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In: Blood Cancer Journal, Springer Science and Business Media LLC, Vol. 9, No. 4 ( 2019-03-18)

Abstract: Disease control at 5 years would be a desirable endpoint for elderly multiple myeloma (MM) patients, but biomarkers predicting this are not defined. Therefore, to gain further insights in this endpoint, a population of 498 newly diagnosed transplant-ineligible patients enrolled in two Spanish trials (GEM2005MAS65 and GEM2010MAS65), has been analyzed. Among the 435 patients included in this post-hoc study, 18.6% remained alive and progression free after 5 years of treatment initiation. In these patients, overall survival (OS) rate at 10 years was 60.8% as compared with 11.8% for those progressing within the first 5 years. Hemoglobin (Hb) ≥ 12 g/dl (OR 2.74, p  = 0.001) and MGUS-like profile (OR 4.18, p  = 0.005) were the two baseline variables associated with long-term disease-free survival. Upon including depth of response (and MRD), Hb ≥ 12 g/dl (OR 2.27) and MGUS-like signature (OR 7.48) retained their predictive value along with MRD negativity (OR 5.18). This study shows that despite the use of novel agents, the probability of disease control at 5 years is still restricted to a small fraction (18.6%) of elderly MM patients. Since this endpoint is associated with higher rates of OS, this study provides important information about diagnostic and post-treatment biomarkers helpful in predicting the likelihood of disease control at 5 years.

Type of Medium: Online Resource

ISSN: 2044-5385

URL: Article

DOI: 10.1038/s41408-019-0176-x

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2019

detail.hit.zdb_id: 2600560-8

In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 1-2

Abstract: Background: Although great strides were made in the management of MM, our best chances to eradicate this malignancy may lie in preventing its progression.Most current models to predict risk of transformation in SMM are commonly established at diagnosis and not reevaluated over time, because some parameters such as tumor burden or genetic abnormalities require invasive bone marrow (BM) aspirates. It could be hypothesized that periodic monitoring of tumor biomarkers is needed to improve risk-stratification of SMM patients, and so would be new minimally-invasive methods that can replace those performed in BM samples. Such methods should also monitor immune profiles, to identify patients with stable tumor burden/genetics but at risk of progression due to lost immune surveillance. Aim: Determine the level of concordance between the tumor/immune landscape in BM vs peripheral blood (PB) of SMM patients, as well as to evaluate immune profiles together with circulating tumor cell (CTC) numbers and genetic alterations every 6 months in PB, as minimally-invasive methods for identification of SMM patients at risk of developing active MM. Methods: 300 patients are planned to be enrolled in the iMMunocell study that includes 24 sites across 8 European countries. PB samples are collected every 6 months during three years for next-generation flow (NGF) cytometry monitoring of CTCs and immune profiles. Additionally, CTCs and various immune cells are FACSorted to evaluate, every 6 months, their molecular profile in SMM patients with stable vs progressive disease. BM samples are taken at baseline and every 12 months according to patients' choice, in which the same methods described previously for PB are performed. An interim analysis was preplanned to the moment when 150 patients were enrolled. Results: A total of 170 SMM patients were enrolled and we report here data on the first 150. Thus far, 18/150 (12%) patients progressed to MM and according to 20/20/20 criteria, 1 had low, 7 intermediate and 10 had high risk SMM. Only 7/18 cases who progressed had & gt;20% BM plasma cells (PC) by morphology. CTCs were detectable in 107/150 (71%) patients at baseline (median of 0.001% [0% - 0.42%] and 0.03 [0 - 21] CTCs/µL of PB). There was no correlation (or only modestly-significant) between the percentage of CTCs and BMPC by morphology (r=0.156, p=0.065) or flow cytometry (r=0.293, p=0.02). Median CTC counts were 0.02, 0.03 and 0.11 in SMM patients with low, intermediate and high risk disease according to 20/20/20 criteria, respectively (p=0.002). Median CTC numbers were significantly different between cases with stable vs progressive disease (0.02 vs 0.11, p=0.005). As compared to those with ≤1 CTC/µL of PB, patients with & gt;1 CTC/uL showed significantly higher risk of transformation (8% vs 47%, p & lt;0.001) with a median time to progression of 6 months. In addition to the 150 PB samples analyzed at baseline, another 139 specimens were processed at 6, 12 and 18 months. The fluctuation in CTC numbers every 6 months was generally low (median, 0.03 CTCs/uL; IQR, 0.003 - 0.12), though in 10% of patient-samples the absolute variation was & gt;0.5 CTCs/uL. Data on the genetic landscape of CTCs analyzed every 6 months from baseline to disease progression will be shown at the meeting. Immune monitoring in patient-paired PB and BM samples at baseline (n=50) uncovered that 48 of 74 innate and adaptive immune cell types measured by multidimensional flow cytometry had similar distribution. Furthermore, we found significant differences in the distribution of three CD8 T cell subsets defined by differential expression of CD28, CD127, PD1, TIGIT, in PB of SMM patients with stable vs progressive disease. In patients with longitudinal PB samples from baseline until progression to active MM (n=7), there was a significant decrease in helper effector memory CXCR3+CCR4+ and cytotoxic CD127+TIGIT+PD1+ T cells, together with a significant increase in adaptive NK cells and Tγδ CD69+ T cells. Conclusions: This is the first study performing CTC and immune monitoring every 6 months in PB samples from patients with SMM. Our results show a significant correlation between CTC counts and stable vs progressive disease, and suggest that CTC kinetics could be complementary to the 20/20/20 criteria for real-time identification of individual SMM patients at risk of developing active MM. Beyond CTC numbers, this study is uncovering key immune cell types associated with disease progression. Disclosures Terpos: Amgen: Honoraria, Research Funding; Genesis: Honoraria, Other: travel expenses , Research Funding; Janssen: Honoraria, Other: travel expenses , Research Funding; Takeda: Honoraria, Other: travel expenses , Research Funding; Celgene: Honoraria; Medison: Honoraria. Raab:Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees, Research Funding; Heidelberg Pharma: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees. Ocio:Sanofi: Consultancy, Honoraria; Secura-Bio: Consultancy; Oncopeptides: Consultancy; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Speakers Bureau; Amgen: Consultancy, Honoraria; MDS: Honoraria; GSK: Consultancy; Takeda: Honoraria; Asofarma: Honoraria. Martinez-Lopez:Novartis: Consultancy; Janssen-cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Research Funding; Incyte: Consultancy, Research Funding; Janssen: Consultancy, Honoraria. de la Rubia:Amgen: Consultancy, Other: Expert Testimony; Celgene: Consultancy, Other: Expert Testimony; Janssen: Consultancy, Other: Expert Testimony; Ablynx/Sanofi: Consultancy, Other: Expert Testimony. Hajek:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pharma MAR: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Roche: Consultancy, Honoraria, Research Funding; Oncopeptides: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Ludwig:Celgene: Speakers Bureau; Janssen: Other: Advisory Boards, Speakers Bureau; Bristol Myers: Other: Advisory Boards, Speakers Bureau; Sanofi: Other: Advisory Boards, Speakers Bureau; Amgen: Other: Advisory Boards, Research Funding, Speakers Bureau; Takeda: Research Funding; Seattle Genetics: Other: Advisory Boards. Goldschmidt:Dietmar-Hopp-Foundation: Other: Grants and/or provision of Investigational Medicinal Product:; Chugai: Honoraria, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Incyte: Research Funding; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Molecular Partners: Research Funding; Johns Hopkins University: Other: Grants and/or provision of Investigational Medicinal Product; Mundipharma GmbH: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; University Hospital Heidelberg, Internal Medicine V and National Center for Tumor Diseases (NCT), Heidelberg, Germany: Current Employment; GlaxoSmithKline (GSK): Honoraria; Adaptive Biotechnology: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Grants and/or provision of Investigational Medicinal Product:, Research Funding; Merck Sharp and Dohme (MSD): Research Funding. Roccaro:European Hematology Association: Research Funding; AstraZeneca: Research Funding; Transcan2-ERANET: Research Funding; Italian Association for Cancer Research (AIRC): Research Funding; Janssen: Other; Celgene: Other; Amgen: Other. San-Miguel:Amgen, BMS, Celgene, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline and Karyopharm: Consultancy, Membership on an entity's Board of Directors or advisory committees. Paiva:SkylineDx: Consultancy; Takeda: Consultancy, Honoraria, Research Funding; Roche: Research Funding; Adaptive: Honoraria; Amgen: Honoraria; Janssen: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; Kite: Consultancy; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2020-136251

Language: English

Publisher: American Society of Hematology

Publication Date: 2020

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 3003-3003

Abstract: Abstract 3003 During the last years, several novel drugs combinations have changed the outcome of Multiple Myeloma (MM) patients; nevertheless, relapse is still the rule for most of these patients, and, therefore, other drugs with novel mechanisms of action are required. The current research in this topic is usually based on the addition of novel drugs to standard of care combinations in order to try to increase their efficacy. Bortezomib + steroids has turned out to be one of these standards, both for induction therapy before high dose melphalan and also for non-trasplant candidates. Zalypsis is a novel marine compound with remarkable preclinical activity in MM, which is currently being explored in a phase I/II trial. We explored the preclinical efficacy of the triple combination of zalypsis, bortezomib and dexamethasone in different models and investigated its mechanism of action. This combination showed high potency when compared to the respective single agents and double combinations, and, in fact, the analysis by the Calcusyn software, evidenced combination indexes in the highly synergistic range (CI 0.2–0.6). This effect was observed not only in the MM1S cell line, but also in freshly isolated cells from MM patients and, most importantly, in a subcutaneous xenograft of a human plasmocytoma in SCID mice. In this last model, we used suboptimal doses of bortezomib and dexamethasone (0.1 mg/Kg and 1 mg/Kg respectively ip, 5 days per week indefinitely) combined with an active dose of zalypsis (0,75 mg/Kg iv weekly for three total doses). Probably due to the low doses used, the double combination of bortezomib + dexamethasone did not show much effect as compared to the control group, and neither bortezomib nor dexamethasone alone could significantly improve the efficacy of Zalypsis. Nevertheless, when the three drugs were combined together, the tumor volume drastically shrunk with differences highly statistically significant (p 〈 0.001) (Figure 1). These results also translated into an improvement in survival for those mice treated with the triple combination. Median survival (range) of 102 days (85-118) for the triple vs 72 days (61-82) for the best double (Zalypsis + Dexamethasone) (Log Rank 〈 0.001) (Figure 2). Regarding toxicity, a moderate body weight loss was observed in all mice receiving combinations that included Zalypsis, which completely recovered after stopping treatment with this drug. Two early deaths (out of 10 mice) were also observed in the group of mice assigned to the triple combination group. These results impelled us to investigate the mechanisms relying under the synergy observed. The triple combination induced caspase dependent apoptosis, demonstrated by Annexin V induction and cleavage of caspases 3, 7, 8, 9 and also PARP. By contrast, the activity on the cell cycle was not evident for this combination, indicating a preferential apoptotic effect and not a substantial antiproliferative one. Of note, two mechanisms seem to be specifically associated to the combination of the three agents: 1. A significant release of Endonuclease-G and Cytochrome-C from the mitochondria into the cytosol was observed, suggesting a role for the intrinsic pathway of apoptosis; and 2. One of the most significant changes induced by the combination was an increase in the levels of AIF (apoptosis inducing factor) in the cytosol and nucleus, which is probably indicating the involvement of caspase independent mechanisms. In line with these results, pretreatment with ZVAD was only able to partially rescue from apoptosis, also indicating the potential activation of a dual mechanism: dependent and independent of caspases. Finally, we had previously shown that Zalypsis acts, at least partially, through the induction of DNA damage, based on a p53 dependent mechanism. In this study, the addition of bortezomib and dexamethasone, further increased the H2AX phosphorylation induced by Zalypsis, suggesting a potentiation of the DNA damaging effect; and the combination was also associated with a clear increase in the levels of p53 protein by WB as compared with the agents in monotherapy. The study of the mechanism of action is currently being completed and final results will be presented at the meeting. In summary, the combination of zalypsis + bortezomib + dexamethasone shows high synergy in MM through the activation of different pathways, and these results provide the rationale for its use in relapsed/refractory MM patients. Disclosures: Cuevas: Pharmamar: Employment. Avilés:Pharmamar: Employment. Pandiella:Pharmamar: Research Funding. San Miguel:Pharmamar: Research Funding; Millenium: Consultancy, Research Funding.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.3003.3003

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 8 ( 2014-08-21), p. 1300-1303

Abstract: MFC is a valuable biomarker to discriminate “true” SBP patients from those with “occult” BM clonal PCs and high-risk of progression to MM.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2014-04-567909

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 108, No. 11 ( 2006-11-16), p. 1989-1989

Abstract: Proteasome inhibition represents a promising novel anticancer therapy, and Bortezomib is a highly selective reversible inhibitor of the 26S subunit of the proteasome complex. Acute Myeloid Leukemia (AML) is a heterogeneous group of diseases in which coexistence of leukemic cells at different stages of differentiation is frequently found, and CD34, a marker of immaturity, has been associated with drug resistance and poorer outcome. In order to explore the activity of Bortezomib in AML, we have evaluated its effectiveness against freshly isolated cells from 27 newly diagnosed AML patients (excluding APL). Mononuclear cells (MNC) were isolated from fresh bone marrow samples by Ficoll-Hipaque density sedimentation. The percentage of blasts after purification was 88±9% (Mean±SD). In order to assess the effective dose of Bortezomib in AML, four cell lines (HL-60, KG-1, HEL y MV4-11) were treated for 24h with increasing doses of Bortezomib. IC50 was 50nM (Range 10nM to 100nM). Based on these results, patients’ samples were treated with Bortezomib for 18 hours. Doxorubicin 1μM was also used for treatment in order to compare with Bortezomib activity in 23 paired samples. Using quadruple staining (Annexin V/CD33/CD34/CD45), the number of apoptotic cells was measured by multiparametric flow cytometry. At least 50.000 events were acquired in a FACScalibur cytometer (BDB). Annexin V+ (AV+) events were quantified over total cellularity, as well as in CD34+, CD34− blast cell fractions and normal residual lymphocytes. The percentage of apoptotic events was corrected according to the proportion of apoptotic cells in the control tube (absence of drug). The proportion of AV+ cells in the total blast cell population was 55±27%. CD34+ and CD34− blast cells populations were separately analyzed (only one leukemic cell population CD34+, or CD34− were detected in 7 and 13 cases, respectively; while in the remaining 6 cases both populations existed). Interestingly, Bortezomib showed similar activity on CD34+ (52±26%, n=13) and CD34− (55±26%, n=19) blast cell populations (p=0.68). Moreover, in the 6 cases in which CD34+ and CD34− leukemic cells coexisted, no difference was detected on the proportion of AV+ events after Bortezomib treatment in both cellular subsets (42±26% and 48±16% respectively, p=NS). In addition, the proportion of AV+ cells within the normal residual lymphocytes with bortezomid was significantly lower (20±12%) when compared with blast cells (p 〈 0.01). Bortezomib was more effective for total blast cells compared to doxorubicin (56±32% vs 40±26%, respectively; p=0.009). Interestingly, when CD34+ and CD34− blast cell populations were separately analyzed, differences were only significant for the CD34+ populations (n=13) (52±26% vs 32±28% AV + cells for Bortezomib and doxorubicin, respectively; p=0.009), with no differences in either CD34− populations or normal residual lymphocytes. In summary, our results show a high antitumour activity of Bortezomib in AML blast cells, with similar efficacy against the more immature CD34+ and more mature CD34− leukemic cell subsets, while the toxicity against residual lymphocytes is significantly lower. These results support a therapeutic role for Bortezomib in adult Acute Myeloid Leukemia.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V108.11.1989.1989

Language: English

Publisher: American Society of Hematology

Publication Date: 2006

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 3170-3170

Abstract: Background: Since survival in AL mainly depends on the extent of organ involvement of patients at presentation, early diagnosis and risk stratification are key to improve patients' outcome. Therefore, together with surrogates of organ involvement, biomarkers identifying patients with MGUS or MM at greater risk of developing AL would be highly valuable to prevent organ damage, to maximize therapeutic efficacy and to improve outcomes in AL. Aim: To investigate the value of multidimensional flow cytometry (MFC) for simultaneous fast diagnostic screening of plasma cell (PC) clonality and risk stratification, as well as to identify immunophenotypic markers useful for the selection of patients with monoclonal gammopathies candidates for monitoring of pre-symptomatic organ damage related to AL. Methods: We used MFC to characterize a large series of patients with newly-diagnosed (ND) AL (N=94) vs MGUS (N=20) and NDMM (N=52), as well as age-matched healthy adults (HA, N=30). For each patient with AL, automated risk stratification was performed using principal component analysis (PCA) based on the relative frequency of bone marrow (BM) PCs, plus the percentage of clonal and normal PCs within the whole BM PC compartment, vs a database containing information on the same three parameters from a total of 1,774 patients, including 497 MGUS and 1,227 NDMM. In parallel, immunophenotypic protein expression profiles (iPEP) of AL patients were clustered using t-SNE, and the comparison between the iPEP of clonal PCs from patients with AL vs MGUS and MM cases was performed using canonical-correlation analysis (CCA). To identify additional immunophenotypic hallmarks of AL, the BM cellular composition in HA, MGUS, AL and MM patients was compared using 2-dimensional minimum spanning tree (MST) force-directed classification to determine the distance among individual cases. Results: PC clonality was detected by MFC in 93/94 (99%) AL patients, whereas an M-component was detectable in 96% of cases by electrophoresis, immunofixation and sFLC. PCA as defined above, identified AL patients displaying an MM-like (n=6) and an MGUS-like (n=38) signature, as well as 49 cases with an intermediate signature between the MGUS and MM reference datasets. Multivariate analysis of baseline prognostic factors for survival, including patients' age, number of organs involved, Mayo staging, the percentage of BM PCs based on cytomorphology and eligibility for ASCT, showed that having an intermediate- or an MM-like profile had an independent adverse effect on patients' progression-free (PFS) and overall survival (OS) (HR:3.4; P≤.02). t-SNE based on the iPEP of clonal PCs revealed two major clusters of AL patients with significantly different PFS, defined by opposite patterns of expression for CD45, CD56 and CD138 (P≤.02). CCA of tumor iPEP showed partial overlap between AL vs MGUS and MM, with progressively higher percentages of cases with a CD38lo, CD45-ve, CD81-ve and CD138lo iPEP being observed from MGUS to AL and MM. In contrast, AL patients displayed significantly lower reactivity for CD56 (P≤ .03). Further characterization of the BM cellular composition allowed the systematic assessment of 16 cell populations and 18 phenotypic parameters that, by MST, mapped AL in between MGUS and MM. Of note, while AL patients displayed a predominantly-clonal PC compartment in the absence of an MM-like tumor PC expansion, the percentage of B-cell precursors was consistently lower in AL patients than in HA, MGUS and MM (P=.004). Thus, using optimal cut-off values to discriminate between AL vs MGUS and MM, we built a scoring model based on the presence of 〈 100% CD56+ve clonal PCs, 〈 0.1% B-cell precursors, 〉 80% clonal PCs within total BM PCs and 〈 2% BM PCs. Overall, a significant (P 〈 .001) association was found between a progressively higher score and the diagnosis of AL, with a 74% accurate classification based on ROC analysis (AUC of 0.74; 95% CI = 0.66 - 0.82; P 〈 .001) of the performance of the scoring model. Conclusions: We demonstrate the value of MFC for fast diagnostic screening of PC clonality in AL and simultaneous automated patient risk-stratification, based on the BM tumor burden and PC phenotype. In addition, our results also provide new immunophenotypic markers for the identification of patients with monoclonal gammopathies that are candidates for monitoring of pre-symptomatic organ damage related to AL. Disclosures Puig: Janssen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding. Ocio:Array Pharmaceuticals: Research Funding; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Pharmamar: Consultancy; BMS: Consultancy; AbbVie: Consultancy; Janssen: Consultancy, Honoraria; Seattle Genetics: Consultancy; Mundipharma: Research Funding; Takeda: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Oriol:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. De La Rubia:Ablynx: Consultancy, Other: Member of Advisory Board. Martinez Lopez:Janssen: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau. Mateos:Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lahuerta:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-119281

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Leukemia, Springer Science and Business Media LLC, Vol. 32, No. 11 ( 2018-11), p. 2427-2434

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-018-0072-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2018

detail.hit.zdb_id: 2008023-2

In: Leukemia, Springer Science and Business Media LLC, Vol. 35, No. 1 ( 2021-01), p. 245-249

Type of Medium: Online Resource

ISSN: 0887-6924 , 1476-5551

URL: Article

DOI: 10.1038/s41375-020-0800-6

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2008023-2

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 245-245

Abstract: Background and Aims: Although recent therapeutic advances have led to an improvement in the outcome of Multiple Myeloma (MM), it still remains an incurable disease, and therefore, new drugs with novel mechanisms of action are needed for myeloma patients. Zalypsis is a new synthetic alkaloid derived from certain marine compounds which has demonstrated significant in vitro and in vivo antitumor activity in different malignancies. It is currently under late Phase I development in solid tumours, with preliminary evidence of activity. In this study, we have analysed the preclinical activity and mechanism of action of Zalypsis in MM. Material and methods: Nine different MM cell lines and BM samples from MM patients and normal donors were used in the study. The mechanism of action was investigated by MTT, Annexin V, cell cycle analysis, Western-blotting and gene expression profile analysis. The in vivo activity was explored in a human subcutaneous plasmocytoma model and immunohistochemistry was performed in selected tumours. Results: Zalypsis turned out to be the most potent antimyeloma agent we have tested so far in our laboratory, with IC50s in picomolar or low nanomolar ranges depending on the cell lines studied. Interestingly, the sensitivity to Zalypsis was independent of the pattern of resistance of the cell lines to conventional antimyeloma agents such as Dexamethasone or Melphalan. It also showed remarkable ex vivo potency in freshly isolated plasma cells from six patients (including two with plasma cell leukemia) and synergized with many other antimyeloma compounds, being the combination of Zalypsis + Lenalidomide + Dexamethasone particularly attractive. Regarding toxicity, Zalypsis preserved the CD34+ hematopoietic progenitor cells from MM and normal donor BM samples. This remarkable activity prompted us to investigate the mechanism of action of the drug. Besides the induction of apoptosis and cell cycle arrest, Zalypsis provoked DNA double strand breaks, which were evidenced by an increase in phospho Histone H2AX and phospho CHK2, followed by a striking overexpression of p53 in MM cell lines bearing wild type forms of this protein. Of note, no other compound currently used in the MM clinic induced such an increase in p53 protein levels. In addition, in a subset of MM cell lines in which p53 was mutated, Zalypsis also provoked DNA double strand breaks and induced cell death, although higher concentrations were required. Changes in the gene expression profile of MM cells treated with Zalypsis were concordant with these results, since important genes involved in DNA damage response were deregulated. This include genes implicated in the ATM repair pathway, such as TLK2, ATR, CHEK2, RAD5 and BRIP1 and other mRNAs related to DNA repair, such as RAD23B, XPC, XRCC1, XRCC5 and GADD45A. These results were confirmed in vivo in a model of human subcutaneous plasmocytoma in SCID mice. Zalypsis (0.8 and 1 mg/Kg) decreased tumour growth and improved survival of mice implanted with MM1S (wild type p53) and OPM-1 (mutated p53) plasmocytomas. Immunohistochemical studies in tumours from treated animals also demonstrated DNA damage with H2AX phosphorylation and p53 overexpression. Conclusion: The potent in vitro and in vivo antimyeloma activity and the singular mechanism of action of Zalypsis uncovers the high sensitivity of tumour plasma cells to double strand breaks, and strongly supports the potential use of this compound in multiple myeloma patients.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.245.245

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 132, No. Supplement 1 ( 2018-11-29), p. 4503-4503

Abstract: Introduction: Disease control at five years would be a desirable endpoint for elderly multiple myeloma (MM) patients; however, the percentage of cases reaching this objective as well as the biomarkers to predict it, are not well defined. Objective and design: In order to gain further insight about long-term disease control ( 〉 5 years progression-free) in elderly MM we have analyzed a homogeneous population of 435 newly-diagnosed transplant-ineligible (TNE) patients enrolled in two consecutive Spanish clinical trials (GEM2005MAS65, GEM2010MAS65), that included both proteasome inhibitors and immunomodulatory drugs. Results: Amongst the 435 patients included in this post-hoc study, only 18.8% remained alive and progression-free after five years of initiating treatment. Noteworthy, in these patients the overall survival (OS) rate at 10-years was 69.4%, as compared to 11.4% for those patients progressing during the first five years (p 〈 0.001). Baseline variables significantly associated with long-term progression free survival in the univariate analysis were younger age, ISS 1, R-ISS 1, hemoglobin ≥ 12g/dl, normal LDH, and standard-risk cytogenetic abnormalities and the presence of a monoclonal gammopathy of unknown significance (MGUS)-like immunophenotypic profile in the bone marrow. Complete responses (CR) and minimal residual disease (MRD) negativity were also associated with long-term progression free survival. In the multivariate analysis, an hemoglobin level ≥12g/dl (OR 2.61; 95% CI 1.47 - 4.61, p=0.001) and a MGUS-like immunophenotypic profile in the bone marrow (OR 3.33; 95% CI 1.30 - 8.54, p=0.002) were the two baseline variables significantly and independently associated with a higher probability of long-term disease-free survival. When the depth of response (including MRD) was included in the logistic regression model, Hb level ≥12g/dl (OR 2.18; p=0.010) and the MGUS-like signature (OR 4.99, p 〈 0.001) retained their independent predictive value along with the achievement of MRD-negativity (OR 4.09, p 〈 0.001). Focusing on the 24 patients with an MGUS-like signature (based on the automated immunophenotyping analysis of the relative frequency of BM plasma cells (PCs) plus the percentage of clonal and normal PCs within the whole BM PC compartment), 50% percent of these patients displayed a long-term disease-free survival, as compared to only 17.5% of the remaining MM patients. The median OS for patients with MGUS-like signature was 90.2 months as compared to 62.6 for the MM-like patients. Most MGUS-like patients (90.5%) achieved a favorable response (10 complete response (CR) and 9 very good partial response (VGPR)). No differences in outcome were observed between VGPR and CR cases (p-value for OS 0.87) among MGUS-like patients. Conclusions: This study revealed that despite the usage of former novel agents, the probability of disease control at five years is still restricted to a small fraction (18.8%) of transplant-ineligible patients that achieve remarkable rates of long-term OS. Here, we identify that the combination of three biomarkers (normal Hb, MGUS-Like signature and MRD negativity) can help todefine elderly MM patients achieving long-term disease control. Our results highlight the presence of an MGUS-like signature in the bone marrow at diagnoses as the most powerful predictor for long-term disease free survival, and could be incorporated in clinical practice in order toimprove the prognostic information given to our patients. Disclosures Rodriguez Otero: Clínica Universidad de Navarra: Employment; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy; Bristol Myers Squibb: Research Funding. Mateos:Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Martinez Lopez:Janssen: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Novartis: Research Funding, Speakers Bureau; Bristol Myers Squibb: Research Funding, Speakers Bureau. Ocio:Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; AbbVie: Consultancy; Pharmamar: Consultancy; Seattle Genetics: Consultancy; BMS: Consultancy; Novartis: Consultancy, Honoraria; Sanofi: Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Mundipharma: Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Array Pharmaceuticals: Research Funding. Puig:Takeda: Consultancy, Honoraria; Celgene: Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding. Oriol:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Bladé:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Lahuerta:Celgene: Honoraria; Amgen: Honoraria; Janssen: Honoraria. San-Miguel:Janssen: Honoraria; Celgene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Novartis: Honoraria; Sanofi: Honoraria; Roche: Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood-2018-99-117431

Language: English

Publisher: American Society of Hematology

Publication Date: 2018

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detail.hit.zdb_id: 80069-7