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  • 1
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 20, No. 2 ( 2014-02), p. S38-
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2014
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  • 2
    In: Blood, American Society of Hematology, Vol. 124, No. 6 ( 2014-08-07), p. 899-906
    Abstract: Carfilzomib 56 mg/m2 provided a high overall response rate with a remarkable duration of response in patients with R/RMM. Nonhematologic grade 3/4 AEs likely related to carfilzomib treatment included hypertension and heart failure.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2014
    detail.hit.zdb_id: 1468538-3
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  • 3
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4257-4257
    Abstract: BACKGROUND: Cardiovascular (CV) events are a known complication to proteasome inhibitor therapy in myeloma. Underlying mechanisms are unknown. We recently completed an investigator initiated, single institution Phase II study of high dose carfilzomib (56mg/m2) in patients with relapsed/refractory MM (NCT01351623). Among 42 response evaluable patients, 11 patients (25%) developed treatment-emergent heart failure of any grade, and 5 patients (11%) developed severe heart failure requiring mechanical ventilation. We undertook a study to identify potential biomarkers that may point to underlying mechanisms of CV events among multiple myeloma patients treated with carfilzomib therapy. METHODS: We performed a nested case-control study with 7 patients who experienced a CV event on our high dose carfilzomib study and had pre-treatment (baseline) plasma stored and 19 case matched controls treated on the same study who did not have a CV event. We screened for 90 proteins known to be associated with CV disease using O-linked glycosylation. We used the Proseek Multiplex CVD I 96x96 platform which is based on the Proximity Extension Assay (PEA) technique. PEA is a 96-plex immunoassay that allows high throughput detection of protein biomarkers in liquid samples. For each biomarker, a matched pair of antibodies linked to unique oligonucleotides (proximity probes) binds to the respective protein target. Upon binding, the unique proximity probes can hybridize to each other and subsequently be detected and quantified by real-time PCR. Mean biomarker levels were compared using a t-test. False discovery rate (FDR) was used for multiple comparisons adjustment. RESULTS: Using samples collected prior to initiation of carfilzomib therapy, in an agnostic statistical model we identified the following four proteins to have altered levels in myeloma patients who developed CV events (p=0.002-0.004, unadjusted; p=0.089, after FDR correction): matrix metalloproteinase-1 (MMP-1, heparin-binding EGF-like growth factor (HB-EGF), TNF-related apoptosis-inducing ligand (TRAIL), and myoglobin (MB). Myeloma patients who developed CV events had 37% lower MMP-1, 15% lower MB, and 4% lower HB-EGF, while TRAIL was 7% higher in patients who developed CV events. Matrix metalloproteinases are a family of proteolytic enzymes responsible, among other functions, for myocardial extracellular protein degradation. Interestingly, several MMP species, including MMP-1, have been identified within the human myocardium and are thought to be dysregulated in congestive heart failure. HB-EGF is a mitogenic and chemotactic glycoprotein that is essential for maintaining normal cardiac function and is known to play an important role in myocardial remodeling. CONCLUSIONS: We found that there was a trend towards lower MMP-1, HB-EGF, and MB levels and higher TRAIL levels in patients with CV events while receiving proteasome therapy. MMP-1 appears to be the most promising potential biomarker based on our data. Our study supports further investigation of these proteins as potential biomarkers for patients at risk of CV events when treated with carfilzomib. Table 1. CV event No CV event N=7 N=19 CKD Proteins1 Mean (SD) Mean(SD) Unadjusted P-value Adjusted P-value MMP_1 1.7 (0.5) 2.7 (0.9) 0.002 0.089 HB_EGF 6.9 (0.2) 7.2 (0.3) 0.004 0.089 TRAIL 8 (0.3) 7.5 (0.5) 0.004 0.089 MB 5 (0.5) 5.9 (0.8) 0.004 0.089 HSP_27 2.2 (0.3) 2.7 (0.8) 0.032 0.528 PDGF_subunit_B 4 (0.7) 5 (1.5) 0.036 0.528 CD40_L 3.4 (0.6) 4.2 (1.2) 0.042 0.533 EGF 3.7 (0.9) 4.7 (1.4) 0.053 0.592 CX3CL1 5.9 (0.2) 5.6 (0.6) 0.092 0.895 TRAIL_R2 4.2 (0.4) 4.6 (0.6) 0.101 0.895 1. Proteins are listed based on the p-value associated with the difference between patients who did and did not have CV events, with lowest p-value on the top. The top 10 biomarkers are shown. Disclosures Ekman: Olink Bioscience: Employment. Grundberg:Olink Bioscience: Employment. Hassoun:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: Research Funding; Novartis: Consultancy. Lesokhin:Aduro: Consultancy; Efranat: Consultancy; Genentech: Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Janssen: Consultancy, Research Funding. Landau:Janssen: Consultancy; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Landgren:Onyx: Honoraria; Celgene: Honoraria; BMJ Publishing: Consultancy; International Myeloma Foundation: Research Funding; Bristol-Myers Squibb: Honoraria; Onyx: Research Funding; Medscape: Consultancy; Medscape: Honoraria; BMJ Publishing: Honoraria; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 4
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. 8016-8016
    Abstract: 8016 Background: Host T-cells mount immune responses (IR’s) against Wilms tumor 1 (WT1) in A*0201 + MM pts through formation of WT1 peptide fragment (RMFPNAPYL)/HLA-A*0201 complex. We report initial results from MM pts immunized with the WT1 heteroclitic peptide mixture galinpepimut-S (GPS) after autoSCT. Methods: 16 MM pts underwent autoSCT with melphalan conditioning followed by (f/b) lenalidomide maintenance starting 3 months (mos) post-SCT. 13/16 pts presented with high-risk (HR) cytogenetics [t(4;14), t(14;16), del17p, 1q21/25 gain and/or del13q]. GPS was administered with montanide s.c. starting 2 wks post-SCT and q.2 wks thereafter x 6 initial doses f/b boosters q.4 wks x 6 additional doses. GM-CSF was given on days -2 and 0 of each cycle. GPS consisted of 4 peptides: WT1-A1: Y*MFPNAPYL; 427-L (long): RSDELVRHHNMHQRNMTKL; 331-L: PGCNKRYFKLSHLQMHSRKHTG, and 122A1-L: SGQAY*MFPNAPYLPSCLES. 2 of the 4 peptides were mutated at a single residue (*) to induce stronger HLA-binding/reduce tolerance. WT1-specific IR’s were assessed by intracellular IFN-g analyses post-challenge with PBMC’s pulsed with a ‘total pool’ of overlapping 15mers along the entire WT1 protein; or each of the 4 WT1 peptides in GPS; or the non-mutated (native) WT1 peptides corresponding to the 2 heteroclitic sequences. Results: 16 pts; median follow-up: 18 mos (range: 5-31 mos) for survivors; median age: 61.6 y. Overall survival (OS) and progression-free survival (PFS) (95% CI) at 18 mos: 0.88 (0.73-0.99) and 0.62 (0.42-0.97) respectively. Current median PFS: 23.6 mos (15.2 - not reached). No 〉 G2 systemic side effects were observed, however, all pts developed local nodularity at the site of injections which resolved over 2 – 6 wks. Both CD8+ and CD4+ IR’s could be detected at various levels and were induced not only against the heteroclitic peptides (within GPS), but also against the corresponding native WT1 peptide sequences as well as the ‘total pool’ of WT1-derived overlapping peptides. Conclusions: Administration of the novel WT1 heteroclitic peptide immunizer GPS post auto SCT demonstrates favorable safety profile along with encouraging mPFS of currently 23.6 mos in this high-risk MM population. Clinical trial information: NCT01827137.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    RVK:
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    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 5
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1785-1785
    Abstract: Background: Programmed cell death 1 (PD-1) protein downregulates T cell activation and is related to immune tolerance. PDL1 up regulation, T cell infiltration, and T cell exhaustion are features, which suggest susceptibility to PD-1 blockade antibodies. Blockade of PD-1 or its ligand PD-L1 has shown promising responses in several malignancies. Although little clinical activity has been seen in patients with relapsed multiple myeloma (MM), the role of the PD-1 pathway and T cell exhaustion in newly diagnosed MM has not been explored. Objective: To determine whether T-cell infiltrate or expression of PD-1 correlates with clinical features and prognosis among patients with newly diagnosed multiple myeloma. Methods: We screened a clinically annotated database of 341 patients seen at MSKCC between 1998 and 2012 that had Multiple Myeloma, received a bone marrow transplant and were consented to a biospecimen research protocol for availability of pre-treatment bone marrow specimens. A total of 64 bone marrow biopsy specimens were identified. Immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded specimens using an anti human CD3 monoclonal antibody (mAb) (Dako, Clone F7.2.38) and an anti human PD-1 mAb (Cell Marque, catalog #315M-95). CD3 and PD1 IHC staining were graded as negative ( 〈 5% for CD3, 〈 1% for PD1), or positive (≥5% for CD3, ≥1% for PD1). Correlative analyses were performed between CD3/PD1 expression and clinical outcome using the following parameters: International Staging System (ISS), cytogenetic risk, progression free survival (PFS), overall survival (OS), and response to treatment. Groups were compared by Fisher's exact test. OS and PFS were assessed by Cox regression and estimated by Kaplan-Meier methods. Results: 23 specimens (36%) were CD3 positive and 10 specimens (16%) were PD-1 positive. All PD-1 positive specimens were CD3 positive. 41 specimens (64%) were CD3 negative ( 〈 5%) and PD1 negative ( 〈 1%). Based on these results, specimens were divided into three groups: Exhausted T-cell infiltrate (CD3+/PD1+), non exhausted T-cell infiltrate (CD3+/PD1-) and no T-Cell infiltrate (CD3-/PD1-). In the exhausted T-cell infiltrate group 30% of patients had ISS stage 3 and 40% had high risk cytogenetics. In the non-exhausted T-cell group 15% of patients had ISS stage 3 and 15% high cytogenetic risk. In the no T-cell infiltrate group 10% had ISS stage 3 disease and 22% high cytogenetic risk. These proportions were not significantly different across the 3 groups. Median OS from 1st auto infusion was 7 years while median PFS was 2.3 years. On univariate analysis, there was no significant difference in PFS between the 3 groups. The presence of CD3 and PD1 T-cells were significantly associated with OS (p-value = 0.04). Median OS from 1st auto infusion was 43 months for the exhausted T-Cell infiltrate group followed by 83 months for the no T-Cell infiltrate group. The non exhausted T-cell group had the highest OS, median not reached; OS by 7-years was 75%. Cytogenetic risk at diagnosis was significantly associated with OS (p-value = 0.03). In a multivariable model, CD3/PD1 staining continued to trend toward an association with OS (p-value = 0.08) and cytogenetic risk remained significant (p-value = 0.05). Conclusions: The presence of T-cells with PD-1 expression was not associated with higher risk disease at MM diagnosis based on cytogenetics and ISS stage. The presence of PD-1 expressing CD3+ T cells trends toward an association with poorer overall survival in newly diagnosed MM, especially compared to non exhausted T-cell infiltrate, suggesting the possibility that T cell exhaustion represents a novel high risk disease characteristic. Further investigation is necessary to assess if the presence of CD3+PD-1+ T cells is an independent prognostic feature in newly diagnosed MM. Figure 1. Overall survival by CD3/PD1 Staining in 64 newly diagnosed myeloma patients. Figure 1. Overall survival by CD3/PD1 Staining in 64 newly diagnosed myeloma patients. Disclosures Giralt: JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding. Landgren:International Myeloma Foundation: Research Funding; Onyx: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Consultancy; BMJ Publishing: Consultancy; Celgene: Honoraria; Onyx: Honoraria; BMJ Publishing: Honoraria; Onyx: Research Funding. Hassoun:Novartis: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Lesokhin:Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Efranat: Consultancy.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 6
    In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 1996-1996
    Abstract: Introduction: Autologous hematopoietic stem cell transplantation (Auto HSCT) has been shown to prolong progression free (PFS) and overall survival (OS) in patients with multiple myeloma (MM), with the depth of response pre-transplant previously correlated with PFS, but not OS. Even in patients receiving proteasome inhibition and immunomodulatory agents as induction, up to 25% of newly diagnosed patients achieve less than a partial response (PR). We aimed to evaluate outcomes after Auto HSCT for patients with primary refractory MM. Methods: Between 1/2009 and 12/2012, we identified 95 newly diagnosed symptomatic MM patients treated at our institution with novel agent induction regimens and upfront Auto HSCT. Based on IMWG criteria, patients were separated into those achieving 〉 = PR (CR, VGPR, PR) and those who are primary refractory (PrRef) as defined by stable or progressive disease (SD/PD) to first line therapy. Characteristics were compared by the Fisher's Exact test. PFS and OS were calculated in a landmark analysis from transplant and estimated by Kaplan-Meier methods and compared by the log rank test. Results: Sixteen patients (17%) had PrRef disease, with a median age of 53 vs 59 yrs in those who achieved 〉 =PR (p=0.04). Demographic and clinical characteristics were otherwise not statistically different between the two groups: 56 vs 65% were male; 69 vs 80% Caucasian; 69 vs 48% had ISS Stage I disease with 19 vs 14% having high risk cytogenetics; 81 vs 84% had lytic lesions; and 31 vs 51% had extramedullary disease at diagnosis in PrRef pts vs 〉 PR pts, respectively. All patients received induction regimens including either bortezomib (44 vs 38%), lenalidomide (31 vs 24%), or both (25 vs 37%) (p=0.68). Compared with 32% of 〉 =PR pts, 94% of the PrRef pts were treated with additional therapy prior to Auto HSCT (p 〈 0.001), with 5/15 achieving VGPR, 6/15 PR, and 4/15 SD/PD prior to Auto HSCT. Tandem Auto HSCT was performed in two PrRef vs one 〉 = PR patient. Response to Auto HSCT was a 38 vs 58%, 25 vs 25%, 38 vs 14%, and 0 vs 4% for CR, VGPR, PR, and SD/PD, in PrRef vs responding pts respectively (p=0.19). Maintenance therapy, primarily with lenalidomide, was given to 69 vs 78% (p=0.52). Median PFS from transplant was 41 months (95% CI 16 - not reached ) in PrRef pts compared to 53 months, (95%CI: 31 - not reached) in 〉 =PR pts (p=0.51). With a median follow-up of 36.5 months (range 9.5-63 months) in surviving patients, median OS from transplant was not reached in either group (p=0.77)(Figures 1 and 2). For the PrRef pts, 3-yr OS from transplant was 77% (95%CI 43-92%) compared to 87% (95%CI 77-93%) in 〉 =PR pts. Conclusion: A small portion of MM patients have primary refractory disease after induction therapy with bortezomib and lenalidomide. Demographic and disease characteristics, other than age, were not able to differentiate these patients. However, Auto HSCT was an effective therapy regardless of response to novel agent based induction therapy. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Hassoun: Celgene: Research Funding; Novartis: Consultancy; Takeda: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees. Lesokhin:Efranat: Consultancy; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Research Funding. Landgren:BMJ Publishing: Honoraria; BMJ Publishing: Consultancy; Onyx: Research Funding; International Myeloma Foundation: Research Funding; Onyx: Honoraria; Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Medscape: Consultancy; Onyx: Consultancy. Landau:Onyx: Honoraria, Research Funding; Spectrum Pharmaceuticals: Honoraria; Takeda: Research Funding; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Janssen: Consultancy. Giralt:SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding; AMGEN: Consultancy, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; TAKEDA: Consultancy, Honoraria, Research Funding.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2015
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  • 7
    In: Biology of Blood and Marrow Transplantation, Elsevier BV, Vol. 21, No. 2 ( 2015-02), p. S203-S204
    Type of Medium: Online Resource
    ISSN: 1083-8791
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2015
    detail.hit.zdb_id: 3056525-X
    detail.hit.zdb_id: 2057605-5
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