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(1) Background: High-dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is the standard consolidation strategy for patients with newly diagnosed multiple myeloma (MM) and for a subset of patients with relapsed/refractory disease. For stem cell mobilization, G-CSF alone or in combination with chemotherapy mobilizing agents and/or plerixafor are commonly used. Ixazomib is an oral proteasome inhibitor with less neurotoxic potential, which previously showed the ability to mobilize stem cells in preclinical studies. (2) Methods: Prospective single-center phase 1 study assessing the efficacy and safety of stem cell mobilization with ixazomib and G-CSF in patients with newly diagnosed or relapsed/refractory MM undergoing HDCT and ASCT. Primary endpoint was percentage of patients achieving a yield of at least 6.0 × 106/kg CD34+ cells within the first apheresis. G-CSF (filgrastim) 10 μg/kg/day was administered subcutaneously (s.c.) from day 1 to day 5 (planned apheresis) and ixazomib 4 mg orally at day 4. Plerixafor 24 mg s.c. was administered if the stem cell mobilization with ixazomib and G-CSF was not sufficient. (3) Results: 19 patients were treated within the study between 06/2020 and 02/2021. The primary endpoint was reached in 17 (89%) patients, with a median of 7.1 × 106/kg CD34+ cells collected within the first apheresis, comparable to previously published results, and only 2 (11%) patients required a second apheresis. Median number of circulating CD34+ cells was 14.0 × 106/L (2.0–95.2) before the administration of ixazomib, and 33.0 × 106/L (4.2–177.0) pre-apheresis. However, 9 (47%) patients required the addition of plerixafor to ensure optimal stem cell collection. (4) Conclusions: The combination of ixazomib and G-CSF showed promising stem cell mobilizing activity in patients with MM prior to HDCT and ASCT. Future larger studies might further investigate the role of ixazomib in stem cell mobilization regimens for MM.

Definite cure remains exceptional in myeloma patients even after high-dose chemotherapy (HDCT) with melphalan (Mel) and autologous stem cell transplantation (ASCT). Thus, improving efficacy of HDCT in MM remains an unresolved issue. This randomized phase II trial compared standard 200 mg/m2 Mel HDCT to experimental HDCT with 200 mg/m2 bendamustine, given both at days −4 and −3, combined with 100 mg/m2 melphalan at days −2 and −1 (BenMel) before ASCT as first-line consolidation in myeloma patients. The primary endpoint aimed to identify at least a 15% improvement in the complete remission rate (stringent CR + CR) after HDCT with BenMel compared with Mel alone. A total of 120 MM patients were 1:1 randomized. The rate of sCR/CR after ASCT was higher in BenMel than in Mel treated patients (70.0% vs. 51.7%; p = 0.039). Three patients in the BenMel group (5.0%) had reversible acute renal insufficiency compared with none in Mel patients. Minimal residual disease negativity (p = 0.375). Our data suggest that BenMel HDCT is safe and improves the sCR/CR rate compared with standard Mel alone.

Considering the expanding therapeutic options for patients with acute myeloid leukemia (AML), minimal residual disease (MRD) diagnostics gain importance for treatment monitoring in this heterogeneo...

Autologous stem cell transplantation (ASCT) as part of the primary therapy in multiple myeloma (MM) is standard practice. In contrast, the role of a second ASCT (ASCT2) and subsequent lenalidomide maintenance for relapsed disease remains unclear. In this study, we analysed 86 consecutive MM patients with a first relapse after prior ASCT receiving either a second ASCT or conventional chemotherapy. After a median follow-up of 37.7 months since first relapse, 54 (62.8%) patients were still alive and 29 (33.7%) without progression. Sixty-one (71.0%) patients received ASCT2 and had better progression-free survival (PFS) (30.2 versus 13.0 mo; P = .0262) and overall survival (OS) rates (129.6 versus 33.5 mo; P = .0003) compared with 25 (29.0%) patients with conventional treatment. Patients relapsing later than 12 months after ASCT1 benefitted from a second ASCT with better PFS2 (P = .0179) and OS2 (P = .0009). Finally, lenalidomide maintenance after ASCT2 was associated with longer PFS (41.0 vs 21.6 mo; P = .0034) and better OS (not yet reached vs 129.6 mo; P = .0434) compared with patients without maintenance. Our data suggest that a second ASCT and lenalidomide maintenance given at first relapse in MM after prior ASCT are associated with better survival rates.

Chemotherapy with G-CSF is used to mobilize peripheral stem cells in multiple myeloma (MM) patients, with plerixafor as a rescue strategy for poorly mobilizing patients. Preclinical studies suggested that the nonsteroidal anti-inflammatory drug meloxicam enhances the mobilization of CD34+ cells. In this single-center study, we evaluated whether adding meloxicam to chemotherapy/G-CSF mobilization increases peripheral hematopoietic CD34+ cell levels and reduces the need of using plerixafor. We prospectively compared two consecutive cohorts of MM patients in first remission mobilized with G-CSF and non-myelosuppressive chemotherapy with vinorelbine or gemcitabine. The second cohort additionally received oral meloxicam. The cohorts comprised 84 patients without meloxicam (-M) and 66 patients with meloxicam (+M). Meloxicam was well tolerated and associated with similar hematologic engraftment after transplantation and equal survival rates. However, the meloxicam group had higher CD34+ cell levels on day 8 of the mobilization procedure (53 200 versus 35 600 CD34+ cells/mL; P=0.007), and fewer patients needed >1 collection day (+M: 6 (9%) patients versus -M: 16 (19%) patients; P=0.04). This resulted in reduced plerixafor administrations (+M: 7 (11%) patients versus -M: 18 (21%) patients; P=0.03) and less costs. Our data suggest that meloxicam enhances the mobilization of hematopoietic CD34+ blood cells in MM patients.Bone Marrow Transplantation advance online publication, 23 October 2017; doi:10.1038/bmt.2017.234.

Introduction: Consolidation of first-line induction treatment in myeloma (MM) patients (pts) with 200 mg/m2 melphalan chemotherapy (HDCT) and autologous stem cell transplantation (ASCT) was established as standard of care three decades ago. However, definite cure in myeloma patients remains exceptional due to residual disease escaping intensive treatment, and almost all patients will ultimately relapse at earlier or later time points following ASCT. Thus, improving efficacy of HDCT in MM remains an unresolved issue. Methods: We performed a phase-II randomized trial comparing standard 200 mg/m2 Melphalan (Mel) HDCT to experimental HDCT treatment with 200 mg/m2 bendamustine, a bifunctional alkylating agent, given at days -4 and -3, combined with 200 mg/m2 melphalan split on days -2 and -1 at 100 mg/m2 (BenMel) before ASCT in MM pts. Patients had up to four cycles of first-line induction treatment with bortezomib, lenalidomide and dexamethasone. After ASCT, pts received lenalidomide maintenance treatment for two years. The primary endpoint was to show a 15% improvement of the rate of complete remission (sCR+CR) after HDCT with BenMel compared to Mel alone. MRD assessment from the bone marrow was performed by multiparameter flow cytometry after hematological engraftment following HDCT/ASCT. MRD negativity was defined as clonal plasma cells below 10(-5). Results: We randomized 120 myeloma pts (60 patients in each arm), with high-risk genetic abnormalities present in 21.3% of the patients. The median age was 63 years (range 35-74). The sCR/CR rate after ASCT before initiation of lenalidomide maintenance treatment was better in the BenMel arm compared to Mel alone (70.0% vs 51.7%; p=.039). The post-ASCT remission rates in detail were sCR 40.0% vs 31.7% (p=.341); CR 30.0% vs 20.0% (p=.205); VGPR 16.7% vs 33.3% (p=.035); and PR 13.3% vs 15.0% (p=.793). MRD negativity assessed in the bone marrow by flow cytometry was observed in 26 (45.6%) of the BenMel treated pts compared to 22 (37.9%) of the Mel pts. Median time until neutrophil engraftment was 11 days after BenMel vs 12 days after Mel (p=.096), and median time until platelet engraftment was 13 days in both arms (p=0.367); all pts had full engraftment of both cell lineages. Prolonged hospitalization duration was seen in BenMel pts (median 19 vs 18 days; p=.006) due to the longer BenMel treatment administration. Fully reversible acute renal insufficiency occurred in three (5%) BenMel pts compared to none of the Mel pts (p=.250). No treatment-related mortality was seen in both groups. ICU admissions were necessary in 3 pts (5%) in the BenMel group (ARDS, septic shock, pulmonary failure), and 2 Mel treated pts (3.3%; due to pulmonary failure and decompensated cardiomyopathy). The PFS rates at 12 months were 95% in BenMel pts and 91% in Mel treated pts (p=.551). OS at 12 months was 96% for both groups (p=.262), and median PFS and OS were not reached in both groups. Conclusions: Our data confirm that high-dose bendamustine combined with melphalan HDCT before ASCT in MM patients is safe and well tolerated. In particular, bendamustine-associated renal toxicity was manageable and reversible in all patients, and hematopoietic engraftment was comparable to standard melphalan HDCT. HDCT with BenMel improves the sCR/CR rate compared to standard melphalan alone. Thus, BenMel HDCT before ASCT warrants further investigation aiming to improve the long-term survival rates of MM patients, eventually combined with new maintenance strategies in the post-transplant period. Figure 1 Disclosures No relevant conflicts of interest to declare.

Whereas the molecular events underlying acute myeloid leukemia (AML) are increasingly identified, dynamics of hematologic recovery following induction chemotherapy remain mysterious. Platelet recovery may vary between incomplete and excess recovery among patients achieving remission. We analyzed platelet recovery after the first induction cycle in 291 consecutive AML patients. We defined excess platelet rebound (EPR) as platelet increase above 500 G/L. We observed EPR in 120 (41.2%) patients. EPR+ patients had lower platelets at diagnosis, higher marrow infiltration, more frequently NPM1 mutations, and were associated with ELN favorable risk. Absence of EPR correlated with complex karyotypes, ELN intermediate-I and adverse risk, and therapy-related AML. Overall survival was better in EPR+ patients than EPR- (median 125 vs 41 months; p = 0.04), as was disease-free survival. By multivariate analysis, EPR+ was an independent parameter associated with favorable survival. Plasma thrombopoietin (TPO) levels at diagnosis indicated EPR+ (p

Introduction: CAR-T cell therapy is likely to be introduced starting from 2021 in patients with relapsed/refractory myeloma (r/r MM) in Europe. In order to qualify for commercial CAR-T treatment, it is assumed that r/r MM patients will have to be exposed to at least three lines of previous treatments including lenalidomide, bortezomib and anti-CD38 treatment. However, the outcome of this particular subgroup of r/r MM patients is largely unknown whereas this knowledge is crucial to estimate the possible benefit of eventual CAR-T treatment. Methods: In this non-interventional, retrospective single-center study, we analyzed all subsequent r/r MM patients treated between 01/2016 (when anti-CD38 treatment was commercially introduced in Switzerland) and 04/2020 at the University Hospital of Bern. Patients were eligible for the study if they had received at least three lines of treatment including one proteasome inhibitor (PI), one immunomodulatory drug (IMID) and one anti-CD38 antibody, and if they were in need of subsequent treatment and effectively received further lines of treatment. Results: Among 56 patients fulfilling the criteria of at least three lines of treatment including PI, IMID and anti-CD38 treatment, only 34 (60%) effectively received subsequent further therapy. This suggests that 40% of r/r MM patients never receive additional treatment after at least three lines of treatment including PI, IMID and anti-CD38 treatment. For patients receiving further treatment, the median number of previous lines of treatment was 4.5 (range 2-12), including autologous stem cell transplantation in 31 (91%) patients. 13 (37%) patients were penta-refractory. The most frequently used treatment options were IMID/dexamethasone treatment in 11 (32%) patients, followed by PI/dexamethasone in 10 (29%) patients. 21 (62%) patients received two or more additional lines of therapy. The median PFS was 6.6 months (range 0–36.6 months), the median TTNT was 7.5 months (range 1.4-24.5 months) and the median OS was 13.5 months, (range 0.1-38 months) for the first subsequent treatment. The overall response rate (ORR) to the first subsequent treatment was 41%, with a median duration of the response of 5 months (range 1-37 months). 12% of the patients achieved VGPR or better, with a median duration of response of 8 months (range 3-37 months). Conclusion: Myeloma patients refractory after at least three lines of anti-CD38/PI/IMID treatment have a poor prognosis with a PFS of 6.6 months and OS of 13.5 months. These data may serve as reference to compare the potential benefit of CAR-T treatment in this group of myeloma patients when available in the near future.

Autologous stem cell transplantation (ASCT) continues to be a critical part of the disease control in younger patients with multiple myeloma (MM). Current evidence suggests that an induction treatm...

INTRODUCTION High-dose chemotherapy (HDCT)/autologous stem cell transplantation (ASCT) is the standard for patients with relapsed/refractory lymphomas and multiple myeloma (MM), thereby improving DFS and OS. Relapse after HDCT/ASCT remains the major cause of death in patients with lymphomas or MM after melphalan-based HDCT. Dose-intensified bendamustine by replacing carmustine in the BEAM regimen (BeEAM) or by combining it with melphalan (BenMel) is a promising strategy to lower the relapse rates.Renal toxicity after BeEAM emerges as a major concern. METHODS We investigated renal toxicity in consecutive lymphoma patients treated with BeEAM and in consecutive MM patients treated with the same dose of 400 mg/m2 bendamustine (split into 200 mg/m2 on two consecutive days) together with full-dosed (200 mg/m2) melphalan. Patients with a history of renal impairment before HDCT were included. We assessed renal damage summarized as acute kidney injury (AKI) by measuring renal parameters on a daily basis starting from the first day of HDCT until the last day of hospitalization for HDCT/ASCT. AKI: rise of s-creatinine ≥26.5 μmol/L in 48 hours or increase to more than or equal to twofold compared to baseline s-creatinine within 7 days (Kidney Disease International Global Organization, KDIGO, criteria). Grading of AKI: KDIGO. Treatment-related AKI (rAKI): occurred within 10 days from the last administration of bendamustine; no relation to sepsis. Consequently, we defined as treatment-unrelated AKI (uAKI) all renal damage occurring because of sepsis or later than 10 days since the last administration of bendamustine. Statistical Analysis Subgroup differences: Chi-squared test, Fisher Exact test. IBM SPSS software version 21. RESULTS Patient characteristics and therapy regimen: 122 consecutive patients with lymphomas or MM who underwent high- dose bendamustine regimen before ASCT in 01/2013-06/2016. Factors related to rAKIOccurrence of rAKI: correlated (p60 years, previous AKI, cardiovascular comorbidities and concomitant nephrotoxic drugs. In addition, rAKI correlated (p=0.004) with cardiovascular complications during hospitalization; details of subgroups analysis: Table 2.No differences in the incidence of rAKI MM (n=7/15; 46.7%) and lymphoma patients (n=44/107; 41.1%), p=0.683. Acute kidney Injury related to High Dose Bendamustine is reversible and manageable • Acute kidney injury related to bendamustine (rAKI): in 51 patients (41.8%); completely reversible in n=50/51 (98.0%). • rAKI: mild to moderate in 90% of affected patients; did not increase TRM after ASCT. • 3/51 patients (5.9%) with rAKI required transient renal dialysis to enable recovery from renal damage, whereas approaches such as additional hydration were sufficient in the vast majority (n=48 with rAKI; 94.1% of this subgroup). • The median duration of rAKI was 7 days (range, 1-22). ­ According to Cox ZL et al., Adverse Drug Events during AKI and its recovery, Clin J Am Soc Nephrol 2013; 8:1070-1078. CONCLUSION • Our data suggest that treatment-related acute renal toxicity is common in lymphoma and MM patients receiving dose-intensified bendamustine HDCT before ASCT. • However, renal impairment is reversible and manageable. • Our data identify a subgroup of patients at increased risk for the development of renal damage following bendamustine-based HDCT. • Such patients should be strictly monitored during hospitalization, and a generous hydration strategy before, during and after administration of bendamustine is recommended. • Assessing the pre-transplant renal risk profile may help to identify those patients, which may not be candidates for bendamustine-based HDCT thereby avoiding prolonged hospitalization due to rAKI and eventual transient dialysis treatment. • Our results may contribute to design appropriate selection criteria for dose-intensified bendamustine as part of the conditioning regimens preceding HDCT/ASCT in lymphoma and MM patients.

Induction chemotherapy in AML patients may have life-threatening side effects requiring intensive care unit (ICU) treatment. We analyzed all AML patients receiving intensive chemotherapy at a single academic center between 01/2006-12/2016. At least one ICU admission was observed in 32% (76/240) patients, and 33% of those died following ICU admission. Whereas the ICU admission proportion remained stable, mortality after ICU admission decreased from 14% (2006-2008) to 3% (2014-2016; p = .056). The number of failing organ systems inversely correlated with surviving ICU admission (p 50% even after 14 days of ICU treatment. Progression-free and overall survival were comparable between ICU surviving patients and patients never needing ICU support. In conclusion, outcome after ICU admission of AML patients has substantially improved in recent years.

The optimal melphalan dose prior to autologous stem cell transplantation (ASCT) is not known for elderly multiple myeloma (MM) patients. We analyzed data of all MM patients ≥65 years (n = 388) enrolled in the observational Swiss Blood Stem Cell Transplantation Registry. The median age was 67 years (65-77). Single ASCT was performed in 344 (88.7%) patients, with 259 patients (75.3%) receiving a melphalan dose of 200 mg/m (MEL200), and 85 patients (24.7%) receiving lower doses (MELlow) (median 140 mg/m, range 70-180 mg/m). MEL200 patients were slightly younger, and had a better renal function, but did not differ with regards to ISS stage, cytogenetic risk, remission status, and KPS. Overall mortality at day 100 was 1.5% without differences between the MEL groups (p = 0.621). Median progression-free survival (PFS) in the MEL200 and the MELlow group was 27.7 and 22.1 months, respectively (p = 0.294). Median overall survival (OS) in the MEL200 and in MELlow group was 91.2 and 61.2 months (p = 0.015). However, multivariate analysis showed no significant association of the melphalan dose and OS (HR 0.734; CI95% 0.264-2.038; p = 0.553). In conclusion, our data reveal no significant differences in safety and PFS for elderly myeloma patients treated with MEL200 or with lower MEL doses.

Mutations within exon 12 of the Nucleophosmin (NPM1) gene are frequent events in acute myeloid leukemia (AML) accounting for 40% of normal karyotype patients, and timely identification of NPM1 mutations is crucial for classification, risk assessment and allocation of consolidation treatment (AML). Consequently, NPM1 mutated AML was acknowledged as a distinct WHO entity. However, different NPM1 mutations are observed, with subtype A being most common, followed by B and D and various rare subtypes. The current paradigm of leukemogenesis indicates that NPM1 mutations act as founder mutations and are highly stable in the course of the disease. Accordingly, the same NPM1 mutation has been shown to be present in late AML relapses occurring more than five years after first diagnosis. We here report a patient with a second manifestation of NPM1 mutated AML occurring eight years after first diagnosis characterized by a shift in the NPM1 mutation subtype as compared to initial diagnosis. The sequential observation of different NPM1 mutations in the same patient asks for careful reconsideration of the concept of late relapses in NPM1 mutated AML.

Consolidation in myeloma patients with high-dose melphalan chemotherapy (Mel HDCT) and autologous transplantation (ASCT) is standard of care since more than 2 decades. However, definite cure remains exceptional despite intensive treatment, and improving effectiveness of HDCT remains an unmet clinical need. Combining intensified bendamustine with melphalan may represent an option. We analyzed safety and efficacy of combining dose-intensified bendamustine (200 mg/m2 on days -4/-3) with high-dose melphalan (100 mg/m2 on days -2/-1) before a second (tandem) ASCT in adverse risk myeloma patients after Mel HDCT/ASCT1. Twelve patients received BenMel conditioning before ASCT2 because of high-risk cytogenetics and/or failure to achieve complete remission (CR) after Mel HDCT/ASCT1. Comparing Mel HDCT/ASCT1 and BenMel HDCT/ASCT2, we observed no differences in hematologic recovery and tolerance. Acute renal injury after BenMel conditioning occurred in 3 (25%) patients, but was reversible in all patients, and there were no treatment related deaths. Complete remission rates were increasing from 42% after Mel/ASCT1 to 75% after BenMel/ASCT2. PFS 1 year after ASCT2 was 67%, and OS was 83%. These data suggest that dose-intensified bendamustine with melphalan conditioning is safe and warrants a prospective randomized comparison to standard melphalan HDCT in myeloma patients.

Background: Whereas the molecular events underlying acute myeloid leukemia (AML) are increasingly identified, dynamics of hematologic suppression and recovery following induction chemotherapy remain enigmatic. In addition, thrombocytopenia at diagnosis is related to deregulated cytokine expression in specific leukemia subtypes rather than on the degree of bone marrow infiltration per se. Similarly, recovery of platelets after the first induction cycle among individual patients can vary from incomplete to excess recovery even if morphologic remission is achieved. In particular, excess platelet rebound (EPR) with values exceeding 500 G/L can be observed in some patients. However, this clinical observation of EPR is poorly understood so far, and its prognostic relevance is unknown. Methods: We analyzed platelet recovery after the first induction cycle in 291 consecutive AML patients receiving at least one cycle of intensive "3+7" based induction treatment. We defined excess platelet rebound (EPR) as a platelet increase above 500 G/L during hematologic recovery after the first induction cycle. Results: We observed EPR in 120 (41.2%) patients. EPR+ patients had lower platelets at diagnosis, higher marrow infiltration, more frequently NPM1 mutations, and were associated with ELN favorable risk. Absence of EPR correlated with complex karyotypes, ELN intermediate-I and adverse risk, and therapy-related AML. Overall survival was better in EPR+ patients than EPR- (median 125 versus 41 months; P=0.04), as was disease-free survival (Figure 1). By multivariate analysis, achievement of EPR+ was an independent parameter associated with favorable survival. Plasma thrombopoietin (TPO) levels at diagnosis indicated EPR+ (p Conclusion: This study suggests that excess platelet rebound (EPR+) defined as platelets exceeding 500 G/L is a common event identified in AML patients after the first induction cycle. EPR+ was predominantly observed in ELN favorable risk AML, and it was associated with significantly better overall and disease-free survival as compared to EPR- patients. In addition, achievement of EPR+ represented an independent prognostic parameter for improved survival in a multivariate analysis, and may contribute to prognostic assessment in AML patients undergoing intensive treatment with intention to cure. Disclosures No relevant conflicts of interest to declare.

Background: In myeloma patients, a non-myelosuppressive regimen combining a single dose of vinorelbine chemotherapy together with G-CSF is safe and effective to harvest peripheral blood progenitor and stem cells (PBSC) before autologous stem cell transplantation (ASCT). Considering its neurotoxic potential, vinorelbine may aggravate pre-existing bortezomib-induced polyneuropathy, and gemcitabine represents an alternative mobilization regimen. We have reported that monotherapy with gemcitabine together with G-CSF can be used as a promising alternative mobilization chemotherapy to vinorelbine, even more so as gemcitabine avoids neurotoxicity associated with vinorelbine Methods: In this prospective phase-II study (ViGeM Trial; NCT# 02791373), we compared in a 1:1 randomization the efficacy and toxicity of vinorelbine or gemcitabine with G-CSF (and, if needed, plerixafor) in 130 evaluable myeloma patients in first remission. The objective of the study is to demonstrate the non-inferiority of gemcitabine versus vinorelbine. The primary endpoint is mobilization success, which is defined as a collected apheresis product comprising at least 6.0×106 CD34+ cells/kg b.w. at day 8 after chemotherapy (vinorelbine or gemcitabine) together with G-CSF in the absence of plerixafor. Results: We observed successful CD34+ mobilization in 75% [95% confidence interval (CI): 63%-85%] of patients in the vinorelbine group versus 49% [95% CI: 36%-62%] with gemcitabine; the pre-specified non-inferiority margin -15% was not reached. More vinorelbine recipients achieved the collection goal in a single-day procedure (78% vs 60%). The median CD34+ yield was 11.4×106/kg b.w. in vinorelbine versus 8.7×106/kg in gemcitabine (P=0.001). At apheresis as well as day +100 following ASCT, polyneuropathy occurred more frequent in vinorelbine recipients. Special attention should be given to the fact that no patients with gemcitabine was observed with grade ≥ 3 polyneuropathy (Table 1). Finally, less patients in the vinorelbine group (1%) needed two apheresis days as compared to 14% in the gemcitabine group, respectively (P=0.007), whereas the use of rescue plerixafor was similar (11% versus 10%). Conclusion: This prospective comparison indicated that non-inferiority of gemcitabine as compared to vinorelbine chemotherapy together with G-CSF stimulation regarding CD34+ mobilization was not reached. Polyneuropathy was aggravated in the vinorelbine cohort, but not in gemcitabine recipients. Our study allows individualization of CD34+ mobilization regimens in myeloma patients. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Vinorelbine and gemcitabine are used for stem cell mobilization in this study and, thus, off-label.

Introduction: An autologous CD3+ cell collection is the first step required for a CAR-T therapy. Up to now, in the commercial setting, one of the available models predicting the time or processed patient blood volume needed in order to gain the minimum-targeted absolute count of CD3+ cells relies on a formula provided by Novartis (Reference Model - RM), which assumes these parameters to be inversely proportional. We here aimed to develop a refined and more precise model, which enables to predict the needed processed blood volume in patients with low pre-apheresis peripheral CD3+ counts for gaining the targeted CD3+ cell count of e.g. 1.0x10⁹, using the patient's pre-apheresis peripheral CD3+ cell values, the collected absolute CD3+ cell counts, and the effectively processed blood volumes (Bern model - BM). Methods: We analyzed 16 lymphocyte apheresis procedures in adult patients (ALL: n=1; B-cell lymphomas: n=15) with a median age of 70.5 years (r 25 - 81 years) performed at the University Hospital Bern, Switzerland, for the production of Kymriah® (Novartis) in the period from December 2018 till July 2019. All cell collections were performed on the Spectra Optia (Terumo BCT©) device. Continuous Mononuclear Cell Collection (CMNC) procedure was used. We measured the peripheral CD3+ cell counts of the patients' blood and the collected products by means of multi-parameter flow cytometry (BD FACSCanto II). The inversely proportional function (RM) did not fit well our data, which was the trigger to look for an alternative function. Best fit of the series of data points and establishing of the function calculation has been performed by using Excel 2019 statistics, using power function modeling. Results: The median peripheral CD3+ cell level at start of apheresis was 1.29x10⁹/ml (r 0.11x10⁹/ml - 2.66x10⁹/ml). Low peripheral CD3+ counts (defined as < 0.7x10⁹/ml) were found in 5 out of 16 patients, whereas 11 patients showed normal peripheral CD3+ counts. Interestingly, in our hands lymphocyte collections at low pre-apheresis CD3+ counts was successful reaching the target >1.0x10⁹ CD3+ cells defined by the manufacturer. The median collection duration was 176 minutes (r 114 - 286 minutes) and the median ratio of processed blood volume to WBV (patient whole blood volume) was 3.1 (r 1.50 - 6.70). There was a significant negative correlation between CD3+ cell levels and blood volume processed/WBV (Spearman rank correlation, r: -0.92, p=0.0285). The median collected CD3+ cell number in the lymphocyte harvests was 6.43 x109 (r 1.88x109 - 11.90x109), fulfilling the required minimum of CD3+ cells in all 16 patients. In Figure 1, each data point labeled by 1-9 or A- G represents an individual patient. The function of RM y=2.5x-1 (plotted in gray) is the intuitive, inverse proportional model provided by Novartis to calculate the minimum targeted cell count for production of Kymriah®. The function of BM y=2.167x-0,759 (plotted in blue) is our empiric model best fitting to our patients' data. Both models provide numerically similar results in case of normal pre-apheresis CD3+ cell counts, but differ significantly in the area of low pre-apheresis CD3+ values. To illustrate all similarities and differences between BM and RM in a single plot, one can present this relation as follows: BM = 2.167(pCD3+)-0,759 is equal to 2.5(pCD3+) -1(RM) * 0.8671(pCD3+)0,241 where pCD3+ is the pre-apheresis CD3+ cell count expressed in 109 cells/ ml. Using this approach we obtain the following final formula: BM = RM * BF where BF (Bern Factor) is defined here as 0.8671 * (pCD3+)0.241. Figure 2 presents a graphic illustration of the formula for the BF. The function in Figure 2 is linking the RM and BM. For low CD3+ values, the BF is lower than for the normal CD3+ values. Conclusion: In the area of lower pre-apheresis CD3+ values, lymphocyte apheresis showed to be more efficient than expected by the manufacturer's model and the collection could be performed faster than assumed. According to our data the function y=2.167x-0,759 is more precise for calculating the needed processed blood volume for gaining the minimum required CD3+ cell count of 1.0x10⁹. Further investigations are needed to evaluate the applicability of the above Bern Model to predict processed blood volumes in patients with low peripheral CD3+ counts and to explain the phenomenon why the collection seems less efficient for patients with normal peripheral CD3+ cells. Disclosures Jalowiec: Pfizer: Other: Travel grant; Amgen: Other: Travel grant; Novartis: Other: Travel grant. Baerlocher:Novartis: Research Funding. Zeerleder:Alexion: Speakers Bureau; Jazz Pharma: Speakers Bureau; Sanofi/Genzyme: Speakers Bureau.

Introduction: Autologous stem cell transplantation (ASCT) following high-dose chemotherapy (HDCT) is a cornerstone in the standard first-line treatment in myeloma (MM) patients. Freezing of the hematopoietic stem cells (HSC) to bypass the time between stem cell collection and completion of HDCT is crucial for this process. Due to the vulnerability of HSC, adding of anti-freezing agents such 5-10 vol% dimethyl-sulfoxide (DMSO) to hematopoietic stem cells is mandatory. DMSO exerts toxic effects after administration, and toxicity of DMSO is dose-related. However, guidelines for this procedure are missing, and transplant centers have implemented varying limitations of maximum total DMSO administration, ranging from 20-70 g per day. At our center, the maximum transplant volume is 300 mL per day with DMSO at 5 vol%. For patients with transfusion volumes above these limits, the transplant procedure is split over several days. Methods: In this single center study, we retrospectively analyzed the impact of multiple day transplantation procedures on survival rates and hematological recovery in 271 patients with MM patients undergoing first melphalan-based ASCT. Results: 244 (90%) received ASCT within a single day, and this group was termed Tx1. The Tx2-3 group comprised 23 patients receiving stem cells on 2 days, and four patients on 3 days. Both groups (Tx1 and Tx2-3) did not differ in clinical characteristics or number/types of induction therapy lines. The remission status pre-transplant was comparable. Plerixafor was given more frequently in Tx2-3 than Tx1 (p=0.0715). At the day of SC collection, peripheral CD34+ counts were lower in Tx2-3. The final administered autograft volume was higher in Tx2-3 patients. The amount of transplanted CD34+ cells/kg b.w. was lower in the Tx2-3 group, mirroring poorer mobilization of CD34+ cells (p Conclusions: Our data suggest that multiple day transplantation is associated with poor CD34+ mobilization and is observed in roughly 10% of myeloma patients. Patients with multiple day transplant procedures had later neutrophil and platelet engraftment, longer hospitalization duration, more febrile episodes, and inferior OS and RFS. This suggests to consider myeloma patients with the need for multiple day transplantation as a patient group at increased risk that needs enhanced surveillance strategies. Disclosures No relevant conflicts of interest to declare.