scholarly journals Molecularly Targeted Therapies in Multiple Myeloma

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Pilar de la Puente ◽  
Barbara Muz ◽  
Feda Azab ◽  
Micah Luderer ◽  
Abdel Kareem Azab
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Tumor Microenvironment ◽  
Cell Signaling ◽  
Targeted Therapies ◽  
Proteasome Inhibitors ◽  
Novel Agents ◽  
Immunomodulatory Drugs ◽  
Therapeutic Outcomes

Multiple myeloma (MM) is a hematological malignancy that remains incurable because most patients will eventually relapse or become refractory to the treatments. Although the treatments have improved, the major problem in MM is the resistance to therapy. Novel agents are currently in development for the treatment of relapsed/refractory MM, including immunomodulatory drugs, proteasome inhibitors, monoclonal antibodies, cell signaling targeted therapies, and strategies targeting the tumor microenvironment. We have previously reviewed in detail the contemporary immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies therapies for MM. Therefore, in this review, we focused on the role of molecular targeted therapies in the treatment of relapsed/refractory multiple myeloma, including cell signaling targeted therapies (HDAC, PI3K/AKT/mTOR, p38 MAPK, Hsp90, Wnt, Notch, Hedgehog, and cell cycle) and strategies targeting the tumor microenvironment (hypoxia, angiogenesis, integrins, CD44, CXCR4, and selectins). Although these novel agents have improved the therapeutic outcomes for MM patients, further development of new therapeutic agents is warranted.

scholarly journals Daratumumab in untreated newly diagnosed multiple myeloma

2019 ◽  
Vol 10 ◽  
pp. 204062071989487 ◽  
Author(s):  
Nadine Abdallah ◽  
Shaji K. Kumar
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibody ◽  
Clinical Trials ◽  
High Risk ◽  
Human Monoclonal Antibody ◽  
Proteasome Inhibitors ◽  
Immunomodulatory Drugs ◽  
Newly Diagnosed ◽  
Infusion Reactions

The treatment of multiple myeloma has evolved markedly in the last decade, but mortality remains high, emphasizing the need for more effective therapies. Daratumumab, a fully human monoclonal antibody targeting CD38, has shown clinical efficacy in relapsed/refractory multiple myeloma both as monotherapy and in combination with other drugs, including novel agents. More recently, promising results have been reported in patients with untreated newly diagnosed multiple myeloma (NDMM). Clinical trials thus far have shown enhanced efficacy and tolerability of several daratumumab-based combinations in both transplant ineligible and eligible patients, without compromising transplant ability. However, benefit in high-risk subpopulations is still unclear. A subcutaneous formulation of daratumumab has been introduced to decrease the risk of infusion reactions, with preliminary results showing non-inferior efficacy. The antimyeloma activity of daratumumab is achieved through multiple mechanisms including direct, Fc-dependent, and immunomodulatory mechanisms. Enhanced efficacy of daratumumab in combination with immunomodulatory drugs and proteasome inhibitors is supported by preclinical data showing synergism. This review will focus on the role of daratumumab in untreated NDMM patients, highlighting the results of major clinical trials, and listing ongoing trials that are evaluating various daratumumab-based combinations in this setting.

Practical Considerations for Antibodies in Myeloma

2018 ◽  
pp. 667-674 ◽  
Author(s):  
Jacob P. Laubach ◽  
Niels van de Donk ◽  
Faith E. Davies ◽  
Joseph Mikhael
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Patient Outcomes ◽  
Great Improvement ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Drug Combinations ◽  
Therapeutic Antibodies ◽  
Immunomodulatory Drugs ◽  
Favorable Safety

The development of the monoclonal antibodies daratumumab and elotuzumab has expanded treatment options for multiple myeloma and led to great improvement in patient outcomes. These agents have favorable safety profiles and synergize effectively with established agents used in the management of myeloma, namely immunomodulatory drugs and proteasome inhibitors. This article reviews the rationale for use of monoclonal antibodies in myeloma, current approved indications for daratumumab and elotuzumab, the manner in which these agents are used in the overall management of myeloma, and specific challenges associated with their use in the clinic. It also highlights other, emerging drug combinations that incorporate daratumumab or elotuzumab and profiles new therapeutic antibodies currently under development.

scholarly journals Current and emerging immunotherapeutic approaches to the treatment of multiple myeloma

2019 ◽  
Vol 10 ◽  
pp. 204062071985417
Author(s):  
Dawn Swan ◽  
Kevin Lynch ◽  
Mark Gurney ◽  
Michael O’Dwyer
Keyword(s):  
Multiple Myeloma ◽  
Immune System ◽  
Immune Evasion ◽  
Proteasome Inhibitors ◽  
Standard Of Care ◽  
Bispecific Antibodies ◽  
Clinical Use ◽  
Immunomodulatory Drugs ◽  
Care Regimes

Multiple myeloma (MM) has a worldwide incidence of 1–5/100,000/year. Outcomes have improved significantly in recent years following incorporation of immunomodulatory drugs and proteasome inhibitors into standard-of-care regimes. MM is profoundly immunosuppressive, enabling immune evasion, proliferation and disease progression. The role of the immune system in MM is becoming increasingly characterized and understood, and numerous therapies are under development or in routine clinical use targeting these elements of MM pathogenesis. In this review we discuss the immunosuppressive effects of MM, then the therapies targeting these defects. Specifically, we review the monoclonal and bispecific antibodies, alongside adoptive cellular therapies currently under investigation.

Pomalidomide-Responsive Extramedullary Myeloma Relapsed after Allogeneic Hematopoietic Transplant and Refractory to Multiple Lines of Chemotherapy

Chemotherapy ◽  
2019 ◽  
Vol 64 (2) ◽  
pp. 110-114 ◽  
Author(s):  
Salvatore Leotta ◽  
Maria Cristina Pirosa ◽  
Uros Markovic ◽  
Luca Scalise ◽  
Anna Bulla ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Proteasome Inhibitors ◽  
Novel Agents ◽  
Immunomodulatory Drugs

Patients who experience extramedullary relapses (EMR) of multiple myeloma (MM) have an adverse prognosis, also in this era of novel agents like proteasome inhibitors and immunomodulatory drugs. We describe the case of an MM patient with EMR at 2 different sites after allogeneic stem cell transplantation. EMR was refractory to bortezomib, anthracycline, and bendamustine, but the patient achieved long-term complete remission (4 years) with pomalidomide and dexamethasone. This supports the hypothesis that this could be due to the graft-versus-myeloma effect during therapy enhanced by pomalidomide.

scholarly journals Emerging agents and regimens for multiple myeloma

2020 ◽  
Vol 13 (1) ◽  
Author(s):  
Yang Yang ◽  
Yi Li ◽  
Huiyao Gu ◽  
Mengmeng Dong ◽  
Zhen Cai
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Clinical Development ◽  
Novel Agents ◽  
Immunomodulatory Drugs ◽  
Car T Cells ◽  
Drug Conjugates ◽  
Car T ◽  
Bite Antibody ◽  
Antibody Drug

Abstract The outcomes of multiple myeloma (MM) have been improved significantly with the therapies incorporating proteasome inhibitors (PI), immunomodulatory drugs, monoclonal antibodies (MoAb) and stem cell transplantation. However, relapsed and refractory MM (RRMM) remains a major challenge. Novel agents and regimens are under active clinical development. These include new PIs such as ixazomib, marizomib, and oprozomib; new MoAbs such as isatuximab and MOR202; novel epigenetic agent ricolinostat and novel cytokines such as siltuximab. Recently, the first XPO-1 inhibitor, selinexor, was approved for RRMM. BCMA-targeted BiTE, antibody–drug conjugates and CAR-T cells have the potential to revolutionize the therapy for RRMM. In this review, we summarized the latest clinical development of these novel agents and regimens.

Immunomodulatory drugs in the treatment of multiple myeloma

2019 ◽  
Vol 49 (8) ◽  
pp. 695-702 ◽  
Author(s):  
Yu Abe ◽  
Tadao Ishida
Keyword(s):  
Multiple Myeloma ◽  
Ubiquitin Ligase ◽  
Proteasome Inhibitors ◽  
Novel Agents ◽  
Immunomodulatory Drugs ◽  
Newly Diagnosed ◽  
Ubiquitin Ligase Complex ◽  
Long Time ◽  
Molecular Mechanism Of Action ◽  
Direct Target

Abstract The prognosis of multiple myeloma was quite poor in the last century, but it has significantly improved with the incorporation of novel agents, immunomodulatory drugs (IMiDs) and proteasome inhibitors. Thalidomide was first developed as a sedative in 1950s, but it was withdrawn from the market because of teratogenicity. In 1990s, however, thalidomide received attention due to the discovery of its anticancer potential derived from antiangiogenic and immunomodulatory activities, and its therapeutic effect on myeloma. In 2006, the U.S. Food and Drug Administration approved the use of thalidomide under strict control for the treatment of multiple myeloma. After that, two new IMiDs, lenalidomide and pomalidomide, were developed for the sake of more antitumor activity and less adverse events than thalidomide. The molecular mechanism of action of IMiDs remained unclear for a long time until 2010 when the protein cereblon (CRBN) was identified as a primary direct target. IMiDs binds to CRBN and alters the substrate specificity of the CRBN E3 ubiquitin ligase complex, resulting in breakdown of intrinsic downstream proteins such as IKZF1 (Ikaros) and IKZF3 (Aiolos). There are many clinical trials of multiple myeloma using IMiDs under various conditions, and most of them show the efficacy of IMiDs. Nowadays lenalidomide plays a central role in both newly diagnosed and relapsed/refractory settings, mainly in combination with other novel agents such as proteasome inhibitors and monoclonal antibodies. This review presents an overview of recent advances in immunomodulatory drugs in the treatment of multiple myeloma.

scholarly journals The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of multiple myeloma

2020 ◽  
Vol 8 (2) ◽  
pp. e000734
Author(s):  
Nina Shah ◽  
Jack Aiello ◽  
David E Avigan ◽  
Jesus G Berdeja ◽  
Ivan M Borrello ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Therapeutic Option ◽  
Proteasome Inhibitors ◽  
Myeloma Cell ◽  
Cell Surface Antigens ◽  
Car T ◽  
Clinical Benefits ◽  
Immunotherapy Of Cancer

Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.

Evolving Paradigms in the Treatment of Newly Diagnosed Multiple Myeloma

2011 ◽  
Vol 9 (10) ◽  
pp. 1186-1196 ◽  
Author(s):  
Alessandra Larocca ◽  
Antonio Palumbo
Keyword(s):  
Multiple Myeloma ◽  
Treatment Options ◽  
Young Patients ◽  
Novel Agents ◽  
Immunomodulatory Drugs ◽  
Newly Diagnosed ◽  
The Past ◽  
Treatment Paradigm ◽  
Novel Agent

The treatment of multiple myeloma has undergone significant changes in the past few years. The introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, has dramatically improved the outcome of this disease and considerably increased the treatment options available. Several trials have shown the advantages linked to the use of novel agents both in young patients, who are considered eligible for transplantation, and elderly patients, for whom a conventional therapy should be considered. These novel agents may increase the efficacy of autologous stem cell transplantation with deeper and long-lasting response. In the transplant setting, different novel agent combinations have proved to be superior to the traditional vincristine-doxorubicin-dexamethasone. Similarly, novel agents have also changed the treatment paradigm of patients not eligible for transplantation, thus replacing the traditional melphalan-prednisone approach. Preliminary data also support the role of consolidation and maintenance therapy to further improve outcomes. This article provides an overview of the latest strategies, including novel agents used to treat patients with multiple myeloma, both in the transplant and nontransplant settings.

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

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.

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

Cancers ◽  
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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