Citations

Abstract Background: The association of pre-existing diabetes mellitus and outcomes among critically ill patients remains unknown.Methods: This retrospective study enrolled patients who were covered by the eICU Collaborative Research Database from 2014 to 2015. DM was the exposure of interest, and diabetic individuals were adjudicated by the medical history, and blood glucose level (BGL). We abstracted basic characteristics, laboratory variables, and primary exposures. ICU mortality was the primary outcome.Results: In a cohort of 134,429 critically ill patients (male 54.4%, median age 66 [54-77] years, BMI 28[24-33] kg/m2), the prevalence of DM was 29%. In comparison with nondiabetics, DM patients were older, more obese, had higher Acute Physiology and Chronic Health Evaluation (APACHE)-IV score, and ICU admission BGL. In comparison with nondiabetics, pre-existing DM was associated with lower ICU mortality (OR: 0.846, 95%CI: 0.791-0.905). In multivariable logistic regression and Cox proportional hazard analyses, pre-existing DM was associated with decreased odds of ICU mortality in hyperglycemic patients (>163 mg/dL), higher APACHE IV score (>67), middle to old age (45-75 years), sepsis and morbid obesity (BMI>35 kg/m2). Also, in comparison with nondiabetics, pre-existing DM was associated with lower mortality among those with higher mean BGL (>128 mg/dL), and higher mortality in lower mean BGL (<107 mg/dL). Conclusions: In comparison with nondiabetics, pre-existing DM is associated with a lower adjusted ICU mortality. This association is stronger in DM patients with hyperglycemia, obesity, sepsis, middle to old age, and higher APACHE IV score.

AbstractBackgroundHepatectomy is standard treatment for colorectal liver metastases; however, it is unclear whether liver metastases from other primary cancers should be resected or not. The Japanese Society of Hepato‐Biliary‐Pancreatic Surgery therefore created clinical practice guidelines for the management of metastatic liver tumors.MethodsEight primary diseases were selected based on the number of hepatectomies performed for each malignancy per year. Clinical questions were structured in the population, intervention, comparison, and outcomes (PICO) format. Systematic reviews were performed, and the strength of recommendations and the level of quality of evidence for each clinical question were discussed and determined. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach was used to assess evidence and make recommendations.ResultsThe eight primary sites were grouped into five categories based on suggested indications for hepatectomy and consensus of the guidelines committee. Fourteen clinical questions were devised, covering five topics: (1) diagnosis, (2) operative treatment, (3) ablation therapy, (4) the eight primary diseases, and (5) systemic therapies. The grade of recommendation was strong for one clinical question and weak for the other 13 clinical questions. The quality of the evidence was moderate for two questions, low for 10, and very low for two.A flowchart was made to summarize the outcomes of the guidelines for the indications of hepatectomy and systemic therapy.ConclusionsThese guidelines were developed to provide useful information based on evidence in the published literature for the clinical management of liver metastases, and they could be helpful for conducting future clinical trials to provide higher‐quality evidence.

Background: Increased parasympathetic activity is thought to play important roles in syncope events of patients with vasovagal syncope (VVS). However, direct measurements of the vagal control are difficult. The novel deceleration capacity (DC) of heart rate measure has been used to characterize the vagal modulation. This study aimed to assess vagal control in patients with VVS and evaluate the diagnostic value of the DC in VVS. Methods: Altogether, 161 consecutive patients with VVS (43±15 years; 62 males) were enrolled. Tilt table test was positive in 101 and negative in 60 patients. Sixty-five healthy subjects were enrolled as controls. DC and heart rate variability in 24-hour ECG, echocardiogram, and biochemical examinations were compared between the syncope and control groups. Results: DC was significantly higher in the syncope group than in the control group (9.6±3.3 versus 6.5±2.0 ms, P <0.001). DC was similarly increased in patients with VVS with a positive and negative tilt table test (9.7±3.5 and 9.4±2.9 ms, P =0.614). In multivariable logistic regression analyses, DC was independently associated with syncope (odds ratio=1.518 [95% CI, 1.301–1.770]; P =0.0001). For the prediction of syncope, the area under curve analysis showed similar values when comparing single DC and combined DC with other risk factors ( P =0.1147). From the receiver operator characteristic curves for syncope discrimination, the optimal cutoff value for the DC was 7.12 ms. Conclusions: DC>7.5 ms may serve as a good tool to monitor cardiac vagal activity and discriminate VVS, particularly in those with negative tilt table test.

Spinal cord stimulation (SCS) is a minimally invasive procedure used for a broad spectrum of chronic pain conditions. Unfortunately, complications can occur that may lead to device explantation. The most common reason for explantation is loss of efficacy (LoE). “Salvage therapy” is the conversion from 1 mode of stimulation to another when LoE occurs. Salvage therapy has been described with multiple modes of stimulation. To our knowledge, salvage therapy with high-frequency SCS for LoE with burst SCS has not been previously described. We present a case of salvage therapy utilizing 10 kHz SCS for LoE with a passive recharge burst SCS.

Abstract Purpose: Airway manipulation is a high-risk procedure due to aerosolization of viral particles. This has become of paramount importance during the COVID-19 pandemic in an effort to protect personnel involved in airway management. We designed and tested a copper frame to support a plastic drape to contain aerosols and allow for reduction of risk during airway management. The “CopperHead” frame allows airway management with minimal limitations in a wide range of scenarios including elective and urgent intubations, management of unstable patients, cardiopulmonary resuscitation (CPR), bronchoscopy, and extubation. The frame was made of copper to utilize its inherent antimicrobial and antiviral properties. Intervention and Measurements: We performed multiple simulations to measure FiO2 accumulation underneath the frame and plastic drape. We also performed defibrillations on a mannequin with the apparatus in place to evaluate for safety during times that the device is not removed prior to defibrillation, as indicated. We then deployed the device throughout our hospital and analyzed the resulting data on procedure success and infection rates in both COVID-positive and COVID-negative cohorts.Main Results: The technique is reproducible and allows for airway manipulation in COVID-19 suspected or confirmed patients. The FiO2 under the copper frame and plastic drape increased, but quickly dispersed when the frame was removed. We performed multiple defibrillations with apparatus in place with no adverse events. We showed that with the device in place, there appears to be no hindrance to successful intubation with 94 successful procedures in 74 patients and an 87% (60/69) first-pass intubation rate, and there were no documented clinicians or respiratory therapy infections through exposures to COVID-19 positive patients.Conclusions: The addition of a copper frame to a plastic drape over patients was an effective way to improve the safety and ease of intubation in the COVID-19 pandemic. This device was well received among our clinicians and served to benefit both intubation and extubation of recovered patients.

Background: Acute chest syndrome (ACS) frequently complicates sickle cell disease (SCD) and is a leading cause of hospitalization and mortality. Many factors have been implicated in ACS, including infections, thrombosis, fat and pulmonary emboli. However, a clear etiology is not defined in 50% of the cases and ACS is considered a clinical endpoint for different pathogenic processes (Vichinsky et al 2000). The non-specific nature of ACS makes diagnostic tests challenging, and there are no serum tests clinical used to aid diagnosis. Procalcitonin (PCT) is a prohormone of calcitonin and serum PCT rises within hours of an inflammatory stimulus. PCT has clinical utility as a marker of severe systemic inflammation, infection, and sepsis (Becker et al. 2008). Few studies have evaluated PCT as a biomarker for ACS in patients presenting with vaso-occlusive crises (VOC). Two studies have reported no difference in PCT (Biemond et al. 2018 and Stankovic et al 2011), while one study reported higher PCT between ACS and VOC (Patel et al 2014). Methods: We retrospectively reviewed 106 patients with SCD who presented to the emergency department with fever and painful crises during 2015-2019. The patients were divided into two categories based on discharge diagnoses - patients with VOC only (n=88) and patients with ACS (n=18). Inclusion criteria for both groups were patients with SCD, 17 years and older and PCT measurement on presentation. Exclusion criteria were defined as patients who had received empiric antibiotics prior to PCT testing. Data collected on presentation included genotype, age, gender, complete blood count, PCT, creatinine, total bilirubin and hydroxyurea use. Length of stay was recorded. Data was analyzed between the two groups using descriptive statistics and accounting for unequal variances, withp-value set at 0.05 for significance. Results: Demographics and clinical characteristics are summarized in Table 1 (Figure). The sample included primarily adult males (77%), with about two-thirds on hydroxyurea. Genotype HbSS (73.6%) was most prevalent followed by HbSC (22.6%) and HbSβ (3.8%). The ACS group had a higher percentage of HbSS, lower use of hydroxyurea and higher mean bilirubin. Mean PCT for the ACS group was 0.52 ng/mL (range, 0.05-2.04), compared to 0.31 ng/mL (range, 0.02-6.82) in the VOC group; withp=0.084. ROC analysis showed a PCT&gt;0.5ng/mL had 39% sensitivity and 85% specificity for ACS in this sample. Conclusion: In this sample, PCT on presentation was higher in those with ACS compared to VOC, but this difference did not achieve statistical significance. Further study in a larger population would be useful to evaluate this finding. Disclosures No relevant conflicts of interest to declare.

Introduction: FL is the most common indolent non-Hodgkin lymphoma in the Western world. FL may cause disease-related symptoms, and patients with high-risk disease usually require systemic therapy. BR is commonly used as first-line therapy for high-risk FL, and the addition of bortezomib to a BR backbone has been studied (Evens A et al. Clin Can Res 2020). Little is known about how these therapeutic options impact patients' health-related quality of life (HRQL). To fill this gap, patient-reported outcomes (PROs) were administered to patients enrolled on E2408 to quantify symptom burden and effects of BR versus BVR induction on HRQL. Methods: Patients (n=258) randomized to receive 6 cycles of BR or BVR induction completed PROs assessing neurotoxicity (FACT/GOG-Ntx) at the beginning of each treatment cycle. Additional PROs measuring fatigue (FACT-F), lymphoma-specific concerns (FACT-Lym) and HRQL (Functional Assessment of Cancer Therapy-General; FACT-G) were completed at baseline, mid-treatment (MT; cycle 3/4) and end of induction (EOI; cycle 6). Paired t-test was used to assess PRO score changes from baseline to MT and EOI within BR or BVR group. Two-sample t-test was used to compare change scores between groups at MT and EOI, respectively. Univariate analyses with a linear model identified patient baseline characteristics and clinical factors (age, sex, stage, performance status, # extra nodal sites, FLIPI, GELF, bone marrow involvement, elevated LDH, palpable splenomegaly, B-symptoms, CRIS) associated with PRO change scores from baseline to EOI, adjusting for treatment group. A multivariate model was built with backward variable selection approach for each of the PROs. Results: As shown in Figure 1, compared with baseline, patients randomized to BVR reported significantly worse FACT/GOG-Ntx scores at cycle 4, which continued to end of induction (FACT/GOG-Ntx change scores -2.91 to -3.73; p &lt; 0.001). Neurotoxicity remained stable for patients treated with BR (Ntx change scores -0.02 to -0.55). FACT-Fatigue scores indicated worse fatigue at MT compared to baseline for patients receiving BVR (-2.7, p&lt;0.05), yet they remained stable for BR. FACT-Lym scores were significantly higher at MT (BR: 2.69, p&lt;0.001; BVR: 2.71, p=0.007) and end of induction (BR: 3.32, p&lt;0.001; BVR: 3.55, p&lt;0.001) compared to baseline, signifying a reduction in lymphoma-related symptoms in both arms. FACT-G scores were comparable between treatment arms at each time-point and did not change significantly from baseline to end of induction. Univariate analyses among all patients identified older age and the absence of palpable splenomegaly at baseline as associated with worse FACT-Lym, FACT-Fatigue, and FACT-G change scores, signifying less improvement in lymphoma-related symptoms, fatigue and HRQL from baseline to end of induction (p&lt;0.01). The presence of B-symptoms at baseline was associated with a greater reduction in lymphoma-related symptoms and fatigue from baseline to end of induction (p&lt;0.01). Higher ECOG performance status was only associated with higher FACT-Fatigue change score, suggesting more improvement in fatigue for those with worse performance status at baseline. A multivariate model generated similar results. Conclusions: Despite worse treatment-related symptoms throughout induction, the addition of bortezomib was associated with comparable overall HRQL to those treated with BR. Both treatments were associated with a reduction in lymphoma-related symptoms from baseline to end of induction, likely contributing to stable HRQL throughout treatment despite treatment-related symptoms. Findings also suggest that a subgroup of patients, particularly those who are older, may experience fewer improvements in lymphoma-related symptoms. This underscores the potential need for closer monitoring and clinical management of these patients. Collectively, results are likely to be encouraging for patients experiencing lymphoma-related symptoms, for whom the symptom burden associated with treatment may be worth the trade-off given the potential for improved disease-related symptom control. Disclosures Evens: Merck: Consultancy, Honoraria, Research Funding; Seattle Genetics: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria; MorphoSys: Consultancy, Honoraria; Research To Practice: Honoraria, Speakers Bureau; Epizyme: Consultancy, Honoraria, Research Funding; Mylteni: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Advani:Celgene, Forty Seven, Inc., Genentech/Roche, Janssen Pharmaceutical, Kura, Merck, Millenium, Pharmacyclics, Regeneron, Seattle Genetics: Research Funding; Astra Zeneca, Bayer Healthcare Pharmaceuticals, Cell Medica, Celgene, Genentech/Roche, Gilead, KitePharma, Kyowa, Portola Pharmaceuticals, Sanofi, Seattle Genetics, Takeda: Consultancy. Ansell:Trillium: Research Funding; Affimed: Research Funding; Regeneron: Research Funding; AI Therapeutics: Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Bristol Myers Squibb: Research Funding; ADC Therapeutics: Research Funding. Winter:Norvartis: Consultancy, Other: DSMB; Ariad/Takeda: Consultancy; CVS/Caremark: Consultancy; Delta Fly Pharma: Consultancy; Amgen: Consultancy; Epizyme: Other: DSMB; Merck: Membership on an entity's Board of Directors or advisory committees, Other: advisory board; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Other: advisory board. Cella:FACIT.org: Membership on an entity's Board of Directors or advisory committees, Other: President; Astellas: Consultancy, Honoraria; Pled Pharma: Research Funding; Janssen: Research Funding; Clovis: Research Funding; Alexion: Research Funding; Apellis: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Kiniksa: Consultancy; IDDI: Consultancy; BMS: Consultancy, Research Funding; ASAHI KASEI PHARMA CORP.: Consultancy; Oncoquest: Consultancy; Mei Pharma: Consultancy; Ipsen: Consultancy, Research Funding; Evidera: Consultancy; DSI: Consultancy, Research Funding; BlueNote: Consultancy; Abbvie: Consultancy, Research Funding; PROMIS Health Org: Membership on an entity's Board of Directors or advisory committees, Other. Kahl:ADC Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche Laboratories Inc: Consultancy; Pharmacyclics LLC: Consultancy; Genentech: Consultancy; Celgene Corporation: Consultancy; AstraZeneca Pharmaceuticals LP: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy; Acerta: Consultancy, Research Funding. Wagner:Celgene Inc.: Membership on an entity's Board of Directors or advisory committees; Connect Multiple Myeloma Registry: Membership on an entity's Board of Directors or advisory committees.

Background: Approximately 5000 snake bites are reported in the United States (US) annually with half of these patients being admitted. Crotalinae species are the most numerous; coral and imported exotic snakes cause a smaller number. Snake venoms are highly stable chemically complex mixtures of proteins. Quantity and composition vary with species and geographic location. Although enzymes contribute to the deleterious effects of the venom, the lethal components may be the smaller low molecular-weight polypeptides. Crotalinae envenomation is known to contain thrombin-like glycoproteins that can induce coagulopathy ranging from asymptomatic lab abnormality to disseminated intravascular coagulopathy (DIC) and life-threatening hemorrhage. In certain geographical areas of the United States thrombocytopenia, hypofibrinogenemia and coagulopathy are common hematological abnormalities, and ones that dictate both a reason for treatment with antivenom as well as an important monitor of therapeutic efficacy. Data on hematological abnormalities following envenomation by crotaline species in Northeast Florida/Southwest Georgia has not been reported before. Methods: We conducted a retrospective review of envenomations that presented to the University of Florida at Jacksonville from April 2013 to October 2018. Patients had to be 16 years or older without any pre-existing hematologic disorder or use of anticoagulant medications. Data including Complete Blood Count, Prothrombin Time (PT), activated Partial Thromboplastin Time (aPTT) and Fibrinogen were measured on presentation, and 4 hours after. Crotaline Fab antivenom (CroFab®) administration was noted if done. Adverse events associated with antivenom therapy, recurrence phenomena, delayed onset of symptoms, and performance of fasciotomy were also recorded. Results: Overall, 119 snakebites were evaluated. The majority were identified as Crotalinae - 25 water moccasin, copperhead or cottonmouth (Agkistrodon piscivorus, Agkistrodon contortrix) bites and 34 rattlesnake (Sistrurus miliarius, Crotalus adamanteus) bites. Male sex dominated the sample with most patients middle-aged (Table 1). More than 80% of patients arrived within 6 hours following the bite. Over 60% of patients received crotaline Fab antivenom. Results are presented in Table 2. Around 12% of patients with water moccasin, copperhead or cottonmouth (Agkistrodon piscivorus, Agkistrodon contortrix) bites had coagulopathy on admission. This compares similarly to data from South Carolina previously showing a 10.89% rate following copperhead bites (Qureshi et al. Blood 2010;116(21):4753). The rate of coagulopathy with rattlesnake bites was however much higher in North Florida at 20.6% - compared to 5.26% in the South Carolina series. Rates of DIC or severe hemorrhage were 8% for water moccasin, copperhead or cottonmouth (Agkistrodon piscivorus, Agkistrodon contortrix) bites and 5.9% for rattlesnake (Sistrurus miliarius, Crotalus adamanteus) bites. When hemostatic defects were looked at separately, the most common abnormality induced was PT/aPTT derangement, followed by hypofibrinogenemia and then thrombocytopenia. This pattern was the same as reported in South Carolina. Recurrence phenomena was observed after 4 hours in a number of patients, however the significance of this remains uncertain as most of these patients remained clinically stable without worsening symptoms. Anaphylactic reaction to the antivenom developed in one patient. Conclusions: In this sample from North Florida, deranged PT/aPTT was the most common hematologic abnormality following envenomation, followed by hypofibrinogenemia and a low rate of thrombocytopenia. Similarities with data from South Carolina were noted, although rattlesnake bites had 4 times higher incidence of coagulopathy in North Florida. DIC or severe hemorrhage was a notable toxicity, affecting 6-8% of Crotalinae cases. Hematologic effects of envenomation do seem to vary by geographic areas in the United States and physicians would benefit from local data to better manage these patients. Disclosures No relevant conflicts of interest to declare.

Background Maintenance therapy improves PFS in NDMM pts. Additional active, well-tolerated treatment options that are suitable for long-term administration are required. The international, multicenter, double-blind, placebo-controlled, phase 3 TOURMALINE-MM4 trial (NCT02312258) of the oral PI ixazomib as maintenance therapy post-induction in non-transplant NDMM pts met its primary endpoint of PFS. Ixazomib demonstrated a significant and clinically meaningful benefit vs placebo, with a manageable and well-tolerated toxicity profile. Feasible, tolerable options for long-term therapy are particularly important in this setting, as pts are often elderly and/or frail. We report herein a subgroup analysis of TOURMALINE-MM4 according to age and frailty status. Methods Pts who achieved ≥partial response (PR) after 6-12 months of standard-of-care induction therapy were randomized 3:2 to ixazomib or placebo maintenance for up to 24 months. The sum of 4 components - age (&lt;75 vs 75-80 vs &gt;80 years; score 0 vs 1 vs 2), the Katz Index of Independence in Activities of Daily Living (ADL; &gt;4 vs ≤4, score 0 vs 1), the Lawton Instrumental ADL Scale (&gt;5 vs ≤5, score 0 vs 1), and the Charlson Comorbidity Index (≤1 vs ≥2, score 0 vs 1) - was used to classify pts as fit (total score: 0), unfit (score: 1), or frail (score: ≥2). Analyses of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 and MY20 modules were conducted to evaluate the effects of treatment on QoL within subgroups defined by frailty status and age. Results In the ixazomib (n=425) vs placebo (n=281) arms, there were similar proportions of pts aged &lt;65, 65-74, and ≥75 years and of pts classified as fit, unfit, and frail (Table 1). Baseline disease and treatment characteristics were generally balanced in ixazomib vs placebo pts across the different age and frailty groups, with some numerical differences observed. In pts aged &lt;65 years, higher rates of International Staging System (ISS) stage III disease and fit pts and a lower rate of complete (CR) or very good partial (VGPR) response post-induction were seen (Table 1). Across frailty groups, a higher rate of CR or VGPR was seen in fit pts, a lower rate of ISS stage III disease was seen in unfit pts, and a higher rate of ISS stage III disease and a lower rate of CR or VGPR were seen in frail pts (Table 1). PFS benefit with ixazomib vs placebo was seen across age groups, with hazard ratios (HRs) of 0.576 (95% confidence interval [CI] 0.299-1.108, p=0.095, median 11.0 vs 9.3 months) in pts aged &lt;65 years, 0.615 (95% CI 0.467-0.810, p&lt;0.001, median 17.9 vs 9.3 months) in pts aged 65-74, and 0.740 (95% CI 0.537-1.019, p=0.064, median 16.7 vs 10.2 months) in pts aged ≥75 years. HRs for time to progression (TTP) were similar to those for PFS. PFS benefit with ixazomib vs placebo was also seen across frailty groups (Figure), with similar HRs for TTP. Rates of grade ≥3 treatment-emergent adverse events (TEAEs), serious TEAEs, and discontinuation due to TEAEs were higher or similar with ixazomib vs placebo across age and frailty subgroups (Table 2). Rates were generally somewhat higher in older age groups and in unfit/frail pts in both arms; nevertheless, rates of discontinuation due to TEAEs across groups were &lt;20%, even in pts aged ≥75 years and frail pts (Table 2). With ixazomib, rates of common gastrointestinal TEAEs were similar across age groups; rash and liver impairment appeared less common and peripheral neuropathy more common in older pts (Table 2). Covariate-adjusted changes in QoL subscales from baseline were estimated at each cycle using repeated measures linear mixed models stratified by frailty status. In all frailty groups, the mean changes in each treatment arm were small over time (&lt;10 points on a 0-100 scale) and similar between arms, indicating that continued treatment with ixazomib vs placebo maintenance did not adversely affect pts' QoL. Analyses by age were generally consistent with the results by frailty. Conclusions Ixazomib as post-induction maintenance therapy in non-transplant NDMM pts results in PFS benefits vs placebo regardless of age or frailty status. Ixazomib appeared generally well tolerated across groups, with TEAE rates in both arms generally elevated in elderly/frail vs younger/fit pts. Ixazomib is a feasible and effective maintenance option for prolonging PFS across this heterogeneous pt population. Disclosures Bringhen: Takeda: Consultancy; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria; Amgen: 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; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Vorog:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Labotka:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Wang:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cherepanov:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Cain:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Manne:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment. Dimopoulos:Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Beigene: Honoraria; Amgen: Honoraria. OffLabel Disclosure: Use of the oral proteasome inhibitor ixazomib as maintenance therapy in patients with newly diagnosed multiple myeloma not undergoing stem cell transplantation