bluuebunny/crossref_metadata_2025_split huggingface dataset:
Multiple Myeloma: Interleukin-15 Antagonizes Bone Morphogenetic Protein-Induced Apoptosis and Growth Inhibition.
Authors: Rekvig Magne , Brenne Anne-Tove , Ro Torstein Baade , Waage Anders , Borset Magne , Sundan Anders 
Published: October 2019

Abstract
Multiple myeloma has two distinct features: Expansion of malignant plasma cells within the bone marrow accompanied by skeletal destruction. Bone morphogenetic proteins (BMPs) have been shown to induce apoptosis and inhibit growth in myeloma cells. BMPs are members of the TGF-β superfamily of proteins capable of inducing bone formation, and regulate proliferation, differentiation and apoptosis. We have investigated myeloma cell apoptosis and proliferation with BMP-4 and −6 in concert with the myeloma cell growth factors interleukin (IL)-2, IL-6, IL-10, IL-15, IL-21, tumor necrosis factor (TNF)-α and insulin-like growth factor (IGF)-1. Eight samples of highly purified myeloma cells from patients and a human myeloma cell line, IH-1 (Brenne AT et al. Blood. 2002 May 15;99(10):3756–62.), were used in this study. Cytokine concentrations used in the referred experiments were for BMP-4 20ng/ml, BMP-6 250ng/ml, IL-15 20ng/ml and IL-6 0,1ng/ml, respectively. Growth inhibition was measured in a proliferation assay by methyl-[3H]-thymidine incorporation and apoptosis by annexin V- FITC-binding/PI-uptake on flow cytometry. IL-15 antagonized growth inhibition (Figure A) and prevented apoptosis induced by BMP-4 (Figure B) and BMP-6 in the myeloma cell line IH-1. IL-15 also antagonized the growth inhibition induced by BMP-4 and/or BMP-6 in three out of eight patient samples. Neither IL-6, nor any of the other investigated cytokines were able to rescue the myeloma cells from growth inhibition and apoptosis induced by BMP-4 and -6. Among the investigated cytokines, we found that IL-15 has a unique capability to antagonize BMP- induced apoptosis and growth inhibition in myeloma cells. We examined cleavage of the proapoptotic protein caspase-3 and found that BMP-4 activated caspase-3 in the IH-1 cell line. This activation of caspase-3 was blocked by IL-15 but not by IL-6. We have demonstrated a possible mechanism for myeloma cells to escape apoptosis and growth-inhibition within the bone marrow. Intramedullar levels of IL-15 and BMPs may play a role in the pathogenesis of multiple myeloma.
Figure A. Proliferation in response to BMP-4 stimulus Figure A. Proliferation in response to BMP-4 stimulus Figure B. Apoptosis in response to BMP-4 stimulus Figure B. Apoptosis in response to BMP-4 stimulus
The BAFF Inhibitor AMG523 Blocks Adhesion and Survival of Human Multiple Myeloma Cells in the Bone Marrow Microenvironment: Clinical Implication.
Authors: Tai Yu-Tzu , Xu Jiangchun , Li Xian-Feng , Breitkreutz Iris , Podar Klaus , Hideshima Teru , Schlossman Robert , Richardson Paul , Munshi Nikhil C. , Anderson Kenneth C. 
Published: October 2019

Abstract
We previously identified a role of B-cell activating factor (BAFF), a member of the tumor necrosis factor superfamily, in localization and survival of MM cells in the BM microenvironment (Cancer Res2006, 66:6675–82). In the present study, we examined the potential therapeutic utility of the BAFF inhibitor, AMG523, for treating human MM using MM lines, either sensitive or resistant to conventional chemotherapy, as well as freshly isolated patient MM cells, in the presence or absence of bone marrow stromal cells (BMSCs). AMG523 induces modest cytotoxicity in MM cell lines and patient MM cells, suggesting a minor role of autocrine mechanism of BAFF for MM growth and survival. In the presence of BMSCs, AMG523 significantly decreased growth and survival in dexamethasone (Dex)-sensitive MM1S, Dex-resistant MM1R, INA6 MM cells and in patient MM cells (n=7), in a dose-dependent manner (0.1–10 μg/ml). BAFF-augmented MM adhesion to BMSCs is also blocked by AMG523 at 0.1 mg/ml in MM lines (MM1S, 28PE, INA6), as well as in freshly isolated patient MM cells (n=4). BAFF protects MM cells against dex- and lenalidomide-induced cytotoxicity; conversely, AMG523 blocks BAFF-induced protection against drug-induced apoptosis. Importantly, pretreatment of AMG523 blocks BAFF-induced activation of AKT, nuclear factor kB, and ERK in MM cells, confirming its inhibitory effect on BAFF-mediated adhesion and survival. We next asked whether AMG523 enhances Dex-, bortezomib-, Lenalidomide-induced MM cell cytotoxicity. AMG523 augments the inhibitory effect of Dex and lenalidomide in patient MM cells in the presence of BMSCs. Since osteoclasts (OCLs) secrete BAFF in the bone marrow microenvironment, we further asked whether AMG523 inhibits protection by MM-OCL interaction. OCLs were derived from peripheral blood mononuclear cells from MM patients after 2-week culture with M-CSF and RANKL, and MM cells were added in the presence or absence of AMG523. OCLs significantly increased MM cell survival, evidenced by annexin V and PI staining followed by flow cytometric analysis; conversely, AMG523 blocked MM cell survival by coculture with OCLs. Taken together, our data demonstrate that the novel therapeutic AMG523 blocks the interaction between BAFF and its receptors in human MM, thereby providing the rationale for clinical trials of AMG523 to improve patient outcome in MM.
Mcl-1, Bcl-xL and Cell Cycle Inhibition by GCS-100: A Novel Therapy for Myeloma.
Authors: Streetly Matthew , Su Bo , Carver Bradley , Schey Stephen A. , Cotter Finbarr E. 
Published: October 2019

Abstract
The marrow stromal cells in multiple myeloma activate multiple signalling pathways via stimulation by the cytokines they secrete. This leads to upregulation of anti-apoptosis, drug resistance, cell cycle and metabolic pathways. Disruption of these signalling networks can lead to myeloma cell death and make them attractive targets for novel therapies. In addition, Bcl-2 family proteins, mcl-1 and bcl-xL are important for the survival of myeloma cells. The modified citrus pectin, GCS-100 has been used safely in Phase I studies for solid tumors, can induce cell death in lymphoma via blocking galectin-3 / Bcl-2 dimerisation and in myeloma cells by mechanisms not fully understood. GCS-100 as well as pro-apoptotic effects, also demonstrates anti-proliferative and anti-angiogenic properties, all of which may be useful in the therapy of myeloma. This study was aimed at elucidating the mechanism of action of this novel agent so as to apply it most effectively to myeloma therapy. Myeloma cell lines RPMI8226 and U266 treated with GCS-100 show induction of apoptosis in a dose and time dependent manner with a loss of cells in the G1 and S phase of cell cycle and a significant increase in G0 / sub-G1 cells. Treatment of RPMI8226 led to a marked reduction of mcl-1 and bcl-xL after 24 hours of treatment. There was no change observed in protein levels of bcl-2 or galectin-3. Activation of NFκB in myeloma cells is associated with proliferation and adhesion molecule upregulation. GCS-100 treatment led to a time dependent reduction in activated IκBα and p65NFκB. Furthermore pre-treatment of myeloma cells with GCS-100 prior to stimulation with TNFα, a known activator of IκBα, inhibited this activation. Similarly, treatment with GCS-100 led to a reduction in the amount of activated Akt (a regulator of cell cycle) and inhibited IGF-1 associated activation of Akt. The effect of GCS-100 on cell cycle regulatory proteins revealed downregulation of cyclin D1, p16INK4A and CDK6 at 24hrs, however, there was no change in expression of CDK4 and p15INK4B. The p21CIP1 was upregulated with a corresponding decrease in protein levels of cyclin E2 and CDK2 but there was no change in p27KIP1. GCS-100 clearly inhibits progression through G1 / S phase of cell cycle. Studies are currently ongoing for primary cells. In conclusion GCS-100 is a novel complex carbohydrate that is effective for the induction of myeloma cell death. It has multi faceted effects in reducing proliferation and induces apoptosis by down regulating crucial anti-apoptotic proteins, cell cycle regulators and signalling proteins and may also act by interfering with the myeloma cell microenvironment. Phase I studies in myeloma have been commenced.
The Pan-Bcl-2 Inhibitor GX15-O70 Induces Apoptosis in Human Myeloma Cells by Noxa Induction and Strongly Enhances Melphalan, Bortezomib or TRAIL-R1 Antibody Apoptotic Effect.
Authors: Gomez-Bougie Patricia , Maïga Sophie , Pellat-Deceunynck Catherine , Jouan Sandrine , Bataille Regis , Amiot Martine 
Published: October 2019

Abstract
GX15-070 belongs to small molecule pan-Bcl-2 inhibitors that mimic BH3-only proteins, therefore it may bind the groove of anti-apoptotic Bcl-2 family members and induce cell death. Mcl-1, an anti-apoptotic protein from the Bcl-2 family, is an essential survival protein for Multiple Myeloma (MM) cells. Mcl-1 displays specific affinity for some BH3-only proteins. In viable MM cells, Mcl-1 strongly interacts with BH3-only Bim protein, keeping in check its pro-apoptotic properties. Consequently, we tested a panel of human MM cell lines (HMCL) (n=9) for GX15-070 apoptosis induction. Apoptosis of HMCL was induced at doses ranging from 0,15 μM to 5 μM. HMCL were differentially sensitive to GX15-07. For most HMCL the maximal apoptotic effect was observed at 2,5 μM of GX15-070. Thus we found 2 very sensitive HMCL (> 60% of death cells), 3 intermediate sensitive HMCL (>30% <60%) and 4 resistant HMCL (<30%). Sensitivity to GX15-070 was not correlated with IL-6 dependence. For further studies 4 HMCL were selected according to GX15-070 apoptosis induction, namely RPMI-8826 (71% ± 4), MDN (64% ± 4), LP1 (43% ± 3) and U266 (22%± 2). After 24 hours treatment, no substantial modifications of the anti-apoptotic proteins (Bcl-2, Bcl-xL and Mcl-1) were induced. Among the BH3-only pro-apopototic proteins examined, only Noxa was consistently induced by GX15-070 in all sensitive HMCL. In contrast, Noxa was not induced in the GX15-070 resistant U266 cell line. Pro-apoptotic multidomain molecules Bax and Bak were not modified by GX15-070.
We also evaluated GX15-070 in combination with other drugs currently used in MM treatment. We wondered if GX15-070 could sensitize HMCL LP1 and/or L363 cells to either Melphalan or PS-341 since both HMCL are weakly sensitive to both agents. HMCL were pre-incubated with GX15-070 for 7h at doses ranging from 0,15 to 5 μM followed by either melphalan or Bortezomib during 24h. GX15-070 displayed an additive apoptotic effect either in combination with melphalan or with Bortezomib for both HMCL. Interestingly, GX15-070 had a synergistic apoptotic effect in combination with a fully human antibody directed against TRAIL-R1, Mapatumumab, Human Genome Sciences, Rockville, MD. Of note, GX15-070/Mapatumumab combination exhibited a synergistic apoptotic effect on the GX15-070 resistant U266 cell line. Ongoing studies are conducted to unravel the contribution of GX15-070 either on the intrinsic or the extrinsic apoptotic pathways and to explore the feasibility of GX15-070 as a MM therapeutic agent.
Bortezomib Down-Regulates HLA Class I and Enhances Natural Killer Cell Mediated Lysis of Myeloma.
Authors: Shi Jumei , Garg Tarun K. , Kellum Rachel E. , Szmania Susann M. , Barlogie Bart , Tricot Guido , van Rhee Frits 
Published: October 2019

Abstract
Introduction: Immunotherapy with Natural Killer (NK) cells may eradicate residual chemotherapy-resistant myeloma (MM) after a state of minimal residual disease has been achieved by autologous stem cell supported high-dose chemotherapy. NK cell activity is regulated by Killer Immunoglobulin-Like Receptors (KIRs). The principal inhibitory ligands of KIRs are HLA Class I molecules (-C and -Bw4) expressed by target cells. NK cells lyse tumor cells that do not display such inhibitory KIR-ligands (KIR-L), such as the K562 cell line. The proteasome is responsible for the generation of peptides that bind to and stabilize Class I molecules at the cell surface. We hypothesized that treatment of MM cells with the proteasome inhibitor bortezomib results in the down-regulation of Class I and thereby sensitizes MM to NK cell mediated lysis.
Methods: MM cell lines and primary MM cells were treated with concentrations of bortezomib easily achievable in vivo. The objectives were to determine a) the optimal concentration of bortezomib to down-regulate Class I, b) the time to maximum down-regulation of Class I, and c) a bortezomib concentration that increases NK-mediated MM killing without affecting NK cell function.
Results: We found that down-regulation of Class I post-bortezomib treatment of the MM cell line, JJN3, and primary MM cells was dose and time dependent. Bortezomib at 10–20nM down-regulated HLA-class I by 63% compared to untreated control cells with maximal down-regulation at 24hrs (Fig.1a). Bortezomib treatment of primary MM cells greatly increased sensitivity to NK cell-mediated lysis, compared to controls (6% vs. 61%) at an E:T ratio of 20:1 (Fig.1b). These bortezomib concentrations did not affect NK cell function.
Conclusions: We observed that bortezomib down-regulates Class I and enhances the sensitivity of MM to NK cell-mediated lysis. Our findings have clear therapeutic implications for MM and other NK cell-sensitive malignancies.
Figure 1a. Bortezomib down-regulates HLA-class I expression on patient myeloma cells. Figure 1a. Bortezomib down-regulates HLA-class I expression on patient myeloma cells. Figure 1b. Increased killing of bortezomib-treated patient myeloma by NK in vitro. Figure 1b. Increased killing of bortezomib-treated patient myeloma by NK in vitro.
An Observational, Retrospective Analysis of Retreatment with Bortezomib of Mulitple Myeloma (MM) Patients.
Authors: Conner Therese M. , Doan QuynhChau D. , LeBlanc Annette L. , Walters Ian B. , Beveridge Roy A. 
Published: October 2019

Abstract
BACKGROUND: The efficacy and safety of single agent bortezomib (btz) in relapsed MM is well established. In that setting, typically 8 cycles of therapy (6 months) are given and treatment stops. However, no therapy is curative and upon relapse, patients are more refractory to subsequent therapies. Until recently, there has been little information on the feasibility and benefits of retreatment with btz. This study was designed to assess the safety and efficacy of btz used as retreatment either as a single agent or in combination with other agents in community oncology practices.
METHODS: MM pts who received at least two btz-based therapies between May 2003 and November 2005 and who had a ≥60-day gap between each treatment were identified from 22 sites using the US Oncology electronic claims warehouse. Data were transcribed from the patient records to a prespecified case report form for analysis. Best response was determined using M-protein values when available: partial response (PR), 50–89% decrease; very good PR (VGPR) or better, ≥90% decrease. In some cases, physician assessments were available without laboratory confirmation in the chart.
RESULTS: Ninety-four patients with relapsed MM met the eligibility requirements. Mean age was 65.9 years, 43% were female, median time from diagnosis to initial btz treatment was 3 years, and median number of therapies prior to first btz treatment was three. Patients received a median of 16 btz doses during the first treatment and a median of 12 doses in the second treatment; the median time between first and second btz treatment was 5 months (range 2–17). Notably, two patients in each treatment period received over 60 btz doses. The majority (55%) of patients received single agent btz without intervening therapies between first and second btz treatment. Of patients evaluable for response, a PR or better was achieved in 44 of 78 (56%) patients in response to initial therapy (26% achieved a VGPR or better) and in 17 of 85 (20%) in response to retreatment. Of patients with a ≥PR, 12 of 39 (31%) responded upon retreatment. Nine percent of patients who did not respond initially achieved a PR when retreated. Of those who achieved a VGPR or better on initial treatment, 18% achieved at least a VGPR on retreatment. The number of patients who stopped treatment due to toxicity was lower with retreatment (27%) compared with initial treatment (39%). Neuropathy and thrombocytopenia were the most common toxicities leading to discontinuation; treatment discontinuation due to neuropathy decreased from 17% on initial treatment to 5% on retreatment. Nine patients received ≥2 btz retreatments.
CONCLUSIONS: Data from the US Oncology claims database for 94 patients retreated with btz (more than two retreatments in some) suggest that retreatment is safe and effective and not associated with new or cumulative toxicities. Btz is an option for repeated therapy in relapsed patients.
The Combination of Cyclophosphamide, Velcade and Dexamethasone (CVD) Induces High Response Rates with Minimal Toxicity Compared to Velcade Alone (V) and Velcade Plus Dexamethasone (VD).
Authors: Davies Faith E. , Wu Ping , Srikanth M. , Jenner Matthew W. , Dines Sharon , Saso Radovan , Morgan Gareth J. 
Published: October 2019

Abstract
Bortezomib (Velcade®), as the first-in-class proteasome inhibitor, has shown to be effective for the treatment of relapsed refractory myeloma. Preclinical and/or clinical studies showed improved activity by combining this agent with a number of conventional chemotherapeutic agents, suggesting synergistic effects. We conducted a retrospective study to assess the efficacy and toxicity profile with Velcade alone and in combination with dexamethasone or cyclophosphamide, and dexamethasone for patients with multiply relapsed myeloma. 11 patients were treated with Velcade alone, 20 with the combination of Velcade and dexamethasone (VD), and 11 with the regimen comprising Velcade, dexamethasone and cyclophosphamide (CVD). Velcade 1.3mg/m2 was given as a single bolus IV on days 1, 4, 8 and 11, dexamethasone 40mg po on the day of Velcade injection and the day thereafter, and cyclophosphamide 500 mg po days 1, 8, 15 of a 21 day cycle for a maximum of 9 cycles of treatment. No patient received prophylactic anticoagulation. Toxicity profiles and response were assessed every 3 weeks. There was no statistical difference of baseline characteristics (age, ISS, number of previous lines of treatment) among the three treatment groups (P>0.05). The overall response rates (CR+PR) within the three groups are 30% (V), 47% (VD), and 64% (CVD) respectively. The CR rate of CVD group is impressive at 27% compared to 5% with VD and 0% with V. The median duration of treatment of three groups (V vs VD vs CVD) are 115 days, 98 days and 116 days respectively (P>0.05). Thrombocytopenia and new/worsening peripheral neuropathy are the most common side effects in each group. Although thrombocytopenia and neutropenia occurred in the CVD group (36% and 27% respectively), it was at a similar frequency as in the groups of VD (50% and 15%) and V (64% and 45%). Grade 3 infection rates were also similar at 18%, 30% and 18% (V vs VD vs CVD). Peripheral neuropathy is the most troublesome side effect, and is the main reason for Velcade dose reduction and/or discontinuation in each group (27% V, 45% VD, 54% CVD). 27% of patients within CVD group required dose reduction of cyclophosphamide due to neutropenia. Median follow up is currently too limited to comment on whether the improved CR rate with CVD translates into an improved progression free survival. In conclusion CVD is a well tolerated regimen producing high overall and complete response rates, with no increase in toxicity compared to VD or V alone, and lacks the toxicity associated with Velcade- melphalan combinations.
Lenalidomide (L) in Combination with Dexamethasone (D) Significantly Improves Time to Progression (TTP) in Non-Stem Cell Transplant Patients (pts) with Relapsed or Refractory (rel/ref) Multiple Myeloma (MM): Analysis from MM-009 and MM-010 Randomized Phase III Clinical Trials.
Authors: Chanan-Khan Asher Alban , Yu Zhinuan , Weber Donna , Chen Christine , Niesvizky Ruben , Spencer Andrew , Attal Michel , Belch Andrew , Prince Miles , Olesnyckyj Marta , Knight Robert , Zeldis Jerome , Dimopoulos Meletius 
Published: October 2019

Abstract
INTRODUCTION: Although autologous stem cell transplant (ASCT) has demonstrated high overall survival (OS) and progression free survival (PFS) in MM pts, for many pts this may not be an option due to comorbid conditions, advance age, aggressive refractory disease or personal preferences. Two phase III studies demonstrated superiority of the LD combination over D alone in rel/ref MM pts resulting in approval of L by the FDA. To evaluate the utility of LD combination in non-transplant pts we examined all pts who were enrolled on the MM-090 and MM-010 clinical trials and compared the efficacy and safety profile of LD combination among pts with no prior ASCT (NT) vs. those who had a prior ASCT (PT).
METHODS: Data set from the 2 phase III trial was queried and pts with or without a previous ASCT identified. Clinical outcome (overall response rate, ORR; time to progression, TTP; overall survival, OS) was compared between the two groups.
RESULTS: Of the 704 pts enrolled 353 (210 in the PT and 143 in the NT group) were randomized to receive LD. Patients demographic are summarized in Table 1. The median dose for L in both group was 25mg. Using the Blade criteria the ORR and CR rates in the PT vs. NT group were 63% (CR =13%) and 55% (CR=16%) p=0.12, while the median TTP was 44.1 and 61.4 (p=0.13), respectively.
Toxicity: Although a higher incidence grade 3/4 neutropenia in the PT vs. NT group (38.1% vs. 27.3, p<.05) was noted the incidence of grade 3/4 thrombocytopenia were comparable (5.7% vs. 6.3%). The incidence for toxicity associated discontinuation of therapy in each arm was 12.9% and 19.6%.
CONCLUSION: Our analysis showed no difference in ORR and CR rates in the 2 groups though there was a trend towards prolong TTP in NT pts. Although there was a slightly higher incidence of grade 3/4 neutropenia, overall there was no impact of prior ASCT on treatment outcome with LD. An interesting observation was that the median time from first pathologic diagnosis was the same for both groups; this observation is encouraging as they offer advantage to pts who may not have a chance to benefit from ASCT and supports the rationale to investigate L based therapies early on in the course of treatment.
Characteristics of patients treated with LD combination. Prior Transplant Group (PT) No Prior Transplant (NPT) P value Median age (range) 59.5 (33–77) 69 (38–86) <0.001 Sex (%) M/F 62.4/37.6 55.2/44.8 0.187 Stage III (%) 60 70.6 0.184 B2M 3.1 4.1 <0.05 Time from first pathologic diagnosis in years (range) 3.4 (0.6–15.7) 2.9 (0.4–14.7) 0.098