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Article: Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression.

Maiso, Patricia / Mogollón, Pedro / Ocio, Enrique M / Garayoa, Mercedes

2021 Volume 13, Issue 11

Abstract: Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma ... ...

Abstract	Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structural and functional abnormalities have been found when characterizing MSCs derived from myeloma patients (MM-MSCs) and comparing them to those from healthy donors (HD-MSCs). Other studies have identified differences in genomic, mRNA, microRNA, histone modification, and DNA methylation profiles. We discuss these distinctive features shaping MM-MSCs and propose a model for the transition from HD-MSCs to MM-MSCs as a consequence of the interaction with myeloma cells. Finally, we review the contribution of MM-MSCs to several aspects of myeloma pathology, specifically to myeloma growth and survival, drug resistance, dissemination and homing, myeloma bone disease, and the induction of a pro-inflammatory and immunosuppressive microenvironment.
Language	English
Publishing date	2021-05-22
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2527080-1
ISSN	2072-6694
ISSN	2072-6694
DOI	10.3390/cancers13112542
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Article ; Online: Phase 1b Study of Isatuximab in Combination With Bortezomib, Cyclophosphamide, and Dexamethasone in Newly Diagnosed, Transplant-ineligible Multiple Myeloma Patients.

Ocio, Enrique M / Bringhen, Sara / Martinez-Lopez, Joaquin / San-Miguel, Jesus / Oliva, Stefania / Rodriguez-Otero, Paula / Le Roux, Nadia / Dong, Yvonne / Doroumian, Severine / Macé, Sandrine / Mateos, Maria-Victoria

HemaSphere

2023 Volume 7, Issue 2, Page(s) e829

Language	English
Publishing date	2023-01-31
Publishing country	United States
Document type	Journal Article
ISSN	2572-9241
ISSN (online)	2572-9241
DOI	10.1097/HS9.0000000000000829
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Article ; Online: Aggressive primary cutaneous CD30+ lymphoproliferative disorder in an organ transplant recipient in sustained complete remission with brentuximab vedotin.

Cañueto, Javier / Ocio, Enrique M / Román-Curto, Concepción

International journal of dermatology

2018 Volume 57, Issue 12, Page(s) e153–e155

MeSH term(s)	Adolescent ; Adult ; Aged ; Aged, 80 and over ; Female ; Humans ; Immunoconjugates/therapeutic use ; Immunologic Factors/therapeutic use ; Immunosuppression/adverse effects ; Kidney Transplantation ; Lymphoma, Large-Cell, Anaplastic/drug therapy ; Lymphoma, Large-Cell, Anaplastic/etiology ; Lymphoma, Large-Cell, Anaplastic/pathology ; Male ; Middle Aged ; Remission Induction ; Transplant Recipients ; Young Adult
Chemical Substances	Immunoconjugates ; Immunologic Factors ; brentuximab vedotin (7XL5ISS668)
Language	English
Publishing date	2018-09-07
Publishing country	England
Document type	Case Reports ; Letter
ZDB-ID	412254-9
ISSN	1365-4632 ; 0011-9059 ; 1461-1244
ISSN (online)	1365-4632
ISSN	0011-9059 ; 1461-1244
DOI	10.1111/ijd.14214
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Article ; Online: Tinostamustine (EDO-S101), an Alkylating Deacetylase Inhibitor, Enhances the Efficacy of Daratumumab in Multiple Myeloma by Upregulation of CD38 and NKG2D Ligands.

Díaz-Tejedor, Andrea / Rodríguez-Ubreva, Javier / Ciudad, Laura / Lorenzo-Mohamed, Mauro / González-Rodríguez, Marta / Castellanos, Bárbara / Sotolongo-Ravelo, Janet / San-Segundo, Laura / Corchete, Luis A / González-Méndez, Lorena / Martín-Sánchez, Montserrat / Mateos, María-Victoria / Ocio, Enrique M / Garayoa, Mercedes / Paíno, Teresa

International journal of molecular sciences

2024 Volume 25, Issue 9

Abstract: 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 ... ...

Abstract	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 anti-MM efficacy of immunotherapy. The aim of the present work was to assess the potential effect of tinostamustine (EDO-S101), a first-in-class alkylating deacetylase inhibitor, in combination with daratumumab, an anti-CD38 monoclonal antibody (mAb), through different preclinical studies. Tinostamustine increases CD38 expression in myeloma cell lines, an effect that occurs in parallel with an increment in CD38 histone H3 acetylation levels. Also, the expression of MICA and MICB, ligands for the NK cell activating receptor NKG2D, augments after tinostamustine treatment in myeloma cell lines and primary myeloma cells. Pretreatment of myeloma cell lines with tinostamustine increased the sensitivity of these cells to daratumumab through its different cytotoxic mechanisms, and the combination of these two drugs showed a higher anti-myeloma effect than individual treatments in ex vivo cultures of myeloma patients' samples. In vivo data confirmed that tinostamustine pretreatment followed by daratumumab administration significantly delayed tumor growth and improved the survival of mice compared to individual treatments. In summary, our results suggest that tinostamustine could be a potential candidate to improve the efficacy of anti-CD38 mAbs.
MeSH term(s)	Multiple Myeloma/drug therapy ; Multiple Myeloma/metabolism ; Multiple Myeloma/pathology ; Humans ; ADP-ribosyl Cyclase 1/metabolism ; ADP-ribosyl Cyclase 1/antagonists & inhibitors ; Animals ; Antibodies, Monoclonal/pharmacology ; Mice ; Cell Line, Tumor ; NK Cell Lectin-Like Receptor Subfamily K/metabolism ; Xenograft Model Antitumor Assays ; Histone Deacetylase Inhibitors/pharmacology ; Histone Deacetylase Inhibitors/therapeutic use ; Membrane Glycoproteins/metabolism ; Drug Synergism ; Histocompatibility Antigens Class I/metabolism ; Histocompatibility Antigens Class I/genetics ; Up-Regulation/drug effects
Chemical Substances	daratumumab (4Z63YK6E0E) ; ADP-ribosyl Cyclase 1 (EC 3.2.2.6) ; Antibodies, Monoclonal ; NK Cell Lectin-Like Receptor Subfamily K ; Histone Deacetylase Inhibitors ; CD38 protein, human (EC 3.2.2.5) ; Membrane Glycoproteins ; KLRK1 protein, human ; Histocompatibility Antigens Class I ; MICB antigen ; MHC class I-related chain A
Language	English
Publishing date	2024-04-26
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms25094718
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Article ; Online: Filanesib for the treatment of multiple myeloma.

Algarín, Esperanza Macarena / Hernández-García, Susana / Garayoa, Mercedes / Ocio, Enrique M

Expert opinion on investigational drugs

2019 Volume 29, Issue 1, Page(s) 5–14

Abstract: ... ...

Abstract	Introduction
MeSH term(s)	Animals ; Antimitotic Agents/administration & dosage ; Antimitotic Agents/pharmacology ; Antineoplastic Combined Chemotherapy Protocols ; Biomarkers, Tumor/metabolism ; Drug Development ; Humans ; Kinesin/antagonists & inhibitors ; Multiple Myeloma/drug therapy ; Multiple Myeloma/pathology ; Thiadiazoles/administration & dosage ; Thiadiazoles/pharmacology
Chemical Substances	Antimitotic Agents ; Biomarkers, Tumor ; KIF11 protein, human ; Thiadiazoles ; filanesib (8A49OSO368) ; Kinesin (EC 3.6.4.4)
Language	English
Publishing date	2019-12-12
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	1182884-5
ISSN	1744-7658 ; 0967-8298 ; 1354-3784
ISSN (online)	1744-7658
ISSN	0967-8298 ; 1354-3784
DOI	10.1080/13543784.2020.1703179
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Article ; Online: ANCHOR: melflufen plus dexamethasone and daratumumab or bortezomib in relapsed/refractory multiple myeloma: final results of a phase I/IIa study.

Ocio, Enrique M / Efebera, Yvonne A / Hájek, Roman / Straub, Jan / Maisnar, Vladimir / Eveillard, Jean-Richard / Karlin, Lionel / Mateos, María-Victoria / Oriol, Albert / Ribrag, Vincent / Richardson, Paul G / Norin, Stefan / Obermüller, Jakob / Bakker, Nicolaas A / Pour, Luděk

Haematologica

2024 Volume 109, Issue 3, Page(s) 867–876

Abstract: Melphalan flufenamide (melflufen), a first-in-class, alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 ...

Abstract	Melphalan flufenamide (melflufen), a first-in-class, alkylating peptide-drug conjugate, demonstrated clinical benefit in combination with dexamethasone in triple-class refractory multiple myeloma (MM). The phase I/IIa ANCHOR study evaluated melflufen (30 or 40 mg) and dexamethasone (40 mg with daratumumab; 20 mg followed by 40 mg with bortezomib; dose reduced if aged ≥75 years) in triplet combination with daratumumab (16 mg/kg; daratumumab arm) or bortezomib (1.3 mg/m2; bortezomib arm) in patients with relapsed/refractory MM refractory to an immunomodulatory agent and/or a proteasome inhibitor and who had received one to four prior lines of therapy. Primary objectives were to determine the optimal dose of melflufen in triplet combination (phase I) and overall response rate (phase IIa). In total, 33 patients were treated in the daratumumab arm and 23 patients received therapy in the bortezomib arm. No dose-limiting toxicities were reported at either melflufen dose level with either combination. With both triplet regimens, the most common grade ≥3 treatment-emergent adverse events were thrombocytopenia and neutropenia; thrombocytopenia was the most common treatment-emergent adverse event leading to treatment discontinuation. In the daratumumab arm, patients receiving melflufen 30 mg remained on treatment longer than those receiving the 40-mg dose. In the daratumumab arm, the overall response rate was 73% and median progression-free survival was 12.9 months. Notably, in the bortezomib arm, the overall response rate was 78% and median progression-free survival was 14.7 months. Considering the totality of the data, melflufen 30 mg was established as the recommended dose for use with dexamethasone and daratumumab or bortezomib for future studies in relapsed/refractory MM.
MeSH term(s)	Humans ; Antibodies, Monoclonal ; Bortezomib/therapeutic use ; Dexamethasone/therapeutic use ; Melphalan/analogs & derivatives ; Multiple Myeloma/diagnosis ; Multiple Myeloma/drug therapy ; Neoplasms, Plasma Cell ; Neutropenia/chemically induced ; Phenylalanine/analogs & derivatives ; Thrombocytopenia ; Aged ; Antineoplastic Combined Chemotherapy Protocols/adverse effects
Chemical Substances	Antibodies, Monoclonal ; Bortezomib (69G8BD63PP) ; daratumumab (4Z63YK6E0E) ; Dexamethasone (7S5I7G3JQL) ; melflufen (3412470A0V) ; Melphalan (Q41OR9510P) ; Phenylalanine (47E5O17Y3R)
Language	English
Publishing date	2024-03-01
Publishing country	Italy
Document type	Clinical Trial, Phase I ; Clinical Trial, Phase II ; Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.283490
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Article ; Online: Melflufen for the treatment of multiple myeloma.

Ocio, Enrique M / Nadeem, Omar / Schjesvold, Fredrik / Gay, Francesca / Touzeau, Cyrille / Dimopoulos, Meletios A / Richardson, Paul G / Mateos, Maria-Victoria

Expert review of clinical pharmacology

2022 Volume 15, Issue 4, Page(s) 371–382

Abstract: Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that takes advantage of increased aminopeptidase activity inside tumor cells to rapidly release alkylating agents therein. Melflufen in combination with ... ...

Abstract	Introduction: Melphalan flufenamide (melflufen) is a first-in-class peptide-drug conjugate that takes advantage of increased aminopeptidase activity inside tumor cells to rapidly release alkylating agents therein. Melflufen in combination with dexamethasone has been evaluated in multiple clinical trials in patients with relapsed/refractory multiple myeloma (MM). Areas covered: This profile covers the unique mechanism of action of melflufen, the preclinical results supporting its activity in cellular models of resistance to chemotherapy, its activity in animal models of MM, and the clinical pharmacokinetics of melflufen. Findings from clinical trials evaluating melflufen, including the pivotal phase II HORIZON study and the phase III OCEAN study, are discussed. Expert opinion: Although MM treatment has improved, patients with disease refractory to multiple standard-of-care drug classes face a dismal prognosis. Melflufen demonstrated efficacy and tolerability in select populations, with an initial approval in the United States in patients with ≥ four previous lines of therapy and triple-class-refractory MM. Results from the phase III OCEAN study - currently under discussion with regulatory agencies in the United States and Europe - are more complex and have been put into context herein. Lastly, melflufen provides a proof-of-concept for the utility of the peptide-drug conjugate platform in relapsed/refractory MM.
MeSH term(s)	Animals ; Antineoplastic Combined Chemotherapy Protocols ; Dexamethasone/therapeutic use ; Europe ; Melphalan/analogs & derivatives ; Melphalan/pharmacology ; Melphalan/therapeutic use ; Multiple Myeloma/chemically induced ; Multiple Myeloma/drug therapy ; Multiple Myeloma/pathology ; Phenylalanine/analogs & derivatives
Chemical Substances	melflufen (3412470A0V) ; Phenylalanine (47E5O17Y3R) ; Dexamethasone (7S5I7G3JQL) ; Melphalan (Q41OR9510P)
Language	English
Publishing date	2022-06-19
Publishing country	England
Document type	Journal Article
ISSN	1751-2441
ISSN (online)	1751-2441
DOI	10.1080/17512433.2022.2075847
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Article ; Online: Expert consensus on the integrated diagnosis of idiopathic multicentric Castleman disease.

Montes-Moreno, Santiago / Climent, Fina / Fraga, Máximo / Luis Patier, José / Robles-Marhuenda, Ángel / García-Sanz, Ramón / Ocio, Enrique M / González García, Andrés / Navarro, José-Tomás

Revista espanola de patologia : publicacion oficial de la Sociedad Espanola de Anatomia Patologica y de la Sociedad Espanola de Citologia

2023 Volume 56, Issue 3, Page(s) 158–167

Abstract: Idiopathic multicentric Castleman disease (iMCD) is rare. The differential diagnosis includes inflammatory, autoimmune and neoplastic disease. The identification of the histopathological features of Castleman disease in the lymph node is the main ... ...

Abstract	Idiopathic multicentric Castleman disease (iMCD) is rare. The differential diagnosis includes inflammatory, autoimmune and neoplastic disease. The identification of the histopathological features of Castleman disease in the lymph node is the main diagnostic criterion. Fifty-three experts from three medical societies (SEMI, SEHH and SEAP) have created a multi-disciplinary consensus document in order to standardise the diagnosis of Castleman disease. Using the Delphi method, specific recommendations for the initial clinical, laboratory and imaging studies have been made for an integrated diagnosis of iMCD as well as for the best way to obtain samples for histopathological confirmation, correct laboratory procedure and interpretation and reporting of results.
MeSH term(s)	Humans ; Castleman Disease/diagnosis ; Consensus ; Diagnosis, Differential
Language	English
Publishing date	2023-02-09
Publishing country	Spain
Document type	Journal Article ; Review
ZDB-ID	2463888-2
ISSN	1988-561X ; 1988-561X
ISSN (online)	1988-561X
ISSN	1988-561X
DOI	10.1016/j.patol.2022.12.003
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Article ; Online: Induction Therapy for Newly Diagnosed Multiple Myeloma.

Paul, Barry / Lipe, Brea / Ocio, Enrique M / Usmani, Saad Z

American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting

2019 Volume 39, Page(s) e176–e186

Abstract: The frontline therapy for newly diagnosed multiple myeloma (MM) has continued to evolve over the last 10 years. There has been a growing emphasis on achieving the best depth of response in the context of minimal residual disease negativity, given its ... ...

Abstract	The frontline therapy for newly diagnosed multiple myeloma (MM) has continued to evolve over the last 10 years. There has been a growing emphasis on achieving the best depth of response in the context of minimal residual disease negativity, given its prognostic correlation with superior overall survival. Another important area of emphasis has been to improve prognostication and staging by including information on disease biology. There also a growing appreciation of global differences in drug access and patterns of care. The current review explores each of these areas and how best to incorporate the emerging induction regimens in to schema of MM therapy.
MeSH term(s)	Antineoplastic Combined Chemotherapy Protocols/adverse effects ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Clinical Decision-Making ; Europe ; Humans ; Molecular Targeted Therapy ; Multiple Myeloma/diagnosis ; Multiple Myeloma/mortality ; Multiple Myeloma/therapy ; Neoplasm Staging ; Neoplasm, Residual ; Prognosis ; Remission Induction ; United States
Language	English
Publishing date	2019-05-17
Publishing country	United States
Document type	Journal Article
ZDB-ID	2431126-1
ISSN	1548-8756 ; 1548-8748
ISSN (online)	1548-8756
ISSN	1548-8748
DOI	10.1200/EDBK_238527
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Article ; Online: Biological Background of Resistance to Current Standards of Care in Multiple Myeloma.

Mogollón, Pedro / Díaz-Tejedor, Andrea / Algarín, Esperanza M / Paíno, Teresa / Garayoa, Mercedes / Ocio, Enrique M

Cells

2019 Volume 8, Issue 11

Abstract: 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 ... ...

Abstract	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 (PIs), immunomodulatory agents (IMiDs), and monoclonal antibodies (mAbs). In some cases, strategies to overcome resistance have been discerned, and an effort should be made to evaluate whether resensitization to these agents is feasible in the clinical setting. Additionally, at a time in which we are moving towards precision medicine in MM, it is equally important to identify reliable and accurate biomarkers of sensitivity/refractoriness to these main therapeutic agents with the goal of having more efficacious treatments and, if possible, prevent the development of relapse.
MeSH term(s)	Drug Resistance, Neoplasm/genetics ; Genetic Background ; Humans ; Molecular Targeted Therapy/adverse effects ; Molecular Targeted Therapy/methods ; Molecular Targeted Therapy/standards ; Multiple Myeloma/drug therapy ; Multiple Myeloma/genetics ; Multiple Myeloma/metabolism ; Precision Medicine/methods ; Precision Medicine/standards ; Standard of Care/standards ; Treatment Outcome
Language	English
Publishing date	2019-11-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells8111432
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