Abstract: Background: Allogeneic hematopoietic cell transplantation (alloHCT) is a complex therapy which can induce a multi-factorial cascade of complications, and potentially lead to patient death. The triggering event(s), sequence and severity of such complications can significantly differ between patients, but in many cases, a so-called "multi-organ failure" (MOF) is usually reported as the leading cause of death. However, a patient's clinical course can be very heterogeneous across and within cause-specific mortalities. Moreover, comorbidities present prior to alloHCT carry their own risks and represent additional confounding factors. Therefore, identification of the exact initial trigger or event leading to MOF in alloHCT patients is a critical step towards early intervention and improvement of patients' outcome. The goal of the current study was to establish and identify the exact cause of death in alloHCT patients where MOF was considered to be the main cause of death. Of note, we specifically focused on VOD/SOS because this life-threatening complication has a mortality exceeding 80% in severe cases, ending usually in MOF, and because VOD/SOS has subtle and dynamic evolution features which are not easy to capture, but could be potentially controlled by appropriate therapy (eg. defibrotide). Patients and Methods: For the purpose of this analysis, we randomly identified 241 adult patients (42% female; median age: 50 years; range 19-73) with acute leukemia (72% AML, 25% ALL, 3% other) allografted between 2010 and 2018 from a matched sibling (29%), unrelated (61%) or haploidentical donor (10%). All patients were reported to the EBMT registry to have died from MOF. Karnofsky score at time of alloHCT was 〉 90 in 87% of patients. Seventy-three percent of patients underwent transplant in complete remission, and conditioning was myeloablative in 70%. Sixty patients (25%) received VOD/SOS prophylaxis treatment, mainly consisting of ursodiol and/or heparin. Patients' files were reviewed in detail in order to capture all early signs and symptoms which occurred prior to MOF, based on the classical Baltimore criteria, modified Seattle criteria, and/or the newly published EBMT criteria. These criteria included bilirubin levels, the presence of hepatomegaly or painful hepatomegaly, ascites, percentage weight gain, hemodynamic instability, and ultrasound/histologically proven VOD/SOS. Results: Using one or more of the above criteria defining VOD/SOS, we identified a total of 67 (28%) patients for whom VOD/SOS could be considered as the trigger for MOF and the leading cause of death. Interestingly, among these 67 patients, only 22 (33%) were originally reported by the centers as having developed VOD/SOS leading to MOF post-transplant. When comparing the group of 67 patients dying of VOD/SOS-related MOF and the remaining 174 patients dying of MOF not related to VOD/SOS (please see attached table), a multivariate regression analysis identified a significant increase in VOD/SOS incidence (odds ratio 3.9; 95%CI, 2.42-6.33; p 〈 10-3) with the presence of hepatic risk factors (scoring from 0 to 5): history of liver disease, transaminases 2.5 times and bilirubin 2 times above normal limits at time of alloHCT, the presence of iron overload and the use of gemtuzumab. Of note, there was no significant detrimental impact of the use of total body irradiation or disease status. The median survival for patients with VOD/SOS-related MOF was 47 days (95%CI, 34-84) compared to 175 (95%CI, 121-234) days for patients with non-VOD/SOS related MOF. Conclusion: The above results suggest that VOD/SOS-related MOF is an under-reported cause of death. It is actually a relatively frequent cause of MOF, accounting for at least 28% of deaths that would otherwise been attributed to MOF of unknown origin. While the MOF concept is a widely used cause of death after alloHCT, having precise categories of cause-specific death from MOF should allow (whenever possible), for earlier specific therapeutic intervention (eg. defibrotide), thus contributing to improved patient outcome. Table Disclosures Labopin: Jazz Pharmaceuticals: Honoraria. Schaap:Celgene: Consultancy; Novartis: Consultancy. Snowden:Jazz: Honoraria; IDMC: Honoraria; Mallinckrodt: Honoraria; Kiadis: Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria; Janssen: Honoraria. Mohty:Jazz Pharmaceuticals: Honoraria, Research Funding.

Abstract: Poor graft function (PGF) is a rare but serious complication of hematopoietic cell transplantation (HCT). Boost of CD34+stem cells could be a therapeutic option but is not always feasible nor successfull. Due to their hematopoietic support properties and immune regulatory effects, multipotent mesenchymal stromal cells (MSC) could be considered a good candidate to help restore bone marrow (BM) niches homeostasis and facilitate hematopoiesis after HCT. Here, we conducted a multicenter prospective study to evaluate the efficacy of MSC perfusion to improve PGF after HCT. Thirty patients (median age 51y, range 11 to 70y) received a single IV administration of third-party donor BM-derived MSC (1-2 x 10 exp6/kg body weight) for PGF after allogeneic HCT (median 151 days after HCT, range 62- 430). PGF was defined as (1) at least one cytopenia (Hb & lt; 80 g/L, absolute neutrophil count [ANC] & lt;0.5 x 10exp9/L, platelet count & lt;20 x 10exp9/L) and/or (2) transfusion dependence. Overall, 3 patients were treated for tri-, 17 for bi- (mainly platelets and red blood cells [RBC]) and 10 for mono- (mainly RBC) lineage cytopenia(s). Only 5/30 patients had isolated or combined severe neutropenia. All patients were screened for full-donor chimerism, absence of disease relapse and absence of any other identifiable cause of cytopenia at inclusion. The primary endpoint was response at day +90 after MSC administration. A significant decrease in RBC and platelet transfusion requirements was observed at day + 90 after MSC (median monthly frequencies of 0 and 0 vs. 5 and 4 before MSC, respectively, p ≤0.001). An increase in ANC was also noted (median 2.500 at day 90 vs. 1.767 x 10exp9/L before MSC, p= 0.04), with 2/5 patients with severe neutropenia having recovered an ANC & gt; 0.5 x 10exp9/L. At day 90 post-MSC, 51.8% (95% CI, 33 - 70.7%) of patients resolved at least one of their cytopenias (overall response, OR) and 40.7% (95% CI, 22.2 - 59.3%) achieved a complete haematological recovery (CR: ANC & gt;0.5 x 10exp9/L and transfusion independence). Corresponding response rates increased at day 180, with 69.2% (95% CI, 51.5 - 86.9%) OR and 61.5% (95% CI, 42.8 - 80.2%) CR, respectively. Overall survival at 1 year post-MSC was 70% (95% CI, 53.6 - 86.3%), with all but one of the d90-responders being alive (1 death to relapse of hematological malignancy). No severe adverse event related to MSC administration was reported during the 1-year follow-up. In conclusion , perfusion of BM-derived MSC from a third party donor appeared to be safe and to improve PGF after allogeneic HCT, although spontaneous amelioration cannot be excluded. Further (ideally comparative) studies are warranted to confirme our results. Disclosures Selleslag: Celyad: Other: Clinical trial research (no honoraria recieved); Novartis: Consultancy, Honoraria, Speakers Bureau.

Abstract: Introduction Multiple myeloma (MM) patients with renal impairment (RI), especially dialysis-dependent (DD) RI, have poorer outcomes than MM patients with normal renal function. Autologous stem cell transplantation (ASCT) is a treatment option, but there is concern at a perceived higher risk of complications which may be limiting consideration of the use of ASCT in this population. The evidence is inconsistent among studies and interpretation is complicated by heterogeneous datasets, some dating to before the availability of novel agents. Finally, the reversibility of RI following ASCT is an important prognostic factor for both survival and quality of life. Aim To evaluate the safety and efficacy of ASCT in MM patients with DD RI transplanted in EBMT centres between 1997 and 2017. Methods Baseline characteristics at diagnosis, patient treatment regimens and clinical outcomes were collected using standardised report forms. OS was defined as the period between the date of ASCT and the date of death or the date of last observation. PFS was defined as the period between the date of ASCT and date of progression/relapse or death of any causes or the date of the last observation. Cox proportional hazard regression analysis was applied to assess risk factors for progression and death. Survival curves were plotted by the Kaplan-Meier method and compared using log-rank test. P & lt;0.05 was judged as statistically significant. Results A total of 109,959 adult MM patients are registered in the EBMT database as having undergone ASCT between 1997 and 2017. We further analysed 118 DD MM patients who had a first ASCT during this period. The median (range) age was 57 (27-71) years. Seventy (59%) patients were males. Forty nine patients (49/94 patients, 52%) had Karnofsky score ≥90. One hundred and ten patients were treated with hemodialysis and eight with peritoneal dialysis. A total of 68 (58%) patients had Light Chain MM, 43 kappa and 25 Lambda. In first-line induction therapy, 47/76 (62%) patients received bortezomib-based regimens. Forty-four (37%) patients achieved at least VGPR pre-ASCT. The median time from diagnosis to ASCT was 0.7 years (0.3-4.9). Melphalan doses were as follows: 140 mg/m2 (n=55, 67%), 70-100 mg/m2 (n=15, 18%), and & gt;140 mg/m2 (n=12, 15%). The times to Neutrophil ( & gt;0.5) and Platelet ( & gt;20) engraftment were 12 (10-37) and 14 (4-128) days, respectively. The 30-day and 100-day transplant-related mortality (TRM) rates were 0.0% and 0.9%, respectively. ASCT was associated with a significant deepening of response (at least VGPR pre- vs post-ASCT: 36/93 (39%) vs 48/93 (52%), p & lt; 0.001). The median PFS was 37 months (95% CI: 24-43) and 5-year PFS was 31% (95% CI: 20-41). The median OS was 102 months (95% CI: 67-129). Five-year OS post-ASCT was 62% (52-72) and 10-year OS 36% (17-55). Thirty-one (26%) DD MM patients achieved dialysis independence. There were no differences in PFS or OS when comparing the 1997-2007 and 2008-2017 cohorts: 5-year PFS - 28% (6-49) vs 31% (19-43) (p=0.7) and 5-year OS - 61% (38-84) vs 63% (51-74) (p=0.9), respectively. On univariate analysis of factors affecting PFS, achievement of an Overall Response Rate (ORR) (CR+VGPR+PR vs. Other) pre-ASCT was associated with a lower risk (HR 0.467, p=0.032) and older age ( & gt;55 years) with a higher risk (HR 1.786, p=0.035) of post-ASCT progression. Age higher than 55 (HR 2.033, 95%CI: 0.992 - 4.166, p=0.053) increased and achievement of at least VGPR pre-transplant (HR 0.494, 95%CI: 0.224 - 1.091, p=0.081, on the verge of statistical significance) decreased the risk of death. Conclusion To the best of our knowledge, the DIADEM study is the largest analysis of ASCT in DD MM pts to date. This cohort of 118 unselected patients had an OS comparable to patients without RI. This may reflect patient selection based on younger age, Karnofsky scores and pre-ASCT response. The low TRM and excellent outcomes support consideration of the use of ASCT in pts with DD RI. Notably, more than a quarter of patients became dialysis independent, an outcome likely to confer an improved Quality-of-Life.. These results can also inform the debate around the role of renal transplantation in younger DD MM patients who do not achieve dialysis independence. Disclosures Snowden: IDMC: Honoraria; Kiadis: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria; Mallinckrodt: Honoraria; Jazz: Honoraria; Gilead: Honoraria. Dreger:MSD: Membership on an entity's Board of Directors or advisory committees, Other: Sponsoring of Symposia; AbbVie, AstraZeneca, Gilead, Janssen, Novartis, Riemser, Roche: Consultancy; AbbVie, Gilead, Novartis, Riemser, Roche: Speakers Bureau; Neovii, Riemser: Research Funding. Illés:Takeda, Seattle: Research Funding; Janssen, Celgene, Novartis, Takeda, Roche, Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees. Basak:Teva: Honoraria; Celgene: Honoraria. Gyan:Pfizer: Honoraria. Hayden:Alnylam: Honoraria; Amgen: Honoraria. Beksac:Amgen: Consultancy; Celgene: Consultancy; Janssen & Janssen: Consultancy; Takeda: Consultancy. Schönland:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Medac: Other: Travel Grant; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees, Research Funding.

Abstract: Autologous hematopoietic cell transplantation (auto-HCT) may be performed in multiple myeloma (MM) patients relapsing after a previous auto-HCT. For those without an adequate dose of stored stem cells, remobilization is necessary. This retrospective study included patients who, following disease relapse after the first auto-HCT(s), underwent stem cell remobilization and auto-HCT performed using these cells. There were 305 patients, 68% male, median age at salvage auto-HCT was 59 years. The median time to relapse after the first-line penultimate auto-HCT(s) was 30.6 months, the median follow-up after salvage auto-HCT 31 months. The 2- and 4-year non-relapse mortality (NRM) after the salvage auto-HCT was 5 and 9%, the relapse incidence 56 and 76%, respectively. Overall survival (OS) after 2 and 4 years was 76 and 52%, progression-free survival (PFS) 39 and 15%. In multivariable analysis an increasing interval between the penultimate auto-HCT and relapse was associated with better OS and PFS, later calendar year of salvage auto-HCT with better OS. In conclusion, salvage auto-HCT performed with cells remobilized after a previous auto-HCT was associated with acceptable NRM. The leading cause of failure was disease progression of MM, which correlated with a shorter interval from the penultimate auto-HCT to the first relapse.