scholarly journals Clinical and Pharmacologic Features of Monoclonal Antibodies and Checkpoint Blockade Therapy in Multiple Myeloma

2019 ◽  
Vol 26 (32) ◽  
pp. 5968-5981 ◽  
Author(s):  
Mattia D’Agostino ◽  
Giulia Gazzera ◽  
Giusy Cetani ◽  
Sara Bringhen ◽  
Mario Boccadoro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Recent Literature ◽  
Proteasome Inhibitors ◽  
Safety Evaluation ◽  
Standard Of Care ◽  
Checkpoint Blockade ◽  
New Drugs ◽  
Immunomodulatory Agents ◽  
Inhibitory Molecules

Background: Survival of multiple myeloma patients has considerably improved in the last decades thanks to the introduction of many new drugs, including immunomodulatory agents, proteasome inhibitors and, more recently, monoclonal antibodies. Methods: We analyzed the most recent literature focusing on the clinical and pharmacologic aspects of monoclonal antibody-based therapies in multiple myeloma, including monoclonal antibodies directed against plasma cell antigens, as well as checkpoint blockade therapy directed against immune inhibitory molecules, used as single agents or in combination therapy. Results: Anti-CD38 monoclonal antibodies including daratumumab, isatuximab and MOR202 have shown outstanding results in relapsed and/or refractory multiple myeloma patients. The addition of daratumumab to bortezomib-dexamethasone or lenalidomidedexamethasone substantially improved patients’ outcome in this patient population. The anti- SLAMF7 molecule elotuzumab in combination with lenalidomide-dexamethasone showed to be superior to lenalidomide-dexamethasone alone, without adding meaningful toxicity. Checkpoint blockade therapy in combination with immunomodulatory agents produced objective responses in more than 50% of treated patients. However, this combination was also associated with an increase in toxicity and a thorough safety evaluation is currently ongoing. Conclusion: Monoclonal antibodies are reshaping the standard of care for multiple myeloma and ongoing trials will help physicians to optimize their use in order to further improve patients’ outcome.

scholarly journals Novel Approaches Outside the Setting of Immunotherapy for the Treatment of Multiple Myeloma: The Case of Melflufen, Venetoclax, and Selinexor

2021 ◽  
Vol 11 ◽  
Author(s):  
Nicola Sgherza ◽  
Paola Curci ◽  
Rita Rizzi ◽  
Pellegrino Musto
Keyword(s):  
Multiple Myeloma ◽  
Recent Literature ◽  
Proteasome Inhibitors ◽  
Genetic Alterations ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Efficacy And Safety ◽  
Immunomodulatory Agents ◽  
Aggressive Disease ◽  
Alternative Approaches

Although the survival rate of patients with multiple myeloma has significantly improved in the last years thanks to the introduction of various classes of new drugs, such as proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies, the vast majority of these subjects relapse with a more aggressive disease due to the acquisition of further genetic alterations that may cause resistance to current salvage therapies. The treatment of these often “triple” (or even more) refractory patients remains challenging, and alternative approaches are required to overcome the onset of that resistance. Immunotherapies with novel monoclonal, drug-conjugated, or bi-specific antibodies, as well as the use of chimeric antigen receptor T cells, have been recently developed and are currently investigated. However, other non-immunologic therapeutic regimens based on melfluflen, venetoclax, or selinexor, three molecules with new mechanisms of action, have also shown promising results in the setting of relapsed/refractory myeloma. Here we report the most recent literature data regarding these three drugs, focusing on their efficacy and safety in multiple myeloma.

New Drugs in Multiple Myeloma

2019 ◽  
Vol 70 (1) ◽  
pp. 521-547 ◽  
Author(s):  
Chutima Kunacheewa ◽  
Robert Z. Orlowski
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Plasma Cell ◽  
Clinical Studies ◽  
Alkylating Agents ◽  
Proteasome Inhibitors ◽  
New Drugs ◽  
Plasma Cell Dyscrasia ◽  
Immunomodulatory Agents ◽  
Large Molecules

Multiple myeloma is diagnosed in over 100,000 patients each year worldwide, has an increasing incidence and prevalence in many regions, and follows a relapsing course, making it a significant and growing healthcare challenge. Recent basic, translational, and clinical studies have expanded our therapeutic armamentarium, which now consists of alkylating agents, corticosteroids, deacetylase inhibitors, immunomodulatory agents, monoclonal antibodies, and proteasome inhibitors. New drugs in these categories, and additional agents, including both small and large molecules, as well as cellular therapies, are under development that promise to further expand our capabilities and bring us closer to the cure of this plasma cell dyscrasia.

scholarly journals Biological Background of Resistance to Current Standards of Care in Multiple Myeloma

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1432 ◽  
Author(s):  
Pedro Mogollón ◽  
Andrea Díaz-Tejedor ◽  
Esperanza M. Algarín ◽  
Teresa Paíno ◽  
Mercedes Garayoa ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Current Knowledge ◽  
Proteasome Inhibitors ◽  
Therapeutic Agents ◽  
Standards Of Care ◽  
Mechanisms Of Resistance ◽  
Immunomodulatory Agents ◽  
Development Of Resistance ◽  
Current Standards

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.

scholarly journals Role and Modulation of NK Cells in Multiple Myeloma

Hemato ◽  
2021 ◽  
Vol 2 (2) ◽  
pp. 167-181
Author(s):  
Marie Thérèse Rubio ◽  
Adèle Dhuyser ◽  
Stéphanie Nguyen
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Nk Cells ◽  
Tumor Cells ◽  
Nk Cell ◽  
Ex Vivo ◽  
Killer Cell ◽  
Proteasome Inhibitors ◽  
Disease Evolution ◽  
Cell Functions

Myeloma tumor cells are particularly dependent on their microenvironment and sensitive to cellular antitumor immune response, including natural killer (NK) cells. These later are essential innate lymphocytes implicated in the control of viral infections and cancers. Their cytotoxic activity is regulated by a balance between activating and inhibitory signals resulting from the complex interaction of surface receptors and their respective ligands. Myeloma disease evolution is associated with a progressive alteration of NK cell number, phenotype and cytotoxic functions. We review here the different therapeutic approaches that could restore or enhance NK cell functions in multiple myeloma. First, conventional treatments (immunomodulatory drugs-IMids and proteasome inhibitors) can enhance NK killing of tumor cells by modulating the expression of NK receptors and their corresponding ligands on NK and myeloma cells, respectively. Because of their ability to kill by antibody-dependent cell cytotoxicity, NK cells are important effectors involved in the efficacy of anti-myeloma monoclonal antibodies targeting the tumor antigens CD38, CS1 or BCMA. These complementary mechanisms support the more recent therapeutic combination of IMids or proteasome inhibitors to monoclonal antibodies. We finally discuss the ongoing development of new NK cell-based immunotherapies, such as ex vivo expanded killer cell immunoglobulin-like receptors (KIR)-mismatched NK cells, chimeric antigen receptors (CAR)-NK cells, check point and KIR inhibitors.

scholarly journals Multiple myeloma: a model for scientific and clinical progress

Hematology ◽  
2014 ◽  
Vol 2014 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Jesus San Miguel
Keyword(s):  
Multiple Myeloma ◽  
Histone Deacetylase Inhibitors ◽  
Plasma Cells ◽  
Residual Disease ◽  
Critical Role ◽  
Proteasome Inhibitors ◽  
New Drugs ◽  
High Dose ◽  
New Treatment ◽  
Almost All

Abstract Multiple myeloma (MM) is a unique cancer paradigm for investigating the mechanisms involved in the transition from a premalignant condition (monoclonal gammopathy of undetermined significance) into a malignant disease (MM). In the pathogenesis of myeloma, the dialogue between plasma cells and their microenvironment is as important as the genotypic characteristics of the tumor clone. MM is genetically highly complex, with almost all patients displaying cytogenetic abnormalities and frequent intraclonal heterogeneity that play a critical role in the outcome of the disease. In fact, it is likely that myeloma will soon no longer be considered as a single entity. This, along with the availability of an unexpected number of new treatment possibilities, has reinforced the need for better tools for prognosis and for monitoring treatment efficacy through minimal residual disease techniques. The outcome of MM patients has significantly improved in the last 2 decades, first through the introduction of high-dose therapy followed by autologous stem cell transplantation and, more recently, due to the use of proteasome inhibitors (bortezomib and carfilzomib) and immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide). Moreover, the need to reexamine the diagnostic criteria of early MM and the possibility of early intervention opens up new therapeutic avenues. New drugs are also emerging, including second- and third-generation proteasome inhibitors and immunomodulators, monoclonal antibodies, histone deacetylase inhibitors, and kinesin spindle protein inhibitors, among others. Our goal is to find a balance among efficacy, toxicity, and cost, with the ultimate aim of achieving a cure for this disease.

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 Salvage Therapy of Multiple Myeloma: The New Generation Drugs

2014 ◽  
Vol 2014 ◽  
pp. 1-14 ◽  
Author(s):  
Alessandra Romano ◽  
Concetta Conticello ◽  
Maide Cavalli ◽  
Calogero Vetro ◽  
Cosimo Di Raimondo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Salvage Therapy ◽  
Proteasome Inhibitors ◽  
New Drugs ◽  
Immunomodulatory Drugs ◽  
The Past ◽  
Results Of Treatment ◽  
Incurable Disease ◽  
New Generation ◽  
Historical Treatment

During the past decade, overall results of treatment of multiple myeloma (MM) have been improved and survival curves are now significantly better with respect to those obtained with historical treatment. These improvements are linked to a deeper knowledge of the biology of disease and to the introduction in clinical practice of drugs with different mechanism of action such as proteasome inhibitors and immunomodulatory drugs (IMiDs). However, MM remains in most cases an incurable disease. For patients who relapse after treatment with novel agents, the prognosis is dismal and new drugs and therapeutic strategies are required for continued disease control. In this review, we summarize new insights in salvage therapy for relapsed/refractory MM as emerging from recent clinical trials exploring the activity of bendamustine, new generation proteasome inhibitors, novel IMiDs, monoclonal antibodies, and drugs interfering with growth pathways.

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