Teresa Paíno

• University of Salamanca

Introduction: GEM Bela-VRd (NCT04802356) is a multicenter, open label clinical trial evaluating the addition of belantamab mafodotin (belamaf), a BCMA-targeting monoclonal antibody-drug conjugate, to the standard VRd regimen (bortezomib, lenalidomide, dexamethasone) for newly diagnosed transplant-eligible multiple myeloma (NDTE MM) patients. Initia...

Immunopeptidomics is the area of knowledge focused on the study of peptides assembled in the major histocompatibility complex (MHC), or human leukocyte antigen (HLA) in humans, which could activate the immune response via specific and selective T cell recognition. Advances in high-sensitivity mass spectrometry have enabled the detailed identificati...

Multiple myeloma is a malignancy characterized by the accumulation of malignant plasma cells in bone marrow and the production of monoclonal immunoglobulin. A hallmark of cancer is the evasion of immune surveillance. Histone deacetylase inhibitors have been shown to promote the expression of silenced molecules and hold potential to increase the ant...

Multiple myeloma (MM) is a blood malignancy having its origin in differentiated B cells.1 The overall survival of MM patients has clearly improved with the use of autologous stem cell transplantation and the more recent introduction of novel therapeutic strategies. However, for the majority of patients, the disease will eventually relapse even afte...

Immunosuppression is a common feature of multiple myeloma (MM) patients and has been associated with disease evolution from its precursor stages. MM cells promote immunosuppressive effects due to both the secretion of soluble factors, which inhibit the function of immune effector cells, and the recruitment of immunosuppressive populations. Alterati...

BH3-mimetics targeting anti-apoptotic proteins such as MCL-1 (S63845) or BCL-2 (venetoclax) are currently being evaluated as effective therapies for the treatment of multiple myeloma (MM). Interleukin 6, produced by mesenchymal stromal cells (MSCs), has been shown to modify the expression of anti-apoptotic proteins and their interaction with the pr...

PD1 expression in CD4+ and CD8+ T cells is increased after treatment in multiple myeloma patients with persistent disease. The GEM-Pembresid trial analyzed the efficacy and safety of pembrolizumab as consolidation in patients achieving at least very good partial response but with persistent measurable disease after first- or second-line treatment....

Background: Proviral Insertion site for Moloney murine leukemia virus (PIM) kinases are overexpressed in hematologic malignancies, including multiple myeloma. Previous preclinical data from our group demonstrated the anti-myeloma effect of the pan-PIM kinase inhibitor PIM447. Methods: Based on those data, we evaluate here, by in vitro and in viv...

A high priority problem in multiple myeloma (MM) management is the development of resistance to administered therapies, with most myeloma patients facing successively shorter periods of response and relapse. Herewith, we review the current knowledge on the mechanisms of resistance to the standard backbones in MM treatment: proteasome inhibitors (PI...

Background: Venetoclax is a BCL-2 inhibitor particularly effective in patients with multiple myeloma (MM) harboring the t(11;14). However, resistance to venetoclax has been linked to MCL-1 overexpression. On the other hand, it is wellknown that MM cells depend on MCL-1 rather than BCL-2 for survival, and this dependence has recently been reported t...

Kinesin spindle protein inhibition is known to be an effective therapeutic approach in several malignancies. Filanesib (ARRY-520), an inhibitor if this proteins, has demonstrated activity in heavily pretreated multiple myeloma patients. The aim of this work was to investigate the activity of filanesib in combination with pomalidomide plus dexametha...

Purpose: The search for new drugs that control the continuous relapses of multiple myeloma is still required. Here, we report for the first time the potent antimyeloma activity of amiloride, an old potassium-sparing diuretic approved for the treatment of hypertension and edema due to heart failure. Experimental Design: Myeloma cell lines and primar...

Background Despite recent advances in the treatment of multiple myeloma (MM), the prognosis of most patients remains poor, and resistance to traditional and new drugs frequently occurs. EDO-S101 is a novel therapeutic agent conceived as the fusion of a histone deacetylase inhibitor radical to bendamustine, with the aim of potentiating its alkylatin...

Despite new advances in multiple myeloma treatment and the consequent improvement in overall survival, most patients relapse or become refractory to treatment. This suggests a need for new molecules and combinations that may further inhibit important survival pathways for these tumour cells. In this context, zalypsis is a novel compound derived fro...

Purpose: PIM kinases are a family of serine/threonine kinases recently proposed as therapeutic targets in oncology. In the present work, we have investigated the effects of the novel pan-PIM kinase inhibitor, PIM447, on myeloma cells and myeloma-associated bone disease using different preclinical models. Experimental Design: In vitro/ex vivo cytoto...

Introduction: Filanesib (ARRY-520) is a highly selective inhibitor of kinesin spindle protein (KSP), a microtubule motor protein active in proliferating cells, which plays an essential role in assembly and maintaining of the bipolar spindle. In cells arrested by KSP inhibition, Mcl-1 is rapidly depleted resulting in cell death, and consequently cel...

Introduction: Filanesib (ARRY-520) is a novel inhibitor of the "kinesin spindle protein" (KSP), which has demonstrated efficacy in heavily pretreated patients with refractory MM, (Lonial et al, ASH 2013). Our preliminary studies demonstrated synergy with standard anti-MM agents, especially with pomalidomide and dexamethasone. This set the stage for...

Background and objectives. PIM kinases (PIM1, PIM2, PIM3) are proteins known to be overexpressed in several hematological malignancies. In particular, in chronic lymphocytic leukemia (CLL) they are involved in cell survival, resistance to apoptosis (especially PIM2 and PIM3) and interactions with the microenvironment (PIM1). The aim of this study w...

Introduction. EDO-S101 is a hybrid molecule of bendamustine plus vorinostat, new in its class. Our group has previously demonstrated that EDO-S101 is effective in vitro in MM cell lines independently of p53 state, and also in a murine plasmacytoma model where it decreases tumor growth and prolongs survival with respect to bendamustine and/or vorino...

Background Alkylating histone deacetylase inhibitors (HDACi) enhance the anticancer efficacy of alkylators by increasing chromatin accessibility and also down regulating DNA repair. EDO-S101 is a first-in-class fusion molecule that combines DNA damaging effect of bendamustine with the pan-HDACi vorinostat. Objectives To study the bi-functional prop...

Introduction: Multiple myeloma (MM) is characterized by the presence of complex karyotypes and chromosome instability, suggesting that cell cycle checkpoints are defective. Filanesib (ARRY-520) is a highly selective, targeted inhibitor of kinesin spindle proteins (KSP), which are required to establish mitotic spindle bipolarity, driving centrosome...

Knowledge about clonal diversity and selection is critical to understand multiple myeloma (MM) pathogenesis, chemoresistance and progression. If targeted therapy becomes reality, identification and monitoring of intraclonal plasma-cell (PC) heterogeneity would become increasingly demanded. Here, we investigated the kinetics of intraclonal heterogen...

The development of resistance to therapy is unavoidable in the history of multiple myeloma (MM) patients. Therefore, the study of its characteristics and mechanisms is critical in the search for novel therapeutic approaches to overcome it. This effort is hampered by the absence of appropriate preclinical models, especially those mimicking acquired...

Despite recent advances in the treatment of multiple myeloma (MM), it remains an incurable disease potentially due to the presence of resistant myeloma cancer stem cells (MM-CSC). Although the presence of clonogenic cells in MM was described three decades ago, the phenotype of MM-CSC is still controversial, especially with respect to the expression...

The identification of subclones in multiple myeloma (MM) could have clinical implications since the complete eradication of all clones is required to prolong patients' survival. Hence, there is an unmet need to fully characterize such subclones. In the present study, we started by investigating using multidimensional (23-color) flow cytometry (MFC)...

The identification of subclones in multiple myeloma (MM) could have clinical implications since the complete eradication of all clones is required to prolong patients’ survival. Hence, there is an unmet need to fully characterize such subclones. In the present study, we started by investigating using multidimensional (23-color) flow cytometry (MFC)...

MRD monitoring is emerging as a powerful prognostic biomarker in MM. In addition to its utility to redefine the depth of response achieved after therapy, the MRD clone represents, from a biological point of view, a very small fraction of tumor cells that are truly chemoresistant, potentially quiescent (not producing M-protein), and able to recapitu...

Introduction Multiple myeloma (MM) is characterized by the accumulation of malignant plasma cells in the bone marrow (BM) and is closely associated with osteolytic lesions, in part due to an increase in the bone-resorptive activity and number of osteoclasts (OCs). The activation of survival pathways in myeloma cells could be the cause of treatment...

Circulating myeloma tumor cells (CTCs) as defined by the presence of peripheral blood (PB) clonal plasma cells (PCs) are a powerful prognostic marker in multiple myeloma (MM). However, the biological features of CTCs and their pathophysiological role in MM remains unexplored. Here, we investigate the phenotypic, cytogenetic, and functional characte...

We read with interest the letter by Van Hoef[1][1] about the article by Paino et al. [2][2] In that study, we were unable to identify a CD20+ population among 8 myeloma cell lines leading us to conclude that CD20 may not be a suitable antigen for the identification of myeloma cancer stem cells.[2][2

4014 Introduction Bone destruction, a hallmark of multiple myeloma (MM), arises as a consequence of the interactions between MM cells and the bone marrow microenvironment, which lead to an increase in the bone-resorptive activity and number of osteoclasts (OC) and a reduction of the bone-forming activity and differentiation of osteoblasts (OB). ML...

726 Circulating Tumor Cells (CTCs) are present in the vast majority of MM patients, but the biologic basis for the movement of CTCs from the bone marrow (BM) to the PB circulation is not clear. Are all BM myelomatous plasma cells (mPCs) capable to egress into PB, or only a specific sub-clone? Do CTCs have stem cell-like features and are enriched by...

Background. MicroRNAs have been demonstrated to be deregulated in multiple myeloma. We have previously reported the downregulation of miR-214 in myeloma compared to normal plasma cells. Design and Methods. The functional role of miR-214 in myeloma pathogenesis was explored by transfection of multiple myeloma cell lines with synthetic miRNAs followe...

Although new therapies have doubled the survival of multiple myeloma patients, this remains an incurable disease. It has been postulated that the so-called myeloma cancer stem cells would be responsible for tumor initiation and relapse but their unequivocal identification remains unclear. Here, we investigated in a panel of myeloma cell lines the p...

134 Introduction The introduction of novel agents has improved the outcome of MM patients, but MM is still considered an incurable disease and the emergence of resistance is the main responsible for this situation. The unraveling of the resistance mechanisms would help to design novel therapeutic strategies (combinations or sequencing treatments)...

Although the majority of patients with acute myeloid leukemia initially respond to conventional chemotherapy, relapse is still the leading cause of death, probably because of the presence of leukemic stem cells that are insensitive to current therapies. We investigated the antileukemic activity and mechanism of action of zalypsis, a novel alkaloid...

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 s...

4077 Several murine models resembling multiple myeloma have been developed in the last years: the subcutaneous plasmocytoma model and the disseminated model, based on the iv or intracardiac injection of MM cells, have been widely used to test the efficacy of novel agents. Nevertheless, it is well known the crucial role that the interaction between...

It is well known that the efficiency of Herpes simplex virus thymidine kinase gene/ganciclovir (HSV-tk/GCV) therapy is improved by the bystander effect, which mainly relies on gap junctional intercellular communication (GJIC). Malignant gliomas communicate poorly through gap junctions, consequently, agents with the ability to increase GJIC are good...

Several murine models resembling multiple myeloma have been developed in the last years: the subcutaneous plasmocytoma model and the disseminated model, based on the iv or intracardiac injection of MM cells, have been widely used to test the efficacy of novel agents. Nevertheless, it is well known the crucial role that the interaction between MM pl...

3792 Poster Board III-728 Background p53 mutation is the most frequent single genetic abnormality found in therapy related AML and is also quite frequent in de novo AML with an incidence between 10% and 25%; Moreover patients with p53 mutations characteristically present complex karyotypes and complicated chromosome rearrangements, leading to an a...

3834 Poster Board III-770 Introduction Multiple myeloma (MM), an hematological malignancy of terminally differentiated plasma cells, is characterized by the presence of bone disease, caused by increased osteoclast (OC) activity and differentiation as well as a reduction in osteoblast (OB) number and function. Dasatinib (BMS-354825) is an oral mult...

Our previous work has shown that tolbutamide increases gap junctional permeability in poorly coupled C6 glioma cells and that this effect is similar and additive to that found with dbcAMP, a well-known activator of gap junctional communication. Furthermore, the increase in gap junctional communication promoted by tolbutamide or dbcAMP is concurrent...