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Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61–65 years (S2, n = 107) and 66–70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray’s p = 0.83) and non-relapse mortality (Gray’s p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n = 502): arms A1:PAd + LEN-2Y (n = 125), B1:PAd + LEN-CR (n = 126), A2:VCD + LEN-2Y (n = 126), B2:VCD + LEN-CR (n = 125). In the LEN-CR group (B1 + B2), n = 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p = 0.60, primary endpoint) nor overall survival (OS) (p = 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p = 0.03) but not PFS (HR = 1.15, p = 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p = 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p = 0.01). LEN MT should be applied beyond CR for at least 2 years.

PURPOSE DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all- trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML). PATIENTS AND METHODS Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety. RESULTS The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms. CONCLUSION The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.

The article Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age, written by Elias K. Mai, Kaya Miah, Uta Bertsch, Jan Dürig, Christof Scheid, Katja C. Weisel, Christina Kunz, Markus Munder, Hans- Walter Lindemann, Maximilian Merz, Dirk Hose, Anna Jauch, Anja Seckinger, Steffen Luntz, Sandra Sauer, Stephan Fuhrmann, Peter Brossart, Ahmet Elmaagacli, Martin Goerner, Helga Bernhard, Martin Hoffmann, Marc S. Raab, Igor W. Blau, Mathias Hänel, Axel Benner, Hans J. Salwender, and Hartmut Goldschmidt for the German-speaking Myeloma Multicenter Group (GMMG), was originally published Online First without Open Access. After publication in volume 35, pages 809–822, the author decided to opt for Open Choice and to make the article an Open Access publication. Therefore, the copyright of the article has been changed to © The Author(s) 2020 and the article is forthwith distributed under the terms of the Creative Commons Attribution. FUNDING Open Access funding enabled and organized by Projekt DEAL.

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Lenalidomide (LEN) maintenance (MT) post autologous stem cell transplantation (ASCT) is standard of care in newly diagnosed multiple myeloma (MM) but has not been compared to other agents in clinical trials. We retrospectively compared bortezomib (BTZ; n = 138) or LEN (n = 183) MT from two subsequent GMMG phase III trials. All patients received three cycles of BTZ-based triplet induction and post-ASCT MT. BTZ MT (1.3 mg/m2 i.v.) was administered every 2 weeks for 2 years. LEN MT included two consolidation cycles (25 mg p.o., days 1–21 of 28 day cycles) followed by 10–15 mg/day for 2 years. The BTZ cohort more frequently received tandem ASCT (91% vs. 33%) due to different tandem ASCT strategies. In the LEN and BTZ cohort, 43% and 46% of patients completed 2 years of MT as intended (p = 0.57). Progression-free survival (PFS; HR = 0.83, p = 0.18) and overall survival (OS; HR = 0.70, p = 0.15) did not differ significantly with LEN vs. BTZ MT. Patients with n = 54 vs. BTZ: n = 84), LEN MT significantly improved PFS (HR = 0.61, p = 0.04) but not OS (HR = 0.46, p = 0.09). In conclusion, the significant PFS benefit after eliminating the impact of different tandem ASCT rates supports the current standard of LEN MT after ASCT.

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m2), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.

The Dutch-Belgian Cooperative Trial Group for Hematology Oncology Group-65/German-speaking Myeloma Multicenter Group-HD4 (HOVON-65/GMMG-HD4) phase III trial compared bortezomib (BTZ) before and after high-dose melphalan and autologous stem cell transplantation (HDM, PAD arm) compared with classical cytotoxic agents prior and thalidomide after HDM (VAD arm) in multiple myeloma (MM) patients aged 18-65 years. Here, the long-term follow-up and data on second primary malignancies (SPM) are presented. After a median follow-up of 96 months, progression-free survival (censored at allogeneic transplantation, PFS) remained significantly prolonged in the PAD versus VAD arm (hazard ratio (HR) = 0.76, 95% confidence interval (95% CI) of 0.65-0.89, P = 0.001). Overall survival (OS) was similar in the PAD versus VAD arm (HR = 0.89, 95% CI: 0.74-1.08, P = 0.24). The incidence of SPM were similar between the two arms (7% each, P = 0.73). The negative prognostic effects of the cytogenetic aberration deletion 17p13 (clone size >= 10%) and renal impairment at baseline (serum creatinine > 2 mg dl(-1)) on PFS and OS remained abrogated in the PAD but not VAD arm. OS from first relapse/progression was similar between the study arms (HR = 1.02, P = 0.85). In conclusion, the survival benefit with BTZ induction/maintenance compared with classical cytotoxic agents and thalidomide maintenance is maintained without an increased risk of SPM.

We investigated subclonal cytogenetic aberrations (CA) detected by interphase fluorescence in situ hybridization (iFISH) in patients with newly diagnosed multiple myeloma (MM) enrolled in the Haemato Oncology Foundation for Adults in the Netherlands (HOVON)-65/German-Speaking MM Group (GMMG)-HD4 phase 3 trial. Patients were either treated with 3 cycles of vincristine, Adriamycin, and dexamethasone or bortezomib, Adriamycin, and dexamethasone and then thalidomide or bortezomib maintenance after tandem autologous transplantation. Subclones were defined either by presence of different copy numbers of the same chromosome loci and/or CA present in at least 30% less and maximally 2/3 of cells compared with the main clone CA. Patients with subclones harbored more frequently high risk (31.0%) or hyperdiploid main clone aberrations (24.8%) than patients with t(11;14) in the main clone (10.1%). Gains and deletions of c-MYC were the only CA that occurred more frequently as subclone (8.1%/20.5%) than main clone (6.2%/3.9%, respectively). Treatment with bortezomib completely overcame the negative prognosis of high-risk CA in patients without subclones, but not in patients with additional subclonal CA. High-risk patients treated without bortezomib showed dismal outcome whether subclones were present or not. Cytogenetic heterogeneity defined by subclonal CA is of major prognostic significance in newly diagnosed MM patients treated with bortezomib within the HOVON-65/GMMG-HD4 trial.

Objectives Randomized comparison of two treatment strategies in frontline therapy of acute promyelocytic leukemia (APL): all-trans retinoic acid (ATRA) and double induction intensified by high-dose cytosine arabinoside (HD ara-C) (German AMLCG) and therapy with ATRA and anthracyclines (Spanish PETHEMA, LPA99). Patients and results Eighty of 87 adult patients with genetically confirmed APL of all risk groups were eligible. The outcome of both arms was similar: AMLCG vs PETHEMA: hematological complete remission 87% vs 83%, early death 13% vs 17% (P = .76), overall survival, event-free survival, leukemia-free survival, cumulative incidence of relapse at 6 years 75% vs 78% (P = .92); 75% vs 68% (P = .29); 86% vs 81% (P = .28); and 0% vs 12% (P = .04, no relapse vs four relapses), respectively. The median time to achieve molecular remission (RT-PCR negativity of PML-RARA) was 60 days in both arms (P = .12). The AMLCG regimen was associated with a longer duration of neutropenia (P = .02) and a higher rate of WHO grade ≥3 infections. Conclusions The small number of patients limits the reliability of conclusions. With these restrictions, the outcomes of both approaches were similar and show the limitations of ATRA and chemotherapy. The HD ara-C-containing regimen was associated with a lower relapse rate in high-risk APL.

We investigated the prognostic impact of time-dependent serum free light chain ratio (FLCr) normalization in 590 patients with secretory multiple myeloma (MM) during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. Serum free light chains (sFLC) were assessed by the Freelite test at baseline, after induction, mobilization, autologous blood stem cell transplantation, consolidation and every three months during maintenance or follow up within two years after the start of maintenance. The proportion of patients with a normal or normalized FLCr increased from 3.6% at baseline to 23.2% after induction and 64.7% after consolidation. The achievement of FLCr normalization at any one time before the start of maintenance was associated with significantly prolonged progression-free survival (PFS) (p &lt, 0.01, hazard ratio (HR) = 0.61, 95% confidence interval (95% CI) = 0.47–0.79) and overall survival (OS) (p = 0.02, HR = 0.67, 95% CI = 0.48–0.93) in multivariable time-dependent Cox regression analyses. Furthermore, reaching immune reconstitution, defined as the normalization of uninvolved immunoglobulins, before maintenance was associated with superior PFS (p = 0.04, HR = 0.77, 95% CI = 0.60–0.99) and OS (p = 0.01, HR = 0.59, 95% CI = 0.41–0.86). We conclude that FLCr normalization during therapy is an important favorable prognostic factor in MM. Therefore, we recommend serial measurements of sFLC during therapy until achieving FLCr normalization, even in patients with secretory MM.

Objective Analysis of the efficiency and toxicity of cyclophosphamide-based stem cell mobilization in patients with relapsed multiple myeloma (RMM). Methods Peripheral blood stem cells (PBSCs) were mobilized with high dose cyclophosphamide (2 g/m2 daily on days 1 and 2) and G-CSF plus pre-emptive/rescue plerixafor in RMM patients (first to third relapse) treated within the ReLApsE trial of the German-Speaking Myeloma Multicenter Group (GMMG). Results Mobilization was initiated with high-dose cyclophosphamide (HD-CY) and G-CSF in 30 patients. Fifteen patients received additional pre-emptive/rescue administration of plerixafor. Stem cell collection was successful (≥2×106 CD34+ cells per kg bw) in 77% (23/30 patients). Patients with prior high-dose melphalan collected a significantly lower median total number of PBSCs than patients without prior high-dose melphalan (3.3×106 vs 17×106 CD34+ cells/kg bw). Toxicity of HD-CY was frequent with 12 serious adverse events (SAE) in 37% of patients (11/30 patients). Infections accounted for the majority of SAE reports. In two patients, SAEs were lethal (septic shock). Conclusions These data proof feasibility of PBSC collection at relapse but emphasize the importance of collection and storage of additional PBSC transplants during first-line treatment when mobilization is more efficient and less toxic.

Background: Despite major advances in therapy, multiple myeloma is still an incurable malignancy in the majority of patients. To increase survival, deeper remissions (i.e. CR) translating into longer PFS need to be achieved. Incorporation of new drugs (i.e. bortezomib and lenalidomide) as induction and maintenance treatment in an intensified treatment concept, including high dose melphalan (200 mg/m2), has resulted in increased CR rates, and is considered the standard of care for younger patients. Elotuzumab in combination with lenalidomide and dexamethasone has given better results as lenalidomide and dexamethasone alone in a phase III trial. The GMMG-HD6 trial will be the first phase III trial investigating the role of elotuzumab in combination with bortezomib, lenalidomide and dexamethasone (VRD) induction/consolidation and lenalidomide maintenance within a high dose concept. Methods: GMMG-HD6 is a randomized, open, multicenter phase III trial. The planned recruitment number is 564 NDMM patients. All patients will receive 4 VRD cycles as induction and undergo peripheral blood stem cell mobilization and harvesting. Thereafter they will be treated with high dose melphalan therapy plus autologous stem cell transplantation followed by 2 cycles of VRD consolidation and lenalidomide maintenance. Patients in arm B1 + B2 will additionally receive elotuzumab in the induction phase, whereas patients in A2 + B2 will be treated with elotuzumab added to consolidation and maintenance. The primary endpoint of the trial is PFS. Secondary objectives and endpoints are OS, CR rates after induction therapy comparing the two arms VRD (A1 + A2) vs VRD + elotuzumab (B1 + B2), CR rates after consolidation treatment, best response to treatment during the study, time to progression (TTP), duration of response (DOR), toxicity and quality of life. Results: Since this is the publication of a study protocol of an ongoing study, no results can be presented. Discussion: This phase III trial is designed to evaluate whether the addition of elotuzumab to an intensified treatment concept with high dose melphalan chemotherapy plus autologous stem cell transplantation and induction, consolidation and maintenance treatment with bortezomib and lenalidomide is able to improve PFS compared to the same concept without elotuzumab. Trial registration: NCT02495922 on June 24th, 2015.

Standard first-line therapy of chronic myeloid leukemia is treatment with imatinib. In the randomized German Chronic Myeloid Leukemia-Study IV, more potent BCR-ABL inhibition with 800 mg ('high-dose') imatinib accelerated achievement of a deep molecular remission. However, whether and when a de-escalation of the dose intensity under high-dose imatinib can be safely performed without increasing the risk of losing deep molecular response is unknown. To gain insights into this clinically relevant question, we analyzed the outcome of imatinib dose reductions from 800 mg to 400 mg daily in the Chronic Myeloid Leukemia-Study IV. Of the 422 patients that were randomized to the 800 mg arm, 68 reduced imatinib to 400 mg after they had achieved at least a stable major molecular response. Of these 68 patients, 61 (90%) maintained major molecular remission on imatinib at 400 mg. Five of the seven patients who lost major molecular remission on the imatinib standard dose regained major molecular remission while still on 400 mg imatinib. Only two of 68 patients had to switch to more potent kinase inhibition to regain major molecular remission. Importantly, the lengths of the intervals between imatinib high-dose treatment before and after achieving major molecular remission were associated with the probabilities of maintaining major molecular remission with the standard dose of imatinib. Taken together, the data support the view that a deep molecular remission achieved with high-dose imatinib can be safely maintained with standard dose in most patients. Study protocol registered at clinicaltrials.gov 00055874.

Korrektur zu 10.1038/s41375-020-0826-9

Background: Novel agents such as IMIDs and proteasome inhibitors have substantially changed the therapeutic landscape in the first line treatment of multiple myeloma (MM). Better response rates and prolonged progression-free survival have lead to an improvement in overall survival (OS) with median values well beyond 5 years. Therefore to assess whether first line therapy strategies have an impact on the prognosis for patients with MM, long-term results of clinical trials with follow up covering >10 years are necessary. Methods: The HOVON-65/GMMG-HD4 study is a prospective randomized trial testing bortezomib+adriamycin+dexamethasone (PAD) for 3 cycles as induction prior to high-dose chemotherapy (HDT) and autologous stem cell transplantation compared to vincristine+adriamycin+dexamethasone (VAD) in the control arm. After one (HOVON) or two (GMMG) HDT maintenance was given for 2 years consisting of bortezomib every 2 weeks in the PAD arm and thalidomide 50 mg daily in the VAD arm. The study results were initially reported in 2012 (1) and with a median follow up of 91 months in 2018 (2). In this analysis we present OS results after a median follow up of 137 months. All hazard ratios (HR) are given with 95% confidence intervals (CI). Results: Overall survival at 12 years was 32% (CI 27-37%) in the VAD arm versus 36% (CI 31-41%) in the PAD arm without significant difference in the univariate Cox model (HR 0.87, CI 0.73 - 1.03, p=0. 11 or in multivariate Cox model including ISS stage and treatment arm (HR 0.87, CI 0.73 - 1.04, p=0.12; the primary analysis) as specified in the study protocol. When other factors including age, sex, ISS stage, WHO performance status, Immunoglobulin-type, Durie and Salmon-stage, LDH, del 13q, study group and renal impairment (RI, defined as serum creatinine ≥ 2 mg/dl) were added to the Cox model, treatment in the PAD arm was a significant factor for improved OS (HR 0.84, CI 0.7 - 1.0, p=0.048). Of the remaining factors age (HR 1.02, CI 1.01 - 1.03, p=0.002), female sex (HR 0.83, CI 0.69 - 0.99, p=0.044), ISS stage (HR 1.19, CI 1.04 - 1.35, p=0.01), WHO performance status (HR 1.32, CI 1.17 - 1.48, pULN (HR 1.44, CI 1.14 - 1.82, p=0.002), del 13q (HR 1.42, CI 1.17 - 1.73, p Discussion: Long-term results of the HOVON-65/GMMG-HD4 trial show that one third of patients receiving HDT with either thalidomide-based or bortezomib-based maintenance are still alive at 12 years. In contrast to earlier analyses with shorter follow up (1,2) the use of bortezomib in the induction and maintenance treatment provided a significant OS benefit when adjusting for other risk in a multivariate Cox model, although not in the primary analysis. A particular OS benefit was found in patients with RI receiving bortezomib before and after HDT and this could completely abolish the negative prognostic impact of RI. Similarly bortezomib used in combination with tandem-HDT improved OS in patients with del17p so that more than a third of these patients with high-risk MM survived more than 10 years. Our results underline that despite the growing options for treatment at relapse the choice of an optimal first-line therapy is of critical prognostic importance, in particular for patients with high-risk myeloma. References: 1) Sonneveld et al., J Clin Oncol, 2012; 30:2946-2955 2) Goldschmidt et al., Leukemia 2018; 32: 383-390 Figure 1 Disclosures Scheid: Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Bertsch:Celgene: Other: travel support; Sanofi: Other: travel support. Zweegman:Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Juno: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria; Adaptive Biotech: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Kersten:Gilead: Honoraria; Kite Pharma: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Miltenyi: Honoraria; Roche: Honoraria, Research Funding; Takeda Oncology: Research Funding; Celgene: Honoraria, Research Funding. Mai:Mundipharma: Other: travel support; Takeda: Honoraria, Other: travel support, Research Funding; Janssen: Consultancy, Honoraria, Other: travel support; Celgene: Consultancy, Honoraria, Other: travel support. Hillengass:Amgen: Consultancy, Honoraria; Janssen: Honoraria. Stilgenbauer:AbbVie, AstraZeneca, Celgene, Gilead Sciences, Inc., GSK, Hoffmann La-Roche, Janssen, Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau. Broyl:Celgene, amgen, Janssen,Takeda: Honoraria. Bos:Kiadis Pharma: Other: Shareholder (of Cytosen, acquired by Kiadis); Celgene: Research Funding. Dührsen:Amgen: Consultancy, Honoraria, Research Funding; CPT: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Roche: Honoraria, Research Funding; Teva: Honoraria; Novartis: Consultancy, Honoraria; Alexion: Honoraria; Gilead: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Honoraria; Celgene: Research Funding. Salwender:Celgene: Honoraria, Other: Travel or accommodations; Sanofi: Honoraria, Other: Travel or accommodations; Takeda: Honoraria, Other: Travel or accommodations; Bristol-Myers Squibb: Honoraria, Other: Travel or accommodations; AbbVie: Honoraria; Amgen: Honoraria, Other: Travel or accommodations; Janssen Cilag: Honoraria, Other: Travel or accommodations. Goldschmidt:Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Molecular Partners: Research Funding; Dietmar-Hopp-Stiftung: Research Funding; Mundipharma: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; John-Hopkins University: Research Funding; Amgen: Consultancy, Research Funding; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Chugai: Honoraria, Research Funding; John-Hopkins University: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Research Funding; Janssen: Consultancy, Research Funding. Sonneveld:Amgen: Honoraria, Research Funding; BMS: Honoraria; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; SkylineDx: Research Funding. OffLabel Disclosure: bortezomib maintenance thalidomide maintenance

Dose-dense induction with the S-HAM regimen was compared to standard double induction therapy in adult patients with newly diagnosed acute myeloid leukemia. Patients were centrally randomized (1:1) between S-HAM (2nd chemotherapy cycle starting on day 8 = “dose-dense”) and double induction with TAD-HAM or HAM(-HAM) (2nd cycle starting on day 21 = “standard”). 387 evaluable patients were randomly assigned to S-HAM (N = 203) and to standard double induction (N = 184). The primary endpoint overall response rate (ORR) consisting of complete remission (CR) and incomplete remission (CRi) was not significantly different (P = 0.202) between S-HAM (77%) and double induction (72%). The median overall survival was 35 months after S-HAM and 25 months after double induction (P = 0.323). Duration of critical leukopenia was significantly reduced after S-HAM (median 29 days) versus double induction (median 44 days)—P < 0.001. This translated into a significantly shortened duration of hospitalization after S-HAM (median 37 days) as compared to standard induction (median 49 days)—P < 0.001. In conclusion, dose-dense induction therapy with the S-HAM regimen shows favorable trends but no significant differences in ORR and OS compared to standard double induction. S-HAM significantly shortens critical leukopenia and the duration of hospitalization by 2 weeks.

BACKGROUND: Initial results from the ongoing GALLIUM trial have shown that patients with follicular lymphoma have a longer progression-free survival after first-line immunochemotherapy with obinutuzumab than with rituximab. The aim of this secondary analysis was to evaluate the prognostic value of PET-CT responses after first-line immunochemotherapy in the GALLIUM study.METHODS: GALLIUM is an open-label, parallel-group randomised, phase 3 trial, which recruited previously untreated patients with CD20-positive follicular lymphoma (grades 1-3a; disease stage III/IV, or stage II with largest tumour diameter ≥7 cm) who were aged 18 years or older and met the criteria for needing treatment. Eligible patients were randomly assigned in a 1:1 ratio to receive intravenous administration of obinutuzumab (1000 mg on days 1, 8, and 15 of cycle 1, then day 1 of subsequent cycles) or rituximab (375 mg/m2 on day 1 of each cycle), in six 21-day cycles with cyclophosphamide, doxorubicin, vincristine, and prednisone (known as CHOP; oral administration) followed by two 21-day cycles of antibody alone, or eight 21-day cycles cyclophosphamide, vincristine, and prednisone (known as CVP; oral administration), or six 28-day cycles with bendamustine, followed by maintenance antibody every 2 months for up to 2 years. The primary endpoint of the trial, investigator-assessed progression-free survival, has been reported previously. This secondary analysis reports PET and CT-based responses at end-of-induction therapy and explains their relation with progression-free and overall survival outcomes in patients with available scans. As per protocol, during the trial, PET scans (mandatory in the first 170 patients enrolled at sites with available PET facilities, and optional thereafter), acquired at baseline and end of induction (PET population), were assessed prospectively by investigators and an independent review committee (IRC) applying International Harmonisation Project (IHP) 2007 response criteria, and retrospectively by the IRC only applying current Lugano 2014 response criteria. IRC members (but not study investigators) were masked to treatment and clinical outcome when assessing response. The landmark analyses excluded patients who died or progressed (contrast enhanced CT-based assessment of progressive disease, or started next anti-lymphoma treatment) before or at end of induction. GALLIUM is registered at ClinicalTrials.gov, number NCT01332968.FINDINGS: 1202 patients were enrolled in GALLIUM between July 6, 2011, and Feb 4, 2014, of whom 595 were included in the PET population; 533 (IHP 2007; prospective analysis), and 508 (Lugano 2014; retrospective analysis) were analysed for progression-free survival (landmark analysis). At end of induction, 390 of 595 patients (65·5% [95% CI 61·6-69·4]) achieved PET complete response according to IHP 2007 criteria, and 450 (75·6% [95% CI 72·0-79·0]) obtained PET complete metabolic response according to Lugano 2014 criteria. With a median of 43·3 months of observation (IQR 36·2-51·8), 2·5-year progression-free survival from end of induction was 87·8% (95% CI 83·9-90·8) in PET complete responders and 72·0% (63·1-79·0) in non-complete responders according to IRC-assessed IHP 2007 criteria (hazard ratio [HR] 0·4, 95% CI 0·3-0·6, pINTERPRETATION: Our results suggest that PET is a better imaging modality than contrast-enhanced CT for response assessment after first-line immunochemotherapy in patients with follicular lymphoma. PET assessment according to Lugano 2014 response criteria provides a platform for investigation of response-adapted therapeutic approaches. Additional supportive data are welcomed.FUNDING: F Hoffmann-La Roche.

Introduction The inclusion of "novel" agents including proteasome inhibitors or IMiD-derivatives in the treatment of multiple myeloma significantly improves patient survival. Results of several study groups suggest incorporating at least one "novel agent" in first-line treatment before and after high-dose chemotherapy (HDT) followed by autologous stem cell transplantation. Here we address four main questions: First, what determines (excellent) long-term survival for different treatment regimen? Second, can we show benefit of novel agents for all patients and molecular subentities, including low risk? Third, can the prognostic impact of molecular entities be explained by different association with response, proliferation, and renal impairment? Fourth, does it matter regarding long-term survival by which agents, i.e. "old" vs. "new", a response was reached? Patients and Methods Patients were included in the prospective phase III HOVON-65/GMMG-HD4-trial (German part, n=354) randomizing VAD-induction, autologous tandem-transplantation and thalidomide-maintenance vs. PAD-induction, tandem-transplantation and bortezomib-maintenance. Plasma cells after CD138-purification were subjected to interphase fluorescence in-situ hybridization and gene expression profiling using Affymetrix U133 2.0 DNA-microarrays. Median follow-up (time to censoring) was 93 months. Results Low proliferation, revised-ISS I and cyto-ISS I delineate excellent long-term survival (70-75% after eight years, both arms). Molecular entities are associated with proliferation-rate, i.e. higher (del17p13, del8p21, del13q14, 1q21+, t(4;14)) or lower proliferation (hyperdiploidy), and response: bad response/survival in case of del17p, bad response/no survival impact (t(11;14)), and good response/bad survival (1q21+, t(4;14), and del13q), depending on the treatment regimen. Thus, it does not hold true that good response = good survival if patients are substratified according to their molecular background. Renal insufficiency is associated with 1q21+, del17p13, and t(4;14). For patients with ≥1 of the chromosomal aberrations del17p13, t(4;14), 1q21+ (i.e. cytogenetic high risk, 27.5% of patients) or renal insufficiency (10.6%), risk is abrogated; in absence of these risk features, no benefit could be shown. Patients reaching a near complete remission or better (≥nCR) with VAD-based regimen, HDT followed by thalidomide maintenance show significantly better survival compared to those reaching ≥nCR after bortezomib-based induction/HDT followed by bortezomib maintenance treatment. Conclusions Taken together, adversely prognostic molecular entities are associated with proliferation but can show association with better or adverse remission. Bortezomib-based upfront treatment abrogates chromosomal high-risk aberrations and renal insufficiency; however, no long-term survival-benefit is evident for those without these risk factors or low proliferation, i.e. the majority of patients. Responses achieved by different regimen are not equal in transmission in long-term survival. Responses (≥nCR) are not equivalent regarding their biological and prognostic role in patients with different molecular background and different treatment regimen. Disclosures Seckinger: Celgene: Research Funding; Sanofi: Research Funding; EngMab: Research Funding. Salwender:Novartis: Honoraria, Other: travel suppport, Research Funding; Amgen: Honoraria, Other: travel suppport, Research Funding; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding; Celgene: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria; Janssen: Honoraria, Other: travel support, Research Funding. Scheid:Celgene: Honoraria; Janssen: Honoraria. Knauf:Janssen: Consultancy; AbbVie: Consultancy; Celgene: Consultancy, Honoraria; Gilead Sciences: Consultancy; Roche: Consultancy; Amgen: Consultancy, Honoraria; Mundipharma: Consultancy. Duehrsen:AbbVie: Consultancy, Honoraria; Amgen: Research Funding; Janssen: Honoraria; Celgene: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Gilead: Consultancy, Honoraria. Dürig:Roche: Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria; Celgene: Honoraria. Schmidt-Wolf:Janssen: Research Funding; Novartis: Research Funding. Haenel:Novartis: Honoraria; Amgen: Honoraria; Roche: Honoraria; Takeda: Honoraria. Raab:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Sonneveld:Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Karyopharm: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Blau:Celgene: Other: Advisory board, Research Funding; Janssen: Other: Advisory board, Research Funding; Amgen: Other: Advisory board; Takeda: Other: Advisory board; Novartis: Other: Advisory boards; BMS: Other: Advisory board. Hillengass:Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding; amgen: Consultancy, Honoraria, Other: Advisory Board; Sanofi: Research Funding; Janssen: Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board. Weisel:Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees. Goldschmidt:Chugai: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria. Hose:Celgene: Honoraria, Research Funding; EngMab: Research Funding; Sanofi: Research Funding.

Up to 20% of patients with multiple myeloma (MM) show signs of peripheral neuropathy (PN) at primary diagnosis.[1][1] Treatment with neurotoxic agents such as bortezomib or thalidomide increases rates of PN in newly diagnosed patients by up to 50%.[2][2] Since subcutaneous (SC) administration

Introduction The ReLApsE trial compared lenalidomide (LEN)/dexamethasone (DEX; Rd) re-induction, salvage high dose chemotherapy (HDCT), autologous stem cell transplantation (ASCT) and LEN maintenance with continuous Rd in relapsed multiple myeloma. Landmark (LM) analyses from salvage HDCT were performed due to the fact that ~30% of patients in the HDCT arm did not receive salvage HDCT/ASCT. These analyses showed a survival benefit in patients actually undergoing salvage HDCT/ASCT. Median PFS and OS from LM were 23.3 vs. 20.1 months (HR 0.74; p=0.09) and not reached vs. 57 months (HR 0.56; p=0.046) favoring the salvage HDCT/ASCT arm. Multivariate LM analyses showed significant associations of the salvage HDCT/ASCT arm with superior PFS (HR 0.6; p=0.01) and OS (HR 0.39; p=0.006). The present analysis aims to dissect treatment efficacy in relevant subgroups and provide clues for treatment stratification. Methods The ReLApsE trial (ISRCTN16345835) compared 3 Rd (LEN 25 mg, d1-21; DEX 40 mg, d1,8,15,22; 4 week cycles) re-induction cycles, HDCT (melphalan 200 mg/m2), ASCT and LEN maintenance (10 mg/d) until PD (arm B, n=139) with Rd until PD (arm A, n=138). Key inclusion criteria were 1-3 prior therapy lines, age ≤ 75, time to PD in case of front-line HDCT/ASCT (TTP1) ≥ 12 months and WHO PS ≤ 2. Exploratory subgroup analyses were performed in the ITT population for PFS/OS using an LM at HDCT (B; n=103) and the contemporaneous Rd cycle 5 (A; n=114). The median interval from randomization to LM was 117/122 days in arm B/A. Heterogeneity of treatment effect was assessed by cox regression with interaction term between treatment and subgroup factor. Results No significant differences in the PFS/OS benefit between arms were observed in subgroups according to baseline ISS (I/II/III; interaction p[i-p]=0.5/0.66), age (1; i-p=0.37/0.22), single vs. tandem front-line HDCT/ASCT (i-p=0.34/0.56), and TTP1 (12-24 vs. 24-48 vs. >48 months; i-p=0.91/0.21). The subgroups according to front-line HDCT/ASCT (yes/no) differed significantly with regard to PFS/OS benefit in arm B (i-p=0.006/0.001). A significant benefit was observed in patients with front-line HDCT/ASCT treated in arm B regarding PFS (HR 0.68, p=0.03; n=107[A]/98[B]) and OS (HR 0.43, p=0.009). Patients without front-line HDCT/ASCT constituted a very small subgroup with imbalances in baseline parameters adversely affecting arm B and had expectably inferior survival in arm B (PFS: HR 4.35, p=0.08; OS: HR 19.83, p=0.0078; n=7[A]/5[B]). The subgroup with baseline LDH upper limit of normal (ULN) differed significantly in PFS benefit in arm B (i-p=0.03) but not in OS benefit (i-p=0.46). Patients with LDHULN (PFS: HR 1.54, p=0.31; n=16[A]/18[B]). The subgroups according to baseline cytogenetic risk and R-ISS showed a trend towards a differential benefit in arm B regarding OS (i-p=0.05 and 0.09) but not PFS (i-p=0.5 and 0.88). Patients with low risk cytogenetics (i.e. absence of t(4;14), del17p, +1q>3 copies and t(14;16)) had significantly superior OS in arm B (HR 0.21; p=0.01; n=57[A]/35[B]), whereas patients with high risk cytogenetics had no significant difference in OS according to trial arm (HR 0.82, p=0.67; n=25[A]/28[B]). Patients with R-ISS I had significantly superior OS in arm B (HR 0.08; p=0.02; n=33[A]/25[B]), whereas no significant difference in OS according to trial arm was seen in patients with R-ISS II (HR 0.72, p=0.42; n=52[A]/43[B]) and R-ISS III (HR 0.65, p=0.6; n=3[A]/5[B]). Conclusions The ReLApsE trial is the first RCT of salvage HDCT/ASCT vs. continuous novel agent treatment. In the absence of a significant survival benefit for the primary endpoint, LM analyses indicated a significant PFS/OS benefit in patients actually undergoing HDCT/ASCT. No heterogeneity of treatment effect was observed according to ISS, age, renal function, response to re-induction, prior therapy lines, single vs. tandem front-line HDCT/ASCT, and TTP1. Subgroup effects regarding PFS and/or OS benefit from HDCT/ASCT were seen favoring patients with front-line HDCT/ASCT and patients with low risk according to LDH, cytogenetics and R-ISS. Disclosures Baertsch: Takeda: Consultancy; Novartis: Consultancy, Research Funding. Raab:Celgene: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Hillengass:Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding; amgen: Consultancy, Honoraria, Other: Advisory Board; Novartis: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Sanofi: Research Funding. Graeven:Roche: Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria. Fenk:Bristol-Meyers Squibb: Honoraria, Other: travel grant; Takeda: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Celgene: Honoraria, Other: Travel grant, Research Funding. Haenel:Takeda: Honoraria; Novartis: Honoraria; Amgen: Honoraria; Roche: Honoraria. Scheid:Amgen: Honoraria; BMS: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding. Salwender:Janssen: Honoraria, Other: travel support, Research Funding; Celgene: Honoraria, Other: travel suppport, Research Funding; Novartis: Honoraria, Other: travel suppport, Research Funding; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding; Amgen: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria. Goldschmidt:Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; Mundipharma: Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; ArtTempi: Honoraria; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Chugai: Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Amgen: Consultancy, Research Funding.

Introduction Salvage high dose chemotherapy (HDCT) followed by autologous stem cell transplantation (ASCT) is used in fit patients with relapsed multiple myeloma (RMM) in clinical practice. However, the role of this approach in the era of continuous novel agent based treatment has not been defined in randomized trials. The ReLApsE trial compared lenalidomide/dexamethasone (Rd) re-induction, salvage HDCT/ASCT and lenalidomide (R) maintenance with standard continuous Rd in a randomized controlled multicenter trial. Methods Between 2010 and 2016, 282 patients were randomized of whom 277 constituted the intention-to-treat (ITT) population (arm B/A n=139/138). Arm B received 3 cycles of Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, 22; 4 week cycles) re-induction, HDCT (melphalan 200 mg/m2), ASCT and R maintenance (10 mg daily) until progression (PD). Arm A was treated with Rd until PD. In both arms stem cells were harvested after the 3rd Rd cycle if no back-up transplant was available. Key inclusion criteria were 1-3 prior therapy lines, age ≤ 75 years, time to PD ≥ 12 months in case of front-line HDCT/ASCT and WHO PS ≤ 2. The primary endpoint was progression free survival (PFS). Secondary endpoints included overall survival (OS), response rates and toxicity. ISRCTN16345835, Eudra CT-No: 2009-013856-61. Results Arm B and A were balanced regarding age (median 61.3 vs. 62.2 years), ISS (I/II/III in 62.6/24.4/13% vs. 59.7/31/9.3%) and WHO PS (0/1/2 in 69.1/30.9/0% vs. 76.1/23.2/0.7%). Almost all patients had only 1 prior therapy line (arm B: 94.2% vs. arm A: 93.5%) and had received front-line HDCT/ASCT (92.8% vs. 94.2%). More patients in arm B had high risk cytogenetic aberrations (HR-CA; 42.9% vs. 31.6%) based on a higher frequency of t(4;14) (20.2% vs. 10.1%). The overall response rate (≥ partial response; ORR) for arm B and A was 77.9% and 74.6% (p=0.57) with 49.3% and 47.1% (p=0.81) achieving ≥ very good partial response as best response. Within a median follow up of 36.3 months, 183 PFS events and 76 deaths occurred. Median PFS in the ITT population was 20.7 months in arm B and 18.8 months in arm A without a statistically significant difference (HR 0.87; 95% CI 0.65-1.16; p=0.34). Median OS was not reached (NR) in arm B vs. 62.7 months in arm A (HR 0.81; 95% CI 0.52-1.28; p=0.37). In arm B, 41 patients (29.5%) did not receive the planned HDCT/ASCT. Thus, exploratory landmark (LM) analyses from HDCT and the contemporaneous Rd cycle 5 in arm A were performed (median interval from randomization to HDCT/Rd cycle 5: 117/122 days; n=103[B]/114[A]). They showed a trend towards superior PFS (23.3 vs. 20.1 months; HR 0.74; p=0.09) and significantly superior OS (NR vs. 57 months; HR 0.56; p=0.046) in arm B vs. A. Multivariate analyses revealed significant associations of treatment in arm B with superior LM PFS (HR 0.6; p=0.01) and LM OS (HR 0.39; p=0.006). Other factors in the LM multivariate models showing significant associations with survival were HR-CA (PFS, OS), number of prior therapy lines (PFS), and age (PFS). The ORR in arm B after HDCT/ASCT was significantly higher than in arm A after Rd cycle 5 (82.3% vs. 69.6%; p=0.04). Grade ≥3 adverse events were reported in 83% (arm B) and 74.5% (arm A; p=0.11). Grade ≥3 leukopenia/neutropenia was reported in 61.5 vs. 24.8% (p Conclusions This is the first RCT comparing salvage HDCT/ASCT with continuous novel agent based treatment. No significant PFS or OS difference was observed in the overall trial population. However, HR-CA were more frequent in the HDCT/ASCT arm and ~30% of patients did not receive the planned HDCT/ASCT. Landmark analyses from the time of HDCT indicate superior PFS and OS in patients actually undergoing salvage HDCT/ASCT. Salvage HDCT/ASCT was safe with an expected increase in hematological as wells as gastrointestinal toxicity but without treatment-related mortality in patients up to the age of 75 years in this multicenter trial. However, the number of patients not undergoing salvage HDCT/ASCT and the approval of more active Rd-based triplet regimens after the initiation of this trial prevents definite conclusions on the role of salvage HDCT/ASCT. Disclosures Goldschmidt: Amgen: Consultancy, Research Funding; Novartis: Honoraria, Research Funding; ArtTempi: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Research Funding; Mundipharma: Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Consultancy, Honoraria, Research Funding; Adaptive Biotechnology: Consultancy; Chugai: Honoraria, Research Funding. Baertsch:Takeda: Consultancy; Novartis: Consultancy, Research Funding. Raab:Celgene: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding. Hillengass:Novartis: Honoraria, Other: Advisory Board; Sanofi: Research Funding; Takeda: Honoraria, Other: Advisory Board; Janssen: Honoraria, Other: Advisory Board; amgen: Consultancy, Honoraria, Other: Advisory Board; BMS: Honoraria, Other: Advisory Board; Celgene: Consultancy, Honoraria, Other: Advisory Board, Research Funding. Graeven:AbbVie: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees. Fenk:Takeda: Honoraria; Bristol-Meyers Squibb: Honoraria, Other: travel grant; Celgene: Honoraria, Other: Travel grant, Research Funding; Janssen: Honoraria; Amgen: Honoraria. Haenel:Novartis: Honoraria; Roche: Honoraria; Amgen: Honoraria; Takeda: Honoraria. Scheid:Novartis: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Honoraria; Celgene: Honoraria; BMS: Honoraria; Amgen: Honoraria. Salwender:Celgene: Honoraria, Other: travel suppport, Research Funding; Janssen: Honoraria, Other: travel support, Research Funding; Novartis: Honoraria, Other: travel suppport, Research Funding; Takeda: Honoraria; Amgen: Honoraria, Other: travel suppport, Research Funding; Bristol-Myers Squibb: Honoraria, Other: travel suppport, Research Funding. Weisel:Amgen, Celgene, Janssen, and Sanofi: Research Funding; Amgen, BMS, Celgene, Janssen, and Takeda: Honoraria; Amgen, BMS, Celgene, Janssen, Juno, Sanofi, and Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Introduction In older patients (pts), host factors such as functional deficits, comorbidities and other age-related factors are increasingly recognized as predictors for outcome of leukemia treatment. Thus, prospective clinical trials increasingly implement functional studies (often termed geriatric assessment) in their pretreatment diagnostic workup. In older, fit AML pts receiving standard chemotherapy, Klepin et al. demonstrated a predictive value of this approach for overall survival (OS) in a single-center study (Blood 2013). We also developed a Frailty Score, assessed at 3 study centers and predicting OS of elderly AML/MDS pts receiving either hypomethylating agents (n=66) or sole best supportive care (n=35; Deschler et al., Haematologica 2013). To validate this score, which is composed of performance status (PS), activities of daily living (ADL) and fatigue, we prospectively assessed these parameters in the DECIDER trial (AMLSG 14-09, NCT00867672). Methods In the DECIDER trial, 200 non-fit AML pts aged >60 years (yr) were randomized between four treatment arms with either decitabine (DAC) alone, or DAC plus all-trans retinoid acid (ATRA) or DAC plus valproic acid (VPA) or DAC plus ATRA and VPA. We assessed PS via ECOG, ADL via Barthel index and fatigue via the EORTC QLQ-C30 questionnaire, which were available for 200, 175 and 156 pts, respectively. Pts with missing ADL and/or fatigue assessments tended to have a lower PS than those with complete data, which may explain at least in part why the assessments could not be performed. The Frailty Score was calculated using ECOG PS as a substitute for the Karnofsky Index (KI, as applied when establishing this score), with ECOG 0-1 taken as corresponding to KI ≥80, and ECOG 2-3 to KI Results For 141 pts with complete data in all 3 parameters building the Frailty Score, median follow-up time was 28 months, and 122 pts had died. The median age of pts at AML diagnosis was 76 yr (range 61-90) and 96 pts (68.1%) were males. Median WBC was 3.100/µl (interquartile range [IQR] 1.400 to 11.500/µl), median platelet count 49.000/µl (IQR 30.000 to 98.000/µl), median hemoglobin (Hb) 9.2g/dl (IQR 8.3 to 10.1g/dl), with median peripheral blasts of 48% (IQR 25 to 76%) and median LDH 287 U/l (IQR 203 to 459 U/l). 32.6% of the pts had adverse genetic risk according to ELN 2010 criteria. 56.7% had relevant comorbidities (HCT-CI ≥3). The majority of pts had a reduced PS (21.3% ECOG 0, 62.4% ECOG 1 and 16.3% ECOG 2-3). When assessing ADL, 30.5% had limitations (ADL 1, ADL Conclusions This previously described pt fitness assessment to calculate the Frailty Score could now be implemented in a multicenter academic trial setting. In our independent, large AML cohort, the score was able to separate pts into groups with different OS, underlining the emerging roles of ADL and fatigue as predictors of outcome, in addition to the already well-established role of PS. A second prospective validation study, in AML pts aged ≥ 60 yr receiving standard "7+3" induction therapy or 10-day DAC (EORTC AML21 "inDACtion vs. induction" trial, NCT02172872), is ongoing. Disclosures Schlenk: Pfizer: Research Funding, Speakers Bureau. Salih:Several patent applications: Patents & Royalties: e.g. EP3064507A1. Bug:Janssen: Other: Travel Grant; Celgene: Honoraria; Jazz Pharmaceuticals: Other: Travel Grant; Amgen: Honoraria; Novartis Pharma: Honoraria, Research Funding; Neovii: Other: Travel Grant; Astellas Pharma: Other: Travel Grant. Germing:Janssen: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Götze:Takeda: Honoraria, Other: Travel aid ASH 2017; Celgene: Honoraria, Research Funding; JAZZ Pharmaceuticals: Honoraria; Novartis: Honoraria. Scholl:Deutsche Krebshilfe: Research Funding; Novartis: Other: Travel support; Jazz Pharma: Membership on an entity's Board of Directors or advisory committees; Carreras Foundation: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; Abbivie: Other: Travel support; Alexion: Other: Travel support; MDS: Other: Travel support. Ganser:Novartis: Membership on an entity's Board of Directors or advisory committees. Döhner:Celator: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Pfizer: Research Funding; Agios: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Honoraria, Research Funding; Pfizer: Research Funding; Astellas: Consultancy, Honoraria; Agios: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celator: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; AROG Pharmaceuticals: Research Funding; Seattle Genetics: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Astellas: Consultancy, Honoraria; Astex Pharmaceuticals: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Janssen: Consultancy, Honoraria; AROG Pharmaceuticals: Research Funding; Bristol Myers Squibb: Research Funding. Lubbert:Teva: Other: Study drug; Celgene: Other: Travel Grant; Janssen: Honoraria, Research Funding.

Background Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. Methods/Design ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and - in absence of available stem cells from earlier harvesting - undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3rd (arm A + B) and the 5th lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. Discussion This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. Trial registration: ISRCTN16345835 (date of registration 2010-08-24). Electronic supplementary material The online version of this article (doi:10.1186/s12885-016-2321-2) contains supplementary material, which is available to authorized users.

Tyrosine kinase inhibitors represent today's treatment of choice in chronic myeloid leukemia (CML). Allogeneic hematopoietic stem cell transplantation (HSCT) is regarded as salvage therapy. This prospective randomized CML-study IIIA recruited 669 patients with newly diagnosed CML between July 1997 and January 2004 from 143 centers. Of these, 427 patients were considered eligible for HSCT and were randomized by availability of a matched family donor between primary HSCT (group A; N=166 patients) and best available drug treatment (group B; N=261). Primary end point was long-term survival. Survival probabilities were not different between groups A and B (10-year survival: 0.76 (95% confidence interval (CI): 0.69-0.82) vs 0.69 (95% CI: 0.61-0.76)), but influenced by disease and transplant risk. Patients with a low transplant risk showed superior survival compared with patients with high- (P

Fluorouracil-based chemoradiotherapy is regarded as a standard perioperative treatment in locally advanced rectal cancer. We investigated the efficacy and safety of substituting fluorouracil with the oral prodrug capecitabine.This randomised, open-label, multicentre, non-inferiority, phase 3 trial began in March, 2002, as an adjuvant trial comparing capecitabine-based chemoradiotherapy with fluorouracil-based chemoradiotherapy, in patients aged 18 years or older with pathological stage II-III locally advanced rectal cancer from 35 German institutions. Patients in the capecitabine group were scheduled to receive two cycles of capecitabine (2500 mg/m(2) days 1-14, repeated day 22), followed by chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) days 1-38), then three cycles of capecitabine. Patients in the fluorouracil group received two cycles of bolus fluorouracil (500 mg/m(2) days 1-5, repeated day 29), followed by chemoradiotherapy (50·4 Gy plus infusional fluorouracil 225 mg/m(2) daily), then two cycles of bolus fluorouracil. The protocol was amended in March, 2005, to allow a neoadjuvant cohort in which patients in the capecitabine group received chemoradiotherapy (50·4 Gy plus capecitabine 1650 mg/m(2) daily) followed by radical surgery and five cycles of capecitabine (2500 mg/m(2) per day for 14 days) and patients in the fluorouracil group received chemoradiotherapy (50·4 Gy plus infusional fluorouracil 1000 mg/m(2) days 1-5 and 29-33) followed by radical surgery and four cycles of bolus fluorouracil (500 mg/m(2) for 5 days). Patients were randomly assigned to treatment group in a 1:1 ratio using permuted blocks, with stratification by centre and tumour stage. The primary endpoint was overall survival; analyses were done based on all patients with post-randomisation data. Non-inferiority of capecitabine in terms of 5-year overall survival was tested with a 12·5% margin. This trial is registered with ClinicalTrials.gov, number NCT01500993.Between March, 2002, and December, 2007, 401 patients were randomly allocated; 392 patients were evaluable (197 in the capecitabine group, 195 in the fluorouracil group), with a median follow-up of 52 months (IQR 41-72). 5-year overall survival in the capecitabine group was non-inferior to that in the fluorouracil group (76% [95% CI 67-82] vs 67% [58-74]; p=0·0004; post-hoc test for superiority p=0·05). 3-year disease-free survival was 75% (95% CI 68-81) in the capecitabine group and 67% (59-73) in the fluorouracil group (p=0·07). Similar numbers of patients had local recurrences in each group (12 [6%] in the capecitabine group vs 14 [7%] in the fluorouracil group, p=0·67), but fewer patients developed distant metastases in the capecitabine group (37 [19%] vs 54 [28%]; p=0·04). Diarrhoea was the most common adverse event in both groups (any grade: 104 [53%] patients in the capecitabine group vs 85 [44%] in the fluorouracil group; grade 3-4: 17 [9%] vs four [2%]). Patients in the capecitabine group had more hand-foot skin reactions (62 [31%] any grade, four [2%] grade 3-4 vs three [2%] any grade, no grade 3-4), fatigue (55 [28%] any grade, no grade 3-4 vs 29 [15%], two [1%] grade 3-4), and proctitis (31 [16%] any grade, one [1%] grade 3-4 vs ten [5%], one [1%] grade 3-4) than did those in the fluorouracil group, whereas leucopenia was more frequent with fluorouracil than with capecitabine (68 [35%] any grade, 16 [8%] grade 3-4 vs 50 [25%] any grade, three [2%] grade 3-4).Capecitabine could replace fluorouracil in adjuvant or neoadjuvant chemoradiotherapy regimens for patients with locally advanced rectal cancer.Roche Pharma AG (Grenzach-Wyhlen, Germany).

Background Chronic myeloid leukemia (CML)-study IV was designed to explore whether treatment with imatinib (IM) at 400mg/day (n=400) could be optimized by doubling the dose (n=420), adding IFN (n=430) or cytarabine (n=158) or using IM after IFN-failure (n=128). Methods From July 2002 to March 2012, 1551 newly diagnosed patients in chronic phase were randomized into a 5-arm study. The study was powered to detect a survival difference of 5% at 5 years. The impact of patients' and disease factors on survival was prospectively analyzed. At the time of evaluation, at least 62% of patients still received imatinib, 26.2% were switched to 2nd generation tyrosine kinase inhibitors. Results After a median observation time of 9.5 years, 10-year overall survival was 82%, 10-year progression-free survival 80% and 10-year relative survival 92%. In spite of a faster response with IM800mg, the survival difference between IM400mg and IM800mg was only 3% at 5 years. In a multivariate analysis, the influence on survival of risk-group, major-route chromosomal aberrations, comorbidities, smoking and treatment center (academic vs. other) was significant in contrast to any form of initial treatment optimization. Patients that reached the response milestones 3, 6 and 12 months, had a significant survival advantage of about 6% after 10 years regardless of therapy. The progression probability to blast crisis was 5.8%. Blast crisis was proceeded by high-risk additional chromosomal aberrations. Conclusions For responders, monotherapy with IM400mg provides a close to normal life expectancy independent of the time to response. Survival is more determined by patients' and disease factors than by initial treatment selection. Although improvements are also needed for refractory disease and blast crisis, more life-time can currently be gained by carefully addressing non-CML determinants of survival. Disclosures Hehlmann: Novartis: Research Funding; BMS: Consultancy. Saussele: Pfizer: Honoraria; Incyte: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding. Pfirrmann: BMS: Honoraria; Novartis: Honoraria. Krause: Novartis: Honoraria. Baerlocher: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria. Bruemmendorf: Novartis: Research Funding. Müller: Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Ariad: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding. Jeromin: MLL Munich Leukemia Laboratory: Employment. Hänel: Roche: Honoraria; Novartis: Honoraria. Burchert: BMS: Honoraria. Waller: Mylan: Consultancy, Honoraria. Mayer: Eisai: Research Funding; Novartis: Research Funding. Link: Novartis: Honoraria. Scheid: Novartis: Honoraria. Schafhausen: Novartis: Honoraria; BMS: Honoraria; Pfizer: Honoraria; Ariad: Honoraria. Hochhaus: Incyte: Research Funding; MSD: Research Funding; Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; ARIAD: Research Funding.

BACKGROUND: The role of bleomycin and dacarbazine in the ABVD regimen (ie, doxorubicin, bleomycin, vinblastine, and dacarbazine) has been questioned, especially for treatment of early-stage favourable Hodgkin's lymphoma, because of the drugs' toxicity. We aimed to investigate whether omission of either bleomycin or dacarbazine, or both, from ABVD reduced the efficacy of this regimen in treatment of Hodgkin's lymphoma.METHODS: In this open-label, randomised, multicentre trial (HD13) we compared two cycles of ABVD with two cycles of the reduced-intensity regimen variants ABV (doxorubicin, bleomycin, and vinblastine), AVD (doxorubicin, vinblastine, and dacarbazine), and AV (doxorubicin and vinblastine), in patients with newly diagnosed, histologically proven, classic or nodular, lymphocyte predominant Hodgkin's lymphoma. In each treatment group, 30 Gy involved-field radiotherapy (IFRT) was given after both cycles of chemotherapy were completed. From Jan 28, 2003, patients were centrally randomly assigned (1:1:1:1) with a minimisation method to the four groups. Because of high event rates, assignment to the AV and ABV groups stopped early, on Sept 30, 2005, and Feb 10, 2006; assignment to ABVD and AVD continued (1:1) until Sept 30, 2009. Our primary objective was to show non-inferiority of the experimental variants compared with ABVD in terms of freedom from treatment failure (FFTF), by excluding a difference of 6% after 5 years corresponding to a hazard ratio (HR) of 1.72, via a 95% CI. Analyses reported here include qualified patients only, and between-group comparisons include only patients recruited during the same period. The trial was registered, number ISRCTN63474366.FINDINGS: Of 1502 qualified patients, 566, 198, 571, and 167 were randomly assigned to receive ABVD, ABV, AVD, or AV, respectively. 5 year FFTF was 93.1%, 81.4%, 89.2%, and 77.1% with ABVD, ABV, AVD, and AV, respectively. Compared with ABVD, inferiority of the dacarbazine-deleted variants was detected with 5 year differences of -11.5% (95% CI -18.3 to -4.7; HR 2.06 [1.21 to 3.52]) for ABV and -15.2% (-23.0 to -7.4; HR 2.57 [1.51 to 4.40]) for AV. Non-inferiority of AVD compared with ABVD could also not be detected (5 year difference -3.9%, -7.7 to -0·1; HR 1.50, 1.00 to 2.26). 178 (33%) of 544 patients given ABVD had WHO grade III or IV toxicity, compared with 53 (28%) of 187 given ABV, 142 (26%) of 539 given AVD, and 40 (26%) of 151 given AV. Leucopenia was the most common event, and highest in the groups given bleomycin.INTERPRETATION: Dacarbazine cannot be omitted from ABVD without a substantial loss of efficacy. With respect to our predefined non-inferiority margin, bleomycin cannot be safely omitted either, and the standard of care for patients with early-stage favourable Hodgkin's lymphoma should remain ABVD followed by IFRT.FUNDING: Deutsche Krebshilfe and Swiss State Secretariat for Education and Research.

We investigated the impact of subcutaneous versus intravenous bortezomib in the MM5 trial of the German-Speaking Myeloma Multicenter Group which compared bortezomib, doxorubicin, and dexamethasone with bortezomib, cyclophosphamide, and dexamethasone induction therapy in newly diagnosed multiple myeloma. Based on data from relapsed myeloma, the route of administration for bortezomib was changed from intravenous to subcutaneous after 314 of 604 patients had been enrolled. We analyzed 598 patients who received at least one dose of trial medication. Adverse events were reported more frequently in patients treated with intravenous bortezomib (intravenous=65%; subcutaneous=56%, P=0.02). Rates of grade 2 or more peripheral neuropathy were higher in patients treated with intravenous bortezomib during the third cycle (intravenous=8%; subcutaneous=2%, P=0.001). Overall response rates were similar in patients treated intravenously or subcutaneously. The presence of International Staging System stage III disease, renal impairment or adverse cytogenetic abnormalities did not have a negative impact on overall response rates in either group. To our knowledge this is the largest study to present data comparing subcutaneous with intravenous bortezomib in newly diagnosed myeloma. We show better tolerance and similar overall response rates for subcutaneous compared to intravenous bortezomib. The clinical trial is registered at eudract.ema.europa.eu as n. 2010-019173-16.

We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P

Background: Many patients with autoimmune hemolytic anemia (AIHA) do not respond to standard therapy and/or may develop severe complications which can be of fatal outcome. There is some evidence that erythropoiesis-stimulating agents (ESAs) may be helpful in the management of such patients. Methods: We describe the effect of ESAs in 12 new patients with therapy-refractory AIHA (7 of warm type and 5 of cold type) and review 5 previously reported cases. Serological testing was performed using standard methods. Results: All patients responded well to treatment with ESAs. At least 5 of the 17 patients demonstrated complete recovery, and none of the patients developed significant adverse reactions due to treatment with ESAs. Conclusion: The mechanism by which ESAs improves hemolysis in AIHA is not completely clear. In addition to increased production and prolonged RBC survival, it may inhibit eryptosis (programmed cell death). ESAs represent a new option in the treatment of decompensated and/or refractory AIHA of warm and cold type. However, more information is required to assess which patients can be treated with ESAs.

6018 Background: This trial was based on the findings that D in addition to PF in induction treatment and C in addition to PF in RM disease both improved outcome in HNSCC. The question was, whether...

Introduction: Multiple myeloma is a heterogeneous disease with survival ranging from months to more than 10 years. Cytogenetic abnormalities (CA) detected by fluorescence in situ hybridization (FISH) are of major prognostic significance, since e.g. patients with del(17p), t(4;14) or gain 1q21 show dismal outcome. We evaluated CA at primary diagnosis and relapse to investigate clonal evolution in patients treated with upfront autologous stem cell transplantation (ASCT). Methods: We identified 128 patients with paired samples at primary diagnosis before the start of therapy (1st FISH) and at relapse after ASCT (2nd FISH). Forty-four patients were initially treated within the GMMG HD4 trial which compared 3 cycles of conventional induction chemotherapy (Arm A) with a bortezomib-based induction therapy (Arm B) followed by tandem ASCT and thalidomide (Arm A) or bortezomib (Arm B) maintenance. Eighty-four non-study patients (NSP) treated outside clinical trials were included who had received comparable induction therapies (bortezomib: n=45, thalidomide: n=11, other: n=28) before ASCT. FISH was performed on purified plasma cells using probes for 1q21, 5p15, 5q35, 8p21, 9q34, 11q23, 13q14, 15q22, 17p13 and 19q13, immunoglobulin H (IgH) translocations, t(11;14), t(4;14) and t(14;16). McNemar`s test was used to assess differences between FISH assessments. Kaplan-Meier method and Cox regression were used to analyze survival differences between patients without CA or with CA only at 1st, 2nd or both FISH assessments. Last follow-up for the whole cohort was performed in 06/2016. Results: Median time to first progression for the whole cohort was 27.0 months (HD4: 29.8 months; NSP: 25.5 months). There were no significant differences in CA as well as remission after induction therapy or ASCT between the HD4 and NSP cohort. The number of patients with high-risk CA was significantly higher after relapse (odds ratio (OR): 6.33; 95% confidence interval (CI): 1.86, 33.42; p Conclusion: We demonstrate clonal evolution and a higher incidence of high-risk CA at relapse after ASCT in a homogeneously treated group of patients. The most common translocations in myeloma are highly conservative. High-risk CA can emerge on a subclonal level during disease progression or might evolve from initially present subclones which results in similar dismal outcome Disclosures Merz: Celgene: Other: Travel grant; Janssen: Other: Travel grant. Hose:Sanofi: Research Funding; EngMab: Research Funding; Celgene: Other: personal fees outside this work. Bertsch:Janssen: Research Funding; Celgene: Research Funding; Chugai: Research Funding. Schmidt-Wolf:Janssen: Research Funding; Novartis: Research Funding. Scheid:Novartis: Other: funding outside this work; Celgene: Other: funding outside this work; Janssen: Other: funding outside this work. Weisel:Amgen: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Onyx: Consultancy; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria. Goldschmidt:Janssen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Chugai: Consultancy, Research Funding; Onyx: Consultancy; Millenium: Consultancy; BMS: Other: fees outside this work. Hillengass:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Amgen: Consultancy, Honoraria; BMS: Honoraria; Celgene: Honoraria; Novartis: Research Funding.

Background: The well-described prognostic impact of tumor characteristics and biology in multiple myeloma (MM), such as the combination of cytogenetics, the International Staging System (ISS) and lactate dehydrogenase (LDH, Moreau et. al., JCO, 2014) as well as frailty (Palumbo et al., Blood, 2015) significantly influence patient outcomes. However, only limited data on the impact of infections during therapy exist (Rajkumar et al., Lancet Oncology, 2010). Therefore, we hypothesized that severe infections during induction therapy (IT) in transplant-eligible MM influence dosage of therapies, treatment responses after IT and survival. Patients and Methods: From 05/2005 until 05/2008, 399 patients were randomly assigned to receive IT with either three cycles of VAD (vincristine, VIN, i.v. 0.4mg, days 1-4; doxorubicine, DOXO, i.v. 9mg/m2, days 1-4; dexamethasone, DEX, p.o. 40mg, days 1-4, 9-12, 17-20; n=201, arm A) or PAD (bortezomib, BTZ, i.v. 1.3mg/m2, days 1, 4, 8, 11; DOXO i.v. 9mg/m2, days 1-4; DEX p.o. 40mg, days 1-4, 9-12, 17-20; n=194, arm B), followed by high-dose melphalan (HDM) and autologous stem cell transplantation (ASCT) and either thalidomide (arm A) or bortezomib (arm B) maintenance within the German part of the joint GMMG-HD4/HOVON65 trial (Sonneveld et al., JCO, 2012). After exclusion of ineligible patients, 395 patients (99.0%) were evaluable for analyses. Any severe infection (equal or greater grade 3, according to the Common Terminology Criteria for Adverse Events, Version 4.0) during IT (at least once, defined from first until last date of application of IT medication) occurred in 105 patients (VAD n=53/198 and PAD n=52/192, 26.9% of all patients, missing data n=5). Results: Among patients with a severe infection during IT in the VAD and PAD arms, total DEX and DOXO doses (equal dosage in VAD/PAD group) were significantly lower (median DEX dose (mg/m2): 689.0 [77.7, 1014.1] vs. 742.3 [0.0, 1324.1], p Overall survival (OS) was significantly shortened in patients with at least one severe infection during IT (median OS: 81.8 months vs. not reached, p=0.04, Figure 1A). OS plots diverged in the early period of observation (< 3 months), driven by infection-related deaths (n=8). A landmark analysis 3 months after registration demonstrated approximated survival curves without significant differences in OS (median OS: 78.8 months vs. not reached, p=0.30, Figure 1B). Similarly, progression-free survival (PFS) was shortened, though not significantly (median PFS: 30.2 vs. 35.0 months, p=0.08). However, since not just death accounts as PFS event, the impact of infection-related deaths on PFS remains smaller than on OS. Accordingly, landmark analyses after 3 months from registration showed again closer survival curves (median PFS: 28.5 vs. 32.4 months, p=0.36). Conclusions: Severe infections have a critical impact on the applied doses of IT and outcome in the early, vulnerable phases of MM therapy. OS for transplant-eligible MM patients with severe infections during IT was significantly shortened, mainly driven by early infection-related deaths (< 3 months). A reduction of DEX doses during PAD/PAd IT in the subsequent GMMG study generation (GMMG-HD4/HOVON65: 480mg/cycle to GMMG-MM5: 240mg/cycle) and the recommendation of antibiotic/antiviral prophylaxis throughout the whole IT led to a reduced rate of severe infections of 12% (PAd) in the GMMG-MM5 trial. Further analyses are needed to elucidate how severe infections can be avoided, and whether there is an overlap between the subgroup of patients with severe infections during IT and patients with known adverse prognostic factors or reduced fitness/pre-existing conditions. (A) Overall survival and (B) landmark analysis on overall survival 3 months after start of induction therapy of patients with or without at least one severe infection (equal or greater grade 3) during induction therapy. Figure 1. Impact of severe infections on overall survival. Figure 1. Impact of severe infections on overall survival. Disclosures Mai: Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant; Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Pfreundschuh:Roche: Honoraria; Amgen, Roche, Spectrum: Research Funding; Boehringer Ingelheim, Celegene, Roche, Spectrum: Other: Advisory board. Duehrsen:Janssen: Honoraria. Hillengass:Janssen-Cilag: Honoraria, Other: Travel support; Celgene: Honoraria, Other: Travel support; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Other: Travel support; Sanofi: Research Funding. Scheid:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees. Weisel:BMS: Consultancy, Honoraria, Other: Travel Support; Onyx: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel Support; Novartis: Other: Travel Support; Noxxon: Consultancy. Blau:MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria; Janssen: Honoraria, Research Funding. Goldschmidt:Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millenium: Honoraria, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Chugai: Honoraria, Research Funding, Speakers Bureau.

During the course of chronic myeloid leukemia (CML) progression to blast crisis (BC) is thought to be caused by genetic instability such as cytogenetic aberrations in addition to the translocation t(9;22)(q34;q11). We have shown previously that major route ACA indicate an unfavorable outcome (Fabarius et al., Blood 2011). We now investigate whether there is a correlation in time between appearance of major route ACA and increase in blast count. Methods: Cytogenetic data and blast count in the peripheral blood were available from 1,290 CML patients recruited to the German CML-studies III (621 patients) and IIIa (669 patients) from January 1995 to January 2004. Treatments were interferon-alpha-based or related allogeneic stem cell transplantation (HSCT). Presence of ACA and major route ACA was considered as a time-dependent covariate. Multivariate proportional hazards models were estimated taking Euro CML score, study III vs. IIIa and stem cell transplantability into account. Cumulative incidences of blast increases were calculated starting at the date of the first ACA or major route ACA, respectively, regarding death as a competing risk. Patients were censored at the date of HSCT with an unrelated donor. Results: 1,287 patients were evaluable with median observation times of 13 and 12 years and a 10-year survival of 48% and 61% in CML studies III and IIIa, respectively. 258 patients progressed to BC with a cumulative 10-year incidence of 20%. 195 patients displayed ACA during the course of disease. 45 patients (15.7%) showed ACA already at diagnosis. 44 patients showed unbalanced minor route, 29 balanced minor route aberrations, 23 -Y. 109 patients showed major route aberrations including 10 with other prior ACA. In a multivariate analysis on 1,257 patients, patients with ACA had a hazard ratio (HR) for a blast increase of between 2.0-2.2 (p 5 years after the diagnosis of any ACA the cumulative incidence for a blast increase was 30% (95%- confidence interval (CI): 23-38%), of a major route ACA 40% (95%- CI: 28-49%). The 6-year probability of death without blast increase was 10%. 14 additional patients received an unrelated transplant of which 6 died. We conclude that ACA, particularly major route ACA, precede an increase of blasts. Major route ACA have to be considered as a prognostic indicator for disease progression at any time. Table 1. Blast increase to HR (univariate): ACA vs. no ACA HR(multivariate)*: ACA vs. no ACA HR (univariate): major route ACA vs. no major route ACA HR (multivariate)*: major route ACA vs. no major route ACA ≥30% 2.409 2.139 2.646 2.203 ≥20% 2.413 2.144 2.656 2.211 ≥15% 2.415 2.161 2.868 2.426 ≥10% 2.416 2.160 2.799 2.357 ≥5% 2.286 2.047 2.719 2.278 ≥1% 2.209 1.999 3.171 2.684 *adjusted to Euro-Score, study (III vs. IIIa) and transplantability Disclosures Saussele: ARIAD: Honoraria; BMS: Honoraria, Other: Travel grant, Research Funding; Pfizer: Honoraria, Other: Travel grant; Novartis Pharma: Honoraria, Other: Travel grant, Research Funding. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Scheid:Janssen-Cilag: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Baerlocher:Geron Corporation: Research Funding; Novartis: Research Funding. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Müller:BMS: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:ARIAD: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Pfirrmann:BMS: Consultancy, Honoraria; Novartis Pharma: Consultancy, Honoraria. Baccarani:Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD Pharmaceuticals, Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; PFIZER: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Hehlmann:BMS: Consultancy; Novartis Pharma: Research Funding.

Background: Peripheral neuropathy (PN) is an important, dose-limiting toxicity of bortezomib (BTZ). Subanalysis of the phase 3 VISTA trial of intravenous (IV) BTZ in newly diagnosed MM patients identified baseline neuropathy as only clinical risk factor for Bortezomib-induced peripheral neuropathy (BiPN). Since subcutaneous (SC) application reduces rates of BiPN, BTZ is mainly applied subcutaneously in current clinical trials and general practice. Data on clinical risk factors for BiPN in the era of SC BTZ are limited. We analyzed risk factors for PN in patients treated with SC or IV BTZ in the prospective randomized MM5 phase III trial of the German Myeloma Multicenter Group (GMMG). Methods: Primary end-points of the MM5 trial were response to VCD (BTZ 1.3 mg/m2, days 1, 4, 8, 11; Cyclophosphamide 900 mg/m2 IV; day 1, Dexamethasone 40 mg/d, orally, days 1-2, 4-5, 8-9, 11-12) compared to PAd (BTZ 1.3 mg/m2, days 1, 4, 8, 11; Doxorubicin 9 mg/m2 IV, days 1-4; Dexamethasone 20 mg/d, orally, days 1-4, 9-12, 17-20) induction therapy with respect to remission and progression-free survival (PFS). Induction therapy was followed by stem cell mobilization and harvest, high-dose therapy and Lenalidomide-based consolidation/maintenance therapy. From 07/2010 until 11/2013, 604 patients were randomly assigned to receive 3 cycles of PAd or VCD. Based on the results by Moreau et al, administration of BTZ was changed from IV to SC in 02/2012 after 314 patients were enrolled. We performed univariate and multivariate testing to analyze the association of different factors with the occurrence of PN ≥ grade 2 according to NCI CTCAE version 4.0 after completion of induction therapy. Factors included: Treatment arm (PAd vs. VCD), route of administration (IV vs. SC), existing baseline PN as well as baseline ISS, creatinine ≥2.0 mg/dl , body mass index (BMI), hemoglobin and calcium levels. Fisher's exact test was used for univariate analyses. A multivariate logistic regression model was adapted to analyze the influence of all factors on the occurrence of PN. In this model the impact of a single factor on PN is measured by an odds ratio (OR) based on a characteristic effect (change of one unit for categorical factors and change of interquartile range for continuous factors). Results: Of the analyzed patients, who received at least one dose of trial medication (PAd: n=150 IV/140 SC; VCD: n=154 IV/140 SC), 61 patients (10.2%) developed PN ≥ grade 2. Rates of PN were higher in patients treated with PAd (n=40; 13.5%) compared to VCD (n=21; 7.0%). Neither the presence of higher ISS stage at baseline, nor the route of administration had an impact on development of PN after 3 cycles of induction therapy in univariate analyses. However, PN was more frequent in IV-treated patients during the third cycle of induction therapy (IV: 7.6%; SC: 1.8%, p = 0.001). Median baseline BMI was significantly higher in patients who developed PN (26.9 kg/m2; 19.5-43.7 kg/m2) compared to patients without PN (25.7 kg/m2; 16.7-44-6 kg/m2, p=0.04). Also baseline hemoglobin levels were higher in patients with PN (12.0 g/dl; 6.8-15.9 g/dl) compared to patients without PN (10.8 g/dl; 5.8-16.3 g/dl, p=0.004). While baseline calcium levels were significantly lower in patients with PN (2.3 mmol/l; 1.6-3.5 mmol/l) compared to patients without PN (2.4 mmol/l; 1.6-5.4 mmol/l, p=0.04), baseline creatinine were not different in both groups. Multivariate logistic regression adjusting for the above mentioned factors confirmed the effect of VCD treatment compared to PAd on the development of PN (OR 0.49, 95% confidence interval (CI) [0.28, 0.89], p=0.02) and the importance of pre-existing PN (OR 3.12, 95% CI [1.26, 7.76], p=0.01). Also baseline calcium (OR 0.71, 95% CI [0.51, 0.99], p=0.04) and hemoglobin levels (OR 1.53, 95% CI [1.01, 2.33], p=0.05) proved to have an impact on the development of PN in the multivariate model. Conclusion: We confirm the importance of pre-existing neuropathic symptoms and the combination partners for BTZ on the development of PN in patients with newly diagnosed MM. We provide first evidence that clinical baseline characteristics, like calcium and hemoglobin levels, might predict the development of PN. This is in line with preclinical studies showing that dysregulation of calcium homeostasis and oxidative stress in the dorsal root ganglion plays a role in the pathogenesis of BiPN. Disclosures Merz: Janssen: Other: Travel grants; Celgene: Other: Travel grants. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Blau:Janssen: Honoraria, Research Funding; MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria. Scheid:Janssen: Honoraria; Celgene: Honoraria. Mai:Mundipharma: Other: Travel Grant; Celgene: Other: Travel Grant; Janssen-Cilag: Other: Travel Grant; Onyx: Other: Travel Grant. Hose:Takeda: Other: Travel grant; EngMab AG: Research Funding. Weisel:Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Noxxon: Consultancy; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding; BMS: Consultancy, Honoraria, Other: Travel Support. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Chugai: Honoraria, Research Funding, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees.

Background: We reported better PFS and OS in transplant eligible patients with newly diagnosed Multiple Myeloma (MM) who were treated with bortezomib during induction and maintenance, when compared with standard treatment in the HOVON-65/GMMG-HD4 trial. (P. Sonneveld et al., J Clin Oncol 30:2946-2955, 2012). Here the long-term follow up data are presented. Methods: 827 eligible patients were randomized to induction therapy with VAD (vincristine, doxorubicin, dexamethasone) or PAD (bortezomib, doxorubicin, dexamethasone) followed by high-dose melphalan (once or twice) and autologous stem cell transplant. Maintenance consisted of daily thalidomide (T) 50 mg (VAD arm) or 2-weekly bortezomib (B) 1.3 mg/m2 (PAD arm) for 2 years. The primary endpoint was progression-free survival (PFS) adjusted for ISS stage. Results: After a median follow up of 91.4 months (maximum 119) 410 patients are alive. Response rates were VAD/HDM/T: CR 25%, ≥VGPR 56%, ≥PR 83%; PAD/HDM/B: CR 37%, ≥VGPR 76%%, ≥PR 91%, The median duration of maintenance therapy was 14 months (thalidomide) and 23 months (bortezomib), respectively. Main reasons for discontinuation were toxicity (T: 31%; B: 11%), disease progression (T: 33%; B: 36%) or normal completion (T: 28%; B: 48%). Of 827 patients in the analysis, 206 are alive without progression/relapse. PFS was significantly better in the bortezomib arm, i.e. median 34 versus 28 months (HR=0.77, 95% CI=0.65-0.90, p=0.001). Median overall survival (OS) was 90 months in the bortezomib arm vs 83 months in the control arm, but 42% at 9 years in both arms. We used the restricted mean survival time (RMST) method to compare OS between the two treatment arms In univariate analysis. The difference in RMST8y was 4.8 months (95% CI 0.2-9.5, p=0.04) in favor of the bortezomib arm. A landmark analysis in patients who had received HDM starting at 12 months showed a significant PFS advantage of bortezomib in all patients (p=0.02), in patients in VGPR/PR (p=0.02) but not in CR (p=0.19). For OS there was no advantage for bortezomib in either group. PFS at 60 months in bortezomib treated patients was not different when single vs double HDM/ASCT was administered, i.e. 28% vs 27%. However, OS at 60 months was 71% vs 60% in favor of double HDM/ASCT (p=0.04). Subgroup analysis was performed based on presence/absence of adverse FISH (CA) in 395 patients treated with double HDM/ASCT. PFS at 60 months for each abnormality (CA or no CA) in bortezomib vs standard arm is given in Table 1 Table 1.PFS at 60 months, %OS at 60 months, %FISHnBortezomib armpStandard armBortezomib armpStandard Armt(4;14) yes/no50/29516% vs 27%0.048% vs 24%52% vs 75%0.0133% vs 64%add(1q) yes/no113/23116% vs 32%0.00510% vs 28%57% vs 79%0.00143% vs 70%del(17p) yes/no39/31222% vs 27%0.475% vs 24%65% vs 72%0.4818% vs 66% These data show that bortezomib treatment combined with double HDM/ASCT significantly improves PFS and OS in patients with del(17p) and almost abrogates the negative impact of this CA. In t(4;14) and add(1q) some improvement is observed, however the negative impact remains significant. In high-risk patients presenting with elevated creatinine >2 mg/dL bortezomib significantly improved PFS at 60 months (32% vs 5%) (p=0.001) and OS at 60 months (66% vs 21% months (p Conclusions: We conclude that bortezomib leads to a significant and lasting improvement of PFS and OS. Bortezomib significantly reduces the high-risk impact of del(17p) and renal impairment on survival. This trial was registered as NTR213; EudraCT no. 2004-000944-26.and supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and an unrestricted grant from Janssen. The GMMG group received grants for this trial by Novartis, AMGEN, Chugai and Roche. Disclosures Sonneveld: SkylineDx: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Research Funding; Amgen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding. Salwender:Celgene: Honoraria; Janssen Cilag: Honoraria; Bristol Meyer Sqibb: Honoraria; Amgen: Honoraria; Novartis: Honoraria. Blau:MSD: Honoraria; Celgene: Honoraria, Research Funding; AMGEN: Honoraria; JAZZ pharm: Honoraria; BMS: Honoraria; Shire: Honoraria; Baxalta: Honoraria; Janssen: Honoraria, Research Funding. Zweegman:celgene: Honoraria, Research Funding; takeda millennium: Honoraria, Research Funding; onyx: Honoraria. Weisel:Noxxon: Consultancy; Janssen Pharmaceuticals: Consultancy, Honoraria, Other: Travel Support, Research Funding; Novartis: Other: Travel Support; Onyx: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Other: Travel Support; BMS: Consultancy, Honoraria, Other: Travel Support; Celgene: Consultancy, Honoraria, Other: Travel Support, Research Funding. Broijl:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. Scheid:Janssen: Honoraria; Celgene: Honoraria. Potamianou:Janssen: Employment. Hose:Takeda: Other: Travel grant; EngMab AG: Research Funding. Kersten:takeda millennium: Research Funding; janssen: Honoraria, Research Funding; roche: Honoraria, Research Funding. Duehrsen:Alexion: Honoraria; janssen: Honoraria. Lokhorst:Janssen: Honoraria, Research Funding; Genmab: Honoraria, Research Funding; Amgen: Honoraria. Goldschmidt:celgene: Honoraria, Research Funding; janssen: Honoraria, Research Funding; novartis: Honoraria, Research Funding; chugai: Honoraria, Research Funding; onyx: Honoraria, Research Funding; millennium: Honoraria, Research Funding; BMS: Honoraria, Research Funding.

Purpose To compare progression-free survival between single and tandem high-dose chemotherapy (HDT) followed by autologous stem-cell transplantation in chemotherapy-sensitive metastatic breast cancer patients. Patients and Methods Between February 1997 and June 2001, 187 patients with complete and partial remission were randomly assigned to receive either one or two cycles of HDT, consisting of thiotepa (125 mg/m2/d for 4 days), cyclophosphamide (1,500 mg/m2/d for 4 days), and carboplatin (200 mg/m2/d for 4 days), followed by autologous stem-cell transplantation. Results One hundred seventy one of 187 randomly assigned patients completed first HDT, but only 52 of 85 completed the second HDT cycle in the tandem HDT arm. The rate of complete remission on an intent-to-treat-basis was 33% in the single-dose HDT arm and 37% in the tandem HDT arm (P = .48). The median progression-free survival times in single and tandem HDT arms were 9.4 and 11.2 months, respectively (one-sided P = .06; two one-sided P = .12), whereas median overall survival time tended to be greater after single versus tandem HDT (29 v 23.5 months, respectively; P = .4). In a multivariate analysis for progression-free survival, tandem HDT (hazard ratio [HR] = 0.71; 95% CI, 0.52 to 0.98; P = .03) and achievement of complete remission after induction chemotherapy (HR = 0.59; 95% CI, 0.37 to 0.96; P = .03) were factors for a better progression-free survival, whereas the factor of three or more sites of metastases (HR = 1.66; 95% CI, 1.12 to 2.47; P = .01) was associated with a worse progression-free survival. Conclusion Despite a trend of improved progression-free survival, tandem HDT cannot be recommended for patients with chemotherapy-sensitive metastatic breast cancer because of a trend for shorter overall survival and higher toxicity compared with single HDT.

Background: In patients with relapsed multiple myeloma (MM), Moreau and colleagues (Lancet Oncol, 2011) demonstrated that subcutaneous (SC) administration of bortezomib (BTZ) significantly reduced rates of adverse events (AE) compared to the intravenous (IV) formulation without loss of efficacy. Prospective data on SC BTZ in newly diagnosed MM are limited. We investigated the impact of SC versus IV BTZ in two different induction therapies for patients with newly diagnosed MM treated within the multicenter, prospective randomized MM5 trial of the German Myeloma Multicenter Group (GMMG). Methods: From 06/2010 until 11/2013, 604 patients were randomly assigned to receive 3 cycles of PAd (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Doxorubicin 9 mg/m2 IV, days 1-4; Dexamethasone 20 mg/d, orally, days 1-4, 9-12 and 17-20) or 3 cycles VCD (BTZ 1.3 mg/m2, days 1, 4, 8 and 11; Cyclophosphamide 900 mg/m2IV; day 1, Dexamethasone 40 mg/d, orally, days 1-2, 4-5, 8-9 and 11-12) for induction therapy. In the MM5 trial, induction therapy is followed by stem cell mobilization and harvest, high-dose therapy and Lenalidomide-based consolidation/maintenance therapy. Primary end points of the ongoing study are response to treatment after induction therapy and progression-free survival. Due to improved AE profile of SC compared to IV BTZ reported by Moreau, the administration of BTZ was changed from IV to SC in 02/2012. Therefore, we were able to perform an explorative analysis of 598 patients who received at least one dose of trial medication (PAd: n=150 IV / 140 SC; VCD: n=154 IV / 140 SC). 14 patients were excluded from the analysis because administration of BTZ was changed after start of induction therapy. We analyzed whether the route of administration influenced the applied cumulative BTZ dose, toxicity and efficacy of PAd and VCD. Results: The cumulative applied BTZ dose was significantly higher in patients treated with SC BTZ (PAd: 28.9 mg; VCD: 28.8 mg) compared to IV-treated patients (PAd: 27.6 mg; VCD: 27.9 mg; p = 0.007). Analysis of reported AEs associated to induction therapy revealed a significantly higher rate in patients treated with IV BTZ (65.1%) compared to SC-treated patients (55.7%, p = 0.02). AE > °II were reported more frequently in the IV group (IV: 52.0%; SC: 43.9%, p = 0.004). In detail, abnormal laboratory findings including leucopenia and thrombocytopenia (IV: 23.0%; SC: 16.4%, p = 0.05), metabolism and nutrition disorders (IV: 12.5%; SC: 5.4%, p = 0.004) and gastrointestinal disorders (IV: 9.9%; SC: 3.9%, p = 0.006) occurred more often in IV-treated patients. Analysis of peripheral neuropathy (PN) ≥ °II revealed no significant differences between IV and SC BTZ during the first two cycles of induction therapy (cycle 1: IV: 1.6%; SC: 2.5%; cycle 2: IV: 2.3%; SC: 3.6%) but PN occurred more often in IV-treated patients during the third cycle of induction therapy compared to the SC group (IV: 7.6%; SC: 1.8%, p = 0.001). Overall response rates (partial response or better) were not influenced by the route of administration in patients treated with PAd (IV: 72.7%; SC: 70.7%; p = 0.79) or VCD (IV: 77.9%; SC: 82.1%; p = 0.39). Analysis of the VCD arm showed that rates of VGPR or better were significantly higher in patients treated with IV BTZ compared to SC-treated patients (IV: 41.6%; SC: 28.6%, p = 0.02). Rates of VGPR or better were also higher for IV-treated patients in the PAd arm but did not reach statistical significance (IV: 36.7%; SC: 31.4%, p=0.39). Patient characteristics including baseline creatinine levels > 2 mg/dl, obesity or age at inclusion > 65 years did not influence efficacy of IV or SC BTZ in both arms. Conclusion: Last year we reported on the favorable toxicity profile and equal efficacy of VCD compared to PAd. With the current analysis we demonstrate that toxicity is further reduced with SC BTZ compared to IV. We therefore recommend VCD as induction therapy. However, we show for the first time a possible loss of efficacy in SC-treated patients. Therefore it remains unclear whether the reduced toxicity justifies the general application of SC BTZ in newly diagnosed, transplant-eligible patients or whether a prolonged treatment (4 x VCD SC) may reduce toxicity while achieving similar efficacy. Further studies are warranted since our results are partially in contrast with the previously presented data in relapsed MM and the ongoing MM5 trial was initially not designed to prospectively investigate the effect of SC or IV BTZ. Disclosures Salwender: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Binding site: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Scheid:Celgene: Honoraria; Janssen: Honoraria. Mai:Janssen: Travel support Other. Hose:Novartis: Research Funding. Schmidt-Wolf:Janssen: Consultancy, Honoraria. Weisel:Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Onyx: Consultancy, Honoraria; BMS: Consultancy; Noxxon: Consultancy. Duerig:Janssen: Consultancy, Honoraria; Celgene: Honoraria. Goldschmidt:Janssen-Cilag: Honoraria, Research Funding, Speakers Bureau; Polyphor: Research Funding; Celgene: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau; Chugai: Research Funding, Speakers Bureau; Onyx: Consultancy, Speakers Bureau; Millenium: Consultancy, Speakers Bureau.

Aim: Analysis of a trial investigating, whether TPFC would be feasible and superior to PFC in patients with RM-HNSCC without limiting comorbidities, based on the findings, that D in addition to PF in induction treatment and C in addition to PF in RM disease both improved outcome in HNSCC. The first analysis was presented at ASCO 2014; here we present the final analysis. Methods: 180 patients were assigned 1:1 to receive either (arm A) P 40 mg/sqm, D 40 mg/sqm, F 2000 mg/sqm days 1 + 8, C 400/250 mg/sqm days 1, 8, 15 q3w or (arm B) standard PFC (P 100 mg/sqm day 1, F 1000 mg/sqm days 1-4, C 400/250 mg/sqm days 1, 8, 15) q3w. Chemotherapy was continued for a maximum of 6 cycles in absence of disease progression or limiting toxicity, followed by C maintenance (500 mg/sqm q2w). Because of excessive toxicity (gastrointestinal and infections) in arm A, P was reduced to 30 and F to 1000 mg/sqm after 20 patients/arm. Results: Median follow-up was 2 years. Toxicity was similar in both arms, with a rate of grade 4 toxicities of 21.3% vs. 30.8% of patients in arms A vs. B. 11.2% vs. 6.6% potentially treatment related deaths were observed in arms A vs. B. Median PFS A vs. B was 5.4 vs. 5.0 mo (HR 0.79, p = 0.375), median OS was 9.8 vs. 9.7 mo (HR 1.39, p = 0.993) and response rates were 38.2% vs. 31.9%, respectively. Conclusions: Despite of the previously described advantage of both components D and C in treatment of HNSCC, the four-drug regimen was not associated with improved median PFS or OS. The efficacy data of the CeFCiD trial are comparable with the results in the EXTREME trial. Disclosure: M. Knoedler: Financial support for conducting this trial by Merck GmbH and Sanofi Aventis for conducting this trial; T. Gauler, A. Dietz, V. Grunwald, J. Stoehlmacher-Williams, O. Guntinas-Lichius and G. Maschmeyer: Merck Serono; U. Keilholz: Merck Serono and Sanofi Aventis. All other authors have declared no conflicts of interest.

Background For curative treatment of younger patients with acute myeloid leukemia (AML) double induction with two cycles of intensive cytarabine/ anthracycline based chemotherapy 21 days apart is the current standard of care. In the prospective randomized AML-CG 2008 trial we asked question whether current results could be improved on by a dose-dense regimen (S-HAM – Sequential High-dose cytArabine and Mitoxantrone) in which the interval between cycles was minimized to 3 days. A prior large one-armed study (AML-CG 2004) had demonstrated a high antileukemic efficacy and shortened neutropenia of the S-HAM regimen as compared to a historical control of standard double induction treatment. The first clinical results of the randomized comparison are presented here. Methods All patients with first diagnosis of a de-novo or secondary AML (excluding APL) that were deemed fit for intensive induction chemotherapy by their treating physician were eligible for this study. Younger patients in the standard arm were treated with one cycle of TAD-9 (standard dose cytarabine and daunorubicine 60mg/m2 for 3 days) and a mandatory second cycle of HAM (high dose cytarabine and mitoxantrone) starting at day 21. Elderly patients were treated with one cycle of HAM followed by a second cycle of HAM only in case of residual leukemia in the day 16 bone marrow aspirate. Patients in the experimental arm all received S-HAM (two sequential cycles of high-dose cytarabine on days 1+2, mitoxantrone days 3+4) with a 3 days interval. Patients in the age cohort 60 – 69 could be allocated to the “younger” or “elderly” cohort according to their biological fitness at the discretion of the treating physician. However high-dose cytarabine dosages were allocated according to chronological age with patients Results 396 patients were randomized into the study with an age range of 18 to 86 years (median 58). The 387 evaluable patients (184 standard, 203 experimental) were well balanced according to their clinical characteristics, cytogenetics, molecular genetics and overall risk profile. For the primary endpoint a higher ORR of 77% for S-HAM could be found as compared to 72% in the standard arm which was however not significant because a 15% difference had been postulated for the study. Non-hematological toxicities did not show any significant differences. However this was in clear contrast to hematological toxicities: Importantly the duration of critical neutropenia was highly significantly reduced by more than 2 weeks from 45 days (standard) to 29 days (S-HAM) counted from day 1 of treatment. Similarly critical thrombocytopenia was reduced by 13 days from 46 days to 33 days. The early death (ED) rate between both arms was identical between both arms. However a subgroup analysis demonstrated a significantly reduced ED rate in patients receiving 1g/m2 S-HAM as compared to all other treatment groups. The respective ED rates for the various time intervals (always counted from day d1 of treatment) for the 1g/m2S-HAM group were as follows: Interval d1-14 1%, d1-30 3%, d1-60 5%, d1-90 10%. Data for overall survival will be available in November 2013. Conclusion The dose-dense induction regimen S-HAM was highly feasible in patients up to the 8th age decade. The antileukemic efficacy was high with an ORR of 77% for the whole group of unselected patients. As compared to standard double induction dose-dense S-HAM reduced critical neutropenia by more than two weeks. Moreover the subgroup of patients receiving the 1g/m2 S-HAM regimen experienced the lowest ED rate ever reported in the AML-CG trials. This underlines that in contrast to our general expectations the concept of dose-density is able to combine high antileukemic efficacy with significantly reduced haematological toxicity in AML, characterising this approach as first candidate for the next standard arm for future trials of the study group. Disclosures: Lengfelder: TEVA/ Cephalon: Research Funding.

Background We investigated if bortezomib during induction and maintenance improves survival in newly diagnosed Multiple Myeloma (MM). Methods 827 eligible patients with newly diagnosed symptomatic MM were randomized to receive induction therapy with VAD (vincristine, doxorubicin, dexamethasone; n=414) or PAD (bortezomib, doxorubicin, dexamethasone; n=413) followed by high-dose melphalan (HDM) and autologous stem cell transplant (ASCT). Maintenance consisted of daily thalidomide 50 mg (VAD) or 2-weekly bortezomib 1.3 mg/m2 i.v. (PAD) for 2 years. The primary analysis was progression-free survival (PFS) adjusted for ISS stage. We here report long-term results of this trial (P. Sonneveld et al., J Clin Oncol 2012;30:2946-2955). Results The number of eligible patients, patient characteristics and disease characteristics are similar to those reported before. The response rates during protocol treatment have improved slightly since all patients have now completed treatment: CR+nCR 49% vs 35%, VGPR 26% vs 21% and ≥PR 91% vs 83% (PAD vs VAD). After a median follow-up of 67 months, 111 of patients treated with VAD and 131 of patients treated with PAD were progression-free and alive. Progression-free survival (PFS) defined as time from randomization until progression, relapse or death (censored at date of alloSCT, if applicable), was superior with PAD when adjusted for ISS, (HR=0.78, 95% CI [0.66-0.91], P=.002) and in multivariate analysis (HR=0.76 (95% CI [0.64-0.90], P=.001). For the secondary endpoint overall survival (OS) the PAD arm was superior when adjusted for ISS (HR=0.80, 95% CI [0.65-1.00], P=.047) as well as in multivariate analysis (HR=0.78, 95% CI [0.63-0.97], P=.027). Landmark analysis from start of maintenance for PFS did not show a significant difference between Thalidomide and Bortezomib maintenance, however, for OS the PAD arm was superior (P=.035) (HR=0.71, 95% CI [0.52-0.98]). Subgroup analysis performed on patients with renal failure at presentation (serum creatinine ≥2 mg/dL; 45 VAD, 36 PAD) showed that the PAD arm was significantly superior for PFS (HR=0.44, 95% CI [0.26-0.75], P=.003) and OS (HR=0.38, 95% CI [0.21-0.69], P Conclusions Bortezomib during induction and maintenance improves CR and achieves superior PFS and OS. Subgroup analysis after long follow-up confirms the favourable outcome in patients with renal failure. Comparison of study subgroup analysis suggests that bortezomib treatment combined with double intensive treatment may be beneficial for PFS/OS. This trial has been registered as NTR213; EudraCT no. 2004-000944-26; ISRCTN: 64455289. This trial was supported by the Dutch Cancer Foundation, the German Federal Ministry of Education and Research and an unrestricted grant from Janssen-Cilag-Ortho Biotech. The GMMG study group received further grants to support this trial by Novartis, AMGEN, Chugai and Roche. Disclosures: Sonneveld: Janssen-Cilag: Honoraria; Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Research Funding; Millenium: Research Funding; Onyx: Research Funding; Celgene: Research Funding. Salwender:janssen: Honoraria. Weisel:Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria. Schmidt-Wolf:janssen: Research Funding; novartis: Honoraria. van de Velde:Janssen Research & Development: Employment; Johnson & Johnson: Equity Ownership. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria. Goldschmidt:janssen: Honoraria, Research Funding; amgen: Research Funding; novartis: Honoraria, Research Funding; chigai: Honoraria, Research Funding; roche: Honoraria, Research Funding.