ALBERT

Description: In patients with multiple myeloma (MM), risk stratification by chromosomal abnormalities may enable a more rational selection of therapeutic approaches. In the present study, we analyzed the prognostic value of 12 chromosomal abnormalities in a series of 354 MM patients treated within the HOVON-65/GMMG-HD4 trial. Because of the 2-arm design of the study, we were able to analyze the effect of a bortezomib-based treatment before and after autologous stem cell transplantation (arm B) compared with standard treatment without bortezomib (arm A). For allanalyzed chromosomal aberrations, progression-free survival (PFS) and overall survival (OS) were at least equal or superior in the bortezomib arm compared with the standard arm. Strikingly, patients with del(17p13) benefited the most from the bortezomib-containing treatment: the median PFS in arm A was 12.0 months and in arm B it was 26.2 months (P = .024); the 3 year-OS for arm A was 17% and for arm B it was 69% (P = .028). After multivariate analysis, del(17p13) was an independent predictor for PFS (P 〈 .0001) and OS (P 〈 .0001) in arm A, whereas no statistically significant effect on PFS (P = .28) or OS (P = .12) was seen in arm B. In conclusion, the adverse impact of del(17p13) on PFS and OS could be significantly reduced by bortezomib-based treatment, suggesting that long-term administration of bortezomib should be recommended for patients carrying del(17p13). This trial is registered at the International Standard Randomised Controlled Trial Number Register as ISRCTN64455289.

Description: Background A lack of objective data exists on differences in treatment practices and outcomes for MM between countries. The EMMOS study aimed to document and describe current treatment regimens and disease progression patterns of MM pts at different stages of the disease in real-world medical practice. Methods Adult pts initiating any new MM therapy, irrespective of treatment line at study entry or therapy type received, were eligible for inclusion in the EMMOS registry. A multi-staged pt/site recruitment model was applied to minimize selection bias; enrollment was stratified by country, region, and practice type. Pts' medical/disease features, treatment history, and remission status were recorded at baseline. Prospective data on treatment, efficacy, and safety were collected electronically every 3 mos until 2 yrs after the last pt enrolled. Responses were investigator-assessed (no predefined criteria). Here we report data from the final analysis of EMMOS. Pts were grouped according to receipt of high-dose chemotherapy/stem cell transplantation in any treatment line (SCT pts, non-SCT pts). Within a given line, pts may have received induction, SCT, consolidation, and/or maintenance therapy; if multiple drug combinations were used within a line, the line grouping was based on the combination received in cycle 1. Results 2358 pts were enrolled between Oct 2010-Oct 2012 in 22 countries in Europe and Africa; the last pt completed follow-up in Oct 2014. Of these, 775 pts had undergone SCT in any treatment line. Baseline characteristics in the prospective phase by starting line are shown in the Table. As expected, there was a higher proportion of younger pts (≤65 yrs) in the SCT vs non-SCT group across all treatment lines, and in both groups a higher proportion of pts in 4th + vs earlier lines with ISS stage III disease. While cytogenetics were evaluated in a small number of pts overall (670/2358 [28%]), these assessments were performed significantly more frequently in SCT vs non-SCT pts (p

Description: Introduction: Gene expression profiling (GEP) has significantly contributed to the elucidation of the molecular heterogeneity of multiple myeloma plasma cells (MMPC) and only recently it has been recommended for risk stratification. Prior to GEP MMPC need to be enriched resulting in an inability to immediately freeze bone marrow aspirates or use RNA stabilization reagents. As a result in multi-center MM trials sample processing delay due to shipping may be an important confounder of molecular analyses and risk stratification based on GEP data. In order to determine the impact of "shipping delay" on MMPC gene expression we analyzed a set of 573 newly diagnosed German MM patients including 230 in-house and 343 shipped samples. Materials and Methods: We included publicly available GEP data of newly diagnosed MM patients treated in the GMMG HD4 and MM5 trials. All samples had been processed in a central laboratory in Heidelberg and include 85 HD4 and 145 MM5 in-house and 97 HD4 and 246 MM5 shipped samples. Prediction of sample status was done on publicly available GEP, including data from the UK, UAMS and MMRC. Differential gene expression was assessed using empirical Bayes statistics in linear models for microarray data. Predictor for shipment status was generated on the MM5 cohort using prediction analysis for microarrays. Pathway enrichment analysis was done using WebGestalt. Risk signatures and molecular subgroups were obtained as previously described. Fisher's exact test was used to compare the subgroup distribution between cohorts. If applicable, results were corrected for multiple testing using the Benjamini-Hochberg method. In all statistical tests, an effect was considered statistically significant if the P-value of its corresponding statistical test was not greater than 5%. Results: Applying the Goeman's global teston the MM5 set showed that "shipping delay" significantly impacted global gene expression (P 1.5-fold and 826 a 〉2-fold difference in expression level. Differentially expressed genes were enriched in processes like ribosome biogenesis, cell cycle, and apoptosis. We observed significantly lower proliferation rates in shipped samples (P

Description: Background: During the last 15 years there has been a substantial improvement in treatment options for patients with multiple myeloma. For patients younger than 65 years high dose chemotherapy with melphalan and autologous stem cell transplantation is still regarded as the standard therapy. This very effective treatment regimen is now widely used for more than 20 years. However, the therapy of elderly patients (〉 70 years) with HDT-ASCT has only been a reserved option for a selected group of patients with a lower biological age. Therefore, for these patients only few studies have analyzed the role of HDT-ASCT regarding overall survival (OS), progression free survival (PFS) and risk assessment-which is our study subject. In addition we want to compare HDT-ASCT with the current standard of treatment for older patients like the continuous lenalidomide and dexamethasone regime (Rd) or bortezomib based regimes. Method: We retrospectively analyzed 62 elderly patients with a median age at ASCT of 71.3 years with multiple myeloma who underwent HDT-ASCT treatment at the Asklepios Hospital Altona in Hamburg, Germany between 2004 and 2013 (3 previously treated with HDT-ASCT and 59 previously untreated). Overall these patients received 86 ASCT. Primary scopes of interest were OS, PFS and treatment related mortality (TRM). Secondary outcome variables were melphalan-dosage, chronic renal failure (Durie Salmon stage A/B), tandem-therapy, ISS-Score, as well as best response after therapy. OS was calculated from beginning of therapy until death of any cause. PFS was calculated from beginning of therapy until progression. Results: The median OS was 60.8 months. TRM was 0%. Median PFS was 33.3 months (n=40). The following factors were significant regarding OS: 1. Chronic renal failure (39 vs. 65.6 months; p=0.03). 2. Higher ISS-Score (ISS III: 33.7 vs. ISS I/II: 76.7 months; p= 0.013). The following factors showed a non statistically significant trend regarding OS: 1. High melphalan dosage, at least once 200mg/m² melphalan, during HDCT-ASCT (70.3 vs. 53 months; p=0.1). 2. Response after therapy (complete remission (CR) / very good partial remission (VGPR): 74.6 vs. partial remission / minimal remission / stable disease: 59.4 months; p= 0.088). 3. Tandem therapy (single transplantation: 60.6 vs. tandem transplantation: 96.3 months; p= 0.127). Conclusion: With a median OS of more than 5 years and a TRM of 0% high dose chemotherapy with melphalan is a valid treatment option for selected elderly patients with multiple myeloma aged 〉 70 years. The median OS and PFS (60.8 months; 33.3 months) in our patient group was higher than published data with lenalidomide or bortezomib based treatments (e.g. Rd), which has a median OS of 58.9 months and a of PFS 26 month (Facon et al. 2015, Clinical Lymphoma Myeloma and Leukemia, Vol: 15, p: e134). At relapse fewer patients are eligible for HDT-ASCT than de novo patients, therefore HDT-ASCT should be used as first line therapy for suitable patients. Adverse effects of long time glucocorticoid, bortezomib and lenalidomide treatment also have a negative impact on the quality of life for myeloma patients and can lead to irreversible medical consequences. Of note, the treatment duration with high dose melphalan is shorter and has a lower cost than other treatment options for multiple myeloma, which can lead to long treatment free intervals and therefore improve the quality of life for patients. Disclosures: No relevant conflicts of interest to declare. Disclosures No relevant conflicts of interest to declare.

Description: Introduction In multiple myeloma, initially, there are increased numbers of osteoclasts showing increased activity, but bone formation by osteoblasts is keeping step. In later stages, parts of the bone remodeling compartments are disrupted by the interaction with myeloma cells leading to increased bone resorption which can no longer be compensated (myeloma bone disease, uncoupling of bone formation and bone resorption). Lenalidomide and bortezomib have been shown to target both, myeloma cells and the microenvironment: lenalidomide inhibits osteoclastogenesis, bortezomib is also able to stimulate osteoblast differentiation leading to increased bone formation. Aim of this study is to evaluate the impact of bortezomib-based induction treatment, high-dose therapy, and lenalidomide consolidation on alterations of bone turnover, i.e. surrogates of osteoblast- (osteocalcin, OC) and osteoclast- (collagen type I fragments, CTX-I) function, and their induction by myeloma cells (DKK1-level). Methods Serum was collected during routine sampling within the GMMG-MM5 trial (EudraCT 2010-019173-16), and levels of CTX-I, OC, and DKK1 were assessed by ELISA in triplicates using commercially available assays according to the manufacturer’s instructions (RnD Systems and Immunodiagnostic Systems). The following time points were assessed: at inclusion (n=365), after induction therapy with either PAd (n=88) or VCD (n=84), stem cell mobilization using CAD (n=69), high-dose melphalan (n=92), and 2 months lenalidomide consolidation (n=92). Up to now, serum samples of 69 patients were measured sequentially at five time points in line with the GMMG-MM5 trial. DKK1 levels were correlated with the expression in CD138-purified myeloma cells (Affymetrix microarrays, n=365). Results Prior to treatment, CTX-I levels are increased, those of OC decreased compared to healthy donors (uncoupled bone turnover). DKK1 protein levels are increased and correlate with DKK1-expression in myeloma cells. After induction therapy, osteoclast activity (CTX-I) is decreased below normal values. PAd unlike VCD further decreases osteoblast activity (OC-levels); DKK1-levels are normalized. Subsequent treatment further decreases DKK1-levels below normal values and blocks osteoclast function. After 2 months lenalidomide consolidation, no normalization of osteoblast activity is found. Conclusion The main impact on bone turnover by bortezomib-based induction treatment is a reduction of osteoclast activity alongside a decrease in DKK1-levels. During the reported period, no normalization of decreased osteoblast function was observed. Disclosures: Seckinger: Novartis Pharma: Research Funding. Goldschmidt:Novartis Pharma: Research Funding. Hose:Novartis Pharma: Research Funding.

Description: Abstract 305 Chromosomal aberrations are important prognostic parameters in multiple myeloma (MM). By using interphase fluorescent in situ hybridization (FISH) on CD138-enriched plasma cells, specific changes in interphase cells can be detected, overcoming the lack of dividing cells required for conventional cytogenetics. We evaluated the association of FISH results and outcome of a subgroup of patients (pts) within the HOVON-65/GMMG-HD4 trial, a prospective, randomized phase III trial for pts with newly diagnosed MM stage II or III according to Salmon & Durie up to 65 years. Pts were randomized to receive three cycles of VAD (arm A; vincristine, adriamycin, dexamethasone) or PAD (arm B; bortezomib, adriamycin, dexamethasone). Hematopoietic stem cells were mobilized using the CAD regimen and G-CSF. All pts received one or two cycles of high dose melphalan (200 mg/m2) with autologous stem cell transplantation followed by maintenance therapy with thalidomide 50 mg daily (arm A) or bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively, for a maximum of 2 years. Sites in Germany, the Netherlands and Belgium participated in this trial (n=833 pts). For the German pts (GMMG, n=399) FISH was performed in a single laboratory prior to start of treatment. Cytospins of CD138 purified plasma cells were subjected to FISH with two-color probe sets for the detection of numerical changes for the following chromosome regions: 1q21/8p21, 6q21/15q22, 9q34/22q11, 11q23/13q14, and 17p13/19q13, as well as for the translocations t(4;14)(p16;q32), t(11;14)(q13;q32), and t(14;16) (q32;q23). As of July 2010 data from the first consecutively enrolled 626 patients of the trial have been analyzed, including 284 GMMG pts. For this analysis, FISH results from 258 (91%) GMMG pts were available (n=131 in arm A; n=127 in arm B). Patient characteristics in the GMMG subgroup are comparable to the analyzed trial population of 626 pts. For all pts the median follow-up time from randomization was 40.3 months (mo.). The most pronounced impact on prognosis was seen for t(4;14), del17p13, and gain1q21, each significantly associated with poor prognosis with respect to progression free survival (PFS) and overall survival (OS). The strongest prognostic impact was found for del17p13. FISH analysis detected del17p13 in 9.4% of pts (A: 12.3% vs. B: 6.4%), t(4;14) in 14.8 % (16.3% vs. 13.4%), and gain 1q21 in 33.7% of pts (33.1% vs. 34.4%). When comparing pts in the two arms for PFS, we found a borderline significance for the interaction between t(4;14) and treatment arm (p=0.06), indicating that the effect of t(4;14) depends on the treatment. Pts with t(4;14) in arm A show a very poor prognosis with a median PFS time only half as long compared to patients without translocation (18 vs. 36 mo.; p=0.003). No such negative effect was observed for patients in arm B with t(4;14) (36 vs. 40 mo.; p=0.97). PAD resulted in improved 3yr-OS rates for pts with t(4;14) (A:39% vs B:76%), while 3yr-OS was 79% and 87% in pts without t(4;14). Median PFS for pts with gain 1q21 was 22 mo. (arm A) vs. 30 mo. (arm B) compared to 41 mo. in both arms for patients without gain 1q21. Pts with gain 1q21 showed a significantly better OS when treated with bortezomib (3yr-OS rates: A: 59%, B: 83%, p=0.016). Del17p13 was significantly associated with poor prognosis in both arms for OS (A: p

Description: Background High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is the established standard-of-care for patients with newly diagnosed multiple myeloma (NDMM) who are young and/or fit. The number of older patients receiving HDT-ASCT is increasing, although they often receive lower-intensity treatment. Novel agent-based consolidation therapy can be used to improve responses following ASCT and prolong progression-free survival (PFS). The proteasome inhibitor bortezomib, given as post-ASCT consolidation therapy, resulted in an improved PFS compared with observation alone (median 33.6 vs 27.8 months, adjusted hazard ratio [HR] 0.70, p=0.0058) in a combined analysis of two phase 3 trials (MMY3012 [DSMM XIb; NCT00416273] and MMY3013 [DSMM X; NCT00416208]; JCO 2015;33:8511). These studies enrolled 222 patients aged ≤60 years and 158 aged 〉60 years. In this post-hoc analysis we investigated the effect of age and related treatment factors on PFS in more detail. Methods In both trials, 371 patients were randomized 1:1 following ASCT to receive four 35-day cycles of bortezomib consolidation (n=186; bortezomib 1.6 mg/m2 IV administered on days 1, 8, 15, and 22) or observation (n=185; no treatment). The primary endpoint was PFS from the start of induction chemotherapy. Response and progression were assessed at the start of each bortezomib cycle and at the end-of-treatment/observation visit (week 25), as well as during the follow-up period of 30-60 months. Patient characteristics and treatments were compared between trials; PFS following randomization was assessed separately for each study. Univariate, bivariate, and multivariate Cox regressions were conducted to evaluate the impact of treatment group, age (≤60 vs 〉60 years), single vs tandem ASCT, melphalan conditioning dose (MEL 60 group), including the HDT regimen received (MEL100 7% vs 10%; MEL140 3% vs 59%; MEL200 88% vs 31%). The rate of double transplantation was similar for the younger and older cohorts (55% vs 59%), likely due to the older patients receiving age-adjusted high-dose melphalan with a lower toxicity, allowing a similar rate of double transplantation as younger patients receiving MEL200. Among the 357 patients included in these analyses, median PFS from start of induction was 33.6 vs 27.8 months with bortezomib consolidation vs observation (log-rank p=0.0243). Median PFS for bortezomib vs observation was 33.6 vs 29.0 months (HR 0.86; p=0.3599) in the younger cohort and 33.4 vs 26.4 months (HR 0.60; p=0.0073) in the older cohort. PFS for older patients who received bortezomib consolidation was very similar to PFS in younger patients (p=0.861); survival curves were superimposable despite the older patients having received less intensive pretreatment. Univariate analysis demonstrated that treatment group (bortezomib vs observation) had an effect on PFS (HR 0.75; exploratory p-value 60 vs ≤60 years; HR 1.30), melphalan dose (200 vs

Description: Background: Internal tandem duplications (ITD) in the receptor tyrosine kinase FLT3 occur in roughly 25% of younger adult patients (pts) with acute myeloid leukemia (AML), implicating FLT3 as a potential target for kinase inhibitor therapy. The multi-targeted kinase inhibitor midostaurin shows potent activity against FLT3 as a single agent but also in combination with intensive chemotherapy. Aims: To evaluate the feasibility and efficacy of midostaurin in combination with intensive induction therapy and as single agent maintenance therapy after allogeneic hematopoietic stem cell transplantation (alloHSCT) or high-dose cytarabine (HIDAC). Methods: The study includes adult pts (age 18-70 years (yrs)) with newly diagnosed FLT3-ITD positive AML enrolled in the ongoing single-arm phase-II AMLSG 16-10 trial (NCT: NCT01477606). Pts with acute promyelocytic leukemia are not eligible. The presence of FLT3-ITD is analyzed within our diagnostic study AMLSG-BiO (NCT01252485) by Genescan-based fragment-length analysis (allelic ratio 〉0.05 required to be FLT3-ITD positive). Induction therapy consists of daunorubicin (60 mg/m², d1-3) and cytarabine (200 mg/m², continuously, d1-7); midostaurin 50 mg bid is applied from day 8 onwards until 48h before start of the next treatment cycle. A second cycle is optional. For consolidation therapy, pts proceed to alloHSCT as first priority; if alloHSCT is not feasible, pts receive three cycles of age-adapted HIDAC in combination with midostaurin from day 6 onwards. In all pts maintenance therapy for one year is intended. This report focuses on the first cohort of the study (n=149) recruited between June 2012 and April 2014 prior to the amendment increasing the sample size; the amendment to the study is active since October 2014. Results: At study entry patient characteristics were median age 54 years (range, 20-70, 34% ≥ 60 yrs); median white cell count (WBC) 48.4G/l (range 1.1-178G/l); karyotype, n=103 normal, n=3 t(6;9), n=2 t(9;11), n=20 intermediate-2 and n=7 high-risk according to ELN recommendations, n=14 missing; mutated NPM1 n=92 (62%). Data on response to first induction therapy were available in 147 pts; complete remission (CR) 58.5%, partial remission (PR) 20.4%, refractory disease (RD) 15% and death 6.1%. A second induction cycle was given in 34 pts. Overall response after induction therapy was CR 75% and death 7.5%. Adverse events 3°/4° reported during the first induction cycle were most frequently gastrointestinal (n=34) and infections (n=81). During induction therapy midostaurin was interrupted, dose-reduced or stopped in 55% of the pts. Overall 94 pts received an alloHSCT, 85 in first CR (n=65 age

Description: The HOVON-65/GMMG-HD4 trial is a prospective, randomized phase III trial to evaluate the efficacy of bortezomib prior to high-dose melphalan (200 mg/m2, HDM) on response and progression-free survival (PFS) in patients with newly diagnosed MM stage II or III according to Salmon & Durie (SD). Until May 2008 in total 833 patients aged 18–65 years were included in the trial. Patients were randomized to receive three cycles of VAD (arm A; vincristin 0,4mg, days 1–4, adriamycin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, and 17–20) or PAD (arm B; bortezomib 1.3 mg/m2, days 1,4,8,11, adriamycin 9 mg/m2, days 1–4, dexamethasone 40 mg, days 1–4, 9–12, and 17–20). Hematopoietic stem cells were mobilized in patients using the CAD regimen (cyclophosphamide 1000 mg/m2 iv day 1, adriamycin 15mg/m2, days 1–4, dexamethasone 40mg, days 1–4) and G-CSF. After stem cell harvesting all patients received one or two cycles of HDM with autologous stem cell transplantation followed by maintenance therapy with thalidomide 50 mg daily (arm A) and bortezomib 1.3 mg/m2 once every 2 weeks (arm B), respectively. As of August 2008 stem cell harvesting data from the first consecutively enrolled 150 patients (75 per arm) were analyzed. The data of the initial 300 patients (150 per arm) will be available by November 2008. Both treatment arms did not differ in age, SD stage of disease, ISS stage, and FISH abnormalities. 132 patients (88%) were treated with CAD plus G-CSF. Dosing and type of G-CSF treatment were comparable in both arms. In all patients stem cell collection was successful and at least two autografts could be harvested (minimal number of stem cells permitted per autograft was 2.0 ×106 CD 34+ cells per kg BW). Induction treatment Days until first leukapheresis Median (range) Number of leukaphereses Median (range) Number of harvested CD34+ stem cells (× 106) per kg BW Median (range) PAD 110 (96–149) 1 (1–4) 10.5 (4.1–37.6) VAD 111 (95–156) 1 (1–5) 9.3 (4.0–37.0) In 64% of the patients in arm A (VAD) and 79% of the patients in arm B (PAD) only one leukapheresis was sufficient for stem cell harvesting. In all patients hematopoietic reconstitution was achieved after HDM followed by autografts harvested after PAD or VAD. We conclude that stem cell harvesting after PAD is very well feasible.

Description: Purpose: The combination of chemotherapy with the chimeric anti-CD20 antibody Rituximab has been reported to be highly active in the treatment of follicular lymphoma. The frequency and dosage of rituximab required to induce the maximum effect in follicular NHL is not defined. To evaluate how often rituximab should be added to standard chemotherapy to achieve maximum remission rates, we have initiated a prospective randomized multicenter phase II study. Methods: Patients (pts) with stage III/IV CD20 positive follicular NHL who were chemotherapy naïve were randomly assigned to receive 6 courses of a standard CHOP-21 chemotherapy, accompanied by rituximab 375 mg/m2 at day 0 only with the first CHOP course (arm A), with the first 3 CHOP courses (arm B) or with all 6 CHOP courses (Arm C). The major endpoint was the rate of molecular remission in bone marrow and peripheral blood in initially t(14;18)-positive pts, assessed by PCR. Other endpoints of the study were overall and complete response rates, toxicity rate and time to progression. Results: Since September 2000, 104 pts with a median age of 57 years (range 30–80) were recruited. 33 pts were randomized to arm A, 35 to arm B and 36 to arm C. So far 69 pts have been documented completely after all 6 cycles and are evaluable for side effects. All three treatment arms were well tolerated. The incidence of adverse events and Grade 4 toxicity was similar in all groups. One treatment related death was observed 2 months after completion of therapy due to hepatitis B. The overall response rate (ORR) of the whole group, which was evaluable in 69 pts so far, was 90 % (62 of 69 pts), with 20 complete and 42 partial remissions. Conclusion: This multicenter, randomized, phase II trial addresses for the first time the optimal frequency and dosage of rituximab infusions in the combined immuno-chemotherapy. In the first interim analysis of the ongoing trial, similar hematologic, gastrointestinal and infectious toxicity was observed in all treatment arms.