Adam Walter-Croneck

Elotuzumab plus lenalidomide/dexamethasone for relapsed or refractory multiple myeloma: ELOQUENT-2 follow-up and post-hoc analyses on progression-free survival and tumour growth

The randomized phase III ELOQUENT‐2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3‐year follow‐up data. Endpoints included progression‐free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post‐hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M‐protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1‐, 2‐ and 3‐year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M‐protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.

Role of reactive oxygen species (ROS), metalloproteinase-2 (MMP-2) and interleukin-6 (IL-6) in direct interactions between tumour cell spheroids and endothelial cell monolayer

Metastasis is a multistep process involving a variety of direct cell—cell, cell—matrix and paracrine interactions. In the present study, we examined some consequences of direct interaction between tumour cells and endothelial cells in vitro. When multicellular spheroids of two human tumour cell lines (HeLa and Hep‐2) were transferred onto a human umbilical vein endothelial cell (HUVEC) monolayer, a peri‐spheroidal zone of damaged endothelial cells was observed after 24 h co‐culture. To determine the cause of this damage, the production levels of superoxide anion (O2 −), interleukin‐6 (IL‐6) and metalloproteinase‐2 (MMP‐2) were measured both in co‐culture and in monocultures of the tumour cell spheroids and endothelial cells. Attachment of HeLa and Hep‐2 cellular spheroids to the HUVEC monolayer resulted in 1.6‐fold and 2.1‐fold increases in O2 − release, respectively. Also, the MMP‐2 level was five times greater in the co‐culture than in the tumour spheroid monoculture. The increase of IL‐6 in the co‐culture model, on the other hand, was only slight. However, a 2 h preincubation of endothelial cells with LPS (10 μg/ml) prior to the transfer of spheroids induced a significant increase in the production of this cytokine compared to an appropriate control (an LPS‐activated endothelial cell monolayer). These results strongly suggest that both ROS and MMP‐2 are involved in endothelial cell injury when tumour cells cross the endothelial barrier. Moreover, IL‐6, which participates in the inflammatory response, may also be involved in the extravasation of tumour cells.

Additional genetic abnormalities significantly worsen poor prognosis associated with 1q21 amplification in multiple myeloma patients

We investigated the prognostic value of amp(1q21) alone and in combination with other abnormalities in newly diagnosed myeloma patients. The study group consisted of 104 patients treated with various induction regimens, mostly thalidomide based (87 patients). Amp(1q21) was detected in 49 (47.1%) of patients; in 26 (25.0%) cases, it was combined with del(13q14), in 7 (6.7%) with del(17p13) and in 15 (14.4%) with t(4;14)(p16;q32). The response rate was significantly better in amp(1q21)‐negative than in amp(1q21)‐positive patients (74.5% vs 55.1%, p = 0.025; complete response 18.2% vs 4.1%, p = 0.024). The median progression‐free survival (PFS) was 33.9 months in patients without amp(1q21) and 10.3 months with this aberration (p = 0.002). The presence of additional abnormalities resulted in significantly shortened PFS when compared with patients with isolated amp(1q21): coexisting del(13q14) resulted in 7.8 vs 29.0 months of PFS (p = 0.024) and del(17p13) resulted in 4.0 vs 24.9 months of PFS (p = 0.034). The presence of amp(1q21) significantly influenced overall survival (OS) as well as PFS resulting in the median OS of 26.6 vs 62.4 months (p = 0.018) in patients without amp(1q21). The presence of additional genetic abnormalities significantly affected OS when compared with patients carrying isolated amp(1q21): for del(13q14) 18.9 vs 58.4 months (p = 0.004) and for del(17p13) 12.0 vs 46.5 months (p = 0.036). On multivariate analysis amp(1q21), del(13q14) and del(17p13) were found to be an independent adverse predictors of shorter PFS and OS. Our results showed that the presence of amp(1q21) was associated with poor prognosis. Moreover additional genetic abnormalities made PFS and OS further shortened. Copyright

A clinical comparison of the efficacy and safety of biosimilar G-CSF and originator G-CSF in haematopoietic stem cell mobilization

BACKGROUND Recombinant granulocyte colony-stimulating factor (G-CSF) is widely used to mobilize haematopoietic stem cells. We compared the efficacy and safety of a biosimilar G-CSF (Zarzio(®), Sandoz Biopharmaceuticals) with the originator G-CSF (Neupogen(®), Amgen) in patients with haematological malignancies. METHODS A total of 108 patients were included in this study, 59 of whom were female (49 male), with an overall median age of 51 years (range 19-69). Patients had multiple myeloma (n=46), non-Hodgkins lymphoma (n=28), Hodgkins lymphoma (n=26), or other diagnosis (n=8). After administration of mobilizing regimens (primarily high-dose etoposide, high-dose cyclophosphamide, intermediate-dose Ara-C or ESHAP), patients were randomized to a standard daily 10 μg/kg dose of biosimilar G-CSF (n=54) or originator G-CSF (n=54). RESULTS Median duration of G-CSF administration was 8 days with both biosimilar G-CSF (range 4-17) and originator G-CSF (range 4-14). Both groups had a median of one apheresis with a median time until first apheresis of 11 days. There were no statistically significant differences between groups in the mean ± SD number of mobilized CD34+ cells/μL in peripheral blood or the number of CD34+ cells/kg body weight. Five patients (9%) in the originator G-CSF group and six patients in the biosimilar G-CSF group (11%) did not mobilize sufficient CD34+ cells. The adverse event profile was similar between groups. CONCLUSIONS A biosimilar G-CSF (Zarzio(®)) demonstrated similar efficacy and safety as the reference originator G-CSF (Neupogen(®)) in hematopoietic stem cell mobilization in patients with haematological malignancies.

Matrix metalloproteinases-1 and -2, and tissue inhibitor of metalloproteinase-2 production is abnormal in bone marrow stromal cells of multiple myeloma patients

We have investigated the production of metalloproteinases (MMP-1, MMP-2, MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in bone marrow stromal cells (BMSCs) of patients with multiple myeloma (MM) and a healthy control. The new findings of this paper is that BMSCs of the MM patients exhibited intrinsic MMP-1, MMP-2 and TIMP-2 overproduction. Production of MMP-1, TIMP-2 and activation of MMP-2 was additionally enhanced in co-cultures of BMSCs with RPMI8226 cells. The ratio between MMP-2 and TIMP-2 was significantly higher in BMSCs of the MM patients than in control. BMSCs of both the control and the MM patients exhibited the presence of MMP-9 latent form, but in co-cultures RPMI8226 cells were the main producers of this metalloproteinase.

The efficacy and safety of the low-thalidomide dose CTD (cyclophosphamide, thalidomide, dexamethasone) regimen in patients with multiple myeloma--a report by the Polish Myeloma Study Group.

Multiple myeloma (MM) remains an incurable disease, but response rates to new drugs are promising, offering the majority of patients a significant prolongation of overall survival. The objective of this study was to evaluate time to progression (TTP), event-free survival (EFS), and overall survival (OS) in MM patients treated with a combination of cyclophosphamide (CY), thalidomide (THAL) and dexamethasone (DEX). This study included 132 untreated and relapsing/resistant patients treated with the low-thalidomide dose CTD regimen. The patients received CY 500 mg/m(2)i.v. or 625 mg/m(2) orally at day 1, THAL 100mg/day á la longue and DEX 20mg/day at days 1-4 and 8-11, every 28 days. Patients received 6-9 cycles; ORR by 3 months was 59.1%, by 6 months 65.6% and by 9 months 75.6%. In patients responding to CTD therapy (CR, nCR, PR), the probability of survival for 20 months was 89.3%. The outpatient low-thalidomide dose CTD regimen is well tolerated and produces a significant response rate both in untreated and relapsing/resistant MM patients.

Matrix metalloproteinase and cytokine production by bone marrow adherent cells from multiple myeloma patients

Abstract.IntroductionCultures of bone marrow stromal cells derived from the bone marrow of multiple myeloma (MM) patients were shown to exhibit several abnormalities compared with control cultures from healthy subjects. The aim of the study was to examine whether cultures of bone marrow adherent cells, at low passage level, exhibit differences in matrix metalloproteinases (MMPs) and cytokine production compared with cultures from normal donors.Materials and MethodsMMP production was evaluated by gel zymography and by ELISA in supernatants of serum-free cultures of bone marrow adherent cells derived from 20 MM patients and 23 healthy controls. Spontaneous and lipopolysaccharide (LPS)- or Newcastle disease virus (NDV)-induced cytokine release was assessed in the supernatants of the cultures by the ELISA method.ResultsBoth cultures produced MMP-1, −2, −3, and −9 under serum-free conditions; however, the levels of MMP-1 and MMP-2 were significantly higher in cultures derived from MM patients, while MMP-3 was significantly higher in control cultures. The level of MMP-9 was comparable in the cultures derived from MM patients and controls. All cultures produced interleukin (IL)-10 and IL-11 spontaneously, but after LPS or NDV induction the levels of IL-10, IL-11, interferon α, and tumor necrosis factor α, were significantly higher in the cultures derived from MM patients than in control cultures.ConclusionsThe results indicate that both the abnormalities in MMP production and the overproduction of cytokines (in the presence of LPS or virus, which mimic inflammatory conditions) may be involved in bone destruction and tumor spread in multiple myeloma.

Zalecenia Polskiej Grupy Szpiczakowej dotyczące rozpoznawania i leczenia szpiczaka plazmocytowego na rok 2012

STRESZCZENIE Nowe leki wprowadzane do leczenia szpiczaka w ostatnich latach pozwalają uzyskac odpowiedź terapeutyczną u przewazającej wiekszości chorych na szpiczaka plazmocytowego. Schematy oparte na talidomidzie i bortezomibie stosowane są obecnie w leczeniu nowo zdiagnozowanych chorych niezaleznie od tego, czy chorzy są kandydatami do chemioterapii duzymi dawkami melfalanu i przeszczepienia krwiotworczych komorek macierzystych, czy nie. W leczeniu chorych opornych na terapie indukującą stosuje sie schematy oparte na lenalidomidzie. Wazną cześcią leczenia chorych na szpiczaka jest leczenie wspomagające i podtrzymujące. W artykule tym przedstawiono rowniez zalecenia dotyczące rozpoznania i leczenia innych dyskrazji plazmocytowych.

Lipid peroxidation products and changes in phospholipid composition induced by indobufen in diabetic platelets

Indobufen is an antiaggregatory drug which first of all inhibits platelet aggregation by interfering with cyclooxygenase enzymes in platelets. We have investigated the influence of indobufen (200 mg twice daily for 10 days) on platelet lipid peroxidation and phospholipid metabolism in diabetic patients. The production of lipid peroxidation products was significantly lower after drug treatment. Indobufen administration, however, had no influence on the fatty acid composition of platelet phospholipids.

Case-adjusted bortezomib-based strategy in routine therapy of relapsed/refractory multiple myeloma shown to be highly effective—A report by Polish Myeloma Study Group

The observational study was aimed at evaluating response, survival and toxicity of bortezomib-based, case-adjusted regimens in real-life therapy of 708 relapsed/refractory MM patients. Bortezomib was combined with anthracyclines, steroids, thalidomide, alkylators or given in monotherapy. The ORR was 67.9% for refractory and 69.9% for relapsed MM. The median PFS was 14 months and OS 57 months. Patients responding to the therapy had the probability of a 4-year OS at 67.0%. No toxicity was noted in 33.1% of patients. Severe events (grade 3/4) were reported in 35.9% of patients: neurotoxicity (16.7%), neutropenia (9.2%), thrombocytopenia (8.5%), and infections (6.5%). Bortezomib-based, case-adjusted regimens are in real-life practice effective in salvage therapy offering reliable survival with acceptable toxicity for relapsed/refractory MM patients.