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Infections are an important cause of morbidity and mortality in newly diagnosed multiple myeloma (NDMM), but the real-world risk using modern induction regimens such as bortezomib, lenalidomide, and dexamethasone (RVd) is not well described. We performed a retrospective single-center cohort study to identify infections and risk factors in patients treated with first-line RVd from January 2014 to January 2020 and collected demographic and clinical data. Of 144 patients treated with RVd for NDMM, 21 patients (14.5%) experienced a bacterial infection during induction, of which 8 (5.5%) were grade 3 infections despite a low rate of antibiotic prophylaxis use (12%). Grade 3 neutropenia occurred in 11% of patients, 2% had febrile neutropenia and there were no deaths from infection. On multivariable analysis, age, smoking history, diabetes, antibiotic use in the 60 days preceding the start of RVd, and high-risk cytogenetics were associated with higher risk of bacterial infection.

Purpose: Sustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma. The gut microbiome is affected by diet, and in turn can modulate host immunity, for example through production of short-chain fatty acids including butyrate. We hypothesized that dietary factors affect the microbiome (abundance of butyrate-producing bacteria or stool butyrate concentration) and may be associated with multiple myeloma outcomes. Experimental Design: We examined the relationship of dietary factors (via a food frequency questionnaire), stool metabolites (via gas chromatography–mass spectrometry), and the stool microbiome (via 16S sequencing - α-diversity and relative abundance of butyrate-producing bacteria) with sustained MRD negativity (via flow cytometry at two timepoints 1 year apart) in myeloma patients on lenalidomide maintenance. The Healthy Eating Index 2015 score and flavonoid nutrient values were calculated from the food frequency questionnaire. The Wilcoxon rank sum test was used to evaluate associations with two-sided P < 0.05 considered significant. Results: At 3 months, higher stool butyrate concentration (P = 0.037), butyrate producers (P = 0.025), and α-diversity (P = 0.0035) were associated with sustained MRD negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (P = 0.009) and sustained MRD negativity (P = 0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins P = 0.01, flavones P = 0.01, and flavanols P = 0.02). Conclusions: This is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production, and sustained MRD negativity in multiple myeloma, providing rationale to evaluate a prospective dietary intervention.

Supplementary Figure S1. Volcano plot showing the difference in the relative abundance of butyrate producers between sustained MRD negative and MRD positive/non-sustained MRD negative.

Purpose:Sustained minimal residual disease (MRD) negativity is associated with long-term survival in multiple myeloma. The gut microbiome is affected by diet, and in turn can modulate host immunity, for example through production of short-chain fatty acids including butyrate. We hypothesized that dietary factors affect the microbiome (abundance of butyrate-producing bacteria or stool butyrate concentration) and may be associated with multiple myeloma outcomes.Experimental Design:We examined the relationship of dietary factors (via a food frequency questionnaire), stool metabolites (via gas chromatography–mass spectrometry), and the stool microbiome (via 16S sequencing - α-diversity and relative abundance of butyrate-producing bacteria) with sustained MRD negativity (via flow cytometry at two timepoints 1 year apart) in myeloma patients on lenalidomide maintenance. The Healthy Eating Index 2015 score and flavonoid nutrient values were calculated from the food frequency questionnaire. The Wilcoxon rank sum test was used to evaluate associations with two-sided P < 0.05 considered significant.Results:At 3 months, higher stool butyrate concentration (P = 0.037), butyrate producers (P = 0.025), and α-diversity (P = 0.0035) were associated with sustained MRD negativity. Healthier dietary proteins, (from seafood and plants), correlated with butyrate at 3 months (P = 0.009) and sustained MRD negativity (P = 0.05). Consumption of dietary flavonoids, plant nutrients with antioxidant effects, correlated with stool butyrate concentration (anthocyanidins P = 0.01, flavones P = 0.01, and flavanols P = 0.02).Conclusions:This is the first study to demonstrate an association between a plant-based dietary pattern, stool butyrate production, and sustained MRD negativity in multiple myeloma, providing rationale to evaluate a prospective dietary intervention.

Monoclonal immunoglobulin deposition disease (MIDD), often associated with plasma cell dyscrasias, predominantly affects the kidneys. In this disease, hematologic response (HR) to treatment can be reliably assessed by International Myeloma Working Group (IMWG) consensus criteria, while uniform criteria for assessing renal response are lacking. We report a retrospective analysis of renal outcomes among 34 patients with MIDD. With most patients treated with bortezomib and autologous stem cell transplantation, 26 of 28 (94%) achieved very good partial HR or better. We demonstrate that both IMWG (based on estimated glomerular filtration rate, eGFR) and amyloid (based on proteinuria) criteria are needed to capture renal response: among 28 evaluable patients, 6 (21%) had isolated proteinuria, while 13 (46%) had isolated decreased eGFR. Using both criteria, which were concordant in patients with both decreased eGFR and proteinuria, 22 of 28 patients (79%) achieved a renal response, including 2 of 7 discontinuing dialyses. All 6 patients (100%) with isolated proteinuria and 7 of 13 (54%) with isolated decreased eGFR achieved renal response, suggesting that isolated proteinuria is an early manifestation of MIDD associated with reversible renal damage. Baseline eGFR predicted renal response (p = .02 by quartile) and survival (p = .02), while HR (CR vs. non-CR) did not, probably because of high HR rate. With a median follow-up of 110 months, the median overall survival was 136 months (95% CI: 79-NR) and median renal survival had not been reached. Prospective studies using uniform renal response criteria are needed to optimize the management of MIDD.

Chronic lymphocytic leukemia (CLL) is associated with immune dysfunction and an increased risk of melanoma. For patients with metastatic melanoma, immunotherapy with checkpoint blocking antibodies is a standard of care. In patients with concomitant CLL and metastatic melanoma, it is not known whether CLL might influence the antimelanoma efficacy or immune-related toxicities of immune checkpoint blockade. Fifteen patients with locally advanced or metastatic melanoma and a concomitant diagnosis of CLL who received pembrolizumab or ipilimumab with or without nivolumab for the treatment of their melanoma at Memorial Sloan Kettering Cancer Center between January 1, 2010, and January 1, 2017, were retrospectively identified. Clinical characteristics including absolute lymphocyte counts during therapy were recorded along with a response to treatment (objective radiographic response, progression-free survival, and adverse events) for each patient. Of 9 response-evaluable patients treated with ipilimumab, 3 (33%) had a partial response, 1 (11%) had stable disease, and 5 (56%) developed progressive disease. Objective tumor responses were also observed with single-agent therapy pembrolizumab and with combination therapy of nivolumab and ipilimumab. Grade 3 or 4 toxicity was observed in 6 of 15 patients (40%), including diarrhea, transaminitis, rash, and hemolytic anemia. Although our retrospective assessment was limited, there was no evidence that CLL responded to the checkpoint blockade. This case series demonstrates that ipilimumab, pembrolizumab, and combined ipilimumab and nivolumab therapies show clinical activity in patients with melanoma and concomitant CLL, at rates consistent with those previously reported. This population may warrant closer surveillance for hematologic immune-related toxicities such as autoimmune hemolytic anemia.

Daratumumab and elotuzumab have demonstrated improvements in overall response rates (ORR) and progression-free survival (PFS) in relapsed/refractory multiple myeloma (RRMM). There is a lack of comparative clinical trials and an even larger lack of consensus on the optimal integration of these novel agents into the treatment paradigm. Clinical outcomes were compared retrospectively in 37 patients who received daratumumab before elotuzumab (dara-first

Patients with multiple myeloma (MM) who achieve minimal residual disease (MRD) negativity after upfront treatment have superior outcomes compared with those who remain MRD+. Recently, associations have been shown between specific commensal microbes and development of plasma cell disorders. Here, we report the association between intestinal microbiota composition and treatment outcome in MM. Microbiota composition of fecal samples collected from 34 MM patients after induction therapy and at the time of flow cytometry–based bone marrow MRD testing was determined by 16S ribosomal RNA sequencing. We observed a higher relative abundance of Eubacterium hallii in the 16 MRD− patients relative to the 18 MRD+ patients. No association was observed between microbial relative abundance and autologous stem cell transplantation history or MM paraprotein isotype. No differences in microbiota α diversity were observed between MRD− and MRD+ patients. The potential association of microbiota composition with treatment response in MM patients is an important parameter for additional correlative and clinical investigation.

Background Infections remain a common cause of morbidity and mortality following hematopoietic stem cell transplant (HSCT). Pneumocystis jiroveci pneumonia (PJP) is an opportunistic infection that can occur in HSCT patients, although the association is best demonstrated in allogeneic HSCT, occurring less commonly in autologous HSCT. However, reports on PJP incidence, timing of infection, and outcomes among autologous HSCT cohorts are limited. Furthermore, while current guidelines recommend 3-6 months of prophylaxis against PJP following autologous HSCT, the optimal duration and even necessity of prophylaxis is not well established. Patients and Methods We performed a retrospective analysis of all consecutive patients who had autologous HSCT at the University of Michigan Blood and Marrow Transplantation program over a 20-year period from 1/1/2000 through 12/31/2019. The cohort consisted of a total of 2082 patients, 1221 male (58.6%), with median age 56 (range 10 months - 77 years, 91.2% ≥ 18 years). Records were searched for use of PJP prophylaxis over 6-month and 2-year follow-up periods post-HCT to determine rates of prophylaxis and choice of agent. Cases of polymerase-chain reaction (PCR)-confirmed PJP occurring within two years of HSCT were identified. The timing, clinical and laboratory features at diagnosis, use of concurrent immunosuppression, treatment, and outcomes were determined. Results Of the 2082 patients undergoing autologous HCT, 704 patients (33.8%) received PJP prophylaxis in the first 6 months following transplant. Prophylaxis rates varied over time, ranging from 14.6% to 80.0% when calculated by year of transplant (Figure 1). Trimethoprim-sulfamethoxazole (TMP-SMX) was the most used prophylaxis agent (70.3%), followed by inhaled pentamidine (31.8%), with intravenous pentamidine (8.1%), dapsone (7.1%), and atovaquone (2.6%) being used less frequently. There were 9 cases of PJP identified in our cohort, with an incidence of 0.43%. There were 6 males, with median age of 50 (range 34 - 69). Cases occurred a median of 126 days following HSCT (range 65 - 496), with 4 cases occurring after 6 months. None of the patients were on PJP prophylaxis at the time of diagnosis, and only 2 patients had received prophylaxis at any point after transplant. In 8 of 9 cases, patients were receiving concurrent pharmacologic immunosuppression in the form of steroids or maintenance brentuximab (Table 1). All patients presented with symptoms compatible with PJP, most often with fevers, dyspnea, and cough. Diagnosis was made by PCR from bronchoalveolar lavage specimen in 8 cases, and from sputum sample in 1 case. All patients were lymphopenic at the time of diagnosis, with median absolute lymphocyte count of 400 cells/µL (range 200 - 1100). Patients were most often treated with TMP-SMX. Three patients required transfer to the intensive care unit and 2 were intubated. Ultimately, 2 patients died from PJP infection; the remaining 7 recovered (Table 2). Conclusion Our analysis reveals that among a large cohort, incidence of PJP following autologous HSCT is low. This was the case even with relatively modest rates of PJP prophylaxis in the first 6 months following transplant. Most cases of PJP occurred in patients receiving additional immunosuppression and often occurred late following transplant. Figure 1 Figure 1. Disclosures Pianko: Karyopharm: Honoraria.

Immune checkpoint blockade has driven a revolution in modern oncology, and robust drug development of immune checkpoint inhibitors is underway in both solid tumors and hematologic malignancies. High response rates to programmed cell death 1 (PD-1) blockade using nivolumab or pembrolizumab in classical Hodgkin lymphoma (cHL) and several variants of non-Hodgkin lymphoma (NHL) revealed an intrinsic biological sensitivity to this approach, and work is ongoing exploring combinations with immune checkpoint inhibitors in both cHL and NHL. There are also preliminary data suggesting antitumor efficacy of PD-1 inhibitors used in combination with immunomodulatory drugs in multiple myeloma, and effects of novel monoclonal antibody therapies on the tumor microenvironment may lead to synergy with checkpoint blockade. Although immune checkpoint inhibitors are generally well tolerated, clinicians must use caution and remain vigilant when treating patients with these agents in order to identify immune-related toxicities and prevent treatment-related morbidity and mortality. Autologous stem cell transplant is a useful tool for treatment of hematologic malignancies and has potential as a platform for use of immune checkpoint inhibitors. An important safety signal has emerged surrounding the risk of graft-versus-host disease associated with use of PD-1 inhibitors before and after allogeneic stem cell transplant. We aim to discuss the facts known to date in the use of immune checkpoint inhibitors for patients with lymphoid malignancies and our hopes for expanding the benefits of immunotherapy to patients in the future. Clin Cancer Res; 24(5); 1002–10. ©2017 AACR.

Introduction Currently, there are three FDA-approved novel multiple myeloma (MM) oral agents commonly used in clinical practice in the United States: two immunomodulators (lenalidomide [len] and pomalidomide [pom]) and one proteasome inhibitor (ixazomib [ixa]). The financial burden faced by patients with MM on these drugs can be considerable due to increasing long-term survival and extended periods of continuous single agent maintenance or multidrug combination regimens. To better understand the financial burden associated with extended use of these medications, we sought to leverage a real-world, all-claims insurance database to examine the outpatient drug copayments, associated fill patterns, and duration of therapy of these MM oral agents, stratified by insurance type. We hypothesize that copayments associated with oral MM agents will comprise a major portion of the overall drug copayment per patient, and fill patterns and duration of therapy of these medications will vary across patients of different insurance types. Methods We utilized outpatient drug claims derived from the 2014-2018 IBM/Truven MarketScan Commercial, Medicare Advantage, and Medicaid all-claims databases and extracted all outpatient claims from patients who filled at least one prescription (≥28-day duration) for len, pom, or ixa. Annual outpatient medication copayment and number of outpatient scripts were calculated for each patient, both for oral MM agents only and all outpatient prescriptions. Copayments were normalized to the cost per annum. Multivariable linear regression was used to compare outcomes between patients of the three insurance types. Results From 2014-2018, we identified 10,750 patients on len, 2,355 patients on pom, and 794 patients on ixa. These included patients with commercial insurance (53.5%), Medicare Advantage (37.8%), and Medicaid (8.7%). The average adjusted annual copayment per patient of len was $445 for commercial, $480 for Medicare Advantage, and $48 for Medicaid (Table 1). Len copayment comprised of 77-83% of the total outpatient drug copayment per patient. For pom, adjusted copayments were $460 for commercial, $749 for Medicare Advantage, and $128 for Medicaid. Pom copayment comprised 54-90% of the total. For ixa, adjusted copayments were $584 for commercial, $448 for Medicare Advantage and $2 for Medicaid. Ixa copayment comprised 7-48% of the total. Patients with commercial insurance generally filled more scripts for oral MM agents per year (6 len, 4 pom, 5 ixa) compared to those with Medicare Advantage (5 len, 5 pom, 4 ixa) and Medicaid (4 len, 4 pom, 4 ixa) (Table 2). However, patients with commercial insurance filled fewer overall outpatient scripts per year (31-37) compared to Medicare Advantage (35-42) and Medicaid (40-52). Insurance type was associated with the number of scripts filled for len (p Among patients on oral MM therapy for more than one year, insurance type was associated with time on therapy for len (828 days for commercial, 873 days for Medicare Advantage, and 791 days for Medicaid, p=0.0004) (Table 3). However, insurance type was not associated with time on therapy for pom (p=0.83) or ixa (p=0.11). Discussion Our results demonstrate that copayments for oral MM agents comprise the majority of total outpatient drug copayments for patients with MM, suggesting that the out-of-pocket costs of these agents may be a key driver of financial burden. In addition to differences observed in the oral MM drug copayments, insurance type was also associated with the number of scripts filled and time on therapy for patients taking len. Thus, this suggests insurance type is also linked to drug utilization patterns and may indicate a differential financial burden in patients with MM on chronic oral therapy. Reducing the cumulative impact of financial toxicity for patients with MM is an important consideration for prescribers, payors, and health systems to achieve optimal clinical outcomes. Although our current dataset lacks diagnostic and treatment data, further correlative studies incorporating care utilization data, including inpatient admissions and outpatient clinical visits, are in progress. Figure 1 Figure 1. Disclosures Pianko: Karyopharm: Honoraria.

Clinical development of Immune checkpoint inhibitors targeting the programmed cell death 1 (PD-1) pathway has led to clinical benefits for patients with multiple solid tumor and hematologic malignancies and has revolutionized modern oncology. High response rates to PD-1 blockade in patients with classical Hodgkin lymphoma and certain subtypes of non-Hodgkin lymphoma highlight an intrinsic biologic sensitivity to this strategy of treatment. Despite early success of checkpoint inhibitor and immunomodulatory drug combinations in phase II studies in multiple myeloma, safety concerns in patients treated with the combination of immunomodulatory drugs and checkpoint inhibitors in myeloma have stalled drug development in this space. Novel combination approaches exploring PD-1 inhibitors with epigenetic modifiers in leukemia are underway.

Background Daratumumab, a monoclonal antibody used to treat relapsed or refractory multiple myeloma, can interfere with protein electrophoresis and immunofixation assays. False-positive immunofixation results due to daratumumab can cause uncertainty regarding the status of a patient's disease and lead to potential misclassification of their response to therapy. The Hydrashift 2/4 Daratumumab assay (Sebia) was recently cleared by the Food and Drug Administration for resolving daratumumab interference on immunofixation. Here, we evaluate the performance of the Hydrashift assay in multiple myeloma patients receiving treatment with daratumumab-based regimens. Methods Waste serum samples from multiple myeloma patients (n = 40) receiving daratumumab were analyzed by standard immunofixation and the Hydrashift assay. Results from these tests were compared and were evaluated along with pretreatment serum protein electrophoresis and immunofixation results, if available. Results The Hydrashift assay shifted the migration of daratumumab in patient samples. In 27 cases, the patient's M protein was distinguishable from daratumumab by standard immunofixation. In these cases, the Hydrashift assay confirmed that the IgGκ band was daratumumab and helped identify the presence of treatment-related oligoclonal bands. There were 11 instances in which the patient's IgGκ M protein comigrated with daratumumab. In all 11 cases, the Hydrashift assay confirmed the presence of residual M protein. Finally, in 2 patients whose pretreatment immunofixation results were not available, the Hydrashift assay confirmed that the IgGκ band visible on immunofixation was due to daratumumab alone. Conclusions The Hydrashift 2/4 Daratumumab assay is a useful tool to clarify the source of an IgGκ band on immunofixation and allow a patient's M protein to be viewed without interference.

As part of the drug development process, combinations utilizing approved or experimental agents are routinely explored. However, developing a rational framework for prioritizing the investigation o...

Detection of lytic bone lesions is crucial in the workup for multiple myeloma and very often dictates the decision to start treatment. Conventional radiography, despite decades of use, is often insufficient for detection of bone disease in multiple myeloma. Modern imaging techniques such as MRI, PET, and CT offer superior detection of myeloma bone disease and extramedullary manifestations of plasma cell dyscrasias. Novel whole-body low-dose computed tomography (WBLDCT) protocols allow for collection of superior image detail of the skeleton at doses of radiation similar to those used for conventional planar radiography. Several studies have shown that WBLDCT has a superior detection rate for lytic bone lesions compared with whole-body X-ray (WBXR), potentially leading to restaging and changes in therapy. MRI and PET provide imaging data important for assessing disease activity and prognostication. Because of several advantages over WBXR, WBLDCT is already the standard imaging technique for use in patients with multiple myeloma in many European institutions. However, the radiographic skeletal survey or WBXR is still the initial study of choice used to screen for myeloma bone disease in many institutions. In this review, we aim to explore the changing landscape of imaging for myeloma bone disease through use of modern imaging techniques. Clin Cancer Res; 20(23); 5888–97. ©2014 AACR.

Background: Minimal Residual Disease (MRD) was clearly demonstrated as a prognostic marker for prognosis in multiple myeloma and has been integrated into IMWG clinical guidelines as one of the response criteria. There is however no consensus yet when and how to use MRD data in clinical practice throughout treatment course. Daratumumab was approved by FDA in different settings after it had been shown as a highly effective agent with a reasonable safety profile in myeloma treatment. It also showed impressive data to achieve MRD negativity. We plan to use the combination of daratumumab, lenalidomide, and dexamethasone upfront, with the addition of Velcade for consolidation if needed, in newly diagnosed multiple myeloma (NDMM) patients. We propose to use an MRD driven adaptive strategy for decision making in myeloma treatment and use daratumumab-based frontline therapy. Trial Design and Methods: We designed this prospective, single-arm, multi-center, phase 2 trial. The primary objective is to determine the rate of MRD negativity after daratumumab-based induction and consolidation therapy if necessary in both transplant eligible and ineligible NDMM patients. The secondary objective is to describe the overall survival, progression free survival, MRD conversion rate after consolidation, quality of life for patients, safety and tolerability of daratumumab-based combination regimens in both transplant eligible and ineligible patient populations, estimation of a successful stem cell mobilization after receiving daratumumab-based induction therapy. The primary endpoint will be MRD-negativity after six cycles of induction, followed by three cycles of consolidation therapy if MRD is positive after induction. We will seek to establish evidence that the true proportion of patients who can achieve MRD negativity after induction + consolidation (if still MRD+ after induction) is high, which we define as any response rate that is at least 23%. Patients with NDMM meeting IMWG diagnostic criteria are eligible for this trial, regardless of transplant candidacy. Patient will have stem cell collection after induction therapy. We will follow the patients' treatment response using IMWG response criteria including MRD status through induction, consolidation, transplant (if applied) and maintenance. Patient will come off the study if disease progression per IMWG response criteria. We plan for MRD testing by next generation sequencing and flow cytometry. This study will enroll 50 eligible patients. A two-stage design will be conducted, with an interim futility analysis after the primary endpoint is available on the first 20 enrolled patients. We will proceed to a final analysis with all 50 patients if at least 2/20 (10%) of patients achieve MRD negativity after consolidation. This trial is anticipated to be open at four academic centers. Conclusion: This multicenter phase 2 trial will apply a novel clinical trial design with an adaptive strategy to treat newly diagnosed myeloma patients based on MRD results. Therapeutic advance with Daratumumab-based combination regimen as frontline therapy may help myeloma patients to achieve higher rate of MRD negativity. Figure Disclosures Ye: AbbVie: Research Funding; Takeda: Research Funding; Celgene: Research Funding; Onyx: Research Funding; Sanofi: Research Funding; Karyopharm: Research Funding; Janssen: Research Funding; MingSight: Research Funding; Portola Pharmaceuticals: Research Funding. Anderson:Amgen, Janssen, Takeda, Celgene: Consultancy, Speakers Bureau. Lipe:amgen: Research Funding; amgen: Consultancy; Celgene: Consultancy. Talpaz:Samus Therapeutics: Research Funding; Imago BioSciences: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; CTI BioPharma: Research Funding; Constellation: Research Funding; Incyte: Research Funding; Novartis: Research Funding.

Background: Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell dyscrasias in which deposition of immunoglobulin light and/or heavy chains results in organ dysfunction, most commonly affecting the kidneys. MIDD can present with new onset hypertension, hematuria, renal insufficiency and proteinuria. The rarity of MIDD contributes to the uncertainty regarding optimal therapy (typically targeting the clonal plasma cells), and the relationship between hematologic response and renal outcome. We report here the experience at Memorial Sloan Kettering Cancer Center and New York Presbyterian Hospital/Weill Cornell Medical Center. Methods: An electronic query of pathology records was performed to identify patients with a biopsy-proven diagnosis of MIDD. Patients were eligible for inclusion in this analysis if they had received treatment and had been subsequently followed at either institution. A retrospective review of clinical records extracted patients' baseline characteristics and treatment history. Hematologic responses were assessed according to International Myeloma Working Group uniform response criteria (Kumar, S. et al 2016 Lancet Oncol 17(8): e328-346) and renal organ responses were evaluated based on changes in serum creatinine (SCr), and proteinuria, a modification of criteria previously reported (Kourelis, T. V., et al 2016, Am J Hematol 91(11): 1123-1128.; Nasr, S.H. et al. 2009, J Am Soc Nephrol 20(9): 2055-2064. The primary objective was to determine the rate of hematologic response after initial therapy. Secondary objectives included: (i) Estimation of renal response rate; (ii) Identification of risk factors associated with renal response using the Wilcoxon Rank Sum and Fisher's Exact Tests. Results: Among 54 patients identified who were diagnosed and started treatment between 1/1999 and 1/2016, 29 met criteria for inclusion. Baseline characteristics at diagnosis included: Median age of 50 (range, 32-79); 17 (59%) were male; 22 (75%) had hypertension. Renal parameters at diagnosis: median SCr of 2.4 mg/dl (range, 0.4-19), median CrCl 23 ml/min (range, 4-131), median proteinuria 2383.7mg/24h (range 4.7-13,000), nephrotic-range proteinuria syndrome in 13 (45%), hematuria in 4/25 pts (16%; 4 unknown), 7 were on hemodialysis (HD) prior to initiation of therapy, and 26 (90%) patients had monoclonal kappa light chain deposits. Hematologic parameters included median free light chain ratio of 67.9 (2.8-1179.0), detectable M-spike in 11 pts with a mean level of 0.6 g/dL and median bone marrow plasmacytosis of 20% (range, 0-90%). Induction treatment regimens included bortezomib in 18 (62%), lenalidomide in 6 (21%), cyclophosphamide in 8 (28%), and 21 (73%) underwent autologous stem cell transplant (ASCT) during the course of their treatment. Outcomes are shown in Table 1. Hematologic response among the 29 pts at completion of first line therapy included an overall response rate (ORR) of 93% with sCR (N=14, 48%); CR (N=5, 17%), VGPR (N=6, 20%), PR (N=2, 6.9%), Not available (N=2, 7%). Renal response (Table 1) among 29 patients included CR (N=9, 31%), PR (N=14, 48%) and End Stage Renal Disease (ESRD) (N=6, 21%). Among 7 patients on HD at baseline, 3 remained on HD despite treatment, while 4 stopped HD after treatment, 2 as a result of the treatment and 2 after renal transplant. 3 patients progressed to ESRD and required HD during treatment. Baseline beta-2 microglobulin (B2M), SCr, and eGFR at diagnosis were factors associated with renal response (p Conclusions: In this cohort, we observed a high rate of hematologic response (65.5% reaching CR) to upfront treatment regimens. A majority of patients received bortezomib-based regimens and ASCT. We observed a large proportion of patients whose renal impairment from MIDD improved significantly after receiving therapy directed at the underlying clonal neoplasm, with 75.8% reaching PR or better, nearly a third of patients achieving a renal CR, and 2/7 patients on HD at diagnosis discontinuing HD after treatment. Our experience presented here serves to inform the treatment approach of patients with MIDD. Given the scarcity of outcome data in MIDD, especially in the era of novel anti-myeloma therapy, prospective studies to optimize the management of these patients are needed. Disclosures Rossi: Celgene: Consultancy. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Korde:Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding. Lesokhin:Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Janssen: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hassoun:Oncopeptides AB: Research Funding.

Background: Multiple myeloma (MM) patients who achieve minimal residual disease (MRD) negative status after upfront treatment have prolonged progression-free and overall survival compared with those who remain MRD(+) (Landgren CO, Devlin SM et al. Bone Marrow Transplant. 2016;51(12):1565-8). Commensal intestinal microbial composition has been associated with treatment outcomes in cancer patients. We sought to evaluate whether the composition of the intestinal microbiota is associated with MRD status in patients with MM. Methods: Stool samples were collected prospectively from 34 patients after completion of upfront therapy for MM at the time of MRD testing. MRD was assessed with next-generation flow cytometry of bone marrow aspirates (sensitivity 10-5). Microbial analysis was performed via sequencing of 16S rRNA V4-V5 regions using the Illumina MiSeq platform and sequence data was analyzed using UPARSE (Edgar RC, Nature Methods 2013;10(10):996-8). The linear discriminant effect size method (LEfSe) (Segata N et al. Genome Biol. 2011;12(6):R60.) was used to compare detected clades among all groups and evaluate for associations with outcomes, using MRD as class and autologous stem cell transplant (ASCT) as subclass. Alpha diversity was calculated by the Inverse Simpson index and differential relative abundance were calculated using the phyloseq package and compared using the Wilcoxon rank sum test on the R statistical computing platform. Results: Among 34 patients evaluable for microbiota composition and MRD status, the median age was 62.5 years and 16 (47.1%) were MRD(-) at time of stool collection. 24 (70.6%) were treated with carfilzomib, lenalidomide, and dexamethasone as induction therapy (MRD(-): 14 (87.5%), MRD(+):10 (55.5%). 4 (28.5%) MRD(-) patients had autologous stem cell transplant(ASCT), compared with 10 (55.5%) who were MRD(+). In the cohort's samples, we observed 19 phyla, 315 genera, 654 species, and 1549 operational taxonomic units (OTUs). There was no significant difference in alpha diversity between MRD(-) (median 12.24, IQR = 8.76-13.98) and MRD(+) patients (median 12.44, IQR = 8.36 -16.23), p=0.6 by Wilcoxon rank sum test. A positive association with MRD negativity was noted with two butyrate-producing organisms, Eubacterium hallii (p=0.001) and Faecalibacterium prausnitzii (p= 0.006). To further evaluate these relationships, we performed a differential abundance analysis of these selected taxa in MRD(+) and MRD(-) patients at the genus and species level. The relative abundance of the genera Eubacterium and Faecalibacterium were higher in fecal samples from MRD(-) patients than MRD(+) patients (Eubacterium MRD(-): median 4.51% (IQR = 2.83 - 7.32%) vs. MRD(+): median 3.07% (IQR = 1.35 - 3.87%), p=0.0326; Faecalibacterium MRD(-): median 1.68% (IQR = 0.69 - 7.48%) vs. MRD(+): median 0.003% (IQR = 0 - 3.19%), p=0.022. The relative abundance of both species of interest were higher in MRD(-) patients than in MRD(+) patients: E. hallii MRD(-): median 2.67% (IQR = 2.11 - 3.98%) vs. MRD(+): median 1.01% (IQR = 0 - 2.16%), p=0.001; F. prausnitzii MRD(-): median 1.43% (IQR = 0.53 - 7.28%) vs. MRD(+): median 0.3%, (IQR = 0 - 2.54%), p=0.022. Other species of Eubacterium and Faecalibacterium were not significantly differentially abundant between the two groups. Conclusions: Intestinal microbiota containing several butyrate-producing anaerobes appear to be associated with MRD-negativity in patients with myeloma, with higher relative abundance of Eubacterium hallii and Faecalibacterium prausnitzii in MRD(-) patients compared with MRD(+) patients. Butyrate and other short-chain fatty acids are biologically active metabolites formed during microbial fermentation of dietary or host-derived carbohydrates, which supply the host with energy and also modulate immunity, including exerting anti-inflammatory functions. Microbes of the genus Eubacterium have been associated with reduced risk of relapse in several hematologic cancers after allogeneic hematopoietic cell transplantation, including MM (Peled JU, Devlin SM et al. J Clin Oncol 2017;35(15):1650-9). This is first study to our knowledge to suggest an association between gut microbiota and MRD status in patients with myeloma and supports further investigation of a potential role for intestinal microbiota in the natural history and treatment of myeloma. Disclosures Peled: Seres Therapeutics: Research Funding. Landgren:Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Lesokhin:Squibb: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Janssen: Research Funding.

We recently showed that acute oxidant-related lung injury (ALI) in rats after application of 2-chloroethyl ethyl sulfide (CEES) is attenuated by the airway instillation of antioxidants. We investigated whether intratracheal administration of antioxidant-containing liposomes immediately after instillation of CEES would attenuate short-term as well as long-term (fibrotic) effects of CEES-induced lung injury. In the acute injury model (4 h after injury), N-acetylcysteine (NAC)-containing liposomes were protective and reduced to baseline levels both the lung permeability index and the appearance of proinflammatory mediators in bronchoalveolar lavage fluids from CEES-exposed lungs. Similar results were obtained when rat alveolar macrophages were incubated in vitro with either CEES or lipopolysaccharide in the presence of NAC-liposomes. When lung fibrosis 3 weeks after CEES was quantitated by using hydroxyproline content, liposomes containing NAC or NAC + glutathione had no effects, but liposomes containing alpha/gamma-tocopherol alone or with NAC significantly suppressed the increase in lung hydroxyproline. The data demonstrate that delivery of antioxidants via liposomes to CEES-injured lungs is, depending on liposomal content, protective against ALI, prevents the appearance of proinflammatory mediators in bronchoalveolar fluids, and suppresses progressive fibrosis. Accordingly, the liposomal strategy may be therapeutically useful in CEES-induced lung injury in humans.

We previously reported that generation of the anaphylatoxin C5a is linked to the development of cardiac dysfunction in sepsis due to C5a interaction with its receptor (C5aR) on cardiomyocytes. Burn injury involves inflammatory mechanisms that can lead to C5a generation as well. In this study, we investigated the effects of C5a blockade on burn-induced cardiac dysfunction. Using a standardized rat model of full thickness scald injury, left ventricular pressures were recorded in vivo followed by in vitro assessment of sarcomere contraction of single cardiomyocytes. Left ventricular pressures in vivo and cardiomyocyte sarcomere contractility in vitro were significantly reduced following burn injury. In the presence of anti-C5a Ab, these defects were greatly attenuated 1, 6, and 12 h after burn injury and completely abolished 24 h after burn. In vitro incubation of cardiomyocytes with bacterial LPS accentuated the impaired contractility, which was partially prevented in cardiomyocytes from burned rats that had received an anti-C5a Ab. Based on Western blot analyses, real-time PCR, and immunostaining of left ventricular heart tissue, there was a significant increase in cardiomyocyte expression of C5aR after burn injury. In conclusion, an in vivo blockade of C5a attenuates burn-induced cardiac dysfunction. Further deterioration of contractility due to the exposure of cardiomyocytes to LPS was partially prevented by C5a-blockade. These results suggest a linkage between C5a and burn-induced cardiac dysfunction and a possible contribution of LPS to these events.

The current studies demonstrate protective and harmful effects of neutrophils (PMN) during experimental sepsis after cecal ligation and puncture (CLP). It is known that CLP induces signaling defects in blood PMN. When PMN were depleted 12 h after CLP, there were dramatic reductions in levels of bacteremia, evidence for reduced liver and renal dysfunction, sharp reductions in serum levels of cytokines (IL-1beta, IL-6, IL-10, TNF-alpha, and IL-2), and improved survival. In contrast, PMN depletion before CLP resulted in substantial increases in bacteremia and no evidence for attenuation of liver and renal failure dysfunction. These data suggest that at the onset of sepsis, PMN are important in regulating the levels of bacteremia, whereas after the onset of sepsis, as they lose innate immune functions, their presence is associated with higher levels of bacteremia and intensified organ dysfunction.

Immune checkpoint blockade has revolutionized the treatment of cancer, with impressive responses seen in a broad variety of tumor types. Blockade of immune checkpoints and immune signaling antibodies has shown promise in multiple types of hematologic malignancies (HMs), with dramatic single agent responses for pembrolizumab and nivolumab in Hodgkin lymphoma (HL). In this review, we outline the current state of immune checkpoint blockade drug development in HMs, and discuss mechanisms of activity and resistance, and highlight potential targets in the immune tumor microenvironment (TME). Blockade of T-cell checkpoint molecules PD-1/PD-L1 and CTLA-4 are the most clinically mature of the immune checkpoint strategies. Novel and upcoming strategies for immune checkpoint blockade drug development in HMs using innovative combinations to modulate immunologic targets shows significant promise as a way to expand the number of patients with blood cancers who could benefit from immunotherapy.

Background Antigenic variation is an effective way by which viruses evade host immune defense leading to viral persistence. Little is known about the inhibitory mechanisms of viral variants on CD4 T cell functions. Results Using sythetic peptides of a HLA-DRB1*15-restricted CD4 epitope derived from the non-structural (NS) 3 protein of hepatitis C virus (HCV) and its antigenic variants and the peripheral blood mononuclear cells (PBMC) from six HLA-DRB1*15-positive patients chronically infected with HCV and 3 healthy subjects, the in vitro immune responses and the phenotypes of CD4+CD25+ cells of chronic HCV infection were investigated. The variants resulting from single or double amino acid substitutions at the center of the core region of the Th1 peptide not only induce failed T cell activation but also simultaneously up-regulate inhibitory IL-10, CD25-TGF-β+ Th3 and CD4+IL-10+ Tr1 cells. In contrast, other variants promote differentiation of CD25+TGF-β+ Th3 suppressors that attenuate T cell proliferation. Conclusions Naturally occuring HCV antigenic mutants of a CD4 epitope can shift a protective peripheral Th1 immune response into an inhibitory Th3 and/or Tr1 response. The modulation of antigenic variants on CD4 response is efficient and extensive, and is likely critical in viral persistence in HCV infection.