The emerging role of carfilzomib combination therapy in the management of multiple myeloma

e19533 Background: Immunotherapy for multiple myeloma (MM) has been of focus in recent years due to its myeloma-specific immune responses. We reviewed literature on non-FDA approved monoclonal antibodies (MoAbs) to highlight future perspectives. Methods: We searched PubMed, EMBASE, Web of Science, Cochrane and Clinicaltrilas.gov to include phase I/II clinical trials. Results: 40 studies (1917 patients) were included. Isatuximab (anti-CD38) and F50067 (anti-CXCR4) were the only MoAbs which produced encouraging results as monotherapy with ORR of 66.7% and 32% respectively. Isatuximab use in combination with Len-Dex produced CBR of 83%, and in combination with pomalidomide and dexamethasone CBR of 73%. Indatuximab Ravtansine, an antibody-drug conjugate, produced ORR 78% and 79% in combination with Len-Dex and pomalidomide + dexamethasone respectively. Conclusions: CD38 remains an important target for further clinical trials in combination therapy. Trials using indatuximab, pembrolizumab, lorvotuzumab, siltuximab, and dacetuzumab in combination therapy produced better outcomes as compared to monotherapies. [Table: see text]

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Sequential therapy compared with combination therapy in multiple myeloma

Archives of Internal Medicine ◽

10.1001/archinte.135.1.163 ◽

1975 ◽

Vol 135 (1) ◽

pp. 163-171 ◽

Cited By ~ 2

Keyword(s):

Multiple Myeloma ◽

Combination Therapy ◽

Sequential Therapy

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The role of nuclear factor-[kappa ]B in the biology and treatment of multiple myeloma

Seminars in Oncology ◽

10.1053/sonc.2001.29542 ◽

2001 ◽

Vol 28 (6) ◽

pp. 626-633 ◽

Cited By ~ 3

Author(s):

James R. Berenson ◽

Hongjin M. Ma ◽

Robert Vescio

Keyword(s):

Multiple Myeloma ◽

Nuclear Factor Kappa B ◽

Nuclear Factor ◽

Nuclear Factor Kappa

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CD38 as an immunomodulator in cancer

Future Oncology ◽

10.2217/fon-2020-0401 ◽

2020 ◽

Vol 16 (34) ◽

pp. 2853-2861

Author(s):

Yanli Li ◽

Rui Yang ◽

Limo Chen ◽

Sufang Wu

Keyword(s):

Multiple Myeloma ◽

Cell Activation ◽

Human Tissues ◽

Transmembrane Glycoprotein ◽

Cell Activation Marker ◽

Research Findings ◽

A Cell ◽

And Function ◽

Human Molecule

CD38 is a transmembrane glycoprotein that is widely expressed in a variety of human tissues and cells, especially those in the immune system. CD38 protein was previously considered as a cell activation marker, and today monoclonal antibodies targeting CD38 have witnessed great achievements in multiple myeloma and promoted researchers to conduct research on other tumors. In this review, we provide a wide-ranging review of the biology and function of the human molecule outside the field of myeloma. We focus mainly on current research findings to summarize and update the findings gathered from diverse areas of study. Based on these findings, we attempt to extend the role of CD38 in the context of therapy of solid tumors and expand the role of the molecule from a simple marker to an immunomodulator.

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The Role of Monoclonal Antibodies in Smoldering and Newly Diagnosed Transplant-Eligible Multiple Myeloma

Pharmaceuticals ◽

10.3390/ph13120451 ◽

2020 ◽

Vol 13 (12) ◽

pp. 451

Author(s):

Elena Zamagni ◽

Paola Tacchetti ◽

Paola Deias ◽

Francesca Patriarca

Keyword(s):

Multiple Myeloma ◽

Monoclonal Antibodies ◽

Immune System ◽

Survival Outcomes ◽

Newly Diagnosed ◽

Cellular Targets ◽

Recent Introduction

The recent introduction of monoclonal antibodies (MoAbs), with several cellular targets, such as CD-38 (daratumumab and isatuximab) and SLAM F7 (elotuzumab), differently combined with other classes of agents, has significantly extended the outcomes of patients with multiple myeloma (MM) in different phases of the disease. Initially used in advanced/refractory patients, different MoAbs combination have been introduced in the treatment of newly diagnosed transplant eligible patients (NDTEMM), showing a significant improvement in the depth of the response and in survival outcomes, without a significant price in terms of toxicity. In smoldering MM, MoAbs have been applied, either alone or in combination with other drugs, with the goal of delaying the progression to active MM and restoring the immune system. In this review, we will focus on the main results achieved so far and on the main on-going trials using MoAbs in SMM and NDTEMM.

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Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development

Antibodies ◽

10.3390/antib8020034 ◽

2019 ◽

Vol 8 (2) ◽

pp. 34 ◽

Cited By ~ 4

Author(s):

Ahmad Iftikhar ◽

Hamza Hassan ◽

Nimra Iftikhar ◽

Adeela Mushtaq ◽

Atif Sohail ◽

...

Keyword(s):

Multiple Myeloma ◽

Clinical Trials ◽

Monoclonal Antibodies ◽

Combination Therapy ◽

Immune Responses ◽

Web Of Science ◽

Cochrane Library ◽

Future Perspectives ◽

Antibody Drug Conjugate ◽

Chemotherapy Agents

Background: Immunotherapy for multiple myeloma (MM) has been the focus in recent years due to its myeloma-specific immune responses. We reviewed the literature on non-Food and Drug Administration (FDA) approved monoclonal antibodies (mAbs) to highlight future perspectives. We searched PubMed, EMBASE, Web of Science, Cochrane Library and ClinicalTrials.gov to include phase I/II clinical trials. Data from 39 studies (1906 patients) were included. Of all the agents, Isatuximab (Isa, anti-CD38) and F50067 (anti-CXCR4) were the only mAbs to produce encouraging results as monotherapy with overall response rates (ORRs) of 66.7% and 32% respectively. Isa showed activity when used in combination with lenalidomide (Len) and dexamethasone (Dex), producing a clinical benefit rate (CBR) of 83%. Additionally, Isa used in combination with pomalidomide (Pom) and Dex resulted in a CBR of 73%. Indatuximab Ravtansine (anti-CD138 antibody-drug conjugate) produced an ORR of 78% and 79% when used in combination with Len-Dex and Pom-Dex, respectively. Conclusions: Combination therapy using mAbs such as indatuximab, pembrolizumab, lorvotuzumab, siltuximab or dacetuzumab with chemotherapy agents produced better outcomes as compared to monotherapies. Further clinical trials investigating mAbs targeting CD38 used in combination therapy are warranted.

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Prognostic relevance of concordant expression CD69 and CD56 in response to bortezomib combination therapy in multiple myeloma patients

Cancer Investigation ◽

10.1080/07357907.2021.1964521 ◽

2021 ◽

pp. 1-15

Author(s):

Nadia El Menshawy ◽

Nora Abo ezz ◽

Doaa Attia ◽

Nashwa Abousamra ◽

Doaa Shahin ◽

...

Keyword(s):

Multiple Myeloma ◽

Combination Therapy ◽

Prognostic Relevance

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Transient Receptor Potential C 1/4/5 Is a Determinant of MTI-101 Induced Calcium Influx and Cell Death in Multiple Myeloma

Cells ◽

10.3390/cells10061490 ◽

2021 ◽

Vol 10 (6) ◽

pp. 1490

Author(s):

Osama M. Elzamzamy ◽

Brandon E. Johnson ◽

Wei-Chih Chen ◽

Gangqing Hu ◽

Reinhold Penner ◽

...

Keyword(s):

Multiple Myeloma ◽

Cell Death ◽

Transient Receptor Potential ◽

Cyclic Peptide ◽

Calcium Influx ◽

Acquired Resistance ◽

Treatment Strategies ◽

Prognostic Indicators ◽

Causative Role

Multiple myeloma (MM) is a currently incurable hematologic cancer. Patients that initially respond to therapeutic intervention eventually relapse with drug resistant disease. Thus, novel treatment strategies are critically needed to improve patient outcomes. Our group has developed a novel cyclic peptide referred to as MTI-101 for the treatment of MM. We previously reported that acquired resistance to HYD-1, the linear form of MTI-101, correlated with the repression of genes involved in store operated Ca2+ entry (SOCE): PLCβ, SERCA, ITPR3, and TRPC1 expression. In this study, we sought to determine the role of TRPC1 heteromers in mediating MTI-101 induced cationic flux. Our data indicate that, consistent with the activation of TRPC heteromers, MTI-101 treatment induced Ca2+ and Na+ influx. However, replacing extracellular Na+ with NMDG did not reduce MTI-101-induced cell death. In contrast, decreasing extracellular Ca2+ reduced both MTI-101-induced Ca2+ influx as well as cell death. The causative role of TRPC heteromers was established by suppressing STIM1, TRPC1, TRPC4, or TRPC5 function both pharmacologically and by siRNA, resulting in a reduction in MTI-101-induced Ca2+ influx. Mechanistically, MTI-101 treatment induces trafficking of TRPC1 to the membrane and co-immunoprecipitation studies indicate that MTI-101 treatment induces a TRPC1-STIM1 complex. Moreover, treatment with calpeptin inhibited MTI-101-induced Ca2+ influx and cell death, indicating a role of calpain in the mechanism of MTI-101-induced cytotoxicity. Finally, components of the SOCE pathway were found to be poor prognostic indicators among MM patients, suggesting that this pathway is attractive for the treatment of MM.

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DNA Damage Response in Multiple Myeloma: The Role of the Tumor Microenvironment

Cancers ◽

10.3390/cancers13030504 ◽

2021 ◽

Vol 13 (3) ◽

pp. 504

Author(s):

Takayuki Saitoh ◽

Tsukasa Oda

Keyword(s):

Multiple Myeloma ◽

Dna Damage ◽

Dna Repair ◽

Tumor Microenvironment ◽

Dna Damage Response ◽

Genetic Instability ◽

Dna Repair Mechanisms ◽

Damage Response ◽

Repair Mechanisms

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by genomic instability. MM cells present various forms of genetic instability, including chromosomal instability, microsatellite instability, and base-pair alterations, as well as changes in chromosome number. The tumor microenvironment and an abnormal DNA repair function affect genetic instability in this disease. In addition, states of the tumor microenvironment itself, such as inflammation and hypoxia, influence the DNA damage response, which includes DNA repair mechanisms, cell cycle checkpoints, and apoptotic pathways. Unrepaired DNA damage in tumor cells has been shown to exacerbate genomic instability and aberrant features that enable MM progression and drug resistance. This review provides an overview of the DNA repair pathways, with a special focus on their function in MM, and discusses the role of the tumor microenvironment in governing DNA repair mechanisms.

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PD-L1/PD-1 Axis in Multiple Myeloma Microenvironment and a Possible Link with CD38-Mediated Immune-Suppression

Cancers ◽

10.3390/cancers13020164 ◽

2021 ◽

Vol 13 (2) ◽

pp. 164

Author(s):

Federica Costa ◽

Valentina Marchica ◽

Paola Storti ◽

Fabio Malavasi ◽

Nicola Giuliani

Keyword(s):

Multiple Myeloma ◽

Bone Marrow ◽

Cell Survival ◽

Immune Suppression ◽

Metabolic Pathways ◽

Therapeutic Strategy ◽

Myeloma Cell ◽

Immune Microenvironment ◽

Potential Use

The emerging role of the PD-1/PD-L1 axis in MM immune-microenvironment has been highlighted by several studies. However, discordant data have been reported on PD-1/PD-L1 distribution within the bone marrow (BM) microenvironment of patients with monoclonal gammopathies. In addition, the efficacy of PD-1/PD-L1 blockade as a therapeutic strategy to reverse myeloma immune suppression and inhibit myeloma cell survival still remains unknown. Recent data suggest that, among the potential mechanisms behind the lack of responsiveness or resistance to anti-PD-L1/PD-1 antibodies, the CD38 metabolic pathways involving the immune-suppressive factor, adenosine, could play an important role. This review summarizes the available data on PD-1/PD-L1 expression in patients with MM, reporting the main mechanisms of regulation of PD-1/PD-L1 axis. The possible link between the CD38 and PD-1/PD-L1 pathways is also reported, highlighting the rationale for the potential use of a combined therapeutic approach with CD38 blocking agents and anti-PD-1/PD-L1 antibodies in order to improve their anti-tumoral effect in MM patients.

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