Efficacy and safety of tixagevimab/cilgavimab as passive immunisation against COVID-19 infections in patients with hematological malignancies.

Monoclonal antibodies, as tixagevimab/cilgavimab, have been introduced as prophylaxis against COVID-19 infections in high-risk populations. However, data on efficacy are limited. This study investigates efficacy and tolerability of tixagevimab/cilgavimab in hematological patients under real-life conditions. Tixagevimab/cilgavimab was administered to 155 hematological patients (March-August 2022) at two Austrian centres. S/RBD-antibody assessments were performed before (T0), four weeks (T1), and six months (T2) after application. Side effects, the occurrence of COVID-19 infections, and the course of S/RBD-antibody titres were analysed retrospectively in relation to clinical variables. 155 hematological patients, who refused tixagevimab/cilgavimab, were included as a control group to compare the frequency of COVID-19 infections. Of all immunised patients (52.3% males; 91% triple vaccinated), 25.8% had a COVID-19 breakthrough infection (76% mild) compared to 43.9% in the control group. Patients with chronic lymphocytic leukaemia (CLL)/lymphoma were at highest risk of a COVID-19 infection (OR = 2.21; 95% CI 1.05-4.65; p = 0.037). After immunisation, a steep increase in median antibody levels (1193.4BAU/ml, IQR 0-2318.94) was observed in 67.8%, followed by a rapid decrease between T1 and T2 (465.95BAU/ml, IQR 0-1900.65.3) with the greatest declines in CLL/lymphoma (848.7BAU/ml, IQR 0-1949.6, p = 0.026). Side-effects occurred in 21.2% (CTCAE I/II). These real-world data indicate that S/RBD antibodies respond rapidly after passive immunisation in all hematological patients without safety concerns. Given the rapid decline in S/RBD antibodies, early booster immunisations should be considered for future scenarios in this vulnerable group.

Poor Mobilizers in Lymphoma but Not Myeloma Patients Had Significantly Poorer Progression-Free Survival after Autologous Stem Cell Transplantation: Results of a Large Retrospective, Single-Center Observational Study.

In our single-center study, 357 myeloma and lymphoma patients between 2009 and 2019 were mobilized with granulocyte colony-stimulating factor (G-CSF 7.5 µg/kg bid for four days) plus a fixed dose of 24 mg Plerixafor when indicated (Plerixafor Group, n = 187) or G-CSF alone (G-CSF Group, n = 170). The target CD34 cell yields were ≥2.0 × 106 CD34+ cells/kg in lymphoma and ≥4.0 × 106 CD34+ cells/kg in myeloma patients to enable putative second transplants in the latter. There were no significant differences in engraftment kinetics or transfusion requirements between the Plerixafor Group and the control group in the myeloma cohort, with lymphoma patients not requiring Plerixafor showing significantly faster neutrophil recovery, a trend to faster platelet recovery, and a significantly lower need for platelet transfusions, probably due to the significantly lower number of CD34-positive cells re-transfused. While in myeloma patients the outcome (overall survival, progression-free survival) following autologous stem cell transplantation (ASCT) was similar between the Plerixafor Group and the control group, hard to mobilize lymphoma patients had significantly poorer progression-free survival (47% vs. 74% at 36 months after ASCT, p = 0.003) with a trend also to poorer overall survival (71% vs. 84%). In conclusion, while there seem to be no differences in stemness capacity and long-term engraftment efficiency between the Plerixafor and the G-CSF Group in lymphoma as well as myeloma patients, poor mobilizing lymphoma patients per se constitute a high-risk population with a poorer outcome after ASCT. Whether disease characteristics and/or a more intense or stem cell-toxic pre-mobilization chemo-/radiotherapy burden in this cohort are responsible for this observation remains to be shown in future studies.

Amp(1q) and tetraploidy are commonly acquired chromosomal abnormalities in relapsed multiple myeloma.

Long-term disease control in multiple myeloma (MM) is typically an unmet medical need, and most patients experience multiple relapses. Fluorescence in situ hybridization (FISH) is the standard technique to detect chromosomal abnormalities (CAs), which are important to estimate the prognosis of MM and the allocation of risk adapted therapies. In advanced stages, the importance of CAs needs further investigation. From 148 MM patients, two or more paired samples, at least one of which was collected at relapse, were analyzed by FISH. Using targeted next-generation sequencing, we molecularly investigated samples harboring relapse-associated CAs. Sixty-one percent of the patients showed a change in the cytogenetic profile during the disease course, including 10% who acquired high-risk cytogenetics. Amp(1q) (≥4 copies of 1q21), driven by an additional increase in copy number in patients who already had 3 copies of 1q21, was the most common acquired CA with 16% affected patients. Tetraploidy, found in 10% of the samples collected at the last time-point, was unstable over the course of the disease and was associated with TP53 lesions. Our results indicate that cytogenetic progression is common in relapsed patients. The relatively high frequency of amp(1q) suggests an active role for this CA in disease progression.

Autologous and Allogeneic Stem Cell Transplantation as Salvage Treatment Options for Relapsed/Refractory Multiple Myeloma: A Single-center Experience over 20 Years.

BACKGROUND/AIM: Despite multiple treatment options, multiple myeloma (MM) remains an incurable disease with poor outcome. PATIENTS AND METHODS: We retrospectively analyzed the outcome of MM patients undergoing an allogeneic (allo-SCT; n=34) or autologous stem cell transplantation (auto-SCT; n=41) as salvage treatment for relapsed/refractory (r/r) disease. RESULTS: After a median observation period of 79.9 months in the auto group and 15.7 months in the allo group, the 5- and 10-year OS rates were 54% and 44% in the auto group and 17% and 4% in the allo group (p=0.0002), respectively. The 5- and 10-year disease-free survival in the auto group was 21% and 8%, and 14% and 5% in the allo group (p=0.0142), respectively. The 5- and 10-year cumulative incidence of relapse/progression in the auto group was 69% and 82%, and 64% and 69% in the allo group (p=0.0759), respectively. The 5- and 10-year non-relapse mortality in the auto group was significantly lower than that in the allo group [5% versus 45% (p=0.0001)]. CONCLUSION: A second autotransplant in selected r/r patients offers an acceptable long-term outcome partly because of the significantly lower treatment-related morbidity and mortality.

Changing Landscape in the Treatment of Adult Acute Lymphoblastic Leukemia (ALL).

Acute lymphoblastic leukemia (ALL) is a rare hematological malignancy characterized by proliferation and accumulation of premature lymphoid blasts. Depending on risk factors, the survival of acute lymphoblastic leukemia has significantly improved over the last decades. During the last years, measurable residual disease (MRD) assessment has evolved into one of the most sensitive markers for prognosis and risk of relapse. For this reason, measurable residual disease detection and monitoring count as standard evaluation in patients with acute lymphoblastic leukemia. Allogeneic stem cell transplantation is still the recommended treatment option for patients with high and highest risk profiles as well as for relapsed or refractory settings. The increased understanding of the pathomechanism and heterogeneity of acute lymphoblastic leukemia has led to the development of several novel therapeutic opportunities such as tyrosine-kinase inhibitors, antibody-based therapies and CAR-T cells with the aim of improving clinical outcomes. Furthermore, the major advances in disease understanding of ALL have led to the identification of different subgroups and better disease stratification. Even though novel therapy targets are constantly developed, acute lymphoblastic leukemia remains a challenging and life-threatening disease. To improve the historically unsatisfying result in therapy of adult acute lymphoblastic leukemia many clinical trials have recently been initiated to determine the optimum combination regimens of novel and old agents for adult acute lymphoblastic leukemia.

High Mortality of COVID-19 Early after Allogeneic Stem Cell Transplantation: A Retrospective Multicenter Analysis on Behalf of the German Cooperative Transplant Study Group.

Recipients of allogeneic stem cell transplantation (alloSCT) are at high risk for contracting infectious diseases with high morbidity and mortality. Coronavirus disease 2019 (COVID-19) is a viral respiratory disease that can lead to severe pneumonia and acute respiratory distress syndrome, with a potentially fatal outcome. In this retrospective study conducted on behalf of the German Cooperative Transplant Study Group, we aimed to analyze risk factors, disease course, and outcomes of COVID-19 in patients who underwent alloSCT. AlloSCT recipients who became infected with SARS-CoV-2 at German and Austrian transplant centers between February 2020 and July 2021 were included. Classification of COVID-19 severity into mild, moderate-severe, or critical disease and division of the course of the pandemic into 4 phases were done according to the German Robert Koch Institute. The main endpoint was overall mortality at the end of follow-up. We further analyzed the need for treatment in an intensive care unit (ICU) and the severity of disease. Risk factors were evaluated using univariate and multivariate analyses, and survival analysis was performed using Kaplan-Meier method. The study cohort comprised 130 patients from 14 transplant centers, with a median age at diagnosis of COVID-19 of 59 years (range, 20 to 81 years) and a median interval between alloSCT and COVID-19 of 787 days (range, 19 to 8138 days). The most common underlying diseases were acute myeloid leukemia (45.4%) and lymphoma (10.8%). The majority of patients (84.9%) were infected in the later phases of the pandemic; 20.8% had moderate-severe disease, 12.3% had critical disease, and 19.2% were treated in an ICU. After a median follow-up of 127 days, overall mortality was 16.2%, 52.0% among patients treated in an ICU. Risk factors for mortality in multivariate analysis were active disease (odds ratio [OR], 4.46), infection with SARS-CoV-2 ≤365 days after alloSCT (OR, 5.60), age >60 years (OR, 5.39), and ongoing immunosuppression with cyclosporine (OR, 8.55). Risk factors for developing moderate-severe or critical disease were concurrent immunosuppression (OR, 4.06) and age >40 years (OR, 4.08). Patients after alloSCT exhibit a substantially increased mortality risk after COVID-19 infection compared with the normal population, without considerable improvement over the course of the pandemic. Risk factors include age, early infection post-alloSCT, and active immunosuppression. Further studies are needed to improve prevention and treatment in this high-risk patient group.

The Agony of Choice-Where to Place the Wave of BCMA-Targeted Therapies in the Multiple Myeloma Treatment Puzzle in 2022 and Beyond.

Since the introduction of first-generation proteasome inhibitors and immunomodulatory agents, the multiple myeloma (MM) treatment landscape has undergone a remarkable development. Most recently, immunotherapeutic strategies targeting the B cell maturation antigen (BCMA) entered the clinical stage providing access to highly anticipated novel treatment strategies. At present, numerous different approaches investigate BCMA as an effective multi-modal target. Currently, BCMA-directed antibody-drug conjugates, bispecific and trispecific antibodies, autologous and allogeneic CAR-T cell as well as CAR-NK cell constructs are either approved or in different stages of clinical and preclinical development for the treatment of MM. This armamentarium of treatment choices raises several challenges for clinical decision making, particularly in the absence of head-to-head comparisons. In this review, we provide a comprehensive overview of BCMA-targeting therapeutics, deliver latest updates on clinical trial data, and focus on potential patient selection criteria for different BCMA-targeting immunotherapeutic strategies.

Rheumatologic diseases impact the risk of progression of MGUS to overt multiple myeloma.

Monoclonal gammopathy of undetermined significance (MGUS), a premalignant condition, is associated with various chronic inflammatory rheumatic diseases (RDs) and is frequently observed as an incidental finding during routine work-up. The association of MGUS and chronic RDs is well established, but the impact of RDs on the risk of transformation into overt multiple myeloma (MM) has not been evaluated so far. MGUS patients diagnosed between January 2000 and August 2016 were identified and screened for concomitant RDs. RDs were grouped into antibody (Ab)-mediated RDs and non-Ab-mediated RDs (polymyalgia rheumatica, large-vessel giant cell arteritis, spondyloarthritis, and gout). Progression to MM was defined as a categorical (yes/no) or continuous time-dependent (time to progression) variable. Of 2935 MGUS patients, 255 (9%) had a concomitant RD. MGUS patients diagnosed with non-Ab-mediated RDs had a doubled risk of progression compared with those without a concomitant RD (hazard ratio, 2.1; 95% CI, 1.1-3.9; P = .02). These data translate into a 5-year risk of progression of 4% in MGUS patients without rheumatologic comorbidity, 10% in those with concomitant non-Ab-mediated RDS, and 2% in those with Ab-mediated RDs. By using the complex risk stratification model that includes myeloma protein (M-protein) concentration, immunoglobulin type, and level of free light chain ratio as variables, patients with non-Ab-mediated RDs (n = 57) had the highest risk for progression (hazard ratio, 6.8; 95% CI, 1.5-30.7; P = .01) compared with patients with Ab-mediated RDs (n = 77). Chronic inflammatory diseases have an impact on the risk of MGUS progressing into overt MM, with a doubled risk of transformation observed in patients with non-Ab-mediated RDs. Future research can elucidate whether comorbidities such as RDs should be included in currently applied prognostic MGUS scores.

Early autologous and allogeneic peripheral blood stem cell transplantation for adult patients with acute B and T cell precursor neoplasms: a 12-year single center experience.

Adult acute lymphoblastic leukemia/lymphoma (ALL/LBL) is a rare and heterogeneous malignancy characterized by uncontrolled proliferation of B or T cell precursor cells. Here, we retrospectively analyzed the outcome of early autologous stem cell transplantation in standard-risk patients in first complete remission (n=24) and of allogeneic transplantation in high and highest risk, and relapsed/refractory patients (n=35). The 10-year overall survival after autologous transplantation was 45%. The 10-year overall survival after allogeneic transplantation was 58%. The cumulative incidence of relapse was 29% after allogeneic and 67% after autologous transplantation. The cumulative incidence of non-relapse mortality was 0% after autologous and 12% after allogeneic transplantation. This retrospective single center analysis in a limited number of standard-risk patients clearly demonstrates that early autologous transplantation in first complete remission leads to an acceptable long-term outcome with a short overall treatment duration of less than 6 months compared with more than 2 years with conventional chemotherapy. More sensitive and standardized methods to detect minimal residual disease (MRD) will further help to identify those patients more accurately who are most likely to benefit from such a short and intensive treatment strategy (i.e., MRD negative standard-risk patients) or those who require early targeted therapy (e.g., blinatumomab) in case of MRD positivity. Early allogeneic transplantation results in long-term survival/cure in nearly two-thirds of all high and highest risk, and relapsed/refractory patients.

Clonal dynamics in a composite chronic lymphocytic leukemia and hairy cell leukemia-variant.

Composite lymphoma is the rare simultaneous manifestation of two distinct lymphomas. Chronic lymphocytic leukemia (CLL) has a propensity for occurring in composite lymphomas, a phenomenon that remains to be elucidated. We applied cytogenetics, droplet digital polymerase chain reaction, and massively parallel sequencing to analyze longitudinally a patient with CLL, who 3 years later showed transformation to a hairy cell leukemia-variant (HCL-V). Outgrowth of the IGHV4-34-positive HCL-V clone at the expense of the initially dominant CLL clone with trisomy 12 and MED12 mutation started before CLL-guided treatment and was accompanied by a TP53 mutation, which was already detectable at diagnosis of CLL. Furthermore, deep sequencing of IGH showed a composite lymphoma with presence of both disease components at all analyzed timepoints (down to a minor clone: major clone ratio of ~1:1000). Overall, our analyses showed a disease course that resembled clonal dynamics reported for malignancies with intratumoral heterogeneity and illustrate the utility of deep sequencing of IGH to detect distinct clonal populations at diagnosis, monitor clonal response to therapy, and possibly improve clinical outcomes.

The prognostic value of additional copies of 1q21 in multiple myeloma depends on the primary genetic event.

Hyperdiploidy (HRD) and specific immunoglobulin heavy locus (IGH) translocations are primary chromosomal abnormalities (CA) in multiple myeloma (MM). In this retrospective study of 794 MM patients we aimed to investigate clinical features and common CA including gain(1q) in separate subgroups defined by primary CA. In the entire group, we confirmed that gain(1q) was associated with short time to next treatment and adverse overall survival (OS). The impact was worse for four or more copies of 1q21 as compared to three copies. However, in a subgroup of patients with clonal gain(11q) and without known primary IGH translocations (CG11q), already three copies of 1q21 were associated with a poor outcome; in the absence of gain(1q), patients in this subgroup had a remarkably long median OS of more than nine years. These cases were associated with HRD, coexpression of CD56 and CD117, male gender, and IgG subtype. In non-CG11q patients, four or more copies of 1q21 (but not three copies) had a significant adverse impact on outcome. Several associations with CA and clinical findings were observed for the defined subgroups. As an example, we found a predominance of early tetraploidy, plasma cell leukemia, and female gender in the t(14;16) subgroup. Our results underscore the importance of subgrouping in MM.

The FMS like Tyrosine Kinase 3 (FLT3) Is Overexpressed in a Subgroup of Multiple Myeloma Patients with Inferior Prognosis.

Therapy resistance remains a major challenge in the management of multiple myeloma (MM). We evaluated the expression of FLT3 tyrosine kinase receptor (FLT3, CD135) in myeloma cells as a possible clonal driver. FLT3 expression was analyzed in bone marrow biopsies of patients with monoclonal gammopathy of undetermined significance or smoldering myeloma (MGUS, SMM), newly diagnosed MM (NDMM), and relapsed/refractory MM (RRMM) by immunohistochemistry (IHC). FLT3 gene expression was analyzed by RNA sequencing (RNAseq) and real-time PCR (rt-PCR). Anti-myeloma activity of FLT3 inhibitors (midostaurin, gilteritinib) was tested in vitro on MM cell lines and primary MM cells by 3H-tymidine incorporation assays or flow cytometry. Semi-quantitative expression analysis applying a staining score (FLT3 expression IHC-score, FES, range 1-6) revealed that a high FES (>3) was associated with a significantly shorter progression-free survival (PFS) in NDMM and RRMM patients (p = 0.04). RNAseq and real-time PCR confirmed the expression of FLT3 in CD138-purified MM samples. The functional relevance of FLT3 expression was corroborated by demonstrating the in vitro anti-myeloma activity of FLT3 inhibitors on FLT3-positive MM cell lines and primary MM cells. FLT3 inhibitors might offer a new targeted therapy approach in a subgroup of MM patients displaying aberrant FLT3 signaling.

Spliced XBP1 Levels Determine Sensitivity of Multiple Myeloma Cells to Proteasome Inhibitor Bortezomib Independent of the Unfolded Protein Response Mediator GRP78.

Background: Mechanisms mediating resistance against the proteasome inhibition by bortezomib (BTZ) in multiple myeloma (MM) cells are still unclear. We analyzed the activation of the unfolded protein response (UPR), induction of prosurvival, and apoptotic pathways after proteasome inhibition in BTZ-sensitive and -resistant cells. Thereafter, these findings from tissue culture were proofed on MM cells of BTZ-sensitive and BTZ-refractory patients. Methods: Proteasomal and ABC transporter activities were measured in sensitive and resistant cell lines by the use of the respective substrates. TP53 gene loss and mutations were determined by cytogenetics and targeted NGS. UPR pathways, proteasome subunit levels and protein secretion were studied by Western Blot analysis, and apoptosis was determined by flow cytometry. MM cell lines were stably transfected with inducible GRP78 expression to study unfolded protein expression. Transient knock-down of GRP78 was done by RNA interference. Splicing of XBP1 and expression of GRP78 was studied by real-time PCR in CD138-enriched MM primary cells of BTZ-refractory and -sensitive patients. Results: BTZ-sensitive cells displayed lower basal proteasomal activities. Similar activities of all three major ABC transporter proteins were detected in BTZ-sensitive and resistant cells. Sensitive cells showed deficiencies in triggering canonical prosurvival UPR provoked by endoplasmic reticulum (ER) stress induction. BTZ treatment did not increase unfolded protein levels or induced GRP78-mediated UPR. BTZ-resistant cells and BTZ-refractory patients exhibited lower sXBP1 levels. Apoptosis of BTZ-sensitive cells was correlating with induction of p53 and NOXA. Tumor cytogenetics and NGS analysis revealed more frequent TP53 deletions and mutations in BTZ-refractory MM patients. Conclusions: We identified low sXBP1 levels and TP53 abnormalities as factors correlating with bortezomib resistance in MM. Therefore, determination of sXBP1 levels and TP53 status prior to BTZ treatment in MM may be beneficial to predict BTZ resistance.

The Plasma Levels of the Angiogenic Cytokine Endocan Are Elevated in Patients with Multiple Myeloma.

BACKGROUND/AIM: Monoclonal gammopathy of unknown significance (MGUS) and smoldering multiple myeloma often precede multiple myeloma (MM). The identification of biomarkers predicting progression to MM might facilitate an earlier diagnosis of MM. Our study assessed the diagnostic value of plasma levels of endocan, a 50-kDa soluble dermatan sulfate proteoglycan produced and secreted by endothelial cells, hitherto unknown in MM, in patients with plasma cell dyscrasia. MATERIALS AND METHODS: Endocan levels were determined in 96 peripheral blood plasma samples by sandwich enzyme-linked immunosorbent assay (ELISA) in healthy controls (n=12), in patients with MGUS (n=17), and in patients newly diagnosed with (n=42) or relapsed/refractory (n=25) MM. RESULTS: Median endocan concentration increased from MGUS (315.00 pg/ml) and healthy controls (316.19 pg/ml) to newly-diagnosed MM (371.82 pg/ml; p=0.027). The low endocan levels (median=246.20 pg/ml) in patients with relapsed/refractory MM were similar to those in healthy controls and patients with MGUS. A cut-off value of >220 pg/ml endocan in peripheral blood discriminated patients newly diagnosed with MM from those with MGUS (area under the curve(AUC)=0.66, 95% confidence interval(CI)=0.55-0.81). CONCLUSION: The plasma levels of endocan can non-invasively differentiate patients newly diagnosed with MM from those with MGUS and should therefore be evaluated prospectively as a potential diagnostic marker.

The metabolomic plasma profile of myeloma patients is considerably different from healthy subjects and reveals potential new therapeutic targets.

INTRODUCTION: Multiple myeloma (MM), a malignant plasma cell disorder, is still an incurable disease. Thus, the identification of novel therapeutic targets is of utmost importance. Here, we evaluated the peripheral blood-based metabolic profile of patients with MM. MATERIAL & METHODS: Peripheral blood plasma levels of 188 endogenous metabolites, including amino acids, biogenic amines, acylcarnitines, glycerophospholipids, sphingomyelins, and hexoses were determined in patients with plasma cell dyscrasias: monoclonal gammopathy of undetermined significance, a precursor stage of MM (MGUS, n = 15), newly diagnosed MM, (NDMM, n = 32), relapsed/refractory MM (RRMM, n = 19) and in 25 healthy controls by mass spectrometry. RESULTS: Patients with NDMM, RRMM and MGUS have a substantially different metabolomic profile than healthy controls. The amount of eight plasma metabolites significantly differs between the NDMM and MGUS group: free carnitine, acetylcarnitine, glutamate, asymmetric dimethylarginine (ADMA) and four phosphatidylcholine (PC) species. In addition, the levels of octadecanoylcarnitine, ADMA and six PCs were significantly different between RRMM and MGUS patients. 13 different concentrations of metabolites were found between RRMM and NDMM patients (free carnitine, acetylcarnitine, creatinine, five LysoPCs and PCs). Pathway analyses revealed a distinct metabolic profile with significant alterations in amino acid, lipid, and energy metabolism in healthy volunteers compared to MGUS/MM patients. CONCLUSION: We identified different metabolic profiles in MGUS und MM patients in comparison to healthy controls. Thus, different metabolic processes, potentially the immunoregulation by indoleamine 2,3 dioxygenase-1 (IDO), which is involved in cancer development and progression supporting inflammatory processes in the tumor microenvironment and glutaminolysis, can serve as novel promising therapeutic targets in MM.

Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies.

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients' survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author's own experiences/views.

Monoclonal gammopathy of renal significance (MGRS) increases the risk for progression to multiple myeloma: an observational study of 2935 MGUS patients.

PURPOSE: Monoclonal gammopathy of undetermined significance (MGUS) is a premalignancy preceding multiple myeloma (MM) or related disorders. In MGUS, renal impairment caused by deposition of the monoclonal immunoglobulins or free light-chains monoclonal gammopathy of renal significance (MGRS) is often associated with high morbidity and mortality. We analysed the prevalence of renal impairment, clinical features and the long-term outcome in 2935 patients with MGUS. METHODS: Between 1/2000 and 8/2016, 2935 adult patients with MGUS were identified in our database. RESULTS: In 44/2935 (1.5%) patients MGRS was diagnosed. In MGRS patients, significantly more progressions to MM were observed than in MGUS patients (18% vs. 3%; P<0.001). MGRS patients showed a higher risk for progression (HR 3.3 [1.5-7.4]) in the Cox model. Median time to progression was 23 years for MGUS and 18.8 years for MGRS patients. Corresponding progression rate was 8.8 [7.2-10.7] per 1000 patient-years (py) for MGUS patients and 30.6 [15.3-61] for the MGRS group. Risk for progression within the first year after diagnosis was 1% [0.6-1.4] in the MGUS group and 10% [4-29] among MGRS patients. CONCLUSION: The significantly higher risk for progression to MM means MGRS patients should be monitored carefully and treated in a specialized centre.

Bendamustine plus Rituximab Versus R-CHOP as First-Line Treatment for Patients with Follicular Lymphoma Grade 3A: Evidence from a Multicenter, Retrospective Study.

BACKGROUND: Rituximab plus bendamustine (R-B) has been demonstrated to improve outcomes and reduce toxicity compared with rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma (FL). Nevertheless, in clinical practice, many centers still prefer R-CHOP to R-B in patients with FL grade 3A (FL3A). Therefore, we retrospectively assessed patients with FL3A treated with either R-CHOP or R-B in five European cancer centers and compared their outcomes. MATERIALS AND METHODS: We retrospectively assessed 132 patients affected by FL grade 3A treated with either R-B or R-CHOP in the first line and evaluated outcome and toxicity according to the type of treatment. This study included 101 patients who were a subgroup of a previously published cohort. RESULTS: R-B was less toxic and achieved a similar percentage of complete remissions compared with R-CHOP (97% vs. 96%, p = .3). During follow-up, 10 (16%) patients relapsed after R-B and 29 (41%) after R-CHOP (p = .001), leading to a median progression-free survival (PFS) of 15 versus 11.7 years, respectively (p = .03). Furthermore, R-B overcame the negative prognostic impact of BCL2 expression (15 vs. 4.8 years; p = .001). However, median overall survival was similar between both groups (not reached for both; p = .8). CONCLUSION: R-B as a first-line treatment of FL3A is better tolerated than R-CHOP and seems to induce more profound responses, leading to a significantly lower relapse rate and prolonged PFS. Therefore, R-B is a valid treatment option for FL grade 3A. IMPLICATIONS FOR PRACTICE: Rituximab plus bendamustine (R-B) has shown to be less toxic and more effective than rituximab, cyclophosphamide, doxorubicin, and prednisone (R-CHOP) in follicular lymphoma grade 3A. Although both regimens can induce a complete remission in >95% of patients, relapses occur more frequently after R-CHOP than R-B, leading to a significantly longer progression-free survival in the latter. R-B is also able to overcome the impact of negative prognosticators, such as BCL2 expression. However, because of the indolent course of this disease and efficient salvage treatments, overall survival was similar in both treatment groups. Therefore, R-B is a valid treatment option in this patient setting.

Expression and release of glucose-regulated protein-78 (GRP78) in multiple myeloma.

INTRODUCTION: Multiple myeloma (MM) is a plasma cell neoplasm that is mostly incurable due to acquired resistance during the treatment course. Thus, we evaluated expression and release of glucose-regulated protein 78 kDa (GRP78/BiP), an endoplasmic reticulum (ER) based pro-survival chaperone involved in immunoglobulin folding and unfolded protein responses. RESULTS: GRP78 protein expression in the ER and on the cell surface did not significantly differ between MGUS, NDMM and RRMM patients although there was a trend to higher surface expression in RRMM. In bone marrow plasma, the amount of released GRP78 protein was not significantly increased between MGUS-, NDMM- and RRMM patients. MM cells of the three cell lines release GRP78 as full-length protein under apoptotic, but not under acidotic or ER-stress conditions. In necrosis, only proteolytic fragments of GRP78 were detected in supernatants of MM cells. MATERIALS AND METHODS: GRP78 protein expression and plasma levels were quantified in bone marrow aspirates of patients with monoclonal gammopathy of undetermined significance (MGUS, n = 29), newly diagnosed MM (NDMM, n = 29) and with relapsed/refractory MM (RRMM, n = 15) by immunohistochemistry and sandwich ELISA. The human MM cell lines U266, NCI-H929 and OPM-2 were used for functional GRP78 release- and processing studies after induction of acidosis, ER stress, apoptosis and necrosis. CONCLUSIONS: Ectopic expression of GRP78 on cell membrane or its release in the microenvironment is not a suitable marker to distinguish MGUS from NDMM and RRMM.