bluuebunny/crossref_metadata_2025_split huggingface dataset:
High-Dose Therapy with Peripheral Blood Stem Cell Transplantation for Patients with Multiple Myeloma: Prognostic Impact of Chromosomal Aberrations and Correlation with the ISS-Score
Authors: Neben Kai , Jauch Anna , Hose Dirk , Cremer Friedrich , Heiss Christiane , Hielscher Thomas , Bertsch Uta , Klein Ulrike , Hillengass Jens , Ho Anthony D. , Goldschmidt Hartmut 
Published: April 2020

Abstract
Multiple Myeloma (MM) is a malignant lymphoproliferative B-cell disease characterized by the accumulation of monoclonal plasma cells in the bone marrow. Acquired genomic aberrations have been shown to significantly impact response to chemotherapy and survival in MM. The aim of our study was to assess the clinical relevance of genomic abnormalities in 306 MM patients treated with high-dose chemotherapy (HDCT) and peripheral stem cell transplantation (PBSCT) in our center.
We analyzed 171 males and 135 females with a median age of 60 years (range 25 – 73 years). According to the international staging system (ISS), MM patients were classified as stage I (46.6%), stage II (36.1%) and stage III (17.4%) at the onset of chemotherapy. All patients underwent frontline HDCT with 200 melphalan mg/m2 and PBSCT according or in analogy to the GMMG-HD3- or GMMG-HD4-trials. Interphase-FISH-analysis was performed on CD138-purified plasma cells using probes for chromosomes 1q21, 6q21, 8p21, 9q34, 11q23, 13q14.3, 15q22, 17p13, 19q13, and 22q11, as well as IgH-translocations t(4;14)(p16.3;q32.3) and t(11;14)(q13;q32.3). For the entire group, the median overall survival (OS) and progression-free survival (PFS) after HDCT was 6.4 and 2.2 years, respectively.
Table 1. Chromosomal abnormalities with significant results (a-level=0.05) on PFS or OS (univariate analysis, unadjusted p-values)
Aberration yes vs. no Frequency % 3-year PFS % P value 3-year OS % P value del(8p21) 19 26 vs. 37 0.01 58 vs. 78 0.02 del(13q14.3) 46 23 vs. 53 &lt;0.001 65 vs. 83 0.03 del(17p13) 10 22 vs. 40 0.02 44 vs. 82 &lt;0.001 t(4;14) 14 10 vs. 42 &lt;0.001 54 vs. 81 0.04 +1q21 35 20 vs. 46 &lt;0.001 67 vs. 85 0.002 +19q13 54 49 vs. 22 0.03 76 vs. 73 0.92
In a first step, we analyzed the prognostic impact of each individual chromosomal aberration on PFS and OS (Table 1). After adjustment for the ISS-score, del(8p21), del(13q14.3), del(17p13), t(4;14) as well as gains of 1q21 and 19q13 preserved significant impact on PFS, while del(17p13), t(4;14) and gain of 1q21 were of statistical significance for OS, indicating that these chromosomal aberrations give prognostic information in addition to the ISS-score. Subsequently, we performed a multivariate analysis including all the chromosomal aberrations analyzed. While del(17p13) and gain of 1q21 showed significant results on OS, del(13q14.3), del(22q11) and gain of 15q22 were significant for PFS.
In conclusion, our results show that the heterogeneity seen in the clinical course of MM patients after HDCT can be correlated with distinct chromosomal aberrations. This analysis may have implications for the risk-adopted management of patients with MM.
Analytical Approaches for the BOAC SNP Panel Association with Progression Free Survival in Myeloma
Authors: Van Ness Brian G. , Ramos Christine , Kumar Vipin , Steinbach Michael , Durie Brian GM , Crowley John , Barlogie Bart , Hoering Antje , Haessler Jeff , Johnson David C , Morgan Gareth J 
Published: April 2020

Abstract
The Bank On A Cure (BOAC) has established DNA banks from multiple cooperative and institutional clinical trials, and platforms for examining the association of genetic variations (SNPs) with disease risk and outcomes in myeloma. We have previously described the development and content of a novel custom SNP panel that contains 3,404 SNPs in 983 genes, representing cellular functions and pathways that may influence disease response, toxicities, complications, and survival. Although survival certainly varies according to tumor heterogeneity (ie. chromosomal abnormalities, gene expression variations) germline variations that influence the microenvironment, drug distribution, drug transport and metabolism, may also have an association with event free survival outcomes. To explore SNP associations with progression free survival (PFS) we compared the BOAC SNP profiles of short term PFS (less than 1 year, n=70) versus long term PFS (greater than 3 years, n=73) in two phase III clinical trials (ECOG E9487 and SWOG S9321). A variety of analytical approaches was undertaken including univariate rank ordering, recursive partitioning, and support vector machine learning tools (SVM). Each of these approaches has advantages and limitations in dealing with type I false positive errors as well as sensitivity and specificity. We included subset validation approaches and randomization of classes to address how robust and predictive different approaches were. From our analysis we conclude germline genomic variations do have an impact on progression free survival, with a subset of SNPs from the panel reaching 76% predictive association and hazard ratios of PFS of 9.6 (CI 4.5, 20.5), p&lt;0.001, using SVM analysis. Based on univariate approaches, we find the most significant variations associated with PFS differences were genes that could be functionally categorized as pharmacologic. The presentation will focus on the analytical approaches, and refinements necessary to assure predictive value compared to random associations. Notwithstanding the clear importance of tumor cell variations in genetic deregulation, we conclude that various functions within the bone marrow and drug response likely interplay as a complex influence on disease progression, response, and survival. This suggests combining gene expression profiles of the tumors with germline SNP profiles may provide more accurate prognosis. These combined analytical approaches are currently being developed with BOAC data bases, and examples will be discussed.
Regulation of Multiple Myeloma Survival and Progression by CD1d
Authors: Spanoudakis Emmanouil , Hu Ming , Naresh Kikkeri , Terpos Evangelos , Melo Valeria , Reid Alistair G , Kotsianidis Ioannis , Rahemtulla Amin , Karadimitris Anastasios 
Published: April 2020

Abstract
Downregulation of conventional HLA molecules from the surface of tumour cells is an important mechanism for tumour immune evasion, survival and progression. Whether CD1d, a non-conventional, glycolipid-presenting HLA class I-like molecule can affect tumour cell survival is not known. To test this we studied expression of surface CD1d on plasma cells from different stages of multiple myeloma (MM) using flow-cytometry. Expressing results as the ratio of the Geo MFI CD1d/isotype IgG1 we found that while CD1d expression was comparable between MGUS (n=8) and newly diagnosed MM patients (n=14; Geo MFI MGUS: 8.61±4.3 vs new MM: 7.1±4.72, p&gt;0.05), in relapsed/advanced disease CD1d was significantly lower (Geo MFI:1.92±0.9, p&lt;0.003 vs MGUS and new MM) and completely lost in 4 out of 5 myeloma cell lines at protein and RNA level. Further, 4 out of 8 paired, same-patient trephine biopsies stained with anti- CD1d showed drastic loss of CD1d expression in advanced compared to early disease. These results confirmed loss of CD1d expression during disease progression and suggested that CD1d impacts negatively on myeloma cell survival. Consistent with this, we found that engagement of CD1d by 2 different anti-CD1d mAbs and as compared to isotypic IgG or media control, induces cell death (i.e., Annexin+) of the CD1d-expressing B lymphoblastoid cell line C1R-CD1d, of myeloma cell lines with retrovirally restored expression of CD1d and purified, CD1d-expressing primary myeloma cells in a dose- and time-dependent manner, coincident with loss of mitochondrial membrane potential (MMP) as assessed by DioC3 staining. Biochemical analysis of relevant cell death pathways showed that MMP loss is associated with overexpression of the pro-apoptotic protein Bax but as demonstrated by immunoblotting and pharmacological inhibition it is caspase- independent. By introducing appropriate CD1d retroviral constructs into CD1d- myeloma cell lines we showed that anti-CD1d-induced cell death requires the cytoplasmic tail but not a Tyr residue critical for lysosomal sorting of CD1d. Finally, we found that anti-CD1d co-operates with anti-myeloma agents in the killing of myeloma cells. Thus, these findings provide evidence linking a novel function of CD1d in the regulation of cell death with tumour survival and progression and might have pathogenetic and therapeutic implications for other CD1d-expressing hematopoietic malignancies as well as myeloma.
Homozygous Deletions Can Be Used to Define a Cell Death Specific Gene Expression Signature Able to Predict Outcome in Myeloma
Authors: Dickens Nicholas J , Walker Brian , Leone Paola E , Jenner Matthew W , Davies Faith , Morgan Gareth J 
Published: April 2020

Abstract
Defining biologically relevant prognostic indices in myeloma is a challenge. The International Staging System (ISS) is important but based on simple clinical data. Cytogenetics, in particular switch translocations and 17p-, are more important biologically, being based on underlying genetic changes. However, these changes do not capture all of the important biological data and so signatures based on global expression analysis have been developed to address these shortcomings. Most signatures to date have been based on expression features correlated with outcome rather than using structural genetic change to define biologically relevant expression features and, as such, although predictive, they may be acting as “bystander” markers rather than being pathologically important themselves. We have used homozygous deletions (HD) to define relevant genes and gene signatures predictive of outcome in a large homogeneously treated set of myeloma patients.
Depletion of Host CD122+ Cells Facilitates Widespread Skeletal Multiple Myeloma Engraftment in NOD/SCID Recipients
Authors: Freeman Lisa M , Petcu Eugene , Smith Robert , Salajegheh Ali , Diamond Peter , Zannettino Andrew Christopher William , Evdokiou Andreas , Luff John , Khalil Dalia , Vari Frank , Catley Lawrence , Hart Derek , Vuckovic Slavica 
Published: April 2020

Abstract
To facilitate human multiple myeloma (MM) engraftment into NOD/SCID recipients, mice were depleted of CD122+ cells (NK and myeloid cells) by antibody-mediated ablation prior to transplantation with the MM cell lines (RPMI8226, RPMI8226-TGL or U226). The MM engraftment, skeletal MM distribution, osteolysis, lambda chain paraprotein and associating disease symptoms in CD122+ cell-depleted and CD122+ cellreplete mice were compared. The CD122+ cell-depleted mice engrafted at a significantly higher frequency with human CD38+, CD56+, PCA-1+ and CD138+ cells. In the CD122+ cell-depleted mice, bioluminescence MM signal involved the whole mouse compared to limited imaging signal in the CD122+ cell-replete mice. The majority 88%–100% of CD122+ cell-depleted mice developed MM engraftment throughout the appendicular and axial skeletons with osteolysis and rare subcutaneous plasmacytomas (11% of mice). Serum paraprotein appeared earlier at 4–5 weeks post-transplant in CD122+ cell-depleted mice and continued to increase during the 12–13 weeks of analysis. The majority, 92% of CD122+ cell-depleted mice developed hind-limb paralysis and had a significantly shortened 45 day survival. Thus, depletion of CD122+ cells reduced resistance to the human MM and produced a new MM xenograft-NOD/SCID model that recapitulates the clinical manifestations of MM and eliminates the major limitations associated with the published MM xenograft-mouse model.
Transgenic Mouse Modeling of Therapeutic Responses in Myeloma
Authors: Van Ness Brian G. , Ramos Christine , Gosse Mary 
Published: April 2020

Abstract
While myeloma is still considered a fatal disease, new therapeutic approaches, including combination of drugs that target different intracellular pathways, have shown marked improvements in response and survival. Yet there are wide variations in responses seen in the patient population. One major source is the variation in chromosomal abnormalities and the genes deregulated among the plasma cell (PC) tumors. Another may be in inherited variations (SNPs) that can have a major influence on drug distribution, transport and metabolism. Our laboratory has developed a transgenic mouse model targeting overexpression of c-myc and bcl-xL in late B cells, that results in early expansion of non-malignant PCs, followed by development of clonal plasma cell malignancies in 100% of the mice. We have reported on cell surface, chromosomal abnormalities, and gene expression profiles of the mouse plasma cell tumors, that demonstrate a very similar profile and heterogeneity to human myelomas. The mouse PC tumors can be adoptively transferred to syngenic recipient mice, as well as grown in culture. The advantage of this model is that the impact of tumor heterogeneity can be assessed in a common germline genetic background in the mice; and an intact immune system is maintained, unlike many common xenograft models. We find that disease progression is variable among tumors and have extended this observed heterogeneity of progression to analysis of drug sensitivity; for example, identifying tumors that are highly sensitive to dexamethasone, and others extremely resistant, and others that show protection in the presence of IL-6. Although bcl-xL expression is important in the initiation of the transgenic malignancy, it was not clear if Bcl-xL was required to maintain the transformed phenotype. To test this, we blocked Bcl-xL with the inhibitor BH3I-2′(Calbiochem). We find that inhibition of Bcl-xL is effective in killing the PC tumors in vitro, and dose is directly related to levels of bcl-xL expression. We also examined various dose combinations of dexamethasone and BH3I-2′ and found an antagonistic relationship of the two drugs. We are in the process of expanding the tumor mouse population to target other therapeutic approaches in the transgenic mouse that models tumor heterogeneity in a common genetic background.
Opposing Effects of Dexamethasone on Lenalidomide Activity in Multiple Myeloma: Additive/Synergistic Effects on Anti-Proliferative Activity on Myeloma Cells and Antagonistic Effects on Immune Function
Authors: Schafer Peter H , Gandhi Anita K , Zhang Ling-Hua , Kang Jian , Capone Lori , Parton Stacey , Wu Lei , Bartlett Blake 
Published: April 2020

Abstract
Lenalidomide (Revlimid®) is approved for the treatment of previously treated multiple myeloma (MM) in combination with dexamethasone. Single agent lenalidomide has direct antiproliferative activity against MM cells and direct immunomodulatory activity via costimulation of T cell and natural killer (NK) cell responses. The ECOG Phase III trial in newly diagnosed MM (E4A03) reported that low dose (40 mg/d on days 1, 8, 15 & 22 of a 28-day cycle) dexamethasone in combination with lenalidomide showed an overall survival advantage when compared with the higher, standard-dose (40 mg/d on days 1-,4, 9–12 & 17–20 of a 28-day cycle) of dexamethasone that is used in combination with lenalidomide. We have examined the pharmacological activity of lenalidomide in combination with dexamethasone with respect to direct MM antiproliferative and T/NK cell stimulation in vitro. Antiproliferative activity against various MM cell lines was associated with increased expression of tumor suppressor genes, including Egr1, Egr3, p21, and p27. The specific tumor suppressor genes induced varied among the MM cell lines, even among those that were sensitive to lenalidomide. Lenalidomide and dexamethasone induced cell cycle arrest in G0/G1 phase, activation of caspases 3/7, and apoptosis in the sensitive cell lines. The combination of lenalidomide and dexamethasone was partially additive in most MM cell lines, while the most dramatic combination effect observed was induction of p21 gene expression and apoptosis in LP-1 MM cells. In contrast to its synergistic effect on MM cell proliferation, dexamethasone was strongly antagonistic to the T and NK cell costimulatory effects of lenalidomide. Specifically, in primary human T cells dexamethasone inhibited lenalidomide-enhanced IL-2 production. Furthermore, in primary human NK cells dexamethasone inhibited lenalidomide-enhanced IFN-γ production. These findings suggest that the lenalidomide plus low-dose dexamethasone regimen may be able to facilitate the MM cell killing via induction of tumor suppressor gene expression, cell cycle arrest, and apoptosis, while allowing lenalidomide to enhance T and NK cell function to a greater magnitude. The enhanced survival with the low-dose dexamethasone schedule in MM patients suggests exploring further dosing schedules of dexamethasone in combination with lenalidomide in this population, with measurement of biomarkers of T and NK cell function.
Targeting PKC: A Novel Role for Beta-catenin in ER Stress and Apoptotic Signaling
Authors: Raab Marc S , Breitkreutz Iris , Tonon Giovanni , Zhang Jing , Fruehauf Johannes , Lin Boris K , Chauhan Dharminder , Hideshima Teru , Munshi Nikhil , Anderson Kenneth C. , Podar Klaus 
Published: April 2020

Abstract
Targeting protein kinase C (PKC) isoforms by the small molecule inhibitor enzastaurin has shown promising pre-clinical activity in a wide range of tumor cells. In this study, we further delineated its mechanism of action in multiple myeloma (MM) cells and found a novel role of b-catenin in regulating growth and survival of tumor cells. Inhibition of PKC leads to rapid accumulation of b-catenin by preventing the phosphorylation required for its proteasomal degradation. Specifically, b-catenin was dephosphorylated at Ser33,37,41 and accumulated in a dose- and time-dependent manner in all cell lines tested (including primary MM cells and 10 MM cell lines, 3 colon cancer, HeLa, as well as HEK 293 cells). Microarray analysis and siRNA-mediated gene silencing in MM cells revealed that accumulated b-catenin activates early ER stress signaling via eIF2a, CHOP and p21, leading to immediate inhibition of proliferation. Conversely, knock-down of components of the ER stress response pathway by siRNA (i.e., CHOP) abrogated the inhibitory effect of enzastaurin on MM cell proliferation. Importantly, accumulated b-catenin also contributes to enzastaurin-induced cell death, since inhibition of b-catenin by siRNA partially rescued HeLa, HEK 293, and MM cells from cell death induced by enzastaurin. Analysis of downstream target molecules revealed a b-catenin -dependent up-regulation of c-Jun, but not of c-Myc or Cyclin D1. c-Jun has been reported to stabilize p73, a pro-apoptotic p53-family member; b-catenin induction by enzastaurin led to p73 (but not p53) activation, which was also abrogated by b-catenin -specific siRNA. In turn, specific knockdown of p73 by siRNA rescued cells from enzastaurin-induced apoptosis. Finally, ectopic overexpression of b-catenin in HeLa and MM cells induced c-Jun expression and p73 activation, followed by apoptotic cell death. In summary, our data reveal a novel role of b-catenin in ER stress-mediated growth inhibition and a new pro-apoptotic mechanism triggered by b-catenin upon inhibition of PKC isoforms, and further demonstrate that p73 represents a novel therapeutic target in MM. Based on these and previous data, enzastaurin is currently under clinical investigation in a variety of hematologic malignancies including MM.
Phase I Study of Elotuzumab (HuLuc63) in Phase I Study of Elotuzumab (HuLuc63) in Relapsed/Refractory Multiple Myeloma
Authors: Zonder Jeffrey A. , Singhal Seema , Bensinger William , Mohrbacher Ann , Hussein Mohamad A. , Munshi Nikhil C. , Caras Ingrid , Singhal Anil , van Rhee Frits 
Published: April 2020

Abstract
Elotuzumab is a humanized monoclonal antibody directed against CS1, a cell surface glycoprotein, which is highly and uniformly expressed in multiple myeloma. Elotuzumab has demonstrated significant anti-tumor activity in pre-clinical mouse models of multiple myeloma (MM). The primary objective of this Phase I study is to evaluate the maximum tolerated dose (MTD) of elotuzumab in patients with relapsed/refractory MM. The study also evaluates the overall safety, pharmacokinetics (PK), biologic activity and clinical response to elotuzumab. Elotuzumab is administered every 2 weeks × 4 doses in six escalating dose cohorts ranging from 0.5 mg/kg to 20 mg/kg. An additional 4 doses may be administered if the patient demonstrates at least stable disease during the initial 4 doses of therapy.
To date, a total of 23 patients, 52% male, with a median age of 64 years and a median of seven prior treatments, have been treated in the six cohorts. In the 2.5 mg/kg cohort, one out of six patients experienced a DLT of Grade 4 increase in serum creatinine which was concomitant to an unrelated serious adverse event (SAE) of sepsis. Four additional elotuzumab-related SAEs in two patients (Grade 2 chills and fever in one subject in the 2.5 mg/kg cohort, Grade 2 chest pressure and bradycardia in another subject in the 10 mg/kg cohort, all requiring overnight hospitalization) have been observed. However, the MTD for elotuzumab has not been reached up to the 10 mg/kg dose. Several patients (10/16) experienced Grade 1 and 2 AEs occurring during or immediately after the first dose including chills, flushing, pyrexia, rigors, dyspnea and fatigue. An increase in serum levels of a number of cytokines such as interferon-gamma and TNF-alpha, and chemokines including IP10 and MCP1 was observed for all patients following the first dose of elotuzumab, peaking between 2–4h after the end of infusion and returning to near baseline levels by 24h. These infusion-related symptoms were not observed during the subsequent dosing of elotuzumab, possibly due to premedication with antihistamines and acetaminophen. Preliminary PK analysis suggests a short serum half-life of 2–4 days at low doses of elotuzumab (0.5–2.5 mg/kg), with an increase to 10–11 days at higher doses (5–10 mg/kg). Cmax levels of 53–114 mcg/mL and 291–384 mcg/mL were observed in the 5 mg/kg and 10 mg/kg cohorts, respectively. Following the completion of 4 doses of elotuzumab, 6 patients demonstrated stable disease, four of these at 5 mg/kg or higher dose levels, according to the EBMT response criteria.
In summary, elotuzumab appears to have a manageable safety profile in patients with relapsed/refractory MM. MTD for elotuzumab has not been reached up to the 10 mg/kg dose. Higher doses of elotuzumab lead to a significant increase in Cmax and half-life. Evaluation of the 20 mg/kg dose cohort is ongoing.