (4.0% of pts had grade 3/4 events). Conclusions: DARA used for induction with CyBorD and maintenance as monotherapy resulted in durable, deep responses in pts with NDMM or RMM, with a 3-year PFS rate of 70% in NDMM irrespective of ASCT status. With longer follow-up, no new safety concerns were identified. Clinical trial information: NCT02951819. [Table: see text]

LBA3 Background: Bortezomib (btz) combined with lenalidomide (len) and dexamethasone (dex) (VRd) is a standard initial therapy for NDMM. Carfilzomib (cfz), a next-generation proteasome inhibitor, in combination with len-dex (KRd) has shown higher efficacy in phase II trials. This randomized phase III trial was designed to examine if KRd improves progression free survival (PFS) compared to VRd in NDMM (current results), and whether indefinite maintenance with len improves OS compared with two-year maintenance (to be analyzed once data matures). Methods: Patients (Pts) with NDMM, were randomized to receive VRd or KRd in a 1:1 fashion for 36 weeks followed by a second randomization (1:1) to indefinite versus two years of len maintenance. Pts without del17p, t (14;16), t(14;20), plasma cell leukemia or high-risk GEP70 profile, were enrolled. VRd arm included btz 1.3 mg/m2 on days(d) 1, 4, 8, and 11 (d 1, 8 for cycles 9-12), len 25 mg d 1-14, and dex 40 mg d 1, 2, 4, 5, 8, 9, 11, 12 of a 3-week (wk) cycle for 12 cycles, while pts in the KRd arm received cfz 36 mg/m2 d 1, 2, 8, 9, 15, 16 with len 25 mg daily on d 1-21 and dex 40 mg wkly, in 4 wk cycles for 9 cycles. Maintenance included len 15mg d 1-21 every 4 wks. The study was designed to detect a hazard ratio (HR)=0.75 with 80% power at 1-sided 2.5% alpha and 399 PFS events (progression or death regardless of intervening therapy). Results: The study accrued 1087 pts (VRd=542, KRd=545). The median age was 65y. Treatment, efficacy, and toxicity data are in the table. At the second of 3 planned interim analyses, with PFS HR=1.04 (95% CI, 0.8 to 1.3, p=0.74), futility was met. Median PFS was VRd=34.4m and KRd=34.6m; no differences were seen based on age (

Background: DARA, a human IgGκ monoclonal antibody targeting CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) and bortezomib and dexamethasone (Vd) for newly diagnosed MM (NDMM) and relapsed MM (RMM), respectively. CyBorD is a commonly used immunomodulatory drug-sparing regimen for MM. In the LYRA (NCT02951819) study, DARA plus CyBorD (DARA-CyBorD) demonstrated efficacy and a tolerable safety profile at the end of induction. Here, we present updated findings examining the effect of monthly DARA maintenance on the efficacy and safety of DARA-CyBorD in NDMM and RMM. Methods: LYRA is an ongoing, single-arm, open-label, phase 2 study conducted at US community oncology centers. Patients (pts) were aged ≥18 years with documented MM per IMWG criteria, an ECOG performance score (PS) of 0-2, and ≤1 prior line of therapy. Pts received 4-8 induction cycles of DARA-CyBorD (cyclophosphamide 300 mg/m2 PO on Days 1, 8, 15, and 22; bortezomib 1.5 mg/m2 SC on Days 1, 8, and 15; and dexamethasone 40 mg PO or IV weekly [qw]) every 28 days. DARA was given at 8 mg/kg IV on Days 1 and 2 of C1, 16 mg/kg qw from C1D8 through C2, 16 mg/kg q2w for C3-6, and 16 mg/kg q4w for C7-8. After induction, eligible pts could undergo autologous stem cell transplantation (ASCT). All pts received up to 12 maintenance cycles with DARA 16 mg/kg IV q4w. Results: A total of 101 (87 NDMM, 14 RMM) pts were enrolled; 100 (86 NDMM, 14 RMM) pts received ≥1 treatment dose. Median age was 63 years; most pts were white (81%), male (64%), had ECOG PS 0-1 (94%) and had IgG (57%) MM; 36% of pts had high cytogenetic risk, defined as a del(17p), t(4:14) or t(14;16) abnormality. NDMM and RMM pts received a median of 6 and 8 cycles, respectively, of induction therapy. Thirty-nine NDMM pts and 1 RMM pt underwent ASCT. Fifty percent of pts received plerixafor; median stem cell yield for NDMM pts was 6.2 x 106 (range 2-15 x 106) CD34+ cells/kg. A total of 85 (75 NDMM, 10 RMM) pts received ≥1 dose of maintenance treatment; 63 (56 NDMM, 7 RMM) pts have received all 12 maintenance cycles. In NDMM pts, ORR was 87%, with 64% ≥VGPR and 12% ≥CR, by the end of induction. By the end of maintenance, ORR, ≥VGPR and ≥CR rates were 97%, 82% and 51% in NDMM pts who underwent ASCT and 83%, 70% and 30% in NDMM pts who did not receive ASCT. In RMM pts, ORR, ≥VGPR and ≥CR rates were 79%, 71% and 29% by the end of induction and 86%, 71% and 64% by the end of maintenance. At a median follow up of 24.8 mo in NDMM pts and 26.6 mo in RMM pts, median duration of response was not reached (NR). Median PFS (Figure) was NR in NDMM pts, regardless of transplant status, and was 21.7 mo in RMM pts; median OS was NR in NDMM pts and was 30.1 mo in RMM pts. In NDMM pts the 24-mo PFS rate was 89% in pts who underwent ASCT and 72% in pts who did not receive ASCT. The 24-mo OS rate was 90% for NDMM pts. In RMM pts, the 24-mo PFS and OS rates were 48% and 64%, respectively. All treated pts had ≥1 TEAE. Common TEAEs (≥25%) included fatigue, nausea, cough, diarrhea, upper respiratory tract infection, back pain, vomiting, insomnia, dyspnea, constipation, and headache. Grade 3/4 TEAEs were reported in 62% of pts; the most common (≥10%) was neutropenia (14%). Serious TEAEs occurred in 33% of pts; the most common (>2%) were pneumonia, atrial fibrillation and pulmonary embolism. TEAEs led to permanent treatment discontinuation in 7% of pts, with 2% related to treatment. TEAEs resulted in death in 2 pts (nephrotic syndrome, sudden death); both unrelated to treatment. Infusion reactions (IRs) occurred in 56% of pts including grades 1-2 in 52% of pts, grade 3 in 3% of pts and grade 4 in 1% of pts. Most common (>5%) IRs were chills, cough, dyspnea, nausea, pruritus, flushing and nasal congestion. Conclusion: Maintenance with DARA monotherapy for 12 mo increased the >CR rate in NDMM and RMM pts, consistent with observations in prior studies that longer DARA treatment improves depth of response. Importantly, the increase in ≥CR rate was associated with durable PFS and OS. The 24-mo PFS rates in NDMM and RMM pts compare favorably with results for DARA-VMP and DARA-Vd in NDMM and RRMM, respectively. Safety profile was consistent with previous reports of DARA, with no new safety concerns observed with longer follow-up. These data indicate that DARA-CyBorD is a safe, effective MM treatment and that DARA maintenance increases depth of response and achieves durable remissions. Disclosures Rifkin: Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Melear:Texas Oncology: Employment; DARA: Speakers Bureau. Faber:Cardinal Health: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Bensinger:Amgen, Celgene: Other: Personal Fees, Research Funding, Speakers Bureau; Takeda, Janssen: Speakers Bureau; Sanofi, Seattle Genetics, Merck, Karyopharm: Other: Grant. Burke:Gilead: Consultancy; Celgene: Consultancy; Roche/Genentech: Consultancy. Narang:Celgene: Speakers Bureau. Stevens:Astellas: Consultancy. Gunawardena:Janssen: Employment, Equity Ownership. Lutska:Janssen: Employment. Qi:Janssen: Employment. Ukropec:Janssen: Employment, Equity Ownership. Qi:Janssen: Employment. Lin:Janssen: Employment, Equity Ownership. Yimer:Amgen: Consultancy; Clovis Oncology: Equity Ownership; Puma Biotechnology: Equity Ownership; Celgene: Honoraria; Seattle Genetics: Honoraria; Janssen: Speakers Bureau; AstraZeneca: Speakers Bureau.

This retrospective analysis aimed to establish the overall cardiac safety profile of bortezomib using patient-level data from one phase 2 and seven phase 3 studies in previously untreated and relapsed/refractory multiple myeloma (MM). Seven clinically relevant primary [congestive heart failure (CHF), arrhythmias, ischaemic heart disease (IHD), cardiac death] and secondary (hypertension, dyspnoea, oedema) cardiac endpoints were defined based on MedDRA v16.0 preferred terms. 2509 bortezomib-treated patients and 1445 patients in non-bortezomib-based control arms were included. The incidence of grade ≥3 CHF was 1·3–4·0% in studies in relapsed/refractory MM and 1·2–4·7% in previously untreated MM (2·0–7·6% all grades), with no significant differences between bortezomib- and non-bortezomib-based arms in comparative studies. Incidences of arrhythmias (1·3–5·9% grade ≥2; 0·6–4·1% grade ≥3), IHD (1·2–2·9% all grades; 0·4–2·7% grade ≥3) and cardiac death (0–1·4%) were low, with no differences between bortezomib-based and non-bortezomib-based arms. Higher rates of oedema (mostly grade 1/2) were seen in bortezomib-based versus non-bortezomib-based arms in one study and a pooled transplant study analysis. Logistic regression analyses of comparative studies showed no impact on cardiac risk with bortezomib-based versus non-bortezomib-based treatment. Bortezomib-based treatment was associated with low incidences of cardiac events., JPL receives research funding from Celgene Corporation, Millennium, Novartis, and Onyx; and is a consultant for Janssen Pharmaceuticals, and Novartis, and has participated in advisory boards for Janssen and Millennium. JJM is a consultant for Millennium Pharmaceuticals Inc., Novartis, Pfizer, Acceleron, and Alnylam. SAF is a consultant for Clovis Oncology, Inc. and ARIAD pharmaceuticals; and receives honoraria from Medtronic. JFSM is a consultant/advisor and receives honoraria from Janssen, Celgene Corporation, Millennium Pharmaceuticals Inc., Novartis, Onyx Pharmaceuticals, and Bristol-Myers Squibb. PS is a consultant/advisor, and receives research funding from Janssen Pharmaceuticals, Celgene Corporation, and Onyx Pharmaceuticals; and receives honoraria from Janssen Pharmaceuticals, and Celgene Corporation. RZO receives research funding from Bristol-Myers Squibb, Celgene Corporation, Millennium Pharmaceuticals Inc., Onyx Pharmaceuticals, and Resverlogix; receives honoraria from Array Biopharma, Bristol-Myers Squibb, Celgene Corporation, Genentech, Millennium Pharmaceuticals Inc., and Onyx Pharmaceuticals; and is a member of advisory boards for Array Biopharma, Bristol-Myers Squibb, Celgene Corporation, Genentech, Merck, Millennium Pharmaceuticals Inc., and Onyx Pharmaceuticals. PM receives honoraria from Janssen, and is a member of advisory boards for Janssen, Millennium Pharmaceuticals Inc., and Onyx Pharmaceuticals. LR receives honoraria from Janssen, and Celgene Corporation. EAF is a consultant and receives honoraria from Celgene Corporation, Millennium Pharmaceuticals Inc., Onyx Pharmaceuticals, and SanofiAventis. PV receives research funding from Takeda Pharmaceuticals, Celgene Corporation, Janssen, GlaxoSmithKline, Acetylon, Oncopeptides, and Amgen; is a consultant for Novartis and Takeda, and has participated in advisory boards for Celgene Corporation, Bristol-Meyers Squibb, and Janssen. M-VM receives honoraria from Janssen, Millennium, and Celgene Corporation. LM is employed by Janssen Research & Development LLC; and has ownership at Johnson & Johnson. HF is employed by Janssen Research & Development LLC. AD is employed by Janssen Global Services LLC; and has ownership at Johnson & Johnson. HvdV is employed by Millennium Pharmaceuticals Inc., Formerly Janssen Research & Development, Division of Janssen Pharmaceuticals NV; and has ownership with Johnson & Johnson. JE, D-LE, LN, HS, and NJ are employed by Millennium Pharmaceuticals Inc. ED was formerly employed by Millennium Pharmaceuticals Inc. KCA is a consultant for Celgene Corporation, Onyx Pharmaceuticals, Sanofi-Aventis, and Gilead; and has equity ownership at Acetylon Pharmaceuticals, and Oncopep. SL is a consultant for Millennium Pharmaceuticals Inc., Celgene Corporation, Novartis, Bristol-Myers Squibb, Onyx Pharmaceuticals, and Merck. PGR is a member of advisory committees for Millennium Pharmaceuticals Inc., Janssen, Novartis, and Celgene Corporation, and has received research funding from Millennium, Celgene, and Bristol Myers Squibb. Writing support during the development of the manuscript was provided by Steve Hill PhD of FireKite, an Ashfield Company, part of UDG Healthcare plc, which was funded by Millennium Pharmaceuticals Inc., and Janssen Global Services LLC.

Background: Dara, a human IgGκ monoclonal antibody that targets CD38, is approved in combination with bortezomib, melphalan, and prednisone (VMP) for the treatment of newly diagnosed (ND) MM. CyBorD is another commonly used immunomodulatory drug-sparing regimen for MM. We evaluated the safety and efficacy of dara-CyBorD and administered the first dara infusion as a split dose over 2 days in pts with NDMM or relapsed MM (RMM) after 1 prior line of therapy. Methods: This is an ongoing, multicenter, single-arm, open-label, phase 2 study conducted at US community oncology centers in pts aged ≥18 years with documented MM per IMWG criteria; measurable disease; ECOG performance score (PS) of 0-2; and ≤1 prior line of therapy. Pts received 4-8 cycles (C) of dara-CyBorD (oral cyclophosphamide 300 mg/m2 on Days 1, 8, 15, and 22; subcutaneous bortezomib 1.5 mg/m2 on Days 1, 8, and 15; and oral or IV dexamethasone 40 mg weekly) every 28 days. Dara was administered at 8 mg/kg IV in 500 ml on Days 1 and 2 of C1, 16 mg/kg weekly from C1D8 through C2, 16 mg/kg every 2 weeks (q2w) for C3-6, and 16 mg/kg q4w for C7-8. After induction, pts could undergo autologous stem cell transplantation (ASCT). All pts receive 12 cycles of maintenance dara 16 mg/kg IV q4w. The primary endpoint was the proportion of pts achieving very good partial response or better (VGPR+) after 4 induction cycles using a computer algorithm based upon IMWG response criteria. Results: A total of 101 (87 ND, 14 RMM) pts were enrolled; 100 (86 ND, 14 RMM) pts received at least 1 dose of study treatment. Median age was 63 years (63 ND, 68 RMM); most pts were white (81%), male (64%), had ECOG PS 0-1 (94%), and had IgG (57%) or IgA (17%) MM; 35% of pts had high-risk cytogenetics defined as del(17p), t(4:14), or t(14;16). Eighty-two ND pts completed at least 4 induction cycles, 55 at least 6 cycles, and 26 the maximum of 8 cycles; 28 ND pts underwent ASCT by the data cutoff date. After 4 induction cycles, 44% of ND pts achieved VGPR+ (5% CR) with an overall response rate (ORR) of 79%. The VGPR+ rate (57%), CR rate (14%), and ORR (71%) were similar in RMM pts. At the end of induction (median 6 cycles), the VGPR+ rate, CR rate, and ORR in ND pts were 56%, 9%, and 81%, respectively. With a median follow up of 7.9 months, median PFS and OS were not reached; the 12-month PFS and OS rates were 87% and 99%, respectively, in ND pts. All 100 evaluable pts experienced ≥1 treatment-emergent adverse event (AE). AEs with incidence ≥20% included fatigue, nausea, diarrhea, cough, insomnia, vomiting, constipation, upper respiratory tract infection, dyspnea, headache, and back pain. Grade ≥3 AEs were reported for 56% of pts; the most common (≥10%) was neutropenia. Serious AEs (SAEs) occurred in 21% of pts; the most common (≥2%) were atrial fibrillation, bacteremia, pulmonary embolism, and mental status changes. AEs led to permanent treatment discontinuation in 3% of pts. Infusion reactions (IRs) occurred in 54% of pts, including 49% at C1D1 and 4% at C1D2; 2 Grade 3 IRs (hypertension, anaphylactic reaction) occurred at C1D1; no Grade ≥4 IRs occurred. The most common (≥5%) IRs were chills, cough, dyspnea, nausea, pruritus, and flushing. Median infusion time was 4.5 hours for C1D1, 3.8 hours for C1D2, and 3.5 hours for subsequent doses. Conclusion: Dara-CyBorD was active and well tolerated in pts with ND and RMM, including pts with high-risk cytogenetics. ORR, VGPR+, and CR rates improved with cycles 5-8 of induction, indicating that longer therapy with dara results in deeper response. Preliminary PFS and OS data in ND pts in the first year are comparable to dara-VMP. The safety profile was consistent with that previously reported for dara, with no new safety signals observed. Split first daratumumab dosing was feasible, reduced Day 1 infusion time, and resulted in a similar IR rate as previously described for single-dose administration. These findings indicate that dara-CyBorD, using a split-dose first infusion, can be safely administered in the community setting and may be an effective treatment option for pts with MM. www.clinicaltrials.gov identifier: NCT02951819 Figure 1. Kaplan-Meier estimate of progression-free survival (PFS) among patients with newly diagnosed multiple myeloma. Disclosures Yimer: AstraZeneca: Speakers Bureau; Puma Biotechnology: Equity Ownership; Clovis Oncology: Equity Ownership; Celgene: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Epizyme: Equity Ownership; Janssen: Speakers Bureau. Melear:Janssen: Speakers Bureau. Faber:Amgen: 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; Cardinal Health: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Bensinger:celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Speakers Bureau; amgen: Speakers Bureau; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Burke:Gilead: Consultancy; Genentech: Consultancy; Celgene: Consultancy; Abbvie: Consultancy; Bayer: Consultancy; Seattle Genetics: Consultancy, Speakers Bureau; Tempus Labs: Consultancy. Narang:Janssen: Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Gunawardena:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Lutska:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Qi:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Ukropec:Janssen Scientific Affairs, LLC: Employment. Qi:Janssen Research & Development, LLC: Employment. Lin:Janssen/ Johnson & Johnson: Employment, Equity Ownership. Rifkin:Amgen: Consultancy; McKesson: Equity Ownership; Boehringer Ingelheim: Consultancy; Celgene: Consultancy; EMD Serono: Consultancy; Takeda: Consultancy; Sandoz: Consultancy.

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of relapsed or progressive disease in the 2013 version of the NCCN Clinical Practice Guidelines in Oncology for Multiple Myeloma. These changes include the addition of new regimens as options for salvage therapy and strategies to mitigate the adverse effects and risks associated with newer regimens for the treatment of multiple myeloma.

Purpose: Tabalumab, a human mAb that neutralizes B-cell–activating factor (BAFF), demonstrated antitumor activity in xenograft models of multiple myeloma. Here we report on a phase I study of relapsed/refractory multiple myeloma patients in which the primary objective was to identify a tolerable and potentially efficacious dose of tabalumab when combined with bortezomib. Experimental Design: Forty-eight patients were enrolled; 20 to the dose-escalation cohort, and 28 to cohort expansion in which a dose of 100 mg of tabalumab was evaluated. All patients had received either prior bortezomib or an immunomodulatory drug; the median number of prior therapies was 3. Bortezomib was administered intravenously on days 1, 4, 8, and 11 of a 21-day schedule. Tabalumab was given every 21 days for 3 cycles, then every 42 days thereafter. Results: The most common grade 3/4 toxicities included thrombocytopenia, neutropenia, pneumonia, and peripheral sensory neuropathy. There were no dose-limiting toxicities, and the maximum tolerated dose was not reached. Pharmacokinetic data suggested serum exposure increased in a greater than dose-proportional manner up to a dose of 100 mg. Out of 46 evaluable patients, 20 had confirmed responses. The median time to progression (9 patients censored) was 4.8 months, and the median response duration (4 patients censored) was 7.2 months. Conclusions: A dose of 100 mg tabalumab in combination with bortezomib was well tolerated and active and is currently under further investigation. Clin Cancer Res; 22(23); 5688–95. ©2016 AACR.

Substantial progress has been made in the clinical management of patients with follicular lymphoma over the past 2 decades. However, the role of autologous and allogeneic stem cell transplantation in these patients remains controversial. Myeloablative chemotherapy or radioimmunotherapy supported by autologous hematopoietic cell transplantation has been shown to lead to a longer progression-free survival and, in some studies, improved survival over standard therapy. However, in the era of rituximab-based therapies used as part of induction or salvage, these historical trials may not be representative. Allogeneic stem cell transplantation offers the advantages of a tumor-free graft and some immunologic graft-versus-lymphoma effects. However, fully myeloablative transplants have high morbidity and mortality rates. Dose-reduced conditioning regimens followed by allogeneic hematopoietic cell transplantation have substantially reduced treatment-related mortality and perhaps will produce better outcomes long-term. This article outlines some historical information regarding stem cell transplantation for follicular lymphoma and discusses recent modifications that may improve outcomes, such as adding radioimmunotherapy to autologous stem cell transplantation or using alternative dose-reduced regimens that could benefit patients with reduced toxicities.

Background: The combination of carfilzomib with lenalidomide and dexamethasone (KRd) is approved in the United States and the European Union (EU) for the treatment of patients with relapsed or refractory multiple myeloma (RRMM). Under these approvals, carfilzomib is administered twice weekly as a 10-minute intravenous (IV) infusion at a dose of 20/27 mg/m2. The phase 1/2 CHAMPION-1 study showed that once-weekly carfilzomib (20/70 mg/m2; 30-minute IV infusion) with dexamethasone was well tolerated and active in patients with RRMM (Berenson et al. Blood. 2016;127:3360−3368). We present initial results from the dose evaluation component of a phase 1b study (NCT02335983) assessing the safety and efficacy of once-weekly carfilzomib with lenalidomide and dexamethasone in patients with MM. Methods: This is an open-label, multicenter, dose-finding, phase 1b study.The primary objective of the study is to evaluate the safety and tolerability of a once-weekly KRd regimen. Secondary objectives included evaluation of the efficacy of a once-weekly KRd regimen. This study consists of 2 parts: a dose-evaluation component in patients with RRMM and a dose-expansion component in both RRMM and newly diagnosed MM (NDMM). Results from the ongoing dose-evaluation component in RRMM are presented. There were 2 planned dose cohorts in the dose-evaluation portion of the study: carfilzomib 56 mg/m2 KRd cohort (56 mg/m2) and carfilzomib 70 mg/m2 KRdcohort (70 mg/m2). All patients received carfilzomib (days 1, 8, and 15), lenalidomide 25 mg (days 1 - 21), and dexamethasone 40 mg (days 1, 8, 15 and 22) on a 28-day cycle (dexamethasone was not administered on day 22 for cycles 9+). Carfilzomib was administered as a 30-minute IV infusion: 20 mg/m2 on cycle 1 day 1 with escalation to the assigned dose level (56 or 70 mg/m2) thereafter. The protocol allowed 8 DLT-evaluable patients to be treated in the 56 mg/m2 and 70 mg/m2 cohorts. Response was assessed by investigators using International Myeloma Working Group Uniform Response Criteria. The data cutoff date for this analysis was June 23, 2016. Results: A total of 22 patients (56 mg/m2, n=10; 70 mg/m2, n=12) with a median age of 69 (range, 50-87) years were enrolled in the dose evaluation component of the study. The median number of prior regimens was 1 (range, 1 - 3) in both cohorts. There were no dose-limiting toxicities observed in any of the 15 dose-evaluable RRMM patients (56 mg/m2 cohort, n=8; 70 mg/m2 cohort, n=7). The median number of cycles started as of data cutoff was 9.5 (range, 3-15) in the 56 mg/m2 cohort and 6.0 (range, 2-9) in the 70 mg/m2 cohort. All patients experienced at least 1 treatment-emergent adverse event (AE). Grade ≥3 AEs occurring in ≥9% of patients, and any AE of interest are shown in Table 1. The only grade ≥3 AEs to occur in ≥2 patients (≥9%) were thrombocytopenia (56 mg/m2, n=2; 70 mg/m2, n=1), decreased neutrophil count (56 mg/m2, n=2; 70 mg/m2, n=1), anemia (56 mg/m2, n=2), and hypertension (56 mg/m2, n=1; 70 mg/m2, n=1). Although the numbers were small, there was no apparent difference in the incidence of dyspnea or hypertension between the 56 and 70 mg/m2 cohorts. Cardiac or renal failure of any grade was not reported at the time of the database snapshot in these patients with RRMM. Response rates after 4 cycles, as assessed by investigators, are shown in Table 2. Two patients in the 56 mg/m2 cohort did not complete 4 cycles: an 87-year old patient developed asymptomatic pulmonary hypertension (detected on a required echocardiogram study) and was taken off therapy; another patient withdrew consent. One patient in the 70 mg/m2 cohort had a partial response after cycle 1 but was found to have progressive disease in cycle 3 (listed as did not complete 4 cycles in Table 2). After 4 cycles, the response rates (investigator assessed), were 70% and 75% in the 56 and 70 mg/m2 cohorts (response assessment for 2 patients in the 70 mg/m2 cohort was missing at the time of the data cutoff). Conclusions: These results demonstrate that carfilzomib administered in a convenient once-weekly schedule in combination with lenalidomide and dexamethasone in patients with RRMM is safe with promising efficacy. The 70 mg/m2 dosing was selected for dose-expansion cohorts in RRMM and NDMM. An update on the expansion cohorts will be presented at the meeting. Disclosures Biran: Onyx: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau. Siegel:Novartis: Honoraria, Speakers Bureau; Amgen: Honoraria, Speakers Bureau; Merck: Honoraria; BMS: Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Takeda: Honoraria, Speakers Bureau. Berdeja:Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Faber:Celgene: Speakers Bureau; Cardinal Health: Honoraria; Gilead: Consultancy, Honoraria. Seneviratne:Novartis Pharmaceuticals: Speakers Bureau. Alsina:Onyx: Speakers Bureau; Millenium Pharmaceuticals: Research Funding; Novartis: Research Funding; Signal Genetics: Consultancy; Onyx: Consultancy. Bensinger:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding, Speakers Bureau. Kimball:Amgen Inc.: Employment, Equity Ownership. Zhou:Amgen Inc.: Employment, Equity Ownership. Landgren:BMS: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding.

Background: Histone deacetylase inhibitors increase acetylation of proteins involved in multiple oncogenic pathways, including the aggresome protein degradation pathway (Blood 2006; 108:3441-9). Preclinical and clinical studies have shown synergism with the combination of proteasome inhibitors (PIs) and histone deacetylase inhibitors (HDACi) such as panobinostat.(PAN) (Cancer Lett 2009; 280:233-41; J Clin Oncol 2011; 29:8075) PAN was approved by the FDA in combination with bortezomib (BTZ) and dexamethasone based on the efficacy demonstrated in the PANORAMA1 trial (Lancet Oncol 2014;15:1195-206). We previously reported the combination of Carfilzomib (CFZ) and PAN in patients (pts) with relapsed and relapsed/refractory MM (Haematologica 2015;100:670-6). The maximum tolerated dose (MTD) of CFZ and PAN was never reached and we extended our original study to investigate higher dose levels. Here we present the final results of the second dose expansion (DL 6). Methods: Pts with MM who relapsed after ≥ 1 prior treatments (tx) were enrolled. PAN was administered orally on days 1, 3, 5, 15, 17, 19 of each 28-day cycle. CFZ was administered IV over 30 min on days 1, 2, 8, 9, 15, and 16. The initial dose escalation portion of the study used a standard 3+3 design to determine the maximum tolerated dose (MTD) of an initial 4 planned dose levels of the combination of CFZ and PAN. MTD was not reached and the maximum planned dose DL 4 (30 mg PAN and 20/45 mg/m2 CFZ) was expanded. The study was then revised to escalate to DL 5 (30 mg PAN plus 20/56 mg/m2 CFZ). Numerous PAN dose reductions resulted in a delivered PAN dose closer to 20 mg so DL 6 (PAN 20 mg and CFZ 20/56 mg/m2) was explored and eventually expanded. Tx continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. Adverse events (AEs) were assessed according to CTCAE V4 and responses were assessed using IMWG criteria (plus minimal responses (MRs) per the EBMT criteria). Results: Here we report the results of the second expansion cohort only (DL 6 (PAN 20 mg and CFZ 20/56 mg/m2). 33 pts were enrolled (61% male, median age 63 (range 49-91), 67% poor risk, 100% exposed to prior PIs, and a median of 2 prior therapies (range 1-7). 48% of pts were refractory to prior PI tx and 51% were refractory to prior immunomodulator (IMiD) tx. Pts completed a median of 7 tx cycles. There were CFZ dose reductions in 16 pts and PAN dose reductions in 21 pts, resulting in an average CFZ dose of 48.4 mg/m2 and average PAN dose of 14.7 mg. To date, 3 (9%) pts remain on active tx overall and 30 pts (91%) have discontinued due to disease progression (36%), toxicity (24%), stem cell transplant (15%), physician discretion or patient request (12%), and death (3%). The most common AEs are shown in Table 1. AEs of note were dyspnea (36%) and neuropathy (18%). There were 2 grade 3/4 cardiac toxicities, congestive cardiac failure and supraventricular tachycardia. There were 7 tx-related serious AEs (SAEs) in 6 pts and no tx-related deaths. 1 pt died on study of unrelated respiratory failure. The ORR was 82% and clinical benefit rate was 88% (6% complete response (CR)/near CR, 30% very good partial response, 47% partial response, 6% MR). ORR for pts refractory to prior PI was 75% and the CBR was 88%. ORR for pts refractory to prior IMiDs was 71% and the CBR was 82%. Median time to best response was 1.9 months (mos). With a median follow up (FU) of 19.6 mos (range 3.8-28 mos), median PFS was 9.69 mos, median TTP was 13.5 mos and median OS was 24.7 mos. Conclusions: The combination of PAN/CFZ is effective with an acceptable safety profile in this refractory population. Efficacy in this cohort (ORR 82%) was similar to the previously published expanded DL4 cohort (ORR 72%). A CFZ dose of 56 mg/m2 with PAN at 20mg as given in this schedule did not appear to result in increased cardiopulmonary toxicity, but dyspnea rates were higher in this cohort than previously reported. GI toxicity was manageable. Further evaluation of this combination at this dose level is warranted. Disclosures Berdeja: Abbvie, Acetylon, Amgen, Bluebird, BMS, Calithera, Celgene, Constellation, Curis, Epizyme, Janssen, Karyopharm, Kesios, Novartis, Onyx, Takeda, Tragara: Research Funding. Gregory:Novartis: Honoraria. Faber:Cardinal Health: Honoraria; Gilead: Consultancy, Honoraria; Celgene: Speakers Bureau. Matous:Takeda Pharmaceuticals International Co.: Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding, Speakers Bureau. Hart:Onyx: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Onyx: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Flinn:Janssen: Research Funding; Gilead Sciences: Research Funding; Pharmacyclics LLC, an AbbVie Company: Research Funding; ARIAD: Research Funding; RainTree Oncology Services: Equity Ownership.

These NCCN Guidelines Insights highlight the important updates/changes specific to the management of Waldenstrom's Macroglobulinemia/Lymphoplasmacytic Lymphoma. These include the addition of regimens containing novel agents as primary and salvage therapy options, inclusion of the updated summary of response categories and criteria from the sixth international workshop on Waldenstrom's Macroglobulinemia, and a section on management of peripheral neuropathy in the accompanying discussion.

The non-Hodgkin’s lymphomas (NHL) represent a diverse group of neoplasms with many different clinical presentations, associated laboratory abnormalities, responsiveness to treatment, and clinical outcome. The cell of origin and stage of maturation arrest prior to uncontrolled proliferation are important to the understanding of this diversity (Table 47.1). In the USA, the incidence of NHL steadily increases from childhood through age 80 years; unlike Hodgkin’s disease, no peak incidence exists for young adults. NHL is the fifth most common malignancy in men and women, respectively, and is among the most rapidly increasing malignancies [1]. They represent the seventh most common cause of death from cancer in the USA, with the age-adjusted incidence being about three times that of Hodgkin’s disease [1]. The incidence of non-Hodgkin’s lymphoma is twice as frequent among whites as blacks, and there is an almost 50 % increase in presentation in males compared with females. The reason for this gender and race predominance is unknown; however, it may reflect a different pattern of occupational exposure or a difference in the immune status of males compared with females. Links among agricultural work (organochlorine-based pesticides), wood products, and organic solvents have been established [2].

Background: FIL (ARRY-520), a specific kinesin spindle protein (KSP) inhibitor, represents a novel class of agent under investigation for the treatment of patients (pts) with MM. Prognosis of pts refractory to immunomodulatory agents (IMiDs) and proteasome inhibitors (PIs) is poor. These pts have a median survival of 9 months underscoring the importance of novel therapeutic strategies incorporating new mechanisms of action. FIL has shown interesting preliminary activity as a single agent as well as in Phase 1 studies in combination with bortezomib (BTZ) and with CFZ, all with a manageable safety profile. Methods: This trial is an ongoing, randomized, multicenter, open-label Phase 2 study for pts with relapsed and refractory MM who received at least 2 prior regimens, including BTZ and an IMiD, and with disease refractory to the last regimen as per IMWG criteria. No prior treatment with CFZ is allowed. Approximately 75 pts will be randomized 2:1 to receive CFZ (20/27 mg/m2 intravenous [IV] on Days 1, 2, 8, 9, 15 and 16) plus FIL (1.25 mg/m2 IV on Days 1, 2, 15 and 16) or single-agent CFZ, at the same dose as in the combination, in a 28-day cycle. Prophylactic filgrastim is administered in the CFZ + FIL arm. The primary endpoint is progression-free survival (PFS). Patients with progressive disease (PD) on CFZ are allowed cross-over to the CFZ + FIL arm if they continue to meet eligibility criteria. Results: As of 15 June 2015, 72 pts have been randomized (23 CFZ, 49 CFZ + FIL) with a median age of 65 years. Pts who could have potentially received ≥ 2 cycles of treatment (20 CFZ, 30 CFZ + FIL) were evaluable for efficacy. These pts were heavily pretreated with a median of 4 and 5 prior regimens in the CFZ and CFZ + FIL arm, respectively. A total of 25% and 30 % of pts, respectively, received prior pomalidomide. The objective response rate (ORR) was 10% in the CFZ arm and 30% in the CFZ + FIL arm. In the CFZ arm, 2 pts achieved a partial response (PR) and 2 pts (10%) achieved an MR. In the CFZ + FIL arm, 3 pts achieved a very good partial response and 6 pts achieved a PR, with 2 additional pts (7%) achieving an MR. In the population of pts who were refractory to both prior BTZ and prior IMiDs, the ORR was 14% and 35%, respectively. Grade 3-4 hematological laboratory abnormalities (≥ 5% of pts) were leukopenia (9% CFZ vs. 21% CFZ + FIL), neutropenia (14% vs. 24%), thrombocytopenia (14% vs. 24%), and anemia (9% vs. 26%). Neutropenia and thrombocytopenia were reversible. No adverse events (AEs) of febrile neutropenia were reported. The only Grade 3-4 non-hematological AE occurring in ≥ 5% of pts was dyspnea (5% vs.11%). The most common reason for treatment discontinuation was confirmed PD (39% vs. 28%) or Investigator discretion in case of unconfirmed PD or clinical PD (17% vs. 12%). Conclusions: The combination of FIL and CFZ was well-tolerated and noticeably increased the ORR compared to CFZ alone in heavily pretreated pts with advanced MM. The preliminary efficacy in pts who are double refractory to IMiDs and BTZ who were randomized to CFZ + FIL appears higher than in pts treated with CFZ alone (in the CFZ arm of this trial and in previously published reports involving such pts). Updated safety and efficacy data, including PFS, will be presented at the meeting. Table. Efficacy evaluable pts (potential to have received ≥ 2 cycles of treatment) CFZ (N = 20) CFZ + FIL (N = 30) Prior regimens, median (range) 4 (2,11) 5 (2,11) N cycles on study, median (range) 4 (1 - 16) 4 (1 - 15+) % ORR (≥ PR) 10 30 % CBR (≥ MR) 20 37 N (%) IMiD & BTZ Refractory 14 (70) 20 (67) % ORR (≥ PR) 14 35 % CBR (≥ MR) 21 40 CBR = clinical benefit rate Disclosures Zonder: Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support. Off Label Use: carfilzomib; treatment of myeloma, but not in combination with filanesib. Usmani:Celgene Corporation: Consultancy, Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Berdeja:Onyx: Research Funding; Array: Research Funding; Takeda: Research Funding; Acetylon: Research Funding; Janssen: Research Funding; BMS: Research Funding; MEI: Research Funding; Celgene: Research Funding; Novartis: Research Funding; Abbvie: Research Funding; Curis: Research Funding. Anderson:Onyx: Speakers Bureau; Takeda: Speakers Bureau; Celgene: Speakers Bureau. Hari:BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Honoraria; Onyx: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Honoraria, Research Funding. Singhal:Celgene: Speakers Bureau. Valent:Takeda/Millennium: Speakers Bureau; Celgene: Speakers Bureau. Faber:Celgene: Consultancy. Schiller:Sunesis: Honoraria, Research Funding. Schreiber:Array BioPharma: Employment. Oliver:Array BioPharma: Employment. Rush:Array BioPharma: Employment. Tunquist:Array BioPharma: Employment. Ptaszynski:Array BioPharma: Employment. Raje:Eli Lilly: Research Funding; Millenium: Consultancy; Takeda: Consultancy; Onyx: Consultancy; Acetylon: Research Funding; BMS: Consultancy; AstraZeneca: Research Funding; Novartis: Consultancy; Amgen: Consultancy; Celgene Corporation: Consultancy; Acetylon: Research Funding.

Background: Proteasome inhibitors (PI) such as bortezomib (BTZ) and carfilzomib (CFZ) have improved the treatment (tx) of MM; however, resistance invariably develops and MM remains an incurable disease. Changes in histone modification are commonly found in human cancers including MM, and several histone deacetylase inhibitors (HDACi) are in clinical development. Panobinostat (PAN) is an oral pan-HDACi which has shown synergy with PIs through inhibition of the proteasome and aggresome pathways. It was recently approved by the FDA in combination with BTZ and dexamethasone based on the results of the PANORAMA1 study demonstrating efficacy, but significant G3 diarrhea (Lancet Oncol 2014;15:1195-206). We have previously reported the combination of CFZ and PAN in pts with relapsed and relapsed/refractory MM with encouraging results (Haematologica 2015;100:670-6). The maximum tolerated dose (MTD) of CFZ and PAN was never reached and we extended our original study to investigate higher dose levels. Here we present a comparison of the initial dose expansion (DL 4) and the subsequent dose expansion (DL 6). Methods: Ps with MM who had relapsed after ≥ 1 prior tx were enrolled. PAN was administered orally on days 1, 3, 5, 15, 17, 19 of each 28-day cycle. CFZ was administered IV over 30 min on days 1, 2, 8, 9, 15, and 16. In the initial dose escalation portion of the study a standard 3+3 design was used to determine the maximum tolerated dose (MTD) of an initial 4 planned dose levels of the combination of CFZ and PAN. The 4 dose levels tested were DL 1 (20 mg PAN and 20/27 mg/m2 CFZ); DL 2 (20 mg PAN and 20/36 mg/m2 CFZ); DL 3 (20 mg PAN and 20/45 mg/m2 CFZ), and DL 4 (30 mg PAN and 20/45 mg/m2 CFZ). MTD was not reached and the maximum planned dose DL 4 was expanded. We then revised the study in order to escalate to DL 5 (30 mg PAN plus 20/56 mg/m2 CFZ). Due to numerous PAN dose reductions resulting in a delivered PAN dose closer to 20 mg, we explored DL 6 (PAN 20 mg and CFZ 20/56 mg/m2). Tx continued until PD or intolerable toxicity. The primary efficacy endpoint was the overall response rate (ORR) (≥ PR). Secondary end points were time to progression (TTP), progression-free survival (PFS) and overall survival (OS), calculated using Kaplan-Meier methods. AEs were assessed according to CTCAE Version 4 and responses were assessed using IMWG criteria (plus MRs as per the EBMT criteria). Results: 80 pts were enrolled (50% male, median age 65 (range 41-91), 58% poor risk, and median of 4.5 prior therapies (1-9)). Prior PI or IMiD exposure and refractory status for all pts and expansion cohorts are shown in Table 1. 34 pts were in the 1st dose expansion (DL 4) and 33 in the 2nd (DL6). 13 (16%) pts remain on active tx overall, 6% of pts on DL 4 and 30% of pts on DL6. The most common all grade toxicities were thrombocytopenia (73%), nausea (69%), diarrhea (64%), and fatigue (51%). There were no significant differences in types or grades of toxicities between the 2 expansion cohorts except for decreased all grade diarrhea favoring DL 6 (71% v 49%). There was 1 tx related death due to heart failure in a pt with a prior history of hypertension and hyperlipidemia. The ORR was 75% (32% ≥ VGPR, 43% PR) for all pts, 72% (37% ≥ VGPR, 34% PR) for DL4 and 84% (34% ≥ VGPR, 50% PR) for DL 6 pts. With a median follow up (FU) of 14.5 mos for all pts, median PFS and TTP were 13.5 and 18.7 mos, respectively. Median OS was not reached. DL4 pts had a median FU of 24.3 mos, median PFS of 17.8 mo, median TTP of 19.5 mo, and median OS of 28.2 mo. The PFS and OS data of DL 6 pts is immature. Conclusions: The PAN/CFZ combination is effective with an acceptable safety profile in this heavily pretreated and highly refractory population. The results of this study compare favorably with the results of the PANORAMA-1 study in both efficacy and toxicity. An increase in CFZ from 45 to 56 mg/m2 did not appear to increase cardiopulmonary toxicity while a decrease in PAN from 30 to 20 mg appeared to have decreased the incidence of diarrhea. Both expansion dose levels tested were highly efficacious and well tolerated. Further evaluation of this combination in this schedule is warranted. Table 1. DL 4 (n=34) DL 6 (n=33) All Pts (n=80) Median # prior therapies, (range) 5 (1-9) 4 (1-9) 4.5 (1-9) Prior PIs 33 (97%) 33 (100%) 79 (99%) Prior IMiDs 31 (91%) 26 (79%) 69 (86%) Refractory to prior PIs 15 (44%) 19 (58%) 37 (46%) Refractory to prior IMiDs 17 (50%) 16 (48%) 42 (53%) Refractory to both prior IMiDs and PIs 8 (24%) 8 (24%) 20 (25%) Refractory to Last Therapy 23 (68%) 27 (81%) 57 (71%) Disclosures Berdeja: Acetylon: Research Funding; MEI: Research Funding; Array: Research Funding; Onyx: Research Funding; Takeda: Research Funding; Curis: Research Funding; Janssen: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Research Funding; Novartis: Research Funding. Gregory:Novartis: Speakers Bureau. Hart:Onyx: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Mace:Spectrum Pharmaceuticals: Consultancy, Honoraria, Speakers Bureau; Bayer: Honoraria, Speakers Bureau; Pfizer: Speakers Bureau. Flinn:Celgene Corporation: Research Funding.

The manuscript by Dr David Siegel and colleagues,[1][1] “Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in 4 phase 2 clinical studies”, provides a comprehensive assessment of the available safety data associated with the new proteasome inhibitor

Glass fiber reinforced PVC has several distinctive and useful properties. Its tensile strength can be twice that of unreinforced PVC. Excellent coupling of the glass fibers to the PVC matrix is required for good retention of tensile strength when exposed to warm water, Its modulus can be twice that of unreinforced PVC and equal to that of wood. PVC's high load carrying capability is not significantly increased to higher temperatures by adding glass fibers as judged by its 264 psi heat deflection temperature. However, by changing the polymeric matrix, glass reinforced vinyl with an increased HDT of 86°C has been produced for higher use temperature. The coefficient of linear thermal expansion of PVC can be cut in half by the addition of glass fibers and has a coefficient equal to that of aluminum. Glass fiber reinforced PVC has exceptionally good resistance to crack propagation and resists shattering as judged by sawing, punching, stapling, and hammering. When properly formulated for weathering resistance, glass fiber reinforced PVC has good color retention, impact retention, and outstanding dimensional stability. As for all glass fiber reinforced plastics, processing equipment must be built for high abrasion resistance for long economical manufacturing runs.

8513 Background: Histone deacetylase inhibitors (HDACi) and proteasome inhibitors (PI) act synergistically through inhibition of the proteasome and aggresome pathways. We have previously reported t...

INTRODUCTION: Patient reported outcomes (PROs) including symptoms and health related quality of life (HRQOL) predict mortality in multiple cancers, such as myeloma, head and neck, lung and prostate cancer. The relationship of PROs with survival is not clear in hematopoietic cell transplantation (HCT). We tested three hypotheses about the relationship between HRQOL and survival after HCT: (1) Pre-HCT HRQOL (particularly physical HRQOL) reflects functional status and predicts survival after allogeneic (allo) HCT independently of traditional risk factors and indices; (2) Post-HCT change in physical HRQOL reflects the “toll” of the HCT and predicts subsequent outcomes, including survival, among early survivors; (3) Since autologous (auto) HCT is associated with lower risks for treatment-related morbidity and mortality, PROs may not be as predictive for this group. METHODS: We tested these hypotheses using data from the 711 participants in BMT CTN 0902 (sponsored by NHLBI and NCI, NCT 01278927), a randomized study of pre-transplant exercise and stress management training for patients undergoing auto or allo HCT. Because the primary analysis for BMT CTN 0902 did not show a significant effect for exercise or stress management training, intervention groups were combined for these analyses. However, auto and allo recipients were analyzed separately because of the expected substantial differences in the subsequent risks for morbidity and mortality in the two populations. The HRQOL measures used were the physical component score (PCS) and mental component score (MCS) from the SF-36, measured pre-HCT and at day 100. RESULTS: Among 310 alloHCT recipients with a median follow-up of 23 months, while there were no pre-HCT clinical covariates (including age, conditioning intensity, donor type, graft source, disease, disease stage) that predicted survival, pre-HCT physical HRQOL (PCS on the SF-36) was strongly prognostic for survival (HR for death of 0.72 per 10 points increase, 95% CI 0.60-0.85, p CONCLUSION: In summary, among alloHCT recipients who participated in BMT CTN 0902, lower pre-HCT physical HRQOL and early decline in physical HRQOL were strongly predictive for worse overall survival and higher transplant-related mortality. These results suggest that patient-reported data are an important component of risk assessment and could assist in clinical decision-making. High-risk individuals could be targeted for different management strategies or more aggressive supportive care interventions to reduce treatment-related morbidity and mortality in this population. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background Due to recent treatment advances, MM patients (pts) are living longer (Kumar et al, Blood 2008), underscoring the importance of patient quality of life and management of adverse events (AEs) related to MM therapy. MM pts are at risk of cardiac events due to age and disease-related factors, as well as cardiotoxicity from treatments including anthracyclines, proteasome inhibitors (PIs), and high-dose therapy. Both of the US FDA-approved PIs, Btz and carfilzomib, have been associated with cardiac events in MM pts, with cardiac toxicity and cardiac adverse reactions included under ‘Warnings and Precautions’ in the respective US labels. The development of Btz, a reversible boronate peptide PI, involved numerous large, controlled clinical trials, providing a benchmark for the expected incidence of heart failure with PIs. Here, we report a retrospective analysis of the risk of heart failure associated with Btz in phase 2 and 3 MM studies leading to regulatory approvals in the US and EU. Methods Study databases were retrospectively analyzed for AEs of grade ≥3 heart failure. In the relapsed/refractory setting, the following studies were included: the phase 2 SUMMIT trial (Btz ± dexamethasone; Richardson et al, NEJM 2003), and the phase 3 APEX (Btz vs dexamethasone; Richardson et al, NEJM 2005), MMY-3001 (Btz + liposomal doxorubicin vs Btz; Orlowski et al, J Clin Oncol 2007), and MMY-3021 (subcutaneous [SC] vs intravenous [IV] Btz; Moreau et al, Lancet Oncol 2011) trials. In the upfront setting, the phase 3 VISTA trial (Btz-melphalan-prednisone [VMP] vs MP; San Miguel et al, NEJM 2008) in transplant-ineligible pts and a pooled analysis of three phase 3 trials (IFM 2005-01, HOVON-65/GMMG-HD4, PETHEMA GEM2005MENOS65) of Btz-based vs non-Btz-based induction (N=779 vs 776; Sonneveld et al, IMW 2013) in transplant-eligible pts were included. Cardiac exclusion criteria typically included NYHA class III/IV (≥II in MMY-3001), myocardial infarction within 6 mos, and ECG evidence of acute ischemia. Heart function tests (primarily ECG) were incorporated in study designs. Heart failure events were analyzed and re-coded for consistency across studies, using standardized MedDRA (v4.0, 8.0, 8.1, 9.0, 9.1, and 10.0) query preferred terms with grouping of clinically related events. Results 2509 pts treated with Btz in the specified phase 2 and 3 trials and an additional 1445 pts treated with non-Btz-based therapies in the control arms of the phase 3 studies were included in this analysis. Pt characteristics and rates of grade ≥3 heart failure by study arm are shown in the table. Among all Btz-treated pts, the rate of grade ≥3 heart failure was 2.0%; the rate was 2.0% in newly diagnosed pts and 1.9% in relapsed and/or refractory pts. In the comparative studies (APEX, VISTA) and pooled pre-ASCT induction analysis, the overall rates across the Btz and non-Btz arms were 2.0% and 1.6%, respectively (p=0.41). Risk factors, including prior anthracycline exposure and history of cardiac complications, were balanced between Btz and non-Btz arms. Conclusions In this retrospective analysis of data from key phase 2 and 3 studies, Btz was associated with a low rate of grade ≥3 heart failure in both the newly diagnosed (2.0%) and relapsed and/or refractory (1.9%) settings. Importantly, across comparative studies, the rate was only marginally higher and not statistically different from the background rate in non-Btz comparator arms. Data from ongoing prospective and comparative studies are necessary to determine whether PIs – including Btz, carfilzomib, and PIs at earlier stages of clinical development – have different cardiotoxicity profiles. Disclosures: San Miguel: Millennium: The Takeda Oncology Company: 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; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: 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. Sonneveld:Jansssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Onyx: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding. 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. Moreau:Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees. Rosiñol:Janssen: Honoraria; Celgene: Honoraria. Moslehi:Alnylam: Consultancy; Novartis: Consultancy; Millennium: The Takeda Oncology Company: Consultancy; Forest Laboratories: Research Funding. Faber:Celgene: Consultancy, Honoraria; Millennium: The Takeda Oncology Company: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria. Voorhees:Acetylon: Research Funding; Millennium: The Takeda Oncology Company: Research Funding; Merck: Research Funding; Janssen: Research Funding; Prolexys Pharmaceuticals: Research Funding; GlaxoSmithKline: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Abbott Laboratories: Consultancy. Marquez:Johnson & Johnson: Equity Ownership; Janssen: Employment. Desai:Janssen: Employment; Johnson & Johnson: Equity Ownership. van de Velde:Janssen: Employment; Johnson & Johnson: Equity Ownership. Elliott:Millennium: The Takeda Oncology Company: Employment. Shi:Millennium: The Takeda Oncology Company: Employment. Dow:Millennium: The Takeda Oncology Company: Employment. Jobanputra:Millennium: The Takeda Oncology Company: Employment. Esseltine:Millennium: The Takeda Oncology Company: Employment; The Takeda Pharmaceutical Company: Equity Ownership. Niculescu:Millennium: The Takeda Oncology Company: Employment. Anderson:Celgene: Consultancy; Onyx Pharmaceuticals: Consultancy; Sanofi-Aventis: Consultancy; Gilead: Consultancy; Acetylon Pharmaceuticals: Equity Ownership; Oncopep: Equity Ownership. Lonial:Merck: Consultancy; Onyx Pharmaceuticals: Consultancy; Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Celgene: Consultancy; Millennium: The Takeda Oncology Company: Consultancy. Richardson:Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Johnson & Johnson: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees.

Following up on single institution studies suggesting that engaging patients in exercise and/or stress reduction techniques during hematopoietic cell transplantation (HCT) improves functional status and quality of life, we conducted a randomized study through the Blood and Marrow Transplant Clinical Trials Network (BMT CTN). METHODS: Patients (n=711) at 21 US centers provided symptom and quality of life data at enrollment. They were randomized to 1 of 4 groups using a 2x2 factorial design, stratified by center and transplant type. Prior to HCT, each group received a 15 minute stress management training session or a 15 minute exercise training session, both, or neither, with trained personnel to discuss the importance of managing stress and/or keeping active during HCT. The 3 intervention groups were also given a DVD, pamphlet and diary to track participation in exercise and/or stress management. The trainer reviewed the goals of practicing the intervention, proper technique, identification of barriers and plans to overcome them. Exercise training also included calculation of target heart rate. The exercise goal was walking 3-5 times a week for at least 20-30 minutes at 50-75% of estimated heart rate reserve. The stress management goal was to use paced abdominal breathing, progressive muscle relaxation with guided imagery, and coping self-statements to decrease stress. The interventionists re-contacted patients at 30 and 60 days after HCT to review the training goals, discuss barriers and provide encouragement. The fourth group was a usual care control group. All groups received a DVD of general information about HCT. Participants provided self-reported assessments at 30, 60, 100 and 180 days after transplant. The primary endpoints were the physical (PCS) and mental (MCS) component subscales of the SF36 at day 100. The study was designed to have 85% power to detect a difference of 0.5 STD in the exercise or stress management groups on each of the two endpoints, maintaining an overall type I error rate of 0.05. Primary analysis was on an intention to treat (ITT) basis with values assigned to patients who died or otherwise did not provide information. Enrollment occurred from January 2011-June 2012. Results The groups were well-balanced for baseline characteristics. There were no differences in the primary endpoints of PCS and MCS at day +100 among any of the groups based on the ITT analysis (Table). Results were similar using other conditional and imputed methods. Higher PCS at day +100 was associated with higher PCS at enrollment (p Conclusions No improvements in functional status as measured by PCS and MCS at day +100 were evident between the groups. Functional status was highly associated with pre-transplant functioning and type of transplant but not with conditioning regimen intensity.TableDay 100 SF36 scoresExercise (n=358) Median (25th-75th)No Exercise (n=353) Median (25th-75th)p-valuePCS37.5 (19.7-46.7)39.7 (27.1-47.7)0.14MCS49.4 (27.3-57.7)50.1 (34.2-57.8)0.33Stress Management (n=356) Median (25th-75th)No Stress Management (n=355) Median (25th-75th)PCS37.8 (22.1-46.6)39.7 (25.7-47.9)0.21MCS50.7 (31.0-58.2)49.1 (30.5-56.8)0.30 Disclosures: No relevant conflicts of interest to declare.

Abstract 447 Background: Tabalumab, a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF), has demonstrated both anti-myeloma activity and osteoclastogenesis inhibition in xenograft models of multiple myeloma (MM). We initially conducted a Phase 1 study with the combination of tabalumab and bortezomib in previously-treated MM patients who were not refractory to bortezomib. The results from the dose escalation (Part A) have been previously reported, where a tabalumab dose of 100 mg was selected based on several factors, most notably the stabilization of the peak to trough concentration ratio. The cohort expansion (Part B) has since completed enrollment, and we now report the preliminary results for the entire study. Methods: The primary objective was to identify a safe and potentially efficacious dose of tabalumab to be combined with bortezomib. Bortezomib was given in a standard biweekly fashion, 1.3 mg/m2 IV on days 1, 4, 8, and 11 of a 21 day cycle, and tabalumab at 1, 10, 30, 100, or 300 mg (Part A) or 100 mg (Part B) IV (30 min) on day 1 in Cycles 1 – 3, 5, and 7. The study was later amended to include dexamethasone to assess safety, and 12 patients received dexamethasone in combination with bortezomib and tabalumab. Response was assessed per IMWG criteria and adverse events per CTCAE v3.0. Pharmacokinetic (PK) and pharmacodynamic (PD) samples were obtained throughout the study, including BAFF, IL-1beta, IL-6, IL-10, VEGF, and TNF-alpha. Results: Forty-eight patients were enrolled to the study; 20 to dose escalation (Part A) and 28 to cohort expansion (Part B). The median age was 65.7 years and 56% were women. The median number of prior therapies was 3 (range 1–10). All patients received either bortezomib or an IMiD; 75% received prior bortezomib and 88% received prior IMiD therapy. The median number of cycles was 5.5 (range 1–28). Grade 3/4 toxicities occurring in two or more patients included peripheral sensory neuropathy, pneumonia, thrombocytopenia, neutropenia, diarrhea, musculoskeletal pain, renal failure acute, fatigue, anemia, neuralgia, and gastrointestinal hemorrhage. Most patients discontinued treatment due to progressive disease or adverse events (neuropathy, neuralgia, fatigue, and thrombocytopenia). Two patients died during study participation - one during treatment from acute respiratory distress syndrome and another during follow-up from multiple myeloma. Confirmed responses included 2 complete responses, 4 very good partial responses, and 16 partial responses. Response associated with lower baseline serum BAFF or IL-6 levels, independent of the tabalumab dose. Also, response in patients treated with tabalumab 100 mg appeared to associate with lower baseline serum levels of IL-10 and undetectable TNF-alpha. With 14 patients censored, the TTP was 4.9 months (95% CI: 4 – 8). With 6 patients censored, the median response duration was 7.3 months (95% CI: 3.5 – 13.9). Conclusions: A 100 mg dose of tabalumab in combination with bortezomib was well tolerated; 22 patients achieved a PR or better despite prior bortezomib and/or IMiD therapy. Response correlated with lower baseline serum BAFF levels, supporting the hypothesis that a higher dose of tabalumab should be evaluated. A three-arm study randomizing patients to the combination(s) of bortezomib, dexamethasone, and tabalumab 100 mg vs. tabalumab 300mg vs. placebo is currently enrolling. Disclosures: Raje: Onyx: Consultancy; Celgene: Consultancy; Millennium: Consultancy; Acetylon: Research Funding; Amgen: Research Funding; Eli-Lilly: Research Funding. Richardson:Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees. Schiller:Eli Lilly & Company: Research Funding. Cohen:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Carpenter:Eli Lilly & Company: Employment. Cronier:Eli Lilly and Company: Employment. Kaiser:Eli Lilly and Company: Employment. Wooldridge:Eli Lilly and Company: Employment. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

Abstract 2040 Background: Consolidative high dose chemotherapy [HDT] and autologous peripheral blood hematopoietic stem cell transplant [auto-HSCT] is an effective treatment modality for multiple myeloma [MM]. Many advances during the last two decades have lead to significantly improved progression free survival [PFS] and overall survival [OS]. Novel agents [thalidomide, lenalidomide and bortezomib] have replaced conventional chemotherapy during induction due to superior response rates. Randomized trials have defined melphalan as the optimal preparative regimen prior to auto-HSCT. Further recent attempts to improve the preparative regimen have included the addition of oral busulfan or bortezomib to melphalan. We performed a single institution, retrospective analysis in order to compare the outcomes of patients with newly diagnosed MM, treated with either conventional chemotherapy or novel agents, who received melphalan versus BEAM [carmustine, etoposide, cytarabine, melphalan] regimens during their first auto-HSCT. Methods: 179 MM patients were treated or referred to the University of Nebraska Medical Center for auto-HSCT between 1999 and 2010. All patients in the analysis were treated with induction regimens that included either VAD [vincristine, doxorubicin, dexamethasone], thalidomide, lenalidomide, or bortezomib. We compared PFS and OS in patients receiving melphalan [140 or 200 mg/m2 (N=103)] versus BEAM [carmustine 300 mg/m2, etoposide 100 mg/m2, cytarabine 100 mg/m2, and melphalan 140 mg/m2 (N=76)]. Characteristics of patients were compared using univariate statistics. The probabilities of PFS and OS were estimated using the Kaplan-Meier method, while the Cox proportional hazard regression analysis was used to evaluate the association between conditioning regimen and PFS or OS while adjusting for significant covariates. Results: No statistical significant differences in age, sex, race, median time from diagnosis to transplant, and disease stage at diagnosis were seen between the two groups. Disease stage at transplant differed between melphalan {CR (complete response) = 5, PR (partial response) = 89, other = 9} versus BEAM {CR = 22, PR = 51, other = 3} [p Conclusions: The use of BEAM as a regimen for newly diagnosed MM patients during their first auto-HSCT was associated with improved PFS and OS when compared to melphalan. BEAM was associated with a reduced risk of disease progression, treatment failure and death. No significant differences were observed based on treatment-related toxicity or treatment related mortality. The improved PFS and OS were independent of the remaining confounding variables in the multivariate analyses with the exception of CR prior to first auto-HSCT and followup time. Therefore, these are potential contributors to the differences in PFS and OS. Further analyses stratified by cytogenetics, induction therapy, therapy after progression of first auto-HSCT and maintenance therapy are required to further characterize the PFS and OS advantage, as well as to potentially identify a specific patient population that may benefit more from BEAM than melphalan. Nevertheless, BEAM appears to be an efficacious, well tolerated preparatory regimen to be considered in future prospective clinical trials. Disclosures: Vose: GSK: Research Funding; Millenium: Research Funding; Celgene: Research Funding; BMS: Research Funding; Exelixis: Research Funding; SBio: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding.

Abstract 842 Background. Autologous stem cell transplantation (ASCT) is a common treatment modality for patients (pts) with lymphoma and myeloma and in certain settings appears to be associated with improved survival. We evaluated the risk of death and its attributable causes in three sequential cohorts of patients undergoing ASCT between 1983 and 2010 to look for possible changes in outcome over time. Methods. Adults ≥ 18 years of age with lymphoma or multiple myeloma who received ASCT between 1983 and 2010 at a university medical center were identified and divided into three cohorts based on time of transplantation: 1983–1990 (I), 1991–2000 (II) and 2001–2010 (III). The primary cause of death (COD) was determined and verified by the attending physician. The risk of dying from a particular cause (relapse, infection, secondary malignancy, organ failure) was compared across time periods using Cox proportional hazards regression while adjusting for age, gender, disease type, stage at transplant, and time from diagnosis to transplant. Results. A total of 2284 pts with lymphoma and myeloma were analyzed, and there were 1215 deaths (with 972 occurring within 5 years of ASCT). Pts transplanted in the more recent time period were older and more likely to be transplanted < 1 year from diagnosis. There was a significant improvement in the 5-year probability of overall survival (OS) over time: 36% vs. 55% vs. 60% (p Conclusion. The OS of patients undergoing ASCT in our institution has improved significantly over the past three decades as assessed in three sequential cohorts. This improvement is related to a measurable decrease in infectious mortality. The reasons for this are likely multifactorial and could include improved supportive care, use of growth factors, cumulative transplant center experience, introduction of peripheral stem cell transplantation vs. bone marrow transplantation, selection of regimens with less toxicity, improved salvage therapies, and patient selection factors. Relapse continues to be the most common cause of death in this patient population with no appreciable change over time. These results suggest that better strategies to improve outcomes are needed which could include better preparative regimens and/or post transplant therapies. Disclosures: Vose: GSK: Research Funding; Millenium: Research Funding; Celgene: Research Funding; BMS: Research Funding; Exelixis: Research Funding; SBio: Research Funding; Pharmacyclics: Research Funding; Genentech: Research Funding.

8012 Background: LY2127399 (LY) is a human mAb that neutralizes membrane-bound and soluble B cell activating factor (BAFF). LY has activity in xenograft models of multiple myeloma (MM) and is being...

Studies show that engaging patients in exercise and/or stress management techniques during hematopoietic cell transplantation (HCT) improves quality of life. The Blood and Marrow Transplant Clinical Trials Network tested the efficacy of training patients to engage in self-directed exercise and stress management during HCT. The study randomized 711 patients at 21 centers to receive 1 of 4 training interventions before HCT: a self-directed exercise program, a self-administered stress management program, both, or neither. Participants completed self-reported assessments at enrollment and up to 180 days after HCT. Randomization was stratified by center and transplant type. There were no differences in the primary endpoints of the Physical Component Summary and Mental Component Summary scales of the Medical Outcomes Study Short Form 36 at day +100 among the groups, based on an intention-to-treat analysis. There also were no differences in overall survival, days of hospitalization through day +100 post-HCT, or in other patient-reported outcomes, including treatment-related distress, sleep quality, pain, and nausea. Patients randomized to training in stress management reported more use of those techniques, but patients randomized to training in exercise did not report more physical activity. Although other studies have reported efficacy of more intensive interventions, brief training in an easy-to-disseminate format for either self-directed exercise or stress management was not effective in our trial.

Outcomes of Patients with Central Nervous System Complications After Allogeneic Hematopoietic Stem Cell Transplantation Mojtaba Akhtari , Jagar Jasem , James O. Armitage , Vamshi K.S. Balasetti , Philip J. Bierman , Edward A. Faber , Pierre Fayad , Abdul Hadi , Fausto Rodriguez Loberiza , Lori Maness , Armando D.A. Rosales , Julie M. Vose , Robert G. Bociek . 1 Internal medicine, University of Nebraska Medical Center, Omaha, NE; 2 College of Public Health, University of Nebraska Medical Center; 3 Internal Medicine, University of Nebraska Medical Center, Omaha, NE; 4 Internal medicine, University of Nebraska Medical Center; 5 Department of Internal Medicine, BMT, University of Nebraska Medical Center, Omaha, NE; 6 University of Nebraska Medical Center; 7 Department of Neurological Sciences, University of Nebraska Medical Center (UNMC); 8 University of Nebraska Medical Center, Omaha, NE; 9 Univ of Nebraska Med Ctr, Omaha, NE; 10 Oncology/Hematology, University of Nebraska Medical Center, Omaha, NE; Hematology/Oncology, University of Nebraska Medical Center, Omaha, NE