Addition of Anti-thymocyte Globulin in Allogeneic Stem Cell Transplantation With Peripheral Stem Cells From Matched Unrelated Donors Improves Graft-Versus-Host Disease and Relapse Free Survival.

Anti-thymocyte globulin (ATG) is commonly used to prevent graft-versus-host disease (GvHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). To evaluate the impact of ATG as part of the GvHD prophylaxis in our institution, we report the outcome of 415 patients with matched unrelated donors (MUD) transplanted for hematological malignancies with or without ATG from 2005 to 2019 at Oslo University Hospital, Norway. The following groups were compared: (1) 154 patients transplanted with peripheral blood stem cells (PBSC) without ATG 2005-2014. (2) 137 patients transplanted with bone marrow stem cells (BMSC) 2005-2019. (3) 124 patients transplanted with PBSC and ATG (PBSC + ATG) 2014-2019. Three years survival was similar in the groups, 61% following allografting with PBSC, 54% with BMSC, and 59% with PBSC + ATG. Acute GvHD grade III-IV was 14%, 14%, and 7%; chronic GvHD was 81%, 32, and 26%; and extensive cGvHD 44%, 15%, and 6% in the corresponding groups. Both acute and chronic GvHD were significantly reduced in the PBSC + ATG-versus the PBSC group (p < 0.05 and p < 0.001 respectively).Transplant-related mortality (TRM) was 33%, 25%, and 17% (p = 0.18). Graft versus host disease and relapse free survival (GRFS) at 3 years was 43 %, 43%, and 64% in the groups. Adding ATG to the GvHD prophylaxis regimen of MUD allo-HSCT with PBSC resulted in a substantial reduction of both acute and chronic GvHD without compromising the disease control, reflected in a superior 3 years GRFS.

Critical COVID-19 is associated with distinct leukocyte phenotypes and transcriptome patterns.

BACKGROUND: Prognostic markers for disease severity and identification of therapeutic targets in COVID-19 are urgently needed. We have studied innate and adaptive immunity on protein and transcriptomic level in COVID-19 patients with different disease severity at admission and longitudinally during hospitalization. METHODS: Peripheral blood mononuclear cells (PBMCs) were collected at three time points from 31 patients included in the Norwegian SARS-CoV-2 cohort study and analysed by flow cytometry and RNA sequencing. Patients were grouped as either mild/moderate (n = 14), severe (n = 11) or critical (n = 6) disease in accordance with WHO guidelines and compared with patients with SARS-CoV-2-negative bacterial sepsis (n = 5) and healthy controls (n = 10). RESULTS: COVID-19 severity was characterized by decreased interleukin 7 receptor alpha chain (CD127) expression in naïve CD4 and CD8 T cells. Activation (CD25 and HLA-DR) and exhaustion (PD-1) markers on T cells were increased compared with controls, but comparable between COVID-19 severity groups. Non-classical monocytes and monocytic HLA-DR expression decreased whereas monocytic PD-L1 and CD142 expression increased with COVID-19 severity. RNA sequencing exhibited increased plasma B-cell activity in critical COVID-19 and yet predominantly reduced transcripts related to immune response pathways compared with milder disease. CONCLUSION: Critical COVID-19 seems to be characterized by an immune profile of activated and exhausted T cells and monocytes. This immune phenotype may influence the capacity to mount an efficient T-cell immune response. Plasma B-cell activity and calprotectin were higher in critical COVID-19 while most transcripts related to immune functions were reduced, in particular affecting B cells. The potential of these cells as therapeutic targets in COVID-19 should be further explored.

Uranium isotope compositions of biogenic carbonates - Implications for U uptake in shells and the application of the paleo-ocean oxygenation proxy.

The application of U isotopes in carbonates as a paleo-ocean oxygenation proxy is based on the critical assumption that the calcareous shell-building organisms incorporate U into their shells without fractionation relative to the U isotopic composition of ambient seawater. Recent studies claim a small, but resolvable, isotopic offset during abiotic and biogenic aragonite precipitation, whereas no isotope fractionation has been recorded during calcite precipitation. Although aragonite is meta-stable and not preserved over geological timescales (>1 Myr) and U precipitates during diagenesis, the U isotope composition of biogenic aragonite is important because aragonite precipitation is an important U sink to carbonate sediments. In contrast, low-magnesium calcite (LMC) is preserved over geological timescales and may provide a reliable fingerprint of ancient ocean chemistry. Therefore, a more general study is needed that compares U isotope compositions of primary marine biogenic carbonate precipitates. We report the U isotope compositions of 32 modern samples from geographically distinct localities in the Atlantic Ocean including corals (Scleractinia, Octocorallia), brachiopods (Articulata), molluscs (Tellina Listeri, Codahia Obicularis) and barnacles as well as one fossil mollusc. These samples reflect variable primary minerals, water temperatures, water depths, pH-values of ambient water, and U concentrations. Several seawater samples have also been measured to compare our methods with those of previously published studies. The analyzed modern corals and brachiopods display U isotopic compositions that are indistinguishable from modern seawater. This suggests that these carbonates have the potential to faithfully record the U isotopic composition of the surrounding seawater in which they form. The analyzed brachiopods are of particular interest as they are composed of the calcium carbonate polymorph LMC that is stable over geological timescales. While this study shows for the first time that LMC phases are robust targets in ancient samples, their low U abundance presents analytical challenges for precise U isotope analyses. We also show that two barnacle shells collected with ambient seawater have U isotopic compositions that are both lighter and heavier than the ambient seawater. The mechanism to explain this offset is not determined, but it demonstrates that at least barnacle shells are not representative of the seawater in which they last lived. Two of three partially fossilized mollusc shells also show resolvable offsets from seawater, likely indicating secondary processes that are known to shift or fractionate U isotopes. Collectively, our new data indicate that: 1) aragonite delivers U with a seawater composition to carbonate sediments, and 2) LMC shells of brachiopods that are stable over geological timescales may be more suitable for reconstructing the U isotope composition of ancient oceans.

The CD34+ Cell Dose Matters in Hematopoietic Stem Cell Transplantation with Peripheral Blood Stem Cells from Sibling Donors.

The effect of CD34+ cell dose in allogeneic hematopoietic stem cell transplantation (HSCT) on overall survival (OS) and incidence of acute and chronic graft-versus-host disease (GvHD) has not been established and few studies have been performed. Our single center analysis included 189 patients with hematological malignancies who received peripheral blood stem cell (PBSC) grafts from sibling donors. Myeloablative conditioning was used in 88 cases and 101 received reduced intensity conditioning. The median CD34+ cell dose was 5.6 × 106/kg (0.6-17.0). In the multivariate analysis, a CD34 cell dose of 6-7 × 106/kg was associated with better OS and lower transplant-related mortality (TRM), while a dose of <5 × 106/kg led to increased relapse and reduced chronic GVHD (cGVHD). A high CD34 cell-dose (>6.5 × 106/kg) correlated with less acute GVHD (aGVHD) II-IV. We conclude that the CD34 cell dose has an impact on the outcome of HSCT from sibling donor PBSCs.

Postremission Consolidation by Autologous Hematopoietic Cell Transplantation (HCT) for Acute Myeloid Leukemia in First Complete Remission (CR) and Negative Implications for Subsequent Allogeneic HCT in Second CR: A Study by the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

After autologous hematopoietic cell transplantation (HCT) in the first complete remission (CR1), patients with acute myeloid leukemia (AML) may relapse and undergo allogeneic HCT in the second complete remission (CR2). The aim of this study was to analyze the outcome of allogeneic HCT performed in CR2 comparing patients with prior consolidation by autologous HCT versus patients with chemotherapy consolidation. Included were 2619 adults with allogeneic HCT in CR2 from 2000 to 2017 with (n = 417) or without (n = 2202) prior autologous HCT. Patient groups were not entirely comparable; patients with prior autologous HCT were younger, had less often a favorable cytogenetic profile, had more commonly donors other than matched siblings, and more often received reduced-intensity conditioning. In multivariate analysis, nonrelapse mortality risks in patients with prior autologous HCT were 1.34 (1.07 to 1.67; P = .01) after adjustment for age, cytogenetic risk, transplant year, donor, conditioning intensity, sex matching, interval diagnosis-relapse, and relapse-allogeneic HCT as compared with chemotherapy consolidation. Similarly, risks of events in leukemia-free survival and graft-versus-host disease, relapse-free survival were higher with prior autologous HCT, 1.17 (1.01 to 1.35), P = .03 and 1.18 (1.03 to 1.35), P = .02, respectively. Risk of death was also higher, 1.13 (0.97 to 1.32), P = .1, but this was not significant. Postremission consolidation with autologous HCT for AML in CR1 increases toxicity of subsequent allogeneic HCT in CR2.

Liver Transplant After Normothermic Regional Perfusion From Controlled Donors After Circulatory Death: The Norwegian Experience.

BACKGROUND: In order to meet the increasing demand for donor organs, the concept of donation after circulatory death (DCD) was reintroduced in Norway, first as a pilot study, followed by the use of DCD as institutional practice. We report the current Norwegian experience with liver transplant after DCD. METHODS: After acceptance from next of kin, life support was withdrawn from patients with devastating brain injury and cardiac arrest observed. After a 5-minute "no-touch" period, extracorporeal membrane oxygenation for post mortem normothermic regional perfusion (NRP) by extracorporeal membrane oxygenator circuit was established. Data from all liver transplant recipients receiving controlled DCD (cDCD) livers in Oslo were analyzed. RESULTS: From 2015 to 2017, a total of 8 patients underwent liver transplant with cDCD and NRP liver grafts in Norway. Median Model for End-Stage Liver Disease score was 26 (range, 6-40). There were no cases of delayed graft function or graft loss. Seven patients have reached 1 year of follow-up, and 1 patient has reached 6 months. Two patients have recurrence of primary disease (primary sclerosing cholangitis and steatohepatitis). All patients had normalized liver function at last follow-up. Two patients underwent procedures for biliary complications. In 1 patient, leakage from the cystic duct was successfully handled endoscopically by stenting. In the other patient, a suspected stricture on magnetic resonance imaging led to an endoscopic retrograde cholangiopancreatography, which did not confirm signs of biliary stenosis. There was 1 instance of hepatic artery stenosis, which was managed with endovascular technique. CONCLUSION: The results after liver transplant using cDCD with NRP are good. The rate of complications seems to be within the same range as when using conventional donation after brain death grafts.

EBMT prospective observational study on allogeneic hematopoietic stem cell transplantation in T-prolymphocytic leukemia (T-PLL).

Preliminary data suggest that allogeneic stem cell transplantation (allo-SCT) may be effective in T-prolymphocytic leukemia (T-PLL). The purpose of the present observational study was to assess the outcome of allo-SCT in patients aged 65 years or younger with a centrally confirmed diagnosis of T-PLL. Patients were consecutively registered with the EBMT at the time of transplantation and followed by routine EBMT monitoring but with an extended dataset. Between 2007 and 2012, 37 evaluable patients (median age 56 years) were accrued. Pre-treatment contained alemtuzumab in 95% of patients. Sixty-two percent were in complete remission (CR) at the time of allo-SCT. Conditioning contained total body irradiation with 6 Gy or more (TBI6) in 30% of patients. With a median follow-up of 50 months, the 4-year non-relapse mortality, relapse incidence, progression-free (PFS) and overall survival were 32, 38, 30 and 42%, respectively. By univariate analysis, TBI6 in the conditioning was the only significant predictor for a low relapse risk, and an interval between diagnosis and allo-SCT of more than 12 months was associated with a lower NRM. This study confirms for the first time prospectively that allo-SCT can provide long-term disease control in a sizable albeit limited proportion of patients with T-PLL.

Novel biomineralization strategy in calcareous foraminifera.

This work shows that calcareous benthic foraminifera are capable of agglutinating sedimentary particles also. In particular, we focus on Melonis barleeanus. Traditionally considered a calcareous species, our data revealed the presence of minute (~3 µm) sedimentary particles (silicate grains) inside the chamber walls of the examined shells. These particles were arranged in a definitive and systematic pattern, and the similar grain chemical characterization and size suggested a relatively high degree of selectivity in both modern and fossil specimens. Based on these results, we propose that M. barleeanus is capable of agglutinating sedimentary particles during the formation of a new chamber. The analysis of other calcareous foraminiferal species (e.g., Cassidulina neoteretis, Lobatula lobatula, Nonionella stella) did not reveal the presence of silicate grains in the shell of the specimens analyzed confirming this to be a characteristic of M. barleeanus. Considering that the isotopic and chemical composition of this species is widely used in paleoclimatic and paleoceanographic reconstructions, we used a mixing model to better constrain the influence of sedimentary particles on M. barleeanus δ18O data. Our model showed that the calcite δ18O would increase by ~0.9-2‰ if 10 wt% of feldspars (i.e., anorthite, albite, orthoclase) and quartz, respectively, were included in the analyzed shell. Based on these results, we emphasize that it is of paramount importance to consider M. barleeanus unusual biomineralization strategy during the interpretation of geological records and to investigate the presence of similar processes in other calcareous foraminiferal species.

Bioturbation and directionality in Earth's carbon isotope record across the Neoproterozoic-Cambrian transition.

Mixing of sediments by moving animals becomes apparent in the trace fossil record from about 550 million years ago (Ma), loosely overlapping with the tail end of the extreme carbonate carbon isotope δ13 Ccarbonate fluctuations that qualitatively distinguish the Proterozoic geochemical record from that of the Phanerozoic. These Precambrian-scale fluctuations in δ13 Ccarbonate (PSF-δ13 Ccarbonate ) remain enigmatic, due to their high amplitude and inclusion of global-scale negative δ13 Ccarbonate values, below anything attributable to mantle input. Here, we note that different biogeochemical-model scenarios plausibly explaining globally synchronous PSF-δ13 Ccarbonate converge: via mechanistic requirements for extensive anoxia in marine sediments to support sedimentary build-up of 13 C-depleted carbon. We hypothesize that bioturbation qualitatively reduced marine sediment anoxia by exposing sediments to oxygenated overlying waters, which ultimately contributed to decreasing the carbon cycle's subsequent susceptibility to PSF- δ13 Ccarbonate . Bioturbation may also have reduced the quantity of (isotopically light) organic-derived carbon available to contribute to PSF- δ13 Ccarbonate via ocean crust carbonatization at depth. We conduct a comparative modelling exercise in which we introduce bioturbation to existing model scenarios for PSF- δ13 Ccarbonate : expressing both the anoxic proportion of marine sediments, and the global organic carbon burial efficiency, as a decreasing function of bioturbation. We find that bioturbation's oxygenating impact on sediments has the capacity to prevent PSF- δ13 Ccarbonate caused by authigenic carbonate precipitation or methanogenesis. Bioturbation's impact on the f-ratio via remineralization is partially offset by liberation of organic phosphate, some of which feeds back into new production. We emphasize that this study is semiquantitative, exploratory and intended merely to provide a qualitative theoretical framework within which bioturbation's impact on long-term, first-order δ13 Ccarbonate can be assessed (and it is hoped quantified in more detail by future work). With this proviso, we conclude that it is entirely plausible that bioturbation made a decisive contribution to the enigmatic directionality in the δ13 Ccarbonate record, from the Neoproterozoic-Cambrian boundary onwards.

A pilot study of single nucleotide polymorphisms in the interleukin-6 receptor and their effects on pre- and post-transplant serum mediator level and outcome after allogeneic stem cell transplantation.

Interleukin (IL)-6 is an important regulator of immunity and inflammation in many diseases. Single nucleotide polymorphisms (SNPs) in the IL-6 gene influence outcome after allogeneic stem cell transplantation (ASCT), but the possible importance of SNPs in the IL-6 receptor has not been examined. We therefore investigated whether SNPs in the IL-6R gene influenced biochemical characteristics and clinical outcomes after ASCT. We examined the IL-6 promoter variant rs1800975 and the IL-6R SNPs rs4453032, rs2228145, rs4129267, rs4845374, rs4329505, rs4845617, rs12083537, rs4845618, rs6698040 and rs4379670 in a 101 population-based cohort of allotransplant recipients and their family donors. Patients being homozygous for the major alleles of the IL-6R SNPs rs2228145 and rs4845618 showed high pretransplant CRP serum levels together with decreased sIL-6R levels; the decreased IL-6R levels persisted 6 months post-transplant. In contrast, patients being homozygous for the minor allele of the IL-6R SNP rs4379670 showed decreased pretransplant CRP levels. Furthermore, the IL-6R rs4845618 donor genotype showed an association with severe acute graft-versus-host disease (GVHD), whereas the donor genotype of the IL-6 SNP rs1800795 was associated with decreased survival 100 days post-transplant. Finally, the recipient genotype of the IL-6R SNP rs4329505 showed a strong association with 2-years non-relapse mortality, and this effect was also highly significant in multivariate analysis. IL-6 and IL-6R SNPs influence the clinical outcome after allogeneic stem cell transplantation.

Allogeneic haematopoietic stem cell transplant in patients with lower risk myelodysplastic syndrome: a retrospective analysis on behalf of the Chronic Malignancy Working Party of the EBMT.

This corrects the article DOI: 10.1038/bmt.2016.266.

Evidence of molybdenum association with particulate organic matter under sulfidic conditions.

The geochemical behavior of molybdenum (Mo) in the oceans is closely linked to the presence of sulfide species in anoxic environments, where Fe availability may play a key role in the Mo scavenging. Here, we show that Mo(VI) is reduced in the presence of particulate organic matter (represented by sulfate-reducing bacteria). Molybdenum was immobilized at the surface of both living cells and dead/lysed cells, but not in cell-free control experiments. Experiments were carried out at four different Mo concentrations (0.1 to 2 mm) to yield cell-associated Mo precipitates with little or no Fe, consisting of mainly Mo(IV)-sulfide compounds with molecular structures similar to Mo enzymes and to those found in natural euxinic sediments. Therefore, we propose that Mo removal in natural sulfidic waters can proceed via a non-Fe-assisted pathway that requires particulate organic matter (dead or living sulfate-reducing bacteria). This pathway has implications for global marine Mo cycling and the current use of Mo-based proxies for paleo-environmental investigations.

Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia.

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56bright NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.

Open Abdomen Treated with Negative Pressure Wound Therapy: Indications, Management and Survival.

BACKGROUND: Open abdomen treatment (OAT) is a significant burden for patients and is associated with considerable mortality. The primary aim of this study was to report survival and cause of mortality after OAT. Secondary aims were to evaluate length of stay (LOS) in intensive care unit (ICU) and in hospital, time to abdominal closure and major complications. METHODS: Retrospective review of prospectively registered patients undergoing OAT between October 2006 and June 2014 at Trondheim University Hospital, Norway. RESULTS: The 118 patients with OAT had a median age of 63 (20-88) years. OAT indications were abdominal compartment syndrome (ACS) (n = 53), prophylactic (n = 29), abdominal contamination/second look laparotomy (n = 22), necrotizing fasciitis (n = 7), hemorrhage packing (n = 4) and full-thickness wound dehiscence (n = 3). Eight percent were trauma patients. Vacuum-assisted wound closure (VAWC) with mesh-mediated traction (VAWCM) was used in 92 (78 %) patients, the remaining 26 (22 %) had VAWC only. Per-protocol primary fascial closure rate was 84 %. Median time to abdominal closure was 12 days (1-143). LOS in the ICU was 15 (1-89), and in hospital 29 (1-246) days. Eighty-one (68 %) patients survived the hospital stay. Renal failure requiring renal replacement therapy (RRT) (OR 3.9, 95 % CI 1.37-11.11), ACS (OR 3.1, 95 % CI 1.19-8.29) and advanced age (OR 1.045, 95 % CI 1.004-1.088) were independent predictors of mortality in multivariate analysis. The nine patients with an entero-atmospheric fistula (EAF) survived. CONCLUSION: Two-thirds of the patients treated with OAT survived. Renal failure with RRT, ACS and advanced age were predictors of mortality, whereas EAF was not associated with increased mortality.

Allogeneic haematopoietic stem cell transplant in patients with lower risk myelodysplastic syndrome: a retrospective analysis on behalf of the Chronic Malignancy Working Party of the EBMT.

We report a retrospective analysis of 246 myelodysplastic syndrome (MDS) patients in the EBMT (The European Society for Blood and Marrow Transplantation) database who were transplanted for International Prognostic Scoring System (IPSS) low or intermediate-1 disease. The majority of these patients (76%) were reclassified as intermediate or higher risk according to R-IPSS. The 3-year overall survival (OS) and PFS were 58% and 54%, respectively. In a multivariate analysis, adverse risk factors for PFS were marrow blast percentage (hazard ratio (HR): 1.77, P=0.037), donor/recipient CMV serostatus (donor-/recipient+: HR: 2.02, P=0.011) and source of stem cells (marrow and non-CR: HR: 5.72, P<0.0001, marrow and CR: HR: 3.17, P=0.027). Independent risk factors for OS were disease status at time of transplant and the use of in vivo T-cell depletion (TCD). Patients who did not receive TCD and were transplanted from an unrelated donor had worse OS (HR: 4.08, P<0.0001). In conclusion, 'lower' risk MDS patients have better outcome than those with 'higher risk' after haematopoietic stem cell transplant (HSCT). Selecting the right source of stem cells, a CMV-positive donor for CMV-positive patients and using in vivo TCD results in the best outcome in these patients. More studies are needed to evaluate the role of HSCT in these patients as compared with conventional treatment.

Safety and efficacy of the combination of pegylated interferon-α2b and dasatinib in newly diagnosed chronic-phase chronic myeloid leukemia patients.

Dasatinib (DAS) and interferon-α have antileukemic and immunostimulatory effects and induce deep responses in chronic myeloid leukemia (CML). We assigned 40 newly diagnosed chronic-phase CML patients to receive DAS 100 mg o.d. followed by addition of pegylated interferon-α2b (PegIFN) after 3 months (M3). The starting dose of PegIFN was 15 µg/week and it increased to 25 µg/week at M6 until M15. The combination was well tolerated with manageable toxicity. Of the patients, 84% remained on PegIFN at M12 and 91% (DAS) and 73% (PegIFN) of assigned dose was given. Only one patient had a pleural effusion during first year, and three more during the second year. After introduction of PegIFN we observed a steep increase in response rates. Major molecular response was achieved in 10%, 57%, 84% and 89% of patients at M3, M6, M12 and M18, respectively. At M12, MR(4) was achieved by 46% and MR(4.5) by 27% of patients. No patients progressed to advanced phase. In conclusion, the combination treatment appeared safe with very promising efficacy. A randomized comparison of DAS±PegIFN is warranted.

Salvage bortezomib-dexamethasone and high-dose melphalan (HDM) and autologous stem cell support (ASCT) in myeloma patients at first relapse after HDM with ASCT. A phase-2 trial.

Until recently, only retrospective studies had been published on salvage high-dose melphalan (HDM) with autologous stem cell 'transplantation' (ASCT). In a prospective, nonrandomized phase-2 study, we treated 53 bortezomib-naïve patients with bortezomib-dexamethasone as induction and bortezomib included in the conditioning regimen along with the HDM. Median progression-free survival (PFS), time to next treatment (TNT) and overall survival (OS) after start of reinduction therapy were 21.6, 22.8 and 46.6 months, respectively. For 49 patients who completed salvage bortezomib-HDM(II) with ASCT, there was no significant difference of PFS and TNT after HDM (II) compared with after the initial HDM(I), and thus patients were their own controls (PFS (I: 20.1 vs II: 19.3 months (P=0.8)) or TNT (I: 24.4 vs II: 20.7 months (P=0.8)). No significant differences in the response rates after salvage ASCT compared with the initial ASCT. Bortezomib-HDM conditioning combo was feasible, and toxicity was as expected for patients treated with bortezomib and ASCT. In conclusion, in bortezomib-naïve patients treated at first relapse with salvage ASCT including bortezomib, PSF and TNT did not differ significantly from initial ASCT and median OS was almost 5.5 years with acceptable toxicity. A recent prospective randomized study confirms salvage ASCT to be an effective treatment.