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Salvage autologous stem cell transplant (sASCT) may be associated with improved survival in multiple myeloma (MM) and is an option for patients with long time to relapse (TTR) after initial Autologous transplant (ASCT1). Due to potential mobilization failure after maintenance therapy (MT), adequate peripheral blood progenitor cells (PBPC) are frequently collected for later sASCT. Evaluate utilization of stored PBPC in MM. Provide a cost analysis of collecting and storing PBPC for sASCT. Determine utilization of sASCT in those eligible who had a prolonged TTR. We included MM patients who received ASCT1 at our institution between 2009 and 2016. Extra day of collection (EDC) was defined as additional collection of ≥2 × 106 cells/kg PBPC for a second transplant. TTR was calculated as months from ASCT1 to relapse. Eligibility for sASCT was defined as TTR ≥18 months without MT or ≥36 months on MT. Patients who underwent tandem transplant (tASCT) (defined as two transplants within 6 months) were excluded from relapse analysis. Patients with inadequate relapse data defined as death or lost to follow up (LTFU) at ≤36 months prior to relapse, or ≤6 months follow up after relapse were excluded. Costs were obtained from the institution charge master. Descriptive statistics were calculated for the final cost benefit analysis. 154 MM patients received ASCT1 from 2009-2016. Median age was 59 years. Median follow up was 151 months. Median TTR was 20 months. 58% were male. Ethnicity was 76% Caucasian and 24% Black. 62% had IgG MM subtype, 23% IgA MM and 15% other. Majority (95%) were European Cooperative Oncology Group (ECOG) 0 or 1. 13% had high risk cytogenetics. 53% received MT. 137(89%) had PBSC stored for sASCT. 3 were used for sASCT and 10 for tASCT. 124 (90.5%) did not use stored cells. 54 (39%) met collection targets for two transplants in single collection while 83 (%) required ≥1 EDC with cumulative 108 EDC. (Figure 1) Cumulative cost savings for plerixafor use, cell collection, processing, analysis and storage was estimated at $2,252,244. (Figure 2). Total 60 doses of plerixafor were used for EDC. (31 patients with 1EDC, 10 with 2EDC and 3 with 3 EDC). 97 patients were studied for relapses. 54 (77.5%) relapsed. 5 deaths and 8 LTFU occurred within ≤6 months of relapse. 42 patients were further analyzed. 25 of them met criteria for sASCT based on TTR and only 2 received sASCT.1 patient with sASCT did not have MT data and was excluded. (Figure 3) Only 25% (24/98) patients who underwent ASCT1 were eligible for sASCT. Only 2% (2/98) received sASCT. Collecting and storing PBPC for sASCT is associated with high cost, but overall utilization at our institution is low. Our findings should be compared against practices at other institutions to help develop guidelines for selection of subset of MM where this practice may be of higher value. [ABSTRACT FROM AUTHOR]

• Microbiome composition present at pretransplantation baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and neutropenic fever, and with the rate of neutrophil engraftment. • The microbial communities present at count nadir are associated with regimen-related gastrointestinal toxicities observed with high-dose melphalan. • Although bacteriome diversity largely recovers within 1 month after transplantation, recovery of oral and gastrointestinal mycobiome diversity takes longer to recover. Microbiome dysbiosis has been associated with adverse outcomes of hematopoietic cell transplantation (HCT). We hypothesized that exposure to high-dose melphalan and antimicrobials in patients undergoing autologous HCT for plasma cell disorders results in oral and gastrointestinal microbial dysbiosis, which in turn is associated with regimen-related toxicities. We conducted a prospective study describing the longitudinal changes in oral and gastrointestinal bacteriome and mycobiome in this patient population. Our findings show that microbiome composition present at baseline is associated with the incidence and severity of post-transplantation nausea, vomiting, and culture-negative neutropenic fever, as well as with the rate of neutrophil engraftment. We also have evidence of an association between the microbial communities at count nadir and the development of regimen-related gastrointestinal toxicities commonly observed after exposure to high-dose melphalan. Although bacteriome diversity largely recovers within 1 month after transplantation, we observed a continuous decrease in oral and gastrointestinal mycobiome diversity, suggesting that the mycobiome requires a longer time to recover compared with the bacteriome. [ABSTRACT FROM AUTHOR]

Highlights • The authors report a comparison of 3 contemporaneous staging systems for newly diagnosed multiple myeloma patients undergoing autologous hematopoietic cell transplantation using the Center for International Blood and Marrow Transplant Research database. • The Revised International Staging System is the most optimal staging system. • The authors recommend that serum lactate dehydrogenase and cytogenetic data be performed on every multiple myeloma patient at diagnosis to allow accurate prognostication. Abstract The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (N = 628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014). Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P <.001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic cell transplant (HCT) is frequently used to treat Multiple Myeloma (MM). Metabolic abnormalities have been reported in patients (pts) undergoing this modality of therapy contributing to catheter requirement and prolonged hospital admission. Incidence and timing of electrolyte imbalances have not thoroughly been investigated. Methods All consecutive MM pts underwent autologous stem cell transplant from Jan 2012 to July 2016 were included. Patient charts were reviewed for the laboratory results of the first four weeks following HCT. Calcium level was corrected for the albumin level. Time to nadir of these abnormalities was recorded as days after stem cell infusion. engraftment speed (ES) was calculated as the period between the first rise in absolute neutrophil count (ANC) and the full engraftment defined as the first day of ANC>500 for three consecutive days. To define impact of oral intake on the electrolyte drop we assess degree of oral mucositis and nauseas using CTCAE v4.0. Results The study included 118 MM pts received transplant. Median age was 60.9 years old (range: 34-78), 65 pts were male (55%) and the rest female. Ninety pts were Caucasian (76%) and 20 were African-American (19%). Eighty two pts had IgG (69%), 24 IgA (21%) and 11 (9%) had light chain myeloma. Sixty pts (51%) achieved Very Good Partial Response, 29 pts (24%) Partial Response and 25 pts (21%) Complete Response before HCT. Twenty pts (22%) were on Lasix, 62 pts (52%) were on PPI, 3 pts (2%) on H2 blocker at the time of HCT. Conditioning regimen included Melphalan 200 and 140 mg/m2 in 108 pts (91%) and 10 pts (9%), respectively, with pre-melphalan amifostine infusion for all pts. Filgrastim daily started on the day after stem cell infusion. The pre-SCT and post-SCT nadir values are listed in Table-1. Median ES was 2 days (range: 0-5) and 40 pts (36%) had ES<2 days. The engraftment occurred at median of 10 days, standard deviation (SD): 1.50 days, after HCT. The median time-to-nadir for both phosphorus and potassium was 10 days, SD: 3.10 days and 4.28 days for phosphorous and potassium, respectively. The drop in P was statistically higher in the group with ES<2 days in comparison to the group with ES ≥ 2 days (median: 1.4 vs. 0.9 mg/dL, p-value: 0.000) as well as the drop in potassium (median: 1.1 vs. 0.7 mmol/L, p-value: 0.039). There was no difference in the calcium or Magnesium drop between two groups based on ES (Figure-1). There was no statistically significant difference between the drop in phosphorus and potassium based on severity of nausea or oral mucositis (Figure-2 and -3). Conclusion Here we defined a correlation between magnitude of the drop in potassium and phosphorous and a steep rise in neutrophil counts around the engraftment period. It can indicate the "genesis syndrome", a massive transfer of electrolytes into rapidly proliferating cells that was described in high grade lymphoma and leukemia before. [ABSTRACT FROM AUTHOR]

Allogeneic transplant (alloHCT) is a curative therapy for patients with acute lymphocytic leukemia (ALL). The curative potential of alloHCT is hampered by relapse, which is the major cause of treatment failure. Overall, relapse rates for these patients are in the range of 30% to 50% with the majority of these relapses occurring within the first year after alloHCT. Currently, there is no standard post-transplant therapy for patients with ALL. Inotuzumab ozogamicin (INO) is a CD22 monoclonal antibody bound to calicheamicin which has been shown to have significant activity against relapsed ALL. We hypothesize that low dose post-alloHCT maintenance therapy of INO will be safe and will reduce relapse rates after alloHCT for ALL. Eligibility included patients aged 16-75 who have undergone alloHCT for CD22+ALL, have a high risk for relapse, have adequate graft and organ function, are between day 40 and 100 post-transplant, do not have active grade III/IV GVHD or any active GVHD of the liver, and have no history of veno-occlusive disease (VOD). The primary objective of this phase I clinical trial is to define a post alloHCT maximum tolerated dose (MTD) of INO. Secondary objectives include describing the safety profile of INO post-alloHCT, determining the rate of VOD, disease free survival (DFS) and overall survival (OS) at 1 year post alloHCT. The trial design is a 3+3 model. The study treatment consists of a total of four 28 day cycles of INO starting at dose level 0 (0.3mg/m2) given on day 1. Dose limiting toxicities (DLT) include VOD, prolonged cytopenia (more than 28 days), and death. If there are no DLTs experienced in a cohort, patients may be enrolled in the next highest dose level (Table 1). As of October 1st, 2019, 9 patients have been treated. One patient went off treatment after 1 cycle of INO (patient choice), two went off treatment after 3 cycles of INO (patient choice and physician choice) and one experienced a DLT due to prolonged thrombocytopenia. We have completed 1 year post-transplant follow up on 5 patients. All patients are alive and in CR. No patients experienced VOD. Significant side effects include thrombocytopenia and neutropenia. The percentage of any aGVHD is 62.5% and the rate of grade III/IV aGVHD is 0%. The percentage of any cGVHD is 42.8%. Patient characteristics are described below (Table 2). In this phase 1 study, INO at doses of 0.3 and 0.4mg/m2 was well tolerated. Thrombocytopenia may be the dose limiting toxicity. The absence of disease recurrence in this small cohort of high risk ALL patients is very promising. [ABSTRACT FROM AUTHOR]

Patients (pts) with rapidly progressive lymphoma and urgent need for therapy have worse prognosis and may not be able to receive CAR-T cells. Decreasing apheresis to infusion time can make CAR-T cells available to this patient population. We present the results of a phase I trial using rapid on-site CAR-T manufacture for relapsed/refractory B cell non Hodgkin lymphoma (NHL). Adult pts with CD19+ B NHL who failed ≥ 2 lines of therapy were enrolled. Autologous T cells were transduced with a lentiviral vector (Lentigen Technology, Inc) encoding antiCD19 binding motif, CD8 linker and TNFRS19 transmembrane region, and 4-lBB/CD3z costimulatory domains. GMP compliant manufacture was done using CliniMACS Prodigy, in a 12 day culture. Dose escalation was done using 3+3 design, with 3 dose levels (0.5, 1 and 2 × 106 CAR-T cells/kg). Lymphodepletion was done with cyclophosphamide (60mg/kg × 1) and fludarabine (25mg/m2/d × 3). As of September 30, 2019, 14 pts were enrolled and treated. Table 1 lists baseline characteristics. 12 pts had refractory NHL, 6 had bulky disease and 9 had symptomatic disease at the time of lymphocyte collection. CAR-T cell product manufacture was successful in all pts. Median transduction rate was 48% [range 29-62] with median culture expansion of 41-fold [range 30-79]. All pts received their infusion of antiCD19 CAR-T cells. CAR-T cell doses were 0.5 × 106/kg (n = 4) and 1 × 106/kg (n = 10). Median apheresis to infusion time was 13 days [range 13–20]. CAR-T persistence, based on vector sequence, peaked in peripheral blood MNCs between days 14-21. All evaluable subjects had persistent CAR-Ts on PCR measurements done on days 30, 60 and 90. CAR-T cell dose did not have an impact in the time to peak in vivo CAR-T cell expansion or in the rate of CAR-T cell persistence (fig 1). Six pts experienced CRS. Five pts had grade 1 – 2 CRS and 1 pt died on day 8 due to CRS. Two pts presented grade 4 CRES, resolved after corticosteroids. No other grade ≥3 non-hematologic toxicity was observed. The most common non – hematologic toxicity was fatigue (n=7). Hematologic toxicity was common, with grade ≥ 3 neutropenia observed in all pts. Among 12 evaluable pts, 8 have achieved complete response (CR) and two had partial response (PR). Two pts did not respond. The CR rate was 67% and overall response rate was 83%. Three pts have died, causes of death include progressive disease (n=2) and CRS (n=1). After a median follow up 4.5 months (range 1 – 14) all responding pts are alive; 1 pt relapsed 6 months after treatment with CD19+ disease and entered CR after antiCD19 antibody drug immunoconjugate. AntiCD19 CAR-T cells with TNFRS19 transmembrane domain have potent clinical activity. The short manufacture times achieved by local CAR-T cell manufacture enables treatment of a very high risk NHL population that would otherwise not be able to receive CAR-T products due to rapidly progressive disease. [ABSTRACT FROM AUTHOR]

Hematopoietic cell transplantation (HCT)-specific comorbidity index (Sorror et al. Blood 2005) is highly recommended by National Marrow Donor Program as a risk assessment tool before HCT. Prior malignancies has one of the highest weighted score of 3 in this risk model. The isolated prognostic value of prior malignancies has not been evaluated in Multiple Myeloma (MM) patients (pts) who underwent autologous HCT (AHCT) in large databases. We hereby used national cancer database (NCDB) to evaluate this. NCDB covers more than 70% of newly diagnosed cancer pts in the U.S. We reviewed NCDB, using ICD-O code of 9732, to identify pts who were diagnosed with MM between 2010 and 2014, underwent systemic treatment within 90 days of the diagnosis, and subsequently AHCT. Prior malignancy was not incorporated into Charlson comorbidity index at NCDB and reported separately. Average annual transplant volume of a cancer center for MM is calculated among pts who met the inclusion criteria. Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Cox hazard analysis was performed to identify independent predictors of OS. We reviewed 12,427 pts and included 4358 pts who met inclusion criteria. Of which, 2481 (57%) were male, 693 (16%) were black, and 412 (10%) had at least one malignancies prior to MM. Median age at the diagnosis and time to initiation of systemic treatment after the diagnosis were 60 years (range: 25 – 80) and 17 days (range: 1 – 90), respectively. The Charlson comorbidity index was 0, 1, and ≥2 for 3646 (84%), 558 (13%), 154 (3%) pts, respectively. Durie-Salmon stage (DSS) at diagnosis was 1, 2, and 3 for 562 (13%), 1040 (24%), 2756 (63%) pts, respectively. Patient and treatment characteristics are compared between prior and no prior malignancy cohorts in table 1. Median follow-up time of pts was 36 months. Five-year OS of MM pts with and without prior malignancies was 75.6% (95% CI: 69.6 – 82.2) and 73.9% (95% CI: 71.6 – 76.2), respectively (p = 0.7) (Figure 1A). On multivariable analysis, each 10-year increase in age (HR 1.14, 95% CI: 1.02 – 1.26, p = 0.017), each 1 increase in comorbidity index (HR 1.24, 95% CI: 1.08 – 1.42, p = 0.002) and year of MM diagnosis (HR 1.15, 95% CI: 1.06 – 1.24, p = 0.0008), DSS 3 vs 1 or 2 (HR 1.38, 95% CI: 1.16 – 1.64, p = 0.0002), immunotherapy prior to AHCT (HR 0.72, 95% CI: 0.61 – 0.86, p = 0.0001), and each 10 increase in annual AHCT volume of a cancer center for MM (HR 0.98, 95% CI: 0.97 – 0.99, p = 0.016) were independent predictors of OS (Table 2). In this large cohort analysis, prior malignancy was not a predictor of OS for MM pts who underwent AHCT. The role of prior malignancies in defining "transplant eligibility" requires future evaluation and the weighted value of this item in the comorbidity index should be considered for downward revision. [ABSTRACT FROM AUTHOR]

Anti-CD19 chimeric antigen receptor T (CAR-T) cells have demonstrated activity against relapsed and refractory aggressive lymphomas. Cytokine release syndrome (CRS) is a well-known complication of CAR-T cell therapy. Tocilizumab, a humanized monoclonal antibody targeting the interleukin 6 receptor, is approved for treatment of CRS. Our institutional standard has been recently modified to prescribe tocilizumab prophylaxis prior to CAR-T cell infusion. We present a retrospective review of the outcomes of subjects treated with and without prophylactic tocilizumab (PT). Relapsed / refractory (r/r) lymphoma treated with anti-CD19 CAR-T cells at our institution were included. Baseline demographic and clinical characteristics, as well as laboratory results were obtained from our Hematologic Malignancies and Stem Cell Therapy Database. Prior to institution of prophylactic tocilizumab, patients received this agent only if they presented evidence of CRS grade 2 or higher. In May 2019, our institutional practice changed to provide PT 8mg/kg, 1 hour prior to infusion of CAR-T cell product. CRS was measured according to the ASTCT Consensus Grading. Positron Emission Tests (PET) scans were done to assess response on Day 30. CART cell vector Persistence was measured using PCR and was done at different time points including Day 30. Fourteen relapsed / refractory lymphoma pts were treated with antiCD19 CAR-T cells; 6 pts received prophylactic tocilizumab. Median follow up was 149 days. CAR-T cells dose was 0.5 × 106 CAR-T cells/Kg dose in 4 pts, while 10 pts received 1 × 106/kg CAR-T. Baseline characteristics are listed in table 1.Both groups were similar. There were no differences in the rate of bulky disease, prior ASCT or number or prior lines of therapy. Baseline lymphocyte counts, C – reactive protein (CRP) and ferritin were also comparable between groups (Table 2). CRS of any grade was observed in 6/8 (75%) of patients without PT vs. 1/6 (17%) in patients treated with PT (p = 0.05). There was a statistically significant difference in the peak CRP, with patients receiving PT having a CRP peak of 0.74mg/dl vs. 15.3mg/dl in patients without PT. Complete response was observed in 5/8 (63%) pts without PT vs. 4/5 patients with PT. All patients had detectable Anti-CD19 CAR-T cells on day 30. Our findings suggest prophylactic tocilizumab is associated with reduced incidence of CRS. This decreased rate of CRS is not associated with impaired disease control and response rates are comparable with those previously reported. Use of PT did not appear to affect CAR-T cell persistence. Subsequent studies should evaluate the optimal CRS prophylaxis schedule in patients treated with CAR-T cell therapies. [ABSTRACT FROM AUTHOR]

Clostridium difficile is the leading cause of infectious diarrhea among hospitalized patients and is a major concern for patients undergoing hematopoietic cell transplantation (HCT). Risk factors and the natural history of C. difficile infection (CDI) are poorly understood in this population. The objective of this study is to determine the incidence of CDI during and after auto-HCT and to identify risk factors for the development of CDI including diagnosis. Methods: We performed a retrospective study to describe the epidemiology, timing, and risk factors for CDI among adult patients who received autologous HCTs at our center from January 2007 through December 2018. CDI was defined any stool C. difficile toxin positive test after the day of stem cell infusion. Results: Overall, 516 patients received auto-HCT for Multiple Myeloma (MM) and lymphoma during the study period, 271 and 245, respectively. Overall, the 1-year incidence of CDI was 6.2% (n=30). Seventy two percent of the patients who developed CDI had lymphoma and 18% had MM (p=0.001). The median time from day of stem cell infusion to CDI positive test was 5 days (range 1:228) for lymphoma pts and 10.5 days (rage 4-42) for MM pts (p-value: 0.269). Median age for MM pts was 54 years and 58 for lymphoma pts (p-value: 0.328). Given the different patient population and therapy history between MM and lymphoma patients, we limit our analysis to MM subset to assess the potential risk factors impacting CDI occurrence after transplant. Previous antibiotic use (i.e., other than acyclovir), co-morbidities and other variables were assessed (Figure-1). Among MM patients, prophylactic antibiotics or corticosteroid use before transplant were not statistically significant associated with CDI. Twenty seven percent of patients with CDI had history of previous CDI vs. only 5% in no-CDI cohort (p-value: 0.001). Lymphopenia was present in 54% of CDI cohort at diagnosis whereas 29% of no-CDI cohort had lymphopenia (p-value: 0.031). Furthermore, chronic kidney disease (CKD) was associated significantly with CDI occurrence (p-value: 0.001). Conclusion: These results suggest lymphoma patients undergoing auto-HCT are at higher risk of developing CDI than MM patients which is different from older reports (Alonso, et al. Clinical infectious diseases. 2012). Our data illustrates pre-transplant prophylactic antibiotics or corticosteroid use is not associated with higher CDI incidence after transplant for MM patients undergoing transplant, while history of previous CDI in the year before transplant, lymphopenia and CKD may be significant predictors. This findings merits further confirmations in larger series. [ABSTRACT FROM AUTHOR]

Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy in induction and maintenance therapy after transplant for patients (pts) with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% (Nardone, et al, Clinical Lymphoma Myeloma and Leukemia. 2013) and importantly heralds a favorable prognosis (Kojima, et al. Blood. 2016) suggesting more robust immune stimulation by this class of drugs; however, lack of optimal management strategy of this toxicity can deprive large subset of pts from maintenance therapy after transplant and lead to potential detrimental impact on survivals. The concurrent weekly dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. Archives of dermatology. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD which may not be achieved by standard weekly Dex. Here, we present our experience with this regimen. In this retrospective study, pts with MM treated with lenalidomide and pomalidomide were reviewed for any IMiD-associated dermatologic toxicity. We followed the same corticosteroid regimen for all IMiD-related rash in our clinic without changing Dex dosing. A total of 160 pts were evaluated. The incidence of rash was found to be 13% (n=21). IMiDs were instituted as part of induction regimen in 71% (n=15) and as maintenance therapy after transplant in 29% (n=6) of pts. Median time to development of rash after IMiD initiation was 28 days (range, 2-232). The rashes were characterized as morbilliform in 86% (n=18), urticaria in 9.5% (n=2) and blisters in 5% (n=1) of pts. Pruritis or pain was associated with 86% of rashes (n=15). According to NCI-CTCAE, rashes were graded as low (I-II) in 89% (n=17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all pts were able to restart the same IMiD either at same (n=5, 24%) or reduced (n=16, 76%) dose with none re-experiencing any dermatologic adverse effect afterward. There was no association between rash development and changes in creatinine clearance (p=0.42). Median eosinophil count at rash development was observed to be significantly higher as compared to eosinophil count at IMiD initiation (380 × 106 vs 130 × 106 respectively, p=0.01). The proposed 3-week corticosteroid regimen showed 100% success rate in terms of reinstituting IMiDs, therefore it may provide a highly effective and practical short term immunosuppression required to enable pts to restart IMiDs. [ABSTRACT FROM AUTHOR]

We conducted a prospective study to determine the longitudinal microbial profile in patients undergoing HCT for multiple myeloma (MM), and whether changes in microbial composition correlate with HCT outcomes and/or toxicities. Samples were collected from 15 patients at baseline (T-2), during marrow aplasia (T+7) and after engraftment (T+30). Ion-Torrent PGM workflow was used. Amplicons generated from 16s rRNA and the ITS genes were sequenced for bacterial and fungal identification, respectively. Relative abundance, diversity and richness were determined at the phylum and genus levels at each time point, in oral and fecal microbiome. Diversity and richness of the oral mycobiome decreased at T+7 from baseline with further decrease noted at T+30. Fecal mycobiome diversity (T-2 vs T+7, p=0.05) and richness decreased from baseline to T+7, and richness trended towards significance (p=0.06) with further decrease at T+30. In fecal samples, lower bacterial diversity at T+7 associated with more severe diarrhea (p= 0.03). Anaerobic targeting antibiotic exposure on or before T+7 affected the bacterial genus diversity (p=0.015) and richness at T+7 (p=0.014). The bacterial genus richness at baseline (p=0.03) and the diversity/richness at T+7 (p=0.01) were associated with fever development on or after T+7. Exposure to anaerobic depleting antibiotics correlated with oral mycobiome genus richness at T+30 (p=0.04). At the bacterial phylum level, the oral community composition changed at T+30 compared to baseline (Bray-curtis p=0.046) and T+7 (Bray-curtis p=0.025). When examining the changes in the mycobiome composition, test for dissimilarity showed a significant difference in the fecal fungal genus between baseline and T+30 (BrayPA p=0.025). In fecal samples, a higher abundance of Bacteriodetes present at T+7 was associated with the severity of diarrhea experienced (p=0.03). Blautia and Ruminococcus , both belonging to the Firmicutes phylum and Clostridium Class, when detected at T+7 were associated with a higher severity of vomiting (p=0.05). In oral samples, the presence of the genus Glomerella at T+7 was negatively associated with rates of neutrophil engraftment (p=0.03). Our results show that oral and fecal microbiota undergo dynamic changes in diversity, composition and relative abundance during the course of transplantation. Bacterial and fungal microbiota present specifically at count nadir could be important players. The relative abundance of particularly the anaerobic bacterial phyla, Bacteroidetes and Firciumtes during marrow aplasia, correlated with post transplant toxicities. We identified a correlation between exposure to anaerobic organism depleting antimicrobials and changes in genus diversity and richness. Baseline microbial diversity/richness and changes coinciding with marrow aplasia correlate with the incidence and severity of post transplant toxicities. [ABSTRACT FROM AUTHOR]

Maintenance therapy has been associated a significantly longer time to disease progression and significantly improved overall survival (OS) among patients with multiple myeloma (MM). However, the impact of maintenance therapy on the nature of MM relapse is largely unknown. Generally relapse can be categorized in two broad categories as symptomatic, or biochemical relapse. We hypothesized that long-term continuous exposure to lenalidomide induces crucial changes in the myeloma microenvironment leading to a discordance between the resurgence of secretory function and the recurrence of aggressive behavior of myeloma cells leading to a higher frequency of biochemical. All MM patients with measurable disease who received HSCT at the University Hospital, Cleveland, OH from 2007 to 2016 were reviewed (Fig. 1). Baseline and treatment characteristics, response status, and monitoring data prior to relapse were extracted. If the serologic relapse had coincided with clinical relapse, defined as per CRAB criteria, patient was categorized as clinical relapse, and otherwise as biochemical relapse. Type of MM was categorized as paraprotein only (PO), paraprotein and light chain (PL), light chain escape (LE) and clinical only (CO) relapse (Table 1). Baseline and treatment characteristics are detailed in Table 2. Study population included 124 pts who relapsed after ASCT (Fig. 1), divided in two cohorts based on history of receiving any maintenance therapy or no maintenance (77 vs. 47 patients, respectively). Median age was 59.8 years old (range: 36-79). The median time from diagnosis to ASCT was 10 months. There was only one CO relapse in the maintenance cohort. There was no difference in rate of high risk disease between two cohorts. The maintenance agents included immunomodulatory drugs in 70 pts (91%), proteasome inhibitors in 5 pts (6%) and a combination of both in 2 pts (3%). PFS was 40.1 months in the maintenance group vs. 29.2 months in the no maintenance group (p=0.0001). There was no statistically significant difference in serum paraprotein values at diagnosis or relapse between the two cohorts (Fig. 1A). LCE was more common in the maintenance group. Thirteen patients (28%) in the no maintenance cohort had CRAB relapse compared to 35 patients (45%) in the maintenance cohort (hazard ratio: 0.71, 95% CI: 0.51-0.92, p=0.031). The type of end organ dysfunction at clinical relapse is shown in bar graphs in Fig. 2B. Taken together, our results suggest that although maintenance therapy postpones disease relapse, it also impacts dynamics of the resurgence of secretory function and shifts the nature of recurrence toward less biochemical relapse. Future studies will employ next generation sequencing combined with high sensitivity flow cytometry to identify the molecular basis of relapse. Genomics and cell surface markers may then more accurately predict relapse in MM patients on maintenance therapy. [ABSTRACT FROM AUTHOR]

Multiple Myeloma (MM) are often treated with high-dose melphalan and autologous stem cell transplant (ASCT). Cardiac toxicity, including Supraventricular tachyarrhythmias (SVT), is a fairly common complication which may be related to Melphalan, the transplanted stem cells or effects of para-proteinemia on the conduction system. Here, we sought to determine the incidence of SVT and its predisposing factors in this setting. Methods We reviewed the 100-day post-ASCT clinical course of all MM patients treated from 2007 to 2017 that had undergone ASCT at our institution. Clinical data, EKG and Echocardiography data were extracted. QRS amplitude was measured in the V2 precordial lead as the distance from the R peak to S peak. Both atrial fibrillation and atrial flutter were classified as SVT. Results A total of 222 patients were included in the study population. Amifostine was used before all ASCT to reduced oral mucositis. Patient median age was 60.6 (range: 36-79), 110 patients (49%) were male and the 112 female (51%). Median pre-ASCT QRS amplitude was 1.7 millivolt (mV) (range: 0.3-4.4). Median QRS duration was 90 millisecond (mS, range: 60-208). Only 166 patients received a pre-ASCT ECHO. Median time of pre-ASCT and post-ASCT ECHO were 38 days (range: 1-333 days) and 55 days (range: 4-118), respectively. Seventeen patients (8%) developed SVT during or after ASCT with a median time of 12 days post-ASCT (range: 1-97 days). Median time of the length of hospital stay between patients without SVT and with SVT was different, 15 vs. 19 days (p-value < 0.001). There was no statistically significant between average melphalan dose utilized as the conditioning regimen, infused CD34 dosage, transplant-associated weight loss, time from diagnosis or length of pre-ASCT exposure to proteasome inhibitors between two cohorts (Table-1 and 2). Also, there was no association between pre-ASCT use of anti-lipid lowering agents, beta-blockers, angiotensin-converting enzyme inhibitor or angiotensin receptor inhibitors. Out of all pre-ASCT comorbidities renal insufficiency (9% vs. 41%, p-value: 0.017) and HTN (49% vs. 76%, p-value: 0.045) were predictor, of SVT occurrence in the univariate analysis. Multivariate analysis indicated that renal insufficiency at baseline (OR: 3.6, 95% CI: 2.1-4.8, p-value < 0.001), left ventricular systolic dysfunction (LVSD, OR: 3.0, CI: 1.1-5.1, p-value: 0.003), and hypertension (OR: 2.5, CI: 1.2-4.6, p-value: 0.028), were significantly associated with the development of SVT after ASCT (Fig. 1). Conclusion Taken together, our results suggest that SVT represents an important cause of morbidity and is associated with longer hospital stay for MM patients undergoing ASCT. The presence of abnormal renal function, LVSD, or hypertension at baseline identifies patients at greater risk of developing SVT following ASCT. [ABSTRACT FROM AUTHOR]

Introduction Tacrolimus (tacro) is commonly used for the prevention of graft vs host disease (GVHD) after allogeneic stem cell transplantation (allo-SCT). Due to concerns of inadequate absorption, tacro is commonly administered intravenously (IV) in the immediate post allogeneic transplant period. Advantages to oral (PO) tacro include decreased need for multi lumen IV catheters, improved patients (pts) convenience, and reduced cost. We retrospectively analyzed differences in safety, tolerability, time to achieve therapeutic levels during the 1st 4 weeks and rates of acute GVHD. Methods IV tacro at 0.02 mg/kg by continuous infusion or PO tacro at 0.03 mg/kg twice daily was started between T-3 and T+5. Levels were assessed 3 times weekly. Dose was titrated to achieve a steady level between 7 and 14 ng/ml. GVHD was graded according to CIBMTR criteria. Results 54 pts were treated between Sep 2016 and July 2018. 21 who received PO tacro and 27 who received IV tacro were studied. 6 pts on PO tacro are still within 100 days post-transplant and will be reported in follow up. The median age was 59 years (range, 21-74), 52% were females, diagnoses were AML (54%), MDS (19%), ALL (15%), CML (6%), NHL (4%) and MF (2%). HCT-CI was 0, 1-3 and >3 in 23%, 54% and 23% of pts, respectively. Donors were match-unrelated (58%), match-related (27%), haploidentical (6%) and double umbilical cord (6%). Conditioning regimens were myeloablative (60%) and reduced intensity (40%). 60% of pts received rabbit ATG (3 mg/Kg). GVHD prophylaxis also included mini-MTX on days +1, +3, +5 and +11 (79%), MMF (15%), and MMF + post-transplant Cy (6%). Pts characteristics were similar between the 2 groups. 7 pts (33%) who initially started on PO tacro switched to IV due to poor absorption (3), mucositis (1), toxicity (1), GVHD (1) and patient's concern (1). Target therapeutic level was reached in 67% vs 81% during week 1, 86% vs 96% during week 2, 95% vs 96% during week 3, and 100% vs 96% during week 4, of pts on PO vs IV tacro, respectively. Median tacro level during the 1st 4 weeks was 12.6 ng/ml vs 11.2 ng/ml, acute kidney injury occurred in 23.8% vs 33.3% (p =.47) and increased bilirubin occurred in 4.7% vs 22.2% (p =.09), in pts on PO vs IV tacro. Posterior reversible encephalopathy was observed in 1 patient on PO tacro. Grade I and Grade II-IV acute GVHD incidence was 47.6% vs 14.8% (p =.01) and 47.6% vs 44.4% (p =.82) of pts on PO vs IV tacro. Stage 1-2 skin aGVHD rate was higher in the PO vs. IV group (90% vs 33.3%; p =.0001). There was no difference in rates of stage 3 skin (4.7% vs 3.7%), stage 1 GI (33.3% vs 33.3%), or stage 2-4 GI (14% vs 7.4%) aGVHD. None of the pts had stage 4 skin or any stage liver aGVHD. Conclusion PO tacro is safe and effective in the prevention of aGVHD in pts receiving myeloablative or RIC allo-SCT. The use of PO tacro during the 1st 4 weeks post-transplant was found to be associated with higher rate of stage 1-2 skin aGVHD and warrants further study. [ABSTRACT FROM AUTHOR]

Achieving and maintaining Complete Response (CR) after autologous hematopoietic cell transplant is the key to improved clinical outcomes in patients (pts) with multiple myeloma (MM). Daratumumab (DARA), an IgG1 Kappa anti-CD38 monoclonal antibody, have shown significant anti-myeloma activity leading to increasing usage in the peri-transplant settings. Frequently, use of DARA may be associated with appearance of low concentration band on serum protein electrophoresis (SPE) impacting CR assessment after transplant. The incidence and factors influencing appearance of this band are largely unknown. This band potentially can be an indirect measurement of the plasma DARA concentration influenced by amount of administered agent and but also with volume of CD38 positive myeloma cells binding to DARA. The objective of this study is to analyze the factors influencing appearance of this band on SPE. Methods: 77 pts who received DARA were retrospectively studied. Pts who did not have available SPE after starting DARA (n: 9) and those who had AL Amyloidosis without Myeloma (n: 3) were excluded. The host and disease characteristics extracted. Pts assigned to two cohorts based on presence (PB) or absence (NB) of the accessory band. The disease response assessment was assessed based on IMWG criteria. Result: Median age for pts in PB and NB was 62 and 64.4 years respectively. All pts received weight-based dosing (16mg/Kg). 31 pts had detectable band assigned to PB cohort and 34 pts without any detectable band assigned to NB. The accessory band appeared over a median of 46 days after starting therapy (range: 7-390 days) and predominantly (74%) during the weekly DARA schedule. No significant difference noted in median weight and serum creatinine between PB and NB cohorts. Median M-spike on SPE at the start of DARA was 1.1 gr/dL (range: 0 - 5.5 gr/dL) in NB cohort vs. 0.3 gr/dL (range: 0 3.8 gr/dL) in PB patients (p-value <0.012). 45% of pts had IgG MM in PB while 55% in NB (p-value: 0.349), 29% of patients had IgA in PB and 20% in NB cohort (p-value: 0.231) and light-chain disease was present in 25% of pts in PB cohort whereas only 4% in NB (p-value: 0.041). 17 pts (55%) had Partial Response (PR) or better in PB while only 5 pts (14%) had PR or better in NB cohort. (p-value: 0.001). In multi-variate analysis the pre-DARA M-spike remained the significant predictor of the band appearance (OR: 2.03, CI: 1.21-4.31, p-value: 0.003). Conclusion: Based on our data, the frequency of detecting this band is not impacted by type of myeloma (i.e., IgG vs. IgA) but by the magnitude of the M-spike. This may be reflective of larger disease volume in bone marrow with less M protein detected in the peripheral blood. The appearance of accessory band associated with DARA treatment during weekly dosing may be a surrogate early marker for predicting disease response. Further large scale studies are required to confirm this findings. [ABSTRACT FROM AUTHOR]

Advent of novel anti-myeloma agents and broader use of stem cell transplant has led to significant improvement in survival of patients (pts) with Multiple Myeloma (MM). However, there are well-described issues with affordability of novel drugs and rapidly escalating price of these agents (Shih et al. JCO 2017), leading to significant disparity among different sociodemographic groups. Hereby, we interrogated the National Cancer Database (NCDB) (which covers 70% of MM patient diagnosed nationwide) to assess impact of insurance type on survival. We also sought to investigate if autologous transplant may overcome socioeconomic effects on survival, by potentially minimizing the need for chronic use of expensive drugs. Methods: Data from 117,926 MM pts diagnosed with MM (ICD-O 9732) between 2005 and 2014 were analyzed. Results: Median age at diagnosis was 67 (19-90); 55% were males. 57% of pts lived in areas where the median income was < $46k/year (individual income data was not available); Primary insurance was Medicare (52%), private insurance (35%) or Medicaid (5%), and 3% were uninsured. 40% were treated in academic institutions. Median follow up was 30.2 (range, 0-145.2) months. By univariate analysis, better OS was observed in pts with primary MM, lower Charlson Comorbidity Index (CCI), treatment in academic institutions, higher median regional income, or private insurance (p <0.001 for all) (Table-1). 96% of pts were treated in facilities located ≤ 120 miles from area of residence. Amongst pts younger than 65 years, 33% of pts with private insurance received transplant compared to 20% of those on Medicare (p<0.001). For those 65 years and older, 11% of privately insured pts were transplanted compared to only 6 % for those on Medicare (p<0.001). Median age of pts on Medicare and private insurance, was 74 and 57 years old, respectively. When restricting the analysis to pts ≥ 65 years old, pts with private insurance had longer OS compared to Medicare pts (p<0.001). Table-2 shows the results of multivariate analysis. There was a statistically significant difference in survival between patients with private insurance and those with Medicare in favor of the private insurance among pts older than 65 years old (41.9 vs. 30.8 months, p <0.001 (Fig-1)). Similarly insurance type was a significant predictor of survival among pts who received therapies other than transplant among pts younger or older than 65 (Fig-2), however when considering pts who received transplant, there was no difference in survival between privately insured pts and Medicare in both age group (Fig-3). Conclusions: Although insurance type and regional income are associated with MM survival among pts who relied on non-transplant modalities, there was no significant impact of these socioeconomic factors on survival of pts that received an autologous transplant in this large database. This finding merits further investigation. [ABSTRACT FROM AUTHOR]

Donor-derived natural killer (NK) cell alloreactivity has been shown to improve clinical outcomes following allogeneic stem cell transplant (HSCT). Host versus graft (HvG) directed NK cell alloreactivity can also occur. Several epitopes of HLA-B and HLA-C are ligands for inhibitory killer immunoglobulin-like receptors (KIRs) that regulate NK cell cytotoxicity. These KIR ligands (KIR-L) may be surrogates of NK cell alloreactivity in the HLA-mismatched setting. To determine the impact of donor/recipient KIR-L mismatch (KIR-L-MM) direction on engraftment, we examined cord blood (CBT) and haploidentical (Haplo) HSCT performed at our institution between 2011 and 2018. We computed KIR-L and direction of KIR-L-MM for recipient/ donor pairs using the KIR ligand calculator (https://www.ebi.ac.uk/ipd/kir/ligand.html). Summary data and the relative risk of graft failure were analyzed. In the CBT cohort (N=70), there were KIR-L mismatches (KIR-L-MM) in the HvG and GvH direction in 32 and 31 recipient-cord blood unit pairs respectively. There were no KIR-L-MM in 26 transplants while seven had KIR-L-MM in both GvH and HvG directions. Overall, 16 CBT failed to engraft (23%). There was an increased risk of graft failure in recipients of HvG KIR-L-MM transplants (R.R 2.15; p=0.063) with this trend most significant when the mismatch was in HLA-C ligand (R.R 2.46; p=0.027); Figure 1. Out of 8 double CBTs where one cord unit had HvG KIR-L-MM, the non-mismatched unit fully engrafted in 7 cases (87.5%). In 6 double CBTs where there was KIR-L-MM from one cord unit in the GvH and the GvG (graft versus other graft) direction, 4 (67%) of such units became the dominant graft. Of 8 double CBTs in which both cord units had KIR-L-MM in the HvG direction there was graft failure in 3 (37.5%). Time to neutrophil engraftment and lymphocyte recovery when engraftment occurred was not significantly impacted by KIR-L-MM. In the Haplo cohort (N=26), all of the 5 graft failures (19%) were KIR-L mismatched only in the GvH direction (R.R 9.53; p=0.114). There were 9 HvG KIR-L-MM transplants and they all engrafted. Fourteen transplant pairs in this cohort had KIR-L-MM in the GvH direction; 2 pairs had both HvG and GvH KIR-L-MM while 3 pairs did not have any KIR-L-MM. Time to neutrophil engraftment was not impacted by GvH or HvG KIR-L-MM. This study suggests an increased likelihood of graft failure in CBT when HvG KIR-L-MM exists. There is also a trend in favor of engrafting the GvH/GvG KIR-L-MM unit in double CBT. These factors should be considered when selecting cord units for CBT. A similar graft failure effect of HvG KIR-L-MM is not seen in this small Haplo cohort; on the contrary the data suggests GvH directed KIR-L-MM associates with graft failure. This association merits exploration in a larger database. [ABSTRACT FROM AUTHOR]