Proteasome inhibitors bortezomib, carfilzomib and ixazomib (approved by the US Food and Drug Administration [FDA]) induce remissions in patients with multiple myeloma (MM), but most patients eventually become resistant. MM and other hematologic malignancies express ubiquitous constitutive proteasomes and lymphoid tissue–specific immunoproteasomes; immunoproteasome expression is increased in resistant patients. Immunoproteasomes contain 3 distinct pairs of active sites, β5i, β1i, and β2i, which are different from their constitutive β5c, β1c, and β2c counterparts. Bortezomib and carfilzomib block β5c and β5i sites. We report here that pharmacologically relevant concentrations of β5i-specific inhibitor ONX-0914 show cytotoxicity in MM cell lines similar to that of carfilzomib and bortezomib. In addition, increasing immunoproteasome expression by interferon-γ increases sensitivity to ONX-0914 but not to carfilzomib. LU-102, an inhibitor of β2 sites, dramatically sensitizes MM cell lines and primary cells to ONX-0914. ONX-0914 synergizes with all FDA-approved proteasome inhibitors in MM in vitro and in vivo. Thus, immunoproteasome inhibitors, currently in clinical trials for the treatment of autoimmune diseases, should also be considered for the treatment of MM.

e18227 Background: Streptococcus pneumoniae remains a leading cause of serious illness, including bacteremia, meningitis, and pneumonia among adults in the United States. Approximately 10% of all patients with invasive pneumococcal disease die of their illness, but case-fatality rates are higher for immunocompromised adults including cancer patients. Current Center for Disease Control (CDC) guidelines recommend routine use of 13-valent (Prevnar 13) and 23-valent (Pneumovax 23) pneumococcal vaccines (PV) for immunocompromised patients. We conducted a quality improvement (QI) project utilizing our electronic medical record (EMR) system to improve PV compliance (PVC) rates in our patients. Methods: We created automatic reminders called best practice alerts (BPA) and linked them to a smart order set within our EMR that appeared upon opening patient charts. The smart set ordered the correct vaccine in sequence based on CDC guidelines. From August 2015- January 2017, we implemented this BPA for one of six hematology providers and the remaining providers were provided with verbal guidelines and reminders to administer PV to their patients. Results: At baseline only 22% of 3000 hematology patients within the practice had received PV. The pilot provider with the BPA linked to a smart order set within the EMR improved PVC within his patients from 23% to 66%. Providers who were just given verbal guidelines improved PVC from an average of 22% to 45%. The difference in the improvement between the pilot provider and the reference group is 21% (p < 0.001). Conclusions: In an EMR era, we took advantage of the tools within our system to improve PVC rates. BPA linked to a smart order set within the EMR provided better means of improving PVC than verbal prompts in high-risk immunocompromised patients. Additionally, the increase in PVC throughout the hematology practice is due to primary care providers using similar reminders within the same EMR. The PV BPA will be conducted as a standard of care in our clinic and will be expanded to oncology patients as well.

The prevalence of EGFR mutations in this population of NSCLC patients was 39.6% with exon 19 mutation being the most common. The observed benefit of addition of chemotherapy over TKI in EGFR mutation-positive group raises the question, can we offer the therapy of chemotherapy-TKI combination to EGFR mutation-positive lung cancer patients as shown in the present study.

The formation of deoxyhemoglobin S (deoxy-Hb S) polymers is the key triggering event for the complex pathophysiologic manifestations of sickle cell anemia (SCA). This polymer formation is associated with a marked right-shifted oxyhemoglobin dissociation curve (decreased affinity, increased P50), which results in a decrease in arterial oxygen saturation (SaO2). There is a delay period (“delay time”) from the formation of deoxy-Hb S to polymerization that is markedly sensitive (to the power of 30–40) to the concentration and solubility changes of deoxy-Hb S. Deoxy-Hb S polymer formation leads to sickle cell vaso-occlusion, a unique characteristic of SCA. This theoretical study, which views SCA as a disease of oxygen transport, provides a novel framework to suggest that a small to modest increase in cardiac index (by decreasing the P50 and thus increasing the SaO2) could change the distribution of the delay times (sec) such that the balance between occlusion and opening of microcirculatory vessels is shifted favoring the opening of these vessels, therefore disfavoring vaso-occlusion. Our approach integrates a mathematical model of oxygen transport in SCA with: (1) the expression relating the solubility of deoxy-Hb S to SaO2, and (2) the kinetic expression relating the delay time to the solubility of deoxy-Hb S.