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Based on the lack of differences in progression-free and overall survival after a median follow-up of 93 months in our HOVON-65/GMMG-HD4 trial (German part; n = 395) randomizing VAD induction (vincristin/adriamycin/dexamthasone)/tandem-transplantation/thalidomide-maintenance vs. PAD induction (bortezomib/adriamycin/dexamethasone)/tandem transplantation/bortezomib maintenance, we discern how chromosomal aberrations determine long-term prognosis by different patterns of association with proliferation and treatment-dependent response, whether responses achieved by different regimens are equal regarding prognosis, and whether subpopulations of patients could be defined as treatable without upfront "novel agents" in cases of limited resources, e.g., in low- or middle-income countries. Serum parameters and risk factors were assessed in 395 patients. CD138-purified plasma cells were subjected to fluorescence in situ hybridization (n = 354) and gene expression profiling (n = 204). We found chromosomal aberrations to be associated in four patterns with survival, proliferation, and response: deletion (del) del17p13, del8p21, del13q14, (gain) 1q21+, and translocation t(4;14) (all adverse) associate with higher proliferation. Of these, del17p is associated with an adverse response (pattern 1), and 1q21+, t(4;14), and del13q14 with a treatment-dependent better response (pattern 2). Hyperdiploidy associates with lower proliferation without impacting response or survival (pattern 3). Translocation t(11;14) has no association with survival but a treatment-dependent adverse response (pattern 4). Significantly fewer patients reach a near-complete response or better with "conventional" (VAD) vs. bortezomib-based treatment after induction or high-dose melphalan. These patients, however, show significantly better median progression-free and overall survival. Molecularly, patients responding to the two regimens differ in gene expression, indicating distinct biological properties of the responding myeloma cells. Patients with normal renal function (89.4%), low cytogenetic risk (72.5%), or low proliferation rate (37.9%) neither benefit in progression-free nor overall survival from bortezomib-based upfront treatment. We conclude that response level, the treatment by which it is achieved, and molecular background determine long-term prognosis. Chromosomal aberrations are associated in four patterns with proliferation and treatment-dependent responses. Associations with faster and deeper responses can be deceptive in the case of prognostically adverse aberrations 1q21+ and t(4;14). Far from advocating a return to "outdated" treatments, if resources do not permit state-of-the-art-treatment, normal renal function and/or molecular profiling identifies patient subpopulations doing well without upfront "novel agents". [ABSTRACT FROM AUTHOR]

Objective: A post hoc subgroup analysis of two phase III trials (NCT00416273, NCT00416208) was carried out to investigate the influence of 100/140 and 200 mg/m² melphalan as well as single/double autologous stem cell transplantation (ASCT) on progression‐free survival (PFS). Additionally, the effect of bortezomib consolidation on PFS was analyzed. Methods: Following induction therapy and high‐dose melphalan with subsequent ASCT, patients with newly diagnosed multiple myeloma (NDMM) were randomized 1:1 to either four 35‐day cycles of bortezomib consolidation (1.6 mg/m² IV on days 1, 8, 15, 22) or observation. Results: Of the 340 patients included in this analysis, 13.5% received 1 × MEL100/140, 22.9% 2 × MEL100/140, 31.2% 1 × MEL200, and 32.4% 2 × MEL200. With higher cumulative melphalan dose, PFS improved (P =.0085). PFS curves of patients treated with 2 × MEL100/140 and 1 × MEL200 were very similar. The superior dose effect of MEL200 over MEL100/140 was non‐existent in the bortezomib consolidation arm but pronounced in the observation arm (P =.0015). Similarly, double ASCT was only beneficial in patients without bortezomib consolidation (P =.0569). Conclusions: Full dose melphalan and double transplantation seem advantageous only as long as patients are not receiving bortezomib consolidation afterwards. [ABSTRACT FROM AUTHOR]

Natural killer (NK)/T-cell lymphomas and large granular lymphocyte (LGL) leukemia are rare lymphoproliferative malignancies with fundamental different prognosis. This prompted us to examine the expression of SLAMF7 also by T-cell lymphoma, NK/T-cell lymphoma, NK-LGL, and T-LGL. Here we found a strong expression of SLAMF7 by IHC comparable to biopsies from patients with multiple myeloma in NK/T-cell lymphoma, whereas no expression by IHC was found on T-cell lymphoma biopsy tissue of 3 patients with T-cell lymphoma and of 1 patient with T-ALL. Lymphoma tissue of a patient (UPN 1) with NK/T-cell lymphoma, nasal type stained positive for SLAMF7 by IHC. [Extracted from the article]

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. [ABSTRACT FROM AUTHOR]

The patient granulocyte-colony stimulating factor (G-CSF) response is represented by the leukocyte peak in the blood induced by a single dose of G-CSF after chemotherapy, and is correlated with subsequent neutropenic infection risk. General patterns for a meaningful risk group stratification, have not yet been determined. Two independent data sets including a total of 306 cases with myeloma or lymphoma and autologous blood stem cell transplant were available. An infection susceptibility curve plotted according to ranked G-CSF responses from a multicenter study reproduced and validated a curve from the previous single center. Two trend changes were seen within these curves at around 11 000 and 22 000 leukocytes/μL, which separated three groups with a high, medium and low risk of infection. While G-CSF response is related to the consecutive duration of neutropenia, it retains additional independent predictive information for infection risk ( p < 0.0001) and, more important, is a tool available before the onset of the critical period. [ABSTRACT FROM AUTHOR]

PURPOSE: Given the high heterogeneity in survival for patients with multiple myeloma, it would be clinically useful to quantitatively predict the individual survival instead of attributing patients to two to four risk groups as in current models, for example, revised International Staging System (R-ISS), R2-ISS, or Mayo-2022-score. PATIENTS AND METHODS: Our aim was to develop a quantitative prediction tool for individual patient's 3-/5-year overall survival (OS) probability. We integrated established clinical and molecular risk factors into a comprehensive prognostic model and evaluated and validated its risk discrimination capabilities versus R-ISS, R2-ISS, and Mayo-2022-score. RESULTS: A nomogram for estimating OS probabilities was built on the basis of a Cox regression model. It allows one to translate the individual risk profile of a patient into 3-/5-year OS probabilities by attributing points to each prognostic factor and summing up all points. The nomogram was externally validated regarding discrimination and calibration. There was no obvious bias or overfitting of the prognostic index on the validation cohort. Resampling-based and external evaluation showed good calibration. The c-index of the model was similar on the training (0.76) and validation cohort (0.75) and significantly higher than for the R-ISS (P <.001) or R2-ISS (P <.01). CONCLUSION: In summary, we developed and validated individual quantitative nomogram-based OS prediction. Continuous risk assessment integrating molecular prognostic factors is superior to R-ISS, R2-ISS, or Mayo-2022-score alone. Better survival prediction in multiple myeloma—multimodal and continuous nomogram (instead of few arbitrary groups) [ABSTRACT FROM AUTHOR]

Simple Summary: Impaired kidney function is a common complication of a certain blood cancer called multiple myeloma. Patients with severe kidney problems are usually left out of medical studies, so data on safety and efficacy of treatments are limited for these patients. The academic phase II GMMG-DANTE trial (NCT02977494) investigated a combination of drugs—daratumumab, bortezomib, and dexamethasone—in patients who had already tried other treatments before, and had severe kidney impairment. Even though the study had to end early, the results were promising. About 67% of the patients had their cancer respond to the treatment, and their kidney function improved. The treatment was overall well tolerated. Renal function impairment (RI) is a common complication in multiple myeloma (MM). However, limited data exist on the safety and efficacy of anti-MM regimens in patients with severe RI, as these patients are frequently excluded from clinical trials. This investigator-initiated multicentric phase II GMMG-DANTE trial evaluated daratumumab, bortezomib, and dexamethasone (DVd) in relapsed or refractory (r/r) MM patients with severe RI. r/rMM patients with ≥1 prior treatment line and a GFR <30 mL/min/1.73 m2 or undergoing hemodialysis were eligible and received eight cycles of DVd followed by daratumumab maintenance. The trial closed prematurely after 22/36 planned patients. The primary endpoint was overall response rate (ORR). Median age of patients was 70 (range 55–89) years, with a median GFR of 20.1 mL/min/1.73 m2 (interquartile range, 9.4–27.3 mL/min/1.73 m2), and eight patients under hemodialysis. Median number of prior lines was two (range 1–10). The trial was successful, albeit with premature termination, as it met its primary endpoint, with an ORR of 67% (14/21). The rates of partial response, very good partial response, and complete response were 29%, 29%, and 10%, respectively (n = 6, 6, and 2). Fourteen patients (67%) achieved renal response. After median follow-up of 28 months, median progression-free survival was 10.4 months; median overall survival was not reached. Higher-grade toxicity was mainly hematologic, and non-hematologic toxicities ≥Grade 3 were mostly infections (24%). The prospective GMMG-DANTE trial investigating DVd exclusively in r/rMM patients with severe RI showed efficacy and safety to be comparable to data from patients without RI. [ABSTRACT FROM AUTHOR]

Light chain amyloidosis (AL) is one of the most common forms of systemic amyloidosis and is caused by the deposition of insoluble fibrils derived from misfolded and aggregated immunoglobulin light chains (LC). To uncover the causes leading to this aggregation, we compared AL LC sequences with those of patients with the related disease multiple myeloma (MM), which do not aggregate in insoluble fibrils in vivo. IGLV2‐14 is one of the most common AL‐associated IGLV subfamilies. Here, we analysed IGLV2‐14 LC sequences of 13 AL and eight MM patients in detail. We found that AL‐associated LCs presented a lower median mutation count (7.0 vs. 11.5 in MM; P = 0.045), as well as an overall composition of less charged amino acids than MM LCs. However, we did not find a mutation that was present in ≥ 50% of the AL and not in the MM sequences. Furthermore, we did not find a significant difference in the isoelectric point (pI) in general, suggesting similar stability of the LCs in AL and MM. However, the subgroup of patients without a detectable heavy chain stood out. Surprisingly, they are characterized by an increase in mutation count (median 7.0 vs. 5.5) and pI (median 7.82 vs. 6.44, P = 0.043). In conclusion, our data suggest that the amount of mutations and the introduction of charges play a crucial role in AL fibril formation, as well as the absence or presence of a potential heavy chain binding partner. [ABSTRACT FROM AUTHOR]

Simple Summary: For multiple myeloma (MM) patients with measurable disease, there is no recommendation to monitor serum free light chains during therapy. However, this could provide important information in terms of prognosis. We investigated the prognostic impact of serum free light chain ratio (FLCr) normalization in 590 patients with secretory MM during first-line treatment within the German-Speaking Myeloma Multicenter Group MM5 trial. We are able to show that there is an increasing percentage of patients who achieve FLCr normalization during therapy. Importantly, we demonstrate that FLCr normalization at any time before the start of maintenance is significantly associated with prolonged progression-free and overall survival in multivariable time-dependent Cox regression analyses. This suggests that FLCr normalization during therapy is an important and simple way to assess prognostic factor in MM and supports the serial measurement of serum free light chains during therapy, even in patients with secretory MM. 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 < 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. [ABSTRACT FROM AUTHOR]

Background: Venetoclax is a highly selective, potent, oral BCL-2 inhibitor, which induces apoptosis in multiple myeloma cells. Venetoclax plus bortezomib and dexamethasone has shown encouraging clinical efficacy with acceptable safety and tolerability in a phase 1 trial. The aim of this study was to evaluate venetoclax plus bortezomib and dexamethasone in patients with relapsed or refractory multiple myeloma.Methods: In this randomised, double-blind, multicentre, phase 3 trial, patients aged 18 years or older with relapsed or refractory multiple myeloma, an Eastern Cooperative Oncology Group performance status of 2 or less, who had received one to three previous therapies were enrolled from 90 hospitals in 16 countries. Eligible patients were randomly assigned (2:1) centrally using an interactive response technology system and a block size of three to receive venetoclax (800 mg per day orally) or placebo with bortezomib (1·3 mg/m2 subcutaneously or intravenously and dexamethasone (20 mg orally). Treatment was given in 21-day cycles for the first eight cycles and 35-day cycles from the ninth cycle until disease progression, unacceptable toxicity, or patient withdrawal. Randomisation was stratified by previous exposure to a proteasome inhibitor and the number of previous therapies. Sponsors, investigators, study site personnel, and patients were masked to the treatment allocation throughout the study. The primary endpoint was independent review committee-assessed progression-free survival in the intention-to-treat population. Safety analyses were done in patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, NCT02755597.Findings: Between July 19, 2016, and Oct 31, 2017, 291 patients were randomly assigned to receive venetoclax (n=194) or placebo (n=97). With a median follow-up of 18·7 months (IQR 16·6-21·0), median progression-free survival according to independent review committee was 22·4 months (95% CI 15·3-not estimable) with venetoclax versus 11·5 months (9·6-15·0) with placebo (hazard ratio [HR] 0·63 [95% CI 0·44-0·90]; p=0·010). The most common grade 3 or worse treatment-emergent adverse events were neutropenia (35 [18%] of 193 patients in the venetoclax group vs seven [7%] of 96 patients in the placebo group), pneumonia (30 [16%] vs nine [9%]), thrombocytopenia (28 [15%] vs 29 [30%]), anaemia (28 [15%] vs 14 [15%]), and diarrhoea (28 [15%] vs 11 [11%]). Serious treatment-emergent adverse events occurred in 93 (48%) patients in the venetoclax group and 48 (50%) patients in the placebo group, with eight (4%) treatment-emergent fatal infections reported in the venetoclax group and none reported in the placebo group. Three deaths in the venetoclax group (two from pneumonia and one from septic shock) were considered treatment-related; no deaths in the placebo group were treatment-related.Interpretation: The primary endpoint was met with a significant improvement in independent review committee-assessed progression-free survival with venetoclax versus placebo plus bortezomib and dexamethasone. However, increased mortality was seen in the venetoclax group, mostly because of an increased rate of infections, highlighting the importance of appropriate selection of patients for this treatment option.Funding: AbbVie and Genentech. [ABSTRACT FROM AUTHOR]

Evidence on volume outcome associations for autologous stem cell transplantation (ASCT) in multiple myeloma (MM) is limited. We investigated ASCT utilization patterns and volume outcome associations in the German National Registry for Stem Cell Transplants (DRST). MM patients with an upfront ASCT between 1998 and 2014 registered in the DRST were included. ASCT utilization increased strongly from 6% to 17% between 1999 and 2013 with the largest increase for patients aged 60–64 years (8–34%). The mean number of ASCTs conducted in the hospitals per year varied (quintiles, Q1:0.0–8.2 to Q5:31.0–102.7). Center volume was not associated with survival after upfront ASCT (lowest vs. highest center volume, hazard ratios and 95% confidence intervals: 0.95 (0.76–1.18), p = 0.92). Our findings may reflect a high standard of care and degree of specialization of centers performing ASCT for MM in Germany. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented which discusses the case of limbic encephalitis with high serum titres of Hu antibodies in a patient with Hodgkin disease.

Background: Personalized and risk-adapted treatment strategies in multiple myeloma prerequisite feasibility of prospective assessment, reporting of targets, and prediction of survival probability in clinical routine. Our aim was first to set up and prospectively test our experimental and analysis strategy to perform advanced molecular diagnostics, i.e., interphase fluorescence in-situ hybridization (iFISH) in ≥ 90% and gene expression profiling (GEP) in ≥ 80% of patients within the first cycle of induction chemotherapy in a phase III trial, seen as prerequisite for target expression-based personalized treatment strategies. Secondly, whether the assessment of risk based on the integration of clinical, cytogenetic, and expression-based parameters ("metascoring") is possible in this setting and superior to the use of single prognostic factors. Methods: We prospectively performed plasma cell purification, GEP using DNA-microarrays, and iFISH within our randomized multicenter GMMG-MM5-trial recruiting 604 patients between July 2010 and November 2013. Patient data were analyzed using our published gene expression report (GEP-R): after quality and identity control, integrated risk assessment (HM metascore) and targets were reported in clinical routine as pdf-document. Results: Bone marrow aspirates were obtained from 573/604 patients (95%) and could be CD138-purified in 559/573 (97.6%). Of these, iFISH-analysis was possible in 556 (99.5%), GEP in 458 (82%). Identity control using predictors for sex, light and heavy chain type allowed the exclusion of potential sample interchanges (none occurred). All samples passed quality control. As exemplary targets, IGF1R-expression was reported expressed in 33.1%, AURKA in 43.2% of patients. Risk stratification using an integrated approach, i.e., HM metascore, delineated 10/77/13% of patients as high/medium/low risk, transmitting into significantly different median progression-free survival (PFS) of 15 vs. 39 months vs. not reached (NR; P < 0.001) and median overall survival (OS) of 41 months vs. NR vs. NR (P < 0.001). Five-year PFS and OS-rates were 5/31/54% and 25/68/98%, respectively. Survival prediction by HM metascore (Brier score 0.132, P < 0.001) is superior compared with the current gold standard, i.e., revised ISS score (0.137, P = 0.005). Conclusions: Prospective assessment and reporting of targets and risk by GEP-R in clinical routine are feasible in ≥ 80% of patients within the first cycle of induction chemotherapy, simultaneously allowing superior survival prediction. [ABSTRACT FROM AUTHOR]

Objective: A post hoc analysis of two phase III trials was carried out to explore the influence of age and treatment factors on the effect of bortezomib consolidation on progression‐free survival (PFS) post autologous stem cell transplantation (ASCT). Methods: Patients with newly diagnosed multiple myeloma were assigned to one of two trials (ClinicalTrials.gov IDs: NCT00416273, NCT00416208), which were conducted in parallel, based on age (18‐60 or 61‐75 years, respectively). Following induction and ASCT, patients were randomized 1:1 to four 35‐day cycles of bortezomib consolidation (1.6 mg/m2 IV on days 1, 8, 15, 22) or observation only. Results: Median PFS with bortezomib consolidation vs observation was 33.6 vs 29.0 months (P = 0.3599) in patients aged 18‐60 years (n = 202), and 33.4 vs 26.4 months (P = 0.0073) in patients aged 61‐75 years (n = 155), respectively. Bortezomib consolidation post‐ASCT appeared to equalize outcomes between older and younger patients who received prior treatment of differing intensity. This suggests that the effect of consolidation may be relative and may depend on the composition and intensity of induction and high‐dose therapy. Conclusion: Older patients receiving less intensive prior treatment could experience a larger PFS benefit from bortezomib consolidation. [ABSTRACT FROM AUTHOR]

Background and objectives: This study describes preferences of German relapsed refractory multiple myeloma (RRMM) patients with novel proteasome inhibitor-based combination treatments.Methods: Patients with a minimum age of 18 years and a diagnosis of RRMM were included. Their preferences were assessed using a discrete choice experiment design, which was developed based on a literature review and two patient focus group discussions. The final discrete choice experiment design consisted of four attributes, namely "therapy application regimen," "time without progression of disease," "possibility of grade ≥3 adverse events (AEs) affecting the blood," and "possibility of grade ≥3 AE heart failure."Results: Analysis was based on 84 patients (36.9% females, mean age 62.7 years, mean multiple myeloma disease duration 5.5 years). Among the tested attributes, "therapy application regimen" was assigned the highest importance for treatment decisions (38.8%), the second important attribute was "time without progression of disease" (38.7%), followed by "possibility of AE heart failure" (13.9%) and "possibility of AEs affecting the blood" (8.6%). Patients preferred oral intake once a day and once a week over other application modes such as oral intake once a day and once a week plus twice-weekly infusions. Furthermore, they preferred longer disease progression-free time and lower risk of grade ≥3 AEs. The highest overall utility was derived for ixazomib + lenalidomide + dexamethasone (utility: 3.218), compared with lenalidomide + dexamethasone (2.769), and carfilzomib + lenalidomide + dexamethasone (1.928).Conclusion: RRMM patients prefer treatments with an all-oral application, a longer disease-progression-free time, and a lower probability of AEs. If patients face tradeoffs, they accept a lower progression-free time and/or higher AE rates to get an all-oral therapy. [ABSTRACT FROM AUTHOR]

SLAMF7 expression in pretreatment formalin-fixed paraffin-embedded mastocytosis bone marrow biopsies derived from five patients with histologically proven SM was evaluated by immuno-histochemical (IHC) staining with SLAMF7-specific antibodies. Bone marrow infiltration of MCs of 60% prior to therapy fell to <5% after therapy (Supplementary Figure 1d/e, Supplemental Data). Cytoreductive therapy in 108 adults with systemic mastocytosis: outcome analysis and response prediction during treatment with interferon-alpha, hydroxyurea, imatinib mesylate or 2-chlorodeoxyadenosine. International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) & European Competence Network on Mastocytosis (ECNM) consensus response criteria in advanced systemic mastocytosis. [Extracted from the article]

Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events ( AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study ( TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes. [ABSTRACT FROM AUTHOR]

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 Re LApsE 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. [ABSTRACT FROM AUTHOR]

Background The aim of this study was to determine the value of upfront autologous transplantation (ASCT) in elderly patients (60–79 years) with myeloma. Methods We analysed relative survival (RS) of patients diagnosed in 1998–2011 and treated with ASCT within 12 months after diagnosis in Germany (n = 3591; German Registry of Stem Cell Transplantation) and compare RS with survival of myeloma patients diagnosed in the same years in Germany (n = 13,903; population-based German Cancer Registries). Results Utilisation of ASCT has increased rapidly between 2000–2002 and 2009–2011 (60–64years: 7.0–43.0%; 65–69 years: 6.6–23.7%; 70–79 years: 0.4–4.0%). Comparison of 5-year RS of patients from the general German myeloma population who have survived the first year after diagnosis with 5-year RS of patients treated with ASCT revealed higher survival for transplanted patients among all age groups (60–64: 59.2% versus 66.1%; 65–69: 57.4% versus 61.7%; 70–79: 51.0% versus 56.6%). RS increased strongly between 2003–2005 and 2009–2011 for the general German myeloma population (+8.5%) and for patients treated with ASCT (+11.8%). Differences in RS between these groups increased over time from +1.9% higher age-standardised survival in transplanted patients in 2003–2005 to 5.2% higher survival in 2009–2011. Conclusion We conclude that upfront ASCT might be a major contributor to improved survival for elderly myeloma patients in Germany. [ABSTRACT FROM AUTHOR]

Background: 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. Results: We compared GEP data of 145 in-house and 246 shipped samples and detected 3301 down-regulated and 3501 up-regulated genes in shipped samples. For 3994 genes we confirmed differential expression in an independent set of 85 in-house and 97 shipped samples. Differentially expressed genes were enriched in processes like ribosome biogenesis, cell cycle, and apoptosis. Among GEP based risk predictors the IFM-15 seemed to underestimate high risk in shipped samples, whereas the GEP70 and the EMC-92 gene signatures were more robust. In order to provide a tool to assess the "shipping effect" in public repositories, we generated a 17-gene predictor for shipped samples with a 10-fold cross validation error rate of 0.06 for the training set and an error rate of 0.15 for the validation set. Conclusion: Sample processing delay significantly influences GEP of MMPC, implying it should be avoided if samples were used for risk stratification. [ABSTRACT FROM AUTHOR]

Sepsis is a major cause of mortality during the neutropenic phase after intensive cytotoxic therapies for malignancies. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. Clinical guidelines on sepsis treatment have been published by others. However, optimal management may differ between neutropenic and non-neutropenic patients. Our aim is to give evidence-based recommendations for haematologist, oncologists and intensive care physicians on how to manage adult patients with neutropenia and sepsis. [ABSTRACT FROM AUTHOR]

Sepsis is a major cause of mortality during the neutropenic phase after intensive cytotoxic therapies for malignancies. Improved management of sepsis during neutropenia may reduce the mortality of cancer therapies. Clinical guidelines on sepsis treatment have been published by others. However, optimal management may differ between neutropenic and non-neutropenic patients. Our aim is to give evidence-based recommendations for haematologist, oncologists and intensive care physicians on how to manage adult patients with neutropenia and sepsis. [ABSTRACT FROM AUTHOR]

More than 18,000 autolgous transplantation were performed in Europe in the year 2009. It as a routine procedure in experienced centres. Even if there is a low mortality rate, infections are a major issue after transplantation, occurring in more than 60 % of the patients. In this review we discuss all aspects of infections after autologous stem transplantation, including epidemiology, diagnostics, therapeutic algorithms, prophylaxis and supportive therapy. [ABSTRACT FROM AUTHOR]

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 all analyzed chromosomal aberrations, progression-free survival (PFS) and over- all 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. (Blood. 2012;119(4): 940-948) [ABSTRACT FROM AUTHOR]

Catheter-related infections (CRI) cause considerable morbidity in hospitalized patients. The incidence does not seem to be higher in neutropenic patients than in nonneutropenic patients. Gram-positive bacteria (coagulase-negative staphylococci, Staphylococcus aureus) are the pathogens most frequently cultured, followed by Candida species. Positive blood cultures are the cornerstone in the diagnosis of CRIs, while local signs of infection are not necessarily present. Blood cultures should be taken from peripheral blood and from the venous catheter. A shorter time to positivity of catheter blood cultures as compared with peripheral blood cultures supports the diagnosis of a CRI. In many cases, a definite diagnosis requires catheter removal and microbiological analysis. The role plate method with semiquantitative cultures has been established as standard in most laboratories. Antimicrobial treatment of CRI should be directed by the in vitro susceptibility of the isolated pathogen. Primary removal of the catheter is mandatory in S. aureus and Candida infections, as well as in case of tunnel or pocket infections. Future studies will elucidate whether the rate of CRI in neutropenic patients may be reduced by catheters impregnated with antimicrobial agents. [ABSTRACT FROM AUTHOR]

A phase 2 trial was performed to study the combination of bortezomib (VELCADE®) with intermediate-dose dexamethasone (DEX), and continuous low-dose oral cyclophosphamide (CY) in patients with relapsed multiple myeloma (MM). Fifty-four patients with advanced MM were enroled to receive eight 3-week treatment cycles with bortezomib 1·3 mg/m2 on days 1, 4, 8, and 11, followed by three 5-week cycles with bortezomib 1·3 mg/m2 on days 1, 8, 15, and 22. Within all cycles, DEX 20 mg/d was given orally on the day of bortezomib injection and the day thereafter. In addition, patients received CY continuous oral treatment at a dose of 50 mg/d p.o. once daily. Fifty patients completing at least one treatment cycle were evaluable for response. Complete, partial, and minor responses occurred in 16%, 66% and 8% of patients, respectively; overall response rate 90% (efficacy analysis). Median event-free survival was 12 months, with a median overall survival of 22 months. Adverse events (AE) of grades 3 or 4 occurring in at least 10% of patients comprised leucopenia, infection, herpes zoster, thrombocytopenia, neuropathy and fatigue. Bortezomib combined with DEX and CY is a highly effective treatment for relapsed MM at an acceptable rate of grade 3/4 AE. Antiviral prophylaxis appears to be mandatory. [ABSTRACT FROM AUTHOR]

Morbidity and mortality in patients with malignancies, especially leukemia and lymphoma, are increased by invasive fungal infections. Since diagnosis of invasive fungal infection is often delayed, antifungal prophylaxis is an attractive approach for patients expecting prolonged neutropenia. Antifungal prophylaxis has obviously attracted much interest resulting in dozens of clinical trials since the late 1970s. The non-absorbable polyenes are probably ineffective in preventing invasive fungal infections, but may reduce superficial mycoses. Intravenous amphotericin B and the newer azoles were used in clinical trials, but their role in antifungal prophylaxis is still not well defined. Allogeneic stem cell transplant recipients are at particularly high risk for invasive fungal infections. Other well described risk factors are neutropenia >10 days, corticosteroid therapy, sustained immunosuppression, graft versus host disease, and concomitant viral infections. The enormous study efforts are contrasted by a scarcity of risk stratified evidence based recommendations for clinical decision making. The objective of this review accumulating information on about 10.000 patients is to assess evidence based criteria primarily regarding the efficacy of antifungal prophylaxis in neutropenic cancer patients. [ABSTRACT FROM AUTHOR]

Infectious complications occur in 60–100% of patients following high-dose chemotherapy (HDC) and autologous hematopoietic stem cell transplantation (HSCT), and are commonly caused by Gram-negative aerobic bacteria (such as Pseudomonas aeruginosa and enterobacteriaceae) and Gram-positive cocci (such as enterococci, streptococci and staphylococci), which should be covered by empiric first-line antibiotic therapy. Less frequently, infections are caused by fungi and anaerobic bacteria, and initial therapy does not necessarily have to cover coagulase-negative staphylococci, oxacillin-resistant S. aureus (MRSA), anaerobic bacteria and fungi. Patients who already receive antibiotics and develop pulmonary infiltrates should immediately be treated with systemic antifungals. Patients with fever and diarrhea or other signs and symptoms of gastrointestinal or perianal infection should be treated with antibiotics covering anaerobic bacteria and enterococci. Clinically stable patients with skin infections or central venous catheter-related infections can be treated with standard empiric antibiotic therapy including a beta-lactam active against Pseudomonas aeruginosa with or without an aminoglycoside, and should only receive glycopeptides if they do not respond to first-line therapy within 72 hours, become clinically unstable, have severe mucositis, or when resistance against the empiric antibiotics is demonstrated. Recombinant hematopoietic growth factors should not be added routinely but may be considered in life-threatening situations such as invasive pulmonary mycoses or sepsis. [ABSTRACT FROM AUTHOR]

Catheter-related infections cause considerable morbidity in hospitalised patients. The incidence does not seem to be higher in neutropenic patients than in non- neutropenic patients. Gram-positive bacteria (coagulase-negative staphylococci, Staphylococcus aureus) are the most frequently cultured pathogens, followed by Candida species. In contrast, Gram-negative bacteria play only a minor role in catheter-related infections. Positive blood cultures are the cornerstone in the diagnosis of catheter-related infections, while local signs of infection are only rarely present. However, a definite diagnosis generally requires the removal of the catheter and its microbiological examination. The role plate method with semiquantitative cultures (Maki) has been established as standard in most laboratories. Other standard procedures use quantitative techniques (Sherertz, Brun-Buisson) and are more sensitive. For therapy of catheter-related infections, antibiotics are administered according to the susceptibility of the cultured organism. Routine administration of gylcopepticed antibiotics is not indicated. Removal of the catheter has to be considered in any case of suspected catheter-related infection and is obligatory in Staphylococcus aureus and Candida infections. Tunnel or pocket infection of long-term catheters is always an indication for removal. In the future, the rate of catheter-related infections in neutropenic patients may be reduced by the use of catheters coated with antimicrobial agents. [ABSTRACT FROM AUTHOR]

A letter to the editor on the adverse effect of DMSO-preserved autologous stem-cells infusion is presented.

Purpose: While recent studies described the role of IKZF1/3 proteins in multiple myeloma (MM) cells, few have highlighted the significance of IKZF1/3 expression in T-cells. In this study we examine the prognostic and predictive value of IKZF1/3 expression in T-cells in patients with MM stage III. Experimental design: We analysed the IKZF1/3 expression levels in T-cells from 45 MM stage I (MMI) and 50 newly diagnosed MM stage III (MMIII) patients, according to Durie-Salmon staging system, by flow cytometry to examine their prognostic and predictive value. We also combined in vivo observations with in vitro assays to determine the effect of IKZF1/3 expression on the T-cell immunophenotype and anti-tumour T-cell response in 162 MMIII patients. Results: We found that high IKZF3, but not IKZF1, expression in T-cells correlates with superior overall survival in MMIII patients treated with immunomodulatory drugs (thalidomide, lenalidomide and pomalidomide). Moreover, we show that higher IKZF3 expression in T-cells inhibits myeloma-specific T-cell response in vitro and that the immunophenotype of patients with high IKZF3 expression shows features that are contrary to the changes induced by immunomodulatory drugs. Although we observed higher IKZF3 expression levels in T-cells from patients with MMIII compared to MMI, IKZF3 expression was unaffected by the tumour microenvironment. Conclusion: In conclusion, IKZF3 expression in T-cells is a predictive value for clinical outcome in MMIII patients treated with immunomodulatory drugs due to its profound modulation of T-cell functionality. [ABSTRACT FROM AUTHOR]