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Introduction The kidney is an important target organ in plasma cell dyscrasias, subjected to various mechanisms of injury such as tubular obstruction, hypercalcemia, and pre-existing disease. Preservation of kidney function in newly diagnosed (ND) multiple myeloma (MM) is of concern as treatment-related toxicity (for instance infections and mucositis) is known to increase with renal impairment (RI). However, even severe MM-induced RI may recover with anti-myeloma treatment. We set out to compare three induction regimens in patients (pts) with transplant-eligible NDMM in terms of renal recovery and toxicity, MM response and associated adverse events (AEs). Pts from two prospective trials (NCT00833560, NCT01685814) were analyzed, provided post-induction (PInd) restaging data was available. They received three 3-week induction cycles with bortezomib (btz), cyclophosphamide, and dexamethasone (dex; VCD); btz, lenalidomide (len), and dex (VRD); or three 4-week cycles with len, adriamycin, and dex (RAD). All pts had to have measurable disease, an estimated glomerular filtration rate (eGFR) of >30 ml/min and to be up to 60 (VCD) and 65 years (yrs) of age, respectively. VCD consisted of intravenous (IV) btz 1.3 mg/m² on day (D) 1, 4, 8, 11; IV cyclophosphamide 900 mg/m2D1; dex 20 mg D 1+2, 4+5, 8+9, 11+12. VRD of subcutaneous (SQ) btz 1.3 mg/m² D 1, 4, 8, 11; len 25 mg, D1-14; dex 20 mg D 1+2, 4+5, 8+9, 11+12; and RAD of len 25 mg D1-21; IV adriamycin 9 mg/m² D1-4; dex 40 mg D 1-4 + 17-20. MethodsThis is a secondary analysis of a phase 2 and a phase 3 study. We hypothesized MM disease response (and in turn, renal recovery) would be best with VRD. GFR was estimated by the MDRD IV or CKD-Epi formulas. The increase (and decrease, respectively) of renal function expressed by "GFRpost induction- GFRscreening" was tested for significance (p 50 ml/min and ≤ 70 ml/min (group II) were observed in 11.6 % of VCD pts, 29.9% of VRD and 25.2 % of RAD pts, respectively. 78.2% of VCD pts, 56.1% of VRD and 63.9% of RAD pts had a baseline eGFR of > 70 ml/min (group III; pPR (p=.0387). In the whole cohort, proportion of patients in eGFR group I had decreased from 10.0 to 3.0% (p +2 ml/min(/1.73m²)/month, respectively. 25.7% of VCD, 29.4% of VRD and 23.3% of RAD pts fell into the +2 ml/min was achieved by 55.2% of VCD vs 42.1% of VRD treated pts, respectively (Figure 1; p +2 ml/min(/1.73m²)/month. It is tempting to speculate that either the difference between SQ and IV btz, differential effects of len and cyclophosphamide on kidney function or non-MM related factors account for these unexpected and discordant renal and MM responses. Kidney-specific AEs, urine protein studies and comorbidities will be presented. Disclosures Mügge: Celgene: Research Funding; Celgene, Janssen: Honoraria. Schreder:Janssen, Celgene: Consultancy, Honoraria. Schaefer-Eckart:Pfizer, Janssen, Celgene: Honoraria. Metzler:Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. Hertenstein:RS Media: Research Funding. Maschmeyer:Gilead, Janssen Cilag, Astra Zeneca; BMS, Merk-Serono: Honoraria. Salwender:Janssen Cilag: Consultancy, Honoraria, Other: Travel grants; Celgene: Honoraria, Other: Travel grants; AMGEN: Honoraria, Other: Travel grants; Sanofi: Honoraria, Other: Travel grants; Bristol-Myers Squibb: Honoraria, Other: Travel grants; Takeda: Honoraria, Other: Travel grants; Oncopeptides: Honoraria, Other: Travel Grants. von Lilienfeld-Toal:Celgene, Oncopeptides: Consultancy, Honoraria. Straka:Celgene, Janssen, AMGEN: Consultancy, Research Funding, Speakers Bureau. Knop:Janssen, AMGEN, Bristol-Myers Squibb, Celgene: Consultancy, Honoraria. OffLabel Disclosure: Lenalidomide, adriamycin, dexamethsone in newly diagnosed multiple myeloma

Introduction Based on improvement of overall survival (OS), lenalidomide (R) maintenance after up-front autologous stem cell transplantation has recently been approved for multiple myeloma (MM) patients (pts). Conversely, in transplant non-eligible (TNE) pts R maintenance after R-based induction improved progression free survival (PFS) but had no impact on OS. First-line treatment with VMP is considered a standard of care for newly diagnosed (ND) TNE pts, but whether maintenance therapy with R after VMP induction can further improve PFS and OS is currently unknown. Aims The prospective phase IIb GERMAIN trial (EudraCT-No: 2012-003023-38) aimed to evaluate the role of R maintenance after VMP induction in ND TNE MM pts. The trial, which planned to include 286 ND TNE MM pts, closed early in December 2017 due to insufficient accrual and high discontinuation rate. The present analysis focuses on the reasons for the high drop out rate. Methods After induction with 6 courses of VMP (Mateos et al., Lancet Oncology 2010), pts achieving at least a partial response (PR) were randomized 1:1 to R 10 mg or placebo (PCB) daily until progression (PD) or unacceptable toxicity. Pts with Results From May 2014 to December 2017 85 pts were enrolled. Median age was 75 years (range 63-87). A significant proportion of pts presented with at least one concomitant illness: 75% were hypertensive, 29% had a cardiac disorder, 37% a metabolic disorder and 19% a chronic kidney disease. Induction was completed by 53 pts and 40 pts entered maintenance randomization (Figure 1). Of patients completing induction therapy 77% achieved at least a PR, including 11% of sCR/CR and 26% of VGPR. Overall 70% of pts discontinued the study; main reasons for trial discontinuation were PD (24%), unacceptable toxicity (17%), investigator decision (16%) and withdrawal of informed consent (12%). Of pts discontinuing treatment, 27 pts (47%) stopped during induction, and in 71% of these cases discontinuation was due to unacceptable toxicities (26%) or investigator (26%) and patients (19%) decision. Only one pt discontinued due to insufficient response during induction. In total 745 adverse events (AE) and 71 serious AEs (SAE) were reported; of these 814 had complete data and were analyzed. During induction 571 AE occurred, of which 110 (19%) were of grade ≥3. Seventy-one pts (86%) reported at least one AE, and 49 (59%) at least one grade ≥3 AE. The most common grade ≥3 AE were: leukopenia (25%), thrombocytopenia (20%), cardiac toxicity (10%), infections (8%), peripheral neuropathy (6%), anemia and gastrointestinal toxicity (5% each). The cumulative probability of development of a grade ≥3 AE at 6 months was 59% (95% CI: 47 to 69%). SAEs during VMP were 54; 39% of pts experienced at least one SAE during induction. The cumulative probability for an SAE at 6 months was 41% (95% CI: 30 to 51%). During induction 4 deaths were recorded, all within the first month of treatment. Of the pts randomized to maintenance treatment 37 received at least one dose of R/PCB and were considered evaluable. Twenty-one pts (36%) discontinued the study during maintenance. Main reason for discontinuation was PD (11 pts, 4 in R and 9 in PCB arm); only 2 pts (both in R arm) discontinued due to AE 2 and 21 months after start of maintenance, respectively. Of the AE recorded during maintenance (n=157, 92 in the R and 65 in the PCB group) 17% were grade ≥3 and 12 were considered SAE. At least one AE and at least one SAE were reported in 29 (78%) and 8 pts (22%), respectively. Four secondary malignancies (1 basal cell carcinoma, 1 AML, 1 bladder cancer and 1 lung cancer) were reported, 1 during VMP induction and 3 during maintenance. Conclusions In comparison to other studies focusing on ND TNE MM pts, our study investigated a remarkably elderly and frail population. In the cohort investigated, treatment with VMP resulted in increased toxicity and higher rate of discontinuation. Nevertheless, in those pts able to complete induction a promising ORR was observed. In elderly and frail MM pts, regimens other than VMP should be considered for induction. Disclosures Brioli: Celgene: Honoraria, Other: Travel support, Research Funding; Janssen: Honoraria. Hänel:Roche: Honoraria; Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria. Pfirrmann:Novartis: Research Funding. von Lilienfeld-Toal:Janssen: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Takeda: Honoraria, Other: Travel support, Research Funding. Fabisch:Novartis: Research Funding. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding. Hochhaus:Incyte: Research Funding; Pfizer: Research Funding; Takeda: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Research Funding. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria.

Introduction High-dose chemotherapy and stem cell transplant (SCT) remains a standard of care in medically fit patients (pts) with newly diagnosed (ND) MM. Induction triplets with at least one of the newer compounds are recommended. Bortezomib (V), lenalidomide (R) and dexamethasone (D; VRD) ranks among the most effective regimens and VRD/SCT was superior to VRD alone in an RCT. In a phase 2 study, we demonstrated RAD induction (lenalidomide 25 mg d1-21; Adriamycin 9 mg/m2 iv d1-4; dexamethasone 40 mg d 1-4 and 17-20 every 4 weeks) followed by SCT to be safe and effective (Knop et al., Leukemia 2017). Therefore, we decided to compare RAD versus (vs) VRD (lenalidomide 25 mg, d1-14; subcutaneous bortezomib 1.3 mg/m2 d 1, 4, 8, 11; dexamethasone 20 mg d 1+2, 4+5, 8+9, 11+12 every 3 weeks) induction (3 cycles each) in an RCT. MethodsThe current study was set up according to a double 2x2-factorial design to enrol transplant-eligible pts up to 65 years. The post-induction (PI) complete response (CR) rate as per IMWG criteria was the efficacy co-primary endpoint. We hypothesized the CR rate following RAD to be non-inferior to VRD which was estimated to be 20%. The study was powered to confirm non-inferiority of RAD at a margin of 10% with a one-sided alpha level of .05. Cytogenetic characterization was performed by fluorescence in situ hybridization (FISH) from CD138-enriched plasma cells. Minimal residual disease (MRD) was assessed by second-generation eight-color flow cytometry (FC; EuroFlow protocol). Bone marrow (BM) samples from baseline and defined restaging time points were analyzed for an acquisition of ⩾107cells/sample. In a subgroup of 103 pts, we evaluated the applicability of comprehensive immunoglobulin (Ig) amplicon next generation sequencing (NGS) to detect molecular MRD markers and to compare the results with FC. NGS-based marker screening was performed in baseline BM. Sequencing libraries were prepared using 2-step PCR employing multiplex primer sets for IGH V-D-J (FR1, FR2 and FR3), IGH D-J and IGK loci (V-J and KDe). For MRD detection, we used 1-step library preparation with the same primer sets. Results476 pts with a median age of 55 (range, 32-65) years were randomized between 05/2012 and 06/2016 and 469 received at least one dose of study drug. High-risk (HR) FISH abnormalities comprised del17p (11.3% of pts); t(4;14) (11.7%); and t(14;16) (4.5%). 232 pts were randomized to receive RAD, and 237 to VRD, respectively. 90.5% of RAD vs 93.7% of VRD pts completed all 3 cycles. PI CR rate was 13.5% (95% CI, 9.4%-18.7%) with RAD vs 13.4% (95% CI, 9.3-18.5) with VRD, (P=.971). Rates of ≥VGPR were 40.6% (50% CI, 34.2%-47.3%) with RAD vs 48.9% (95% CI, 42.3-55.6%) with VRD (P=.076). In pts with HR cytogenetics, rates of ≥VGPR were 43.3% (RAD) vs. 59.3% (VRD; P=.096). From 317 pts with paired samples, 33/151 (21.9%) of RAD vs 45/166 (27.1%) of VRD pts were FC MRD negative (P=.169) following induction at a median sensitivity level of 6.73x10-6. 197/239 positive pts (82.4%%) had MRD levels above 0.01%, and 42 (17.6%), between 0.0001 and 0.01%. Flow MRD negativity as per IMWG MRD criteria (Kumar et al, Lancet Oncol 2016) was seen in 8/151 (5.2%) pts with RAD vs 6/166 (3.6%) with VRD (P=.27). The remainder of pts did not (yet) fulfil IMWG CR for various reasons. NGS marker screening identified at least 1 Ig marker in 98/103 evaluable patients. To date, 47/98 pts were analyzed for NGS MRD following induction. Four out of 47 (8.5%) subjects were sequencing negative (3/4 post-VRD) with all of them also being IMWG FC MRD negative. One VRD patient died during induction for a mortality rate of 0.2 %. 62.1% of RAD vs 55.3% of VRD pts experienced at least one serious adverse event (SAE; p=.16). SAEs with relationship to study drugs of at least °3 severity occurred in 26.3% (RAD) vs 23.6% (VRD) pts (p=.523). ConclusionsTo the best of our knowledge, this is the first RCT to compare two R-based triplets in SCT-eligible pts. The co-primary efficacy endpoint was met with identical PI CR rates of around 13% for RAD and VRD, respectively. However, a trend emerges to favor VRD over RAD in terms of at least VGPR including HR FISH subjects. Analysis of MRD by multicolor FC showed 5% of pts to be already IMWG flow MRD-negative. Results for all 98 pts evaluable for NGS MRD will be presented. As of yet, too few progression events have occurred to estimate the second co-primary endpoint, 3-year progression-free survival. Longitudinal response and MRD analysis are ongoing. Disclosures Langer: Celgene: Consultancy. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria; Bristol Myers Squibb: Honoraria; Amgen: Honoraria. Blau:Amgen: Other: Advisory board; BMS: Other: Advisory board; Novartis: Other: Advisory boards; Takeda: Other: Advisory board; Janssen: Other: Advisory board, Research Funding; Celgene: Other: Advisory board, Research Funding. Rollig:Janssen: Research Funding; Bayer: Research Funding. Dechow:AMGEN: Consultancy; Celgene: Honoraria. Gramatzki:Affimed: Research Funding. Brümmendorf:Merck: Consultancy; Janssen: Consultancy; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Schmidt:Gilead: Honoraria, Other: Travel Grants; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grants; Celgene: Honoraria. Knop:Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding.

Introduction MEL at the dose of 200 mg/m2 (MEL200) is considered the standard conditioning regimen before ASCT in MM patients (pts). Lower doses of 140 mg/m2 (MEL140) or 100 mg/m2 (MEL100) are used when toxicity is a concern. Whether these lower doses are equally effective is still a matter of debate and available data are conflicting. Aims and Methods To compare full dose with reduced dose MEL, we performed a retrospective analysis on MM pts in all disease stages treated at Jena University Hospital between 2003 and 2017. Statistical analysis included descriptive statistics and Cox regression. Progression free survival (PFS) and overall survival (OS) were calculated from the time of ASCT. Here, preliminary data on 187 pts are presented. For pts receiving more than one ASCT (n=69), only data on the first ASCT were included in the analysis. Pts treated with MEL140 and MEL100 were pooled (MELRed group). Results Of 187 ASCTs, 163 were performed as first-line and 24 as salvage therapies. Median follow up of the entire population was 77 months (range 3-172). Induction treatment included at least 1 novel agent (immunomodulatory drugs, IMiDs or proteasome inhibitors, PI) in 119 pts, whilst 68 pts received conventional chemotherapy. Median number of induction cycles before ASCT was 3 (range 1-10). Prior to ASCT 31 pts (17%) had achieved at least a very good partial remission (VGPR). MEL200 was used in 112 (60%) and MELRed in 75 pts (40%, 72 MEL140 and 3 MEL100). There was no difference in the two groups in the number of transplant performed as first line or as salvage therapy (p=0.54), as well as in the rate of pts achieving at least a VGPR before ASCT (17% vs. 16%, for MEL200 and MELRed respectively, p=0.84). More pts treated with MEL200 received induction treatment containing novel agents (70% vs. 55% for MEL200 and MELRed respectively, p=0.037). High quality responses (≥VGPR) after ASCT were higher in the MEL200 group: 89% of pts treated with MEL200 vs. 73% of those receiving MELRed, p=0.005. The main reasons for MEL dose reduction were older age (40%) and renal insufficiency (29%). Median age (range) and creatinine values (range) were 55 (35-68) vs. 63 (47-70) years (p2 (83% vs. 99% for MEL200 and MELRed respectively, p=0.001). Toxicities and duration of hospitalization of the two groups are depicted in Table 1. The higher response rate seen in pts treated with MEL200 translated in a longer median PFS (43 vs. 27 months for MEL200 and MELRed respectively, p=0.023) and OS (66% vs. 51% at 5 years for MEL200 and MELRed respectively, p=0.046). Multivariate analysis included CCI >2, response before and after ASCT ≥VGPR, disease stage at ASCT, age >65 years, treatment with new drugs, glomerular filtration rate ≥60 ml/min at the time of ASCT and treatment with MEL200. Disease stage (HR 0.57, 95% CI 0.331-0.978, p=0.041) and MEL200 (HR 0.49, 95% CI 0.295-0.802, p=0.005) were associated with an improved PFS, whilst none of the above mentioned variables had an impact on OS. Conclusion In comparison with MELRed, MEL200 provides favorable responses and improves PFS and OS with only moderate increase of toxicity in this retrospective pts cohort. At least in pts treated with standard-induction therapy, MEL200 should be considered the standard conditioning regimen for ASCT eligible MM pts. Disclosures Brioli: Janssen: Honoraria; Celgene: Honoraria, Other: Travel support, Research Funding. Mügge:Amgen: Honoraria; Novartis: Honoraria; Janssen: Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria, Research Funding. Scholl:Abbivie: Other: Travel support; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Novartis: Other: Travel support; Deutsche Krebshilfe: Research Funding; Alexion: Other: Travel support; MDS: Other: Travel support; Carreras Foundation: Research Funding. Hilgendorf:Novartis: Other: Travel support, Research Funding; Medac: Other: Travel support, Research Funding. Sayer:RIEMSER Pharma GmbH: Honoraria. Ernst:Novartis: Research Funding. Hochhaus:Incyte: Research Funding; Novartis: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Bristol-Myers Squibb: Research Funding. von Lilienfeld-Toal:Takeda: Honoraria, Other: Travel support, Research Funding; Novartis: Honoraria, Other: Travel support, Research Funding; Celgene: Honoraria, Other: Travel support, Research Funding; Janssen: Honoraria, Other: Travel support, Research Funding.

Introduction: Panobinostat (PAN) is a potent pan-deacetylase inhibitor that targets multiple myeloma (MM) cells via its epigenetic effects as well as its effect on the aggresome. In the PANORAMA 1 phase 3 trial, the combination of PAN, bortezomib (BTZ), and dexamethasone (Dex; PAN+BTZ+Dex) significantly increased progression-free survival compared with placebo plus BTZ and Dex, leading to approval in Europe of the combination for the treatment of patients with MM who have received ≥ 2 prior regimens, including BTZ and an immunomodulatory agent. The purpose of this expanded treatment protocol (ETP) is to further evaluate safety and to provide panobinostat prior to commercial availability to patients with relapsed/refractory MM who have received ≥ 2 prior lines of therapy but for whom satisfactory treatment alternatives are not available. Methods: Panobinostat-ETP is a multicenter, open-label, ETP study of PAN+BTZ+Dex in adult patients with MM relapsed and/or refractory to ≥ 2 prior lines of therapy. During treatment phase (TP) 1 of the study, patients received oral PAN 20 mg (days 1, 3, 5, 8, 10, and 12) plus intravenous or subcutaneous BTZ 1.3 mg/m2 (days 1, 4, 8, and 11) for eight 21-day cycles. Patients with ≥ stable disease proceeded to TP2, with maintained PAN and less frequent BTZ dosing (days 1 and 8) for an additional 8 cycles. In both phases, oral Dex 20 mg was administered on the days of and after BTZ treatment. Reduction to once-weekly BTZ was allowed prior to TP2 as a dose reduction strategy. Results: A total of 49 patients with a median age of 67 years (range, 45-85 years) were enrolled in the study. Patients were heavily pretreated; 73.5% received ≥ 3 prior lines of therapy. Most patients (n = 43 [87.8%]) received subcutaneous BTZ, while 3 (6.1%) received intravenous BTZ, and another 3 (6.1%) received both. The median duration of treatment with PAN+BTZ+Dex was 67 days (range, 12-305 days). The most common grade 3/4 hematologic laboratory abnormalities were thrombocytopenia (51.0%), anemia (12.2%), and neutropenia (10.2%). The most common nonhematologic grade 3/4 treatment-emergent adverse events (AEs) were diarrhea (14.3%), fatigue (8.2%), infection (6.1%), and nausea (6.1%). Common gastrointestinal treatment-emergent AEs of any grade included diarrhea (51.0%), constipation (16.3%), and nausea (16.3%). Interestingly, in the patients receiving subcutaneous BTZ, the rates of grade 3/4 diarrhea (11.6%), thrombocytopenia (48.8%), anemia (14.0%), and neutropenia (11.6%) were lower than those seen with intravenous BTZ administration in the phase 3 PANORAMA 1 trial (25%, 57%, 16.8%, and 24.1%, respectively). Two patients died while on treatment; one due to disease progression and the other due to infection. Common serious AEs included diarrhea (12.2%) and thrombocytopenia, atrial fibrillation, infection, pneumonia, and syncope (all 6.1%); serious AEs of atrial fibrillation and syncope were higher than in PANORAMA 1 (1.0% and 1.3%, respectively). AEs led to PAN, BTZ, and Dex dose adjustment in 36.7%, 42.9%, and 16.3% of patients, respectively; the most common AE leading to dose adjustment or temporary interruption was thrombocytopenia (all-grade, 30.6%; grade 3/4, 28.6%). Efficacy data will be reported after sufficient follow-up. Conclusions: Overall, the safety results from panobinostat-ETP, albeit in an older population of patients with more advanced MM, support those generated in PANORAMA 1, with only a slight increase in atrial fibrillation, potentially because of the older population. In the subgroup of patients receiving subcutaneous BTZ, rates of diarrhea and hematologic toxicities, AEs of interest with PAN+BTZ+Dex therapy, appear to be reduced compared with PANORAMA 1 data with intravenous BTZ administration; however, because of the small size of this study, these results should be interpreted with caution. Further clinical experience with the use of subcutaneous BTZ in this combination will help to determine the potential impact of the route of BTZ administration on tolerability. Disclosures Guenther: Takeda: Consultancy, Honoraria; Celgene: Honoraria; Novartis: Consultancy, Honoraria. Mügge:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Cilag: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Bristol Myers-Suibb: Honoraria. Schjesvold:Janssen: Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lechner:Novartis: Honoraria. Gisslinger:Novartis: Consultancy, Honoraria; AOP Orphan: Consultancy, Honoraria; Baxalta: Consultancy, Honoraria. Greil:Novartis: Honoraria, Research Funding; Janssen Cilag: Honoraria, Research Funding. Gunsilius:Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria; Novartis: Membership on an entity's Board of Directors or advisory committees. Weisel:Amgen: Consultancy, Honoraria; Bristol Myer-Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Munder:Janssen: Honoraria; Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Takeda: Honoraria. Kiani:Novartis: Consultancy, Honoraria, Speakers Bureau. Campello-Iddison:Novartis: Employment, Equity Ownership. Einsele:Janssen: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau.

Introduction: Due to continuous research and novel agents, today´s treatment choices for MM patients (pts) are numerous. In order to provide best tolerable and adjusted treatment, it is desirable to objectively assess individuals' biological fitness and comorbidities (CM), rather than using pts' chronological age alone (Bron et al. Haematologica 2016). Therefore, it is necessary to define new functional and geriatric test tools that are suitable to rate CM and therapy-related risks. Methods: This prospective multicenter functional geriatric assessment (F-GA) was attentively performed in newly diagnosed (ND) MM pts within German DSMM study centers prior to initiation of antimyeloma treatment, which reflected pts´ baseline health status. Moreover, a follow-up F-GA was conducted ~12 months after this baseline assessment. The F-GA included: 1. rating of fitness by a) physicians and b) pts, 2.Karnofsky Performance Status (KPS), 3.pain scale, 4.Instrumental activity of daily living (IADL), 5.Activity of daily living (ADL), 6.SF12-QoL questionnaire, 7.malnutrition, 8.Mini-Mental status (MMS), 9.geriatric depression scale (GDS) and 10. Timed Up and Go Test (TUGT). In addition, established CM scores were determined: a) Initial-Myeloma Comorbidity Index (I-MCI) and b) Revised-MCI (R-MCI), c) International Myeloma working group (IMWG) score, d) Charlson Comorbidity Index (CCI), e) Hematopoietic Cell Transplantation Specific-Comorbidity Index (HCT-CI), f) Kaplan Feinstein (KF), g) eGFR/ß2MG. The trial protocol was approved by the ethics committees. All pts provided written informed consent and all procedures were conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization and GCP Guidelines. Results: A total of 289 newly diagnosed MM pts of all age groups have already been included in this prospective multicenter trial. Characteristics of pts were typical for tertiary centers with a median age of 62 years (range: 27-85), hemoglobin of 11.0g/dl (5-17), eGFR of 70ml/min/1.73qm (7-163), ß2-MG of 3 mg/l (1-38) and bone marrow plasma cell infiltration of 40% (0-100). Pts estimated their fitness with a median of 3 (1-6) and pain level of 2 (0-10). In line, their frailty assessment revealed a median KPS of 80% (30-100) and TUGT of 10 (4-80). Median functional results were for the ADL 5 (2-6), for the IADL 8 (1-8) and for malnutrition 3 (0-14). The MMS revealed only a slight cognitive deficiency of 28 (15-30) and GDS of 2 (0-13). CM scores showed a median I-MCI of 0 (0-3), R-MCI of 4 (0-9), IMWG of 1 (0-4), CCI of 2 (0-8), HCT-CI of 2 (0-9), KF of 1 (0-3), eGFR/ß2MG score of 1 (0-2). Most relevant F-GA-tools for PFS and OS - according to our current results - seem to be the TUGT, R-MCI and IMWG scores. Those 122 pts that have already received both baseline (T0) and follow-up assessments (T1) showed notable and significant improvement in some of these tests (Tab. 1), e.g. ADL, R-MCI, IMWG, CCI, HCT-CI scores, whereas others, such as the IADL and KF remained almost constant. Pain, depression and malnutrition also improved, albeit to as yet insignificant extends. For 66 pts the second assessment has to be done within the next month, 60 patients died since the start of this trial, 40 of those within the first 12 months and 85 pts dropped out without a second assessment. Conclusion: To the best of our knowledge, this is the first extensive prospective, multicenter F-GA that determines most valuable disease risks, functional tests and CM scores in MM pts. Our results suggest that relevant parameters in MM pts are the KPS, fitness rating by physicians and pts, ADL, TUGT, frailty, malnutrition, pain due to osteolyses, and renal function, whereas the IADL, MMS, GDS and lung function seem less revealing. Most predictive test tools are the R-MCI- and IMWG-scores that distinguish fit, intermediate-fit and frail pts most precisely. The results of our follow-up-assessment demonstrate that pts´ health status may significantly improve upon treatment. We continue this F-GA in an even larger prospective multicenter cohort to consolidate these results which will be presented at the meeting. Disclosures Langer: Celgene: Consultancy; Takeda: Consultancy; Janssen: Consultancy; Amgen: Consultancy; Novartis: Consultancy. Knop:Takeda: Consultancy. Engelhardt:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/Accommodation/Expenses , Research Funding; MSD: Consultancy, Honoraria.

Background: In the pivotal phase 3 FIRST trial, continuous lenalidomide plus low-dose dexamethasone (Rd) improved progression-free survival (PFS), overall survival (OS), and response compared with fixed-duration treatment (Tx) with either Rd or the combination of melphalan-prednisone-thalidomide (MPT) in transplant-ineligible NDMM pts (Facon, Blood 2013). Here we examine if pts achieving complete remission (CR) or at least very good partial response (≥ VGPR) equally benefit from continuous Rd. Methods: Pts were randomized to continuous Rd until progressive disease (PD; N= 535); Rd for 18 cycles (72 weeks) (Rd18; N = 541); or MPT for 12 cycles (72 weeks) (N = 547). The primary endpoint was PFS (continuous Rd vs. MPT). The secondary endpoints included OS, response rate (assessed using IMWG criteria), time to response, duration of response (DOR), time to Tx failure, time to next antimyeloma Tx, health-related quality of life, and safety. With a data cutoff of May 24, 2013, the median follow-up was 37.0 months (mos). Results: In pts who achieved ≥ VGPR, median PFS was significantly longer (NR) with continuous Rd compared with Rd18 (31.0 mos; HR = 0.46; P < 0.01) or MPT (34.7 mos; HR = 0.55; P < 001). Even greater benefit of continuous Rd was observed compared with Rd18 or MPT in pts who achieved CR, where the median PFS with continuous Rd was NR vs. 45.2 mos with Rd18 (HR = 0.29; P < 0.01) and 44.6 mos with MPT (HR = 0.28; P < 0.01) (Table 1). In the intent-to-treat population, duration of response (DOR) was 35 mos with continuous Rd, which was significantly longer of almost a year vs. Rd18 (22.1 mos; HR = 0.60; P < 0.01) or MPT (22.3; HR = 0.63; P < 0.01). Importantly, the DOR was significantly longer with continuous Rd vs. Rd18 or MPT across all response categories, including pts with CR. Median duration of CR was NR vs. 43.6 mos in pts receiving continuous Rd vs. Rd18 (HR = 0.29; P < 0.01); ≥ VGPR, NR vs. 29.9 mos (HR = 0.46; P < 0.01); and ≥ PR, 35 mos vs. 22.1 mos (HR = 0.60; P < 0.01). In pts who achieved CR, 88% were disease-free after 36 mos with continuous Rd vs. 55% Rd18 and 54% MPT. In terms of OS, only interim data on continuous Rd vs. Rd18 or MPT on depth of response in the subgroups is presented in table 1. Conclusions: The DOR was significantly longer (12-18 mos) as was PFS in pts treated with continuous Rd vs. Rd18 or MPT regardless of the depth of response. The benefits of continuous Rd were more pronounced in pts who achieved a greater depth of response (≥ VGPR). These data suggest that continuing Tx after best response may further help in controlling the disease and delaying PD, especially in pts achieving CR. Longer follow-up may be needed to determine the impact of response quality on OS in pts receiving continuous Tx. Abstract 3458. Table 1. PFS, DOR, and OS in pts with NDMM CR (n = 209) ≥ VGPR (n = 618) ≥ PR (n = 1140) ≤ SD (n = 483) ITT pts (N = 1623) Median PFS (mos) Rd NR NR 37.7 3.7 27.4 Rd18 45.2 31.0 24.0 4.6 21.3 MPT 44.6 34.7 26.3 4.9 21.8 PFS, HR (95% CI); P-value Rd vs. MPT 0.28 (0.13–0.61); P < 0.01 0.55 (0.40–0.76); P < 0.01 0.67 (0.55–0.82); P < 0.01 1.60 (1.22–2.11); P < 0.01 0.68 (0.56–0.83); P < 0.01 Rd vs. Rd18 0.29 (0.15–0.58); P < 0.01 0.46 (0.34–0.60); P < 0.01 0.60 (0.49–0.72); P < 0.01 1.10 (0.82–1.48); P = 0.53 0.68 (0.55–0.83); P < 0.01 Median DOR (mos) Rd NR NR 35.0 – 35.0 Rd18 43.6 29.9 22.1 – 22.1 MPT 41.9 31.8 22.3 – 22.3 DOR, HR (95% CI); P-value Rd vs. MPT 0.27 (0.13–0.59); P < 0.01 0.54 (0.39–0.74); P < 0.01 0.63 (0.51–0.76); P < 0.01 – 0.63 (0.51–0.76); P < 0.01 Rd vs. Rd18 0.29 (0.15–0.59); P < 0.01 0.46 (0.35–0.61); P < 0.01 0.60 (0.50–0.72); P < 0.01 – 0.60 (0.50–0.72); P < 0.01 Median OS (mos) Rd NR NR 55.1 33.2 55.1 Rd18 NR NR NR 26.8 53.6 MPT NR NR NR 31.6 48.2 OS, HR (95% CI); P-value Rd vs. MPT 0.59 (0.23–1.49); P = 0.26 0.77 (0.50–1.180; P = 0.23 0.85 (0.64–1.11); P = 0.23 0.98 (0.72–1.33); P = 0.89 0.78 (0.64–0.96); P < 0.02 Rd vs. Rd18 0.84 (0.34–2.07); P = 0.71 0.82 (0.56–1.22); P = 0.33 0.90 (0.69–1.17); P = 0.45 0.97 (0.70–1.35); P = 0.85 0.90 (0.73–1.10); P =0.31 CI, confidence interval; ITT, intent-to-treat. Disclosures Bahlis: Celgene: Honoraria, Research Funding. Off Label Use: Lenalidomide used in newly diagnosed multiple myeloma patients. Stoppa:Celgene, Janssen: Honoraria. Decaux:Celgene and Janssen-Cilag : Consultancy, Honoraria. Marit:Celgene, Janssen: Congress expenses Other. Demuynck:Janssen-Cilag: Honoraria. Ervin-Haynes:Celgene: Employment. Leupin:Celgene: Employment. Marek:Celgene: Employment, Equity Ownership. Chen:Celgene: Employment. Facon:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Background High-dose chemotherapy followed by autologous stem cell transplant (ASCT) has been the mainstay of first-line treatment in multiple myeloma for nearly two decades. As the majority of patients (pts.) will experience relapse, we continuously are in need of effective salvage strategies such as the era of the “novel agents” is offering. The “next generation” compounds such as pomalidomide or carfilzomib significantly improve prognosis. However, virtually all drug combinations need to be delivered continuously through (subsequent) disease progression, thereby contributing to exhaustion of bone marrow function. This in turn leads to compromised full-dose treatment, which would be necessary to conquer refractory disease. Given these challenges and considering a long interval since the initial exposure to melphalan (Mel) a further autotransplant seems reasonable. Whether a third autotransplant still is effective in patients who have initially received tandem ASCT and may overcome therapy-induced exhausted bone marrow function is unclear. Therefore, we assessed the outcomes of pts. receiving a third melphalan-based salvage ASCT (ASCT3). Methods We queried the databases of six German myeloma centres for cases that were offered a third autotransplant after uniform melphalan-based tandem ASCT as part of their first-line therapies. Results 55 pts. with a median age of 58 years at diagnosis (range, 36 – 72) and of 63 (range, 38 – 77) at ASCT3 were identified. ASCT3 was performed at a median of 63 (range, 14 – 355) months (mos.) from myeloma primary diagnosis and a median interval from initial tandem autotransplant of 51 (range, 5 – 131) mos. Median progression-free survival (PFS) from primary tandem transplant had been 23 mos. (range, 4 – 94). 45 pts. (82%) had either received bortezomib and/or lenalidomide, and 37 pts. both. Eleven pts. had been double refractory and 23 pts. at least had been refractory to one of the novel agents prior to their 3rd transplant. In 45 cases cytogenetic analysis had been available, of which 9.1% could be classified as ”high-risk” (17p13 del, t(4;14), t(14;16), amp1q21, del1p). At ASCT3, median administered Mel-dose had been 100mg/m2 (range, 30-200). 50 pts. received autografts, which had been harvested at first-line treatment while 5 pts. had successfully undergone additional stem cell mobilisation. Median number of re-infused CD34+ cells was 3.0 (range, 0.4 – 15.7) x 10exp6/kg body weight with all patients achieving stable engraftment. A remarkable improvement of platelet count (PLT) and haemoglobin (Hb) within 3 mos. of ASCT3 could be achieved. PLT improvement occurred in 53% and Hb improvement (when compared to pre-ASCT3 values) in 64% of pts. Beyond that, overall response rate (partial response (PR) or better) was 59% with 8 pts. (15%) achieving CR, 6 pts. (11%) VGPR and an additional 18 pts. (33%) PR, respectively. 23 pts. (42%) suffered from grade 3 non-hematologic toxicities and in one case a grade 4 toxicity was documented. Non-relapse mortality (NRM) within 3 mos. after ASCT3 was 5%. Median PFS after ASCT3 was 6 mos. for the whole group and 2 mos. for the group with “high risk” cytogenetics (p=0,06), respectively, whereas median OS (30 mos.) was identical. In case of double-refractory myeloma, PFS did not differ significantly (3 mos. vs. 7 mos., p=0.35) whereas there was a significant difference in median OS (12 mos. vs. 35 mos., p=0.002) in comparison with non-refractory pts., respectively. Conclusions Our analysis indicates that salvage ASCT at late relapse is feasible and associated with a 6 mos.’ additional PFS interval but also contributes to improved hematopoietic function. Pts. may thus tolerate further conventional lines of treatment what is suggested by an OS of 30 mos. In addition, ASCT offers a substantial treatment-free interval when compared to either “next generation” novel drug. In this series, unfavourable cytogenetics were associated with a trend for worse PFS but not OS outcomes, meanwhile being double refractory was linked with clearly inferior OS. Interestingly, median duration of storage of their autografts of 52 mos. (range, 1 – 154) did not impair engraftment after salvage transplant. Disclosures No relevant conflicts of interest to declare.

Background Induction triplets with at least one of the “novel drugs” and steroids with or without chemotherapy are deemed standard of care in newly diagnosed multiple myeloma (MM). Medically fit patients (pts) remain candidates for subsequent autologous (auto) stem cell transplant (SCT) while the use of allogeneic (allo) SCT is an ongoing matter of debate. We had previously shown the RAD regimen to be well tolerated and highly effective in relapsed and relapsed/refractory disease. Based on the overall results we decided to further evaluate the combination in first-line treatment. Methods The current phase II trial was designed to include pts up to 65 years of age with newly diagnosed, symptomatic MM. Four 4-week RAD induction cycles (lenalidomide 25 mg/day, d 1-21; infusional adriamycin 9 mg/m², d1-4; oral dexamethasone 40 mg, d1-4 and 17-20; pegfilgrastim 6 mg, d 6) were followed by stem cell chemomobilization. Pts received either tandem auto SCT (melphalan 200 mg/m²; Mel) or auto followed by allo SCT. Allo SCT (conditioning regimen: treosulfan/fludarabine) was reserved for pts featuring at least one cytogenetic or serologic risk factor who had a matched sibling or unrelated donor available. Target dose for subsequent lenalidomide maintenance (R-maint; for one year) was 10 mg/d for tandem Mel and 5mg/d for auto/allo pts. Primary endpoint was response (at least VGPR) following second SCT. Results 190 pts with a median age of 55 (range, 30-66) years were recruited by 17 German centers between 8/2009 and 4/2012. 103 pts (56%) had ISS stage II/III disease and 165 pts are evaluable for molecular cytogenetic abnormalities assessed by fluorescence in situ hybridisation (FISH). Incidences were as follows: 29.6% had deletion of (del) chromosome 13q, 11.5% showed translocation (t) (4;14), 9% presented with del 17p, and 0.6% had a t(14;16). 163 pts completed all 4 RAD cycles and 47 underwent allogeneic SCT. 60 pts following tandem Mel and 15 pts after auto-allo SCT proceeded to R-maint. Median number of maintenance cycles was significantly higher in tandem Mel compared with auto-allo pts (12 versus 3; p=.01). Rate of at least (≥) VGPR increased from 47.9% following RAD induction to 60.6% following double SCT. Accordingly, post-induction complete response (CR)/stringent CR rate of 7.9% increased to 31%. In pts with FISH results, ≥ VGPR rate was 44% with t(4;14)/t(14;16)/del 17p versus 53% without those abnormalities, respectively (p=.34). Following double SCT, ≥ VGPR was increased to 63% [t(4;14)/t(14;16)/del 17 pts.] versus 65%, respectively (p=.84). Response was not different with either transplant strategy. No treatment-related mortality occurred during RAD induction, while non-relapse mortality at one year from allo SCT was 10.6%. Incidences of pneumonia, venous thromboembolism, and febrile neutropenia were 11, 7.2, and 5.3%, respectively. Preliminary overall survival results will be presented. Conclusions Our data show RAD induction to be very effective in newly diagnosed MM and to be well tolerated. By subsequent double SCT, a high number of CR/sCR was added. Correlative studies suggests response to be independent of known unfavourable cytogenetic prognosticators, such as t(4;14) and del 17p while time-to-event data will be needed to ultimately confirm a lenalidomide-based triple regimen being able to overcome adverse cytogenetic risk. Administration of R-maint to auto-allo pts was challenging despite a lenalidomide target dose of 5 mg/day. Disclosures Knop: Celgene GmbH: Consultancy, Honoraria. Off Label Use: Use of lenalidomide, doxorubicin, and dexamethasone in newly diagnosed multiple myeloma. Einsele:Celgene GmbH: Consultancy, Research Funding. Bargou:Amgen Inc.: Consultancy, Honoraria, Other.

131 Introduction. Autologous stem cell transplantation (ASCT) after cytoreductive induction is considered standard of care for younger patients (pts) with multiple myeloma (MM). The previous standard of induction, the Vincristin-Adriamycin-Dexamethasone (VAD) combination, achieves inferior results compared with induction regimens which combine the proteasome inhibitor Velcade (V = Bortezomib) with Dexamethasone (D)(=VD) and a cytostatic drug such as Doxorubicin (PAD = VD plus Doxorubicin). Velcade-based induction therapy was shown to translate into better myeloma control after high dose melphalan and to lead to prolonged progression-free survival. In order to find a more efficacious and safer drug combination for induction therapy in MM, we tested the combination of Velcade with Cyclophosphamide and Dexamethasone (VCD). Methods. This trial was designed as an open, prospective, multi-center, uncontrolled, combined phase II/III study. As previously reported (Kropff M et al., Ann Hematol 2009), in the first 30 pts the optimal dose of iv Cyclophosphamide in combination with V and D was defined as 900 mg/m2 on d1. Between 03/2006 and 03/2009 we enrolled an additional 370 pts up to 60 years of age with untreated MM to receive three 3-week cycles of induction treatment with V 1.3 mg/m2 iv d1,4,8,11; D 40 mg/d orally d1,2,4,5,8,9,11,12; and C 900mg/m2 iv d1 before scheduled high dose melphalan and ASCT. The primary endpoint of the study is response rate on day 63 after 3 cycles of VCD according to EBMT and IMWG criteria. Results. Final data from 400 pts from 39 German centers will be presented at the meeting. In the currently evaluable 300 pts (mean age 52.3 years; 1.7% stage I, 21.3% stage II, 77.0% stage III) molecular cytogenetic analysis showed a prevalence of 13q- in 38%, of t[4;14] in 13% and of 17p- in 12% of pts (no changes in 35%). All 300 pts (88.3% of whom completed three cycles) were included in the intent-to-treat analysis. Overall response rate (ORR = CR+PR) was 84%, with 10% CR and 74% PR, 5.7% MR, 7.3% NC and 2.3% PD. The negative prognostic impact of 13q- or t[4;14] was abrogated (ORR normal 87.3%, 13q- 83.7%, t[4;14] 90.0%), the unfavorable influence of p53 loss in the 17p- subgroup was still detectable (ORR 69.2%) but this did not reach statistical significance. VGPR rates will be reported at the meeting. Serious adverse events were documented in 78/300 (26.0%) patients. Death rate was remarkably low (1.3%, of which one was not related to the trial medication). 155/300 (52%) of pts experienced grade 3/4 non-serious AEs and of these leucopenia (93/300 pts= 31%), thrombocytopenia (7%), neutropenia (6%), anaemia (5%) were the most frequent events. 80 AEs grade 3 or 4 and 45 SAEs were of infectious origin and occurred in 47/300 pts. 80/130 SAEs (61.5%) were at least possibly related to Velcade. 101/300 pts (34%) developed episodes of peripheral neuropathy. PNP was grade 1 in 62/300 pt (20.7%), grade 2 in 31/300 pt (10.3%) and grade 3 in 7/300 pts (2.3%). Conclusion. This analysis demonstrates that proteasome inhibition by Velcade in combination with Dexamethasone and iv Cyclophosphamide (VCD) is an induction regimen for newly diagnosed MM which is highly effective in a short period of time, has a rather low toxicity profile and is feasible for administration in an outpatient setting. Based on these characteristics, VCD qualifies to become a new standard for MM induction therapy. | Response to VCD | % | |:---------------:| --- | | ORR | 84 | | CR | 10 | | PR | 74 | | MR | 5.7 | | SD | 7.3 | | PD | 2.3 | Table 1: Response to study therapy (intent-to-treat set, according to investigator, n=300) | | Responding patients (≥ PR) | |:-------------------:| -------------------------- | ---- | | n | % | | No FISH abnormality | 69/79 | 87.3 | | 13q- | 72/86 | 83.7 | | t(4;14) | 27/30 | 90 | | 17p- | 18/26 | 69.2 | | Other | 68/77 | 88.3 | Table 2: Response by result of cytogenetic analysis (intent-to-treat set, according to investigator, n=300) Disclosures: Einsele: OrthioBiotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Off Label Use: Bortezomib is licensed as monotherapy for use in relapsed/refractory MM and in combination with melphalan/Prednisone in the first-line treatment of MM pts ineligible for HD-MEL and ASCT. . Liebisch: OrthoBiotech: Consultancy, Honoraria. Langer: OrthoBiotech: Consultancy. Kropff: OrthoBiotech: Consultancy, Honoraria. Kroger: OrthoBiotech: Honoraria. Ostermann: OrthoBiotech: Honoraria. Mugge: OrthoBiotech: Honoraria. Wolf: OrthoBiotech: Honoraria. Gramatzki: OrthoBiotech: Consultancy, Honoraria. Maschmeyer: OrthoBiotech: Travel Grant. Sezer: OrthoBiotech: Consultancy, Honoraria. Heidemann: OrthoBiotech: Honoraria. Jager: OrthoBiotech: Honoraria. Dechow: Celgene: Research Funding. Simon: OrthoBiotech: Honoraria. Straka: OrthoBiotech: Consultancy, Honoraria, Research Funding. Fingerle-Rowson: orthoBiotech: Employment. Knop: OrthoBiotech: Honoraria.

Introduction: Acute GvHD has, despite established immunosuppressive prophylaxis regimens, significant impact on acute morbidity and mortality following allogeneic stem cell transplantation (SCT). In the unrelated or even non-matched unrelated situation new GvHD-prophylaxis regimens balancing GvHD and graft-versus-leukaemia effect are needed. EC-MPS and mycophenolate mofetil [MMF] are effective immunosuppressants by inhibition of T- and B-cell proliferation. Primary study aims in this ethical board approved, prospective, single-centre, open phase II trial were (1) feasibility of prolongatedly started oral EC-MPS and (2) reduction in the rate of GvHD in unrelated allogeneic SCT. Patients and Methods: EC-MPS [Myfortic ®] 720 mg twice a day orally starting at day +10 after SCT in addition to standard GvHD prophylaxis, consisting of cyclosporine (CSA) 3 mg/kg continuous intravenous infusion with or without methotrexate (MTX) 15 mg/m2 day +1 and 10 mg/m2 day +3,+6,+11 intravenous push, was evaluated. According to the protocol, EC-MPS was tapered from day +40, if no acute GvHD-signs were present. 54 patients, including 8 patients from a previous pilot trial, with advanced haematological malignancies (n=28) or in first remission of acute leukaemia (n=26) between 8/03 and 12/07 were evaluated. The patients had either a 10/10 HLA-matched (n=32) or a 8-9/10 HLA mismatched unrelated donor (n=22). 32 (59%) patients received 40 mg/kg antithymocyte globulin (ATG), with 8 Gray total body irradiation (TBI) and cyclophosphamide (CY), or with fludarabine 120mg/m2, busulfan 8mg/kg or treosulfan 8–12 mg/kg. 12 or 8 Gray TBI and 120 mg/kg CY followed by MTX i.v. were administered to 22 (41%) patients. Results: A median of 5.7 (range: 0.9–9.9) unmanipulated G-CSF-mobilized CD-34 positive stem cells per kg were given on day 0. All of the 23 women and 31 men (median age 48 years (range: 20–65)), except one patient, showed a leukocyte engraftment on median day +14 (range: 9–35). Platelet engraftment was observed on median day +17 (range: 9–132). In 12 patients (22%) initially i.v. MMF (1g twice a day) instead of oral study medication was given temporarily, mostly due to severe mucositis. In six patients (11%) EC-MPS (on day +14, 17, 22, 32, 37, 76) had to be discontinued, due to severe nausea (n=2), neurological toxicity (n=2), graft failure (n=1) and protocol violation (n=1). Acute GvHD grade II-IV was observed in 27 (52%) patients, including 8 (15%) with grade III and 4 (7.5%) with grade IV. The incidence of chronic GvHD was 63 % (n=29) [limited chronic GvHD: 54 % (n=15), extended chronic GvHD: 14% (n=4)] of the 46 patients surviving >100 days after SCT. With 10/10 HLA-matched donors GvHD grade II-IV was seen in 44% (n= 14) [grade III and IV n=5 (16%)], whereas with non fully-matched donors the incidence was 59 % (n=13) [grade III and IV n=7 (32%)]. Chronic GvHD incidence was 50% (14/28) in the fully matched donor situation in contrast to 83% (15/18) in the non-fully matched situation. The conditioning regimen with ATG resulted in a GvHD grade II-IV incidence of 39% (n=12) [GvHD grade III/IV: 19% (n=6)], compared to 68% (n=15) [GvHD grade III/IV: 27% (n=6)] without ATG. With a median follow-up of 16 months (range: 1–56) 28 patients (52%) are alive, 18 fully HLA-matched stem cell recipients (56%) and 10 mismatched HLA recipients (45%). Survival with or without ATG was 50% (n=16) and 55% (n=12), respectively. Twenty-six (48%) patients have died; 12 (22%) due to relapse, 10 (19%) due to acute/chronic GvHD, and 4 (7%) due to infection/secondary cancer without GvHD. Conclusions: EC-MPS with a 10 day prolongated start after transplantation combined with initial standard GvHD prophylaxis in the unrelated stem cell transplantation setting seems to be feasible. Mucositis was the main course for oral intake problems. The toxicity drop-out rate of 7 % should be considered. The analysis of all evaluable patients in the pilot and the prospective trial yielded effectiveness in reducing severe GvHD Grade III/IV, especially in combination with ATG. The MPS application regimen failed to show less incidence of chronic GvHD in the non-fully matched unrelated donor setting. GvHD prevention trials in the future should incorporate new drugs with a different pathway of T-cell inhibition or tolerance induction, respectively.