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.

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.

Selinexor: a first-in-class SINE compound for treatment of relapsed refractory multiple myeloma

2020 ◽  
Vol 16 (19) ◽  
pp. 1331-1350 ◽  
Author(s):  
Shambavi Richard ◽  
Joshua Richter ◽  
Sundar Jagannath
Keyword(s):  
Multiple Myeloma ◽  
Poor Prognosis ◽  
Proteasome Inhibitors ◽  
Resistance Mechanisms ◽  
Mechanisms Of Action ◽  
Epigenetic Alterations ◽  
Oral Agent ◽  
Immunomodulatory Agents ◽  
Tumor Suppressor Proteins ◽  
Functional Inactivation

The progression of multiple myeloma is accompanied by complex cytogenetic and epigenetic alterations that include mutation or functional inactivation of tumor suppressor proteins and overexpression of oncoproteins. Patients whose myeloma is refractory to the three major classes of drugs including immunomodulatory agents, proteasome inhibitors and anti-CD38 monoclonal antibodies have a very poor prognosis. Drugs with novel mechanisms of action that can bypass resistance mechanisms are sorely needed for this group of patients. Selinexor represents a novel, oral agent with an innovative mechanism of action that offers a significant therapeutic advance in this group of heavily treated patients. Moreover, this novel mechanism may provide additional options for patients with less refractory disease.

scholarly journals How I treat myeloma with new agents

Blood ◽  
2017 ◽  
Vol 130 (13) ◽  
pp. 1507-1513 ◽  
Author(s):  
Philippe Moreau
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Histone Deacetylase Inhibitors ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Mechanisms Of Action ◽  
Third Generation ◽  
New Agents ◽  
Immunomodulatory Agents ◽  
The Third

Abstract At present, multiple classes of agents with distinct mechanisms of action are available for the treatment of patients with multiple myeloma (MM), including alkylators, steroids, immunomodulatory agents (IMiDs), proteasome inhibitors (PIs), histone deacetylase inhibitors (DACIs), and monoclonal antibodies (mAbs). Over the last 5 years, several new agents, such as the third-generation IMiD pomalidomide, the second-generation PIs carfilzomib and ixazomib, the DACI panobinostat, and 2 mAbs, elotuzumab and daratumumab, have been approved, incorporated into clinical guidelines, and have transformed our approach to the treatment of patients. These agents may be part of doublet or triplet combinations, or incorporated into intensive strategies with autologous stem cell transplantation. In this review, I discuss the different treatment options available today for the treatment of MM in frontline and relapse settings.

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.

New drugs in multiple myeloma: mechanisms of action and phase I/II clinical findings

2008 ◽  
Vol 9 (12) ◽  
pp. 1157-1165 ◽  
Author(s):  
Enrique M Ocio ◽  
María-Victoria Mateos ◽  
Patricia Maiso ◽  
Atanasio Pandiella ◽  
Jesús F San-Miguel
Keyword(s):  
Multiple Myeloma ◽  
Phase I ◽  
Mechanisms Of Action ◽  
Clinical Findings ◽  
New Drugs

Anti-Malarial Drug Resistance

2022 ◽  
pp. 233-250
Author(s):  
Manish Kumar Dwivedi ◽  
Prashant Kumar Singh
Keyword(s):  
Natural Products ◽  
Protozoan Parasite ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
Efficacy And Safety ◽  
Infected Female ◽  
Traditional Medicines ◽  
Anopheles Mosquitoes ◽  
Synthetic Drugs ◽  
Life Threatening

Malaria is a life-threatening infectious disease caused by a protozoan parasite of the genus Plasmodium. It is transmitted through the bites of infected female Anopheles mosquitoes. The global burden is estimated to be around 219 million cases in 87 countries. Natural compounds have been used primarily in the traditional medicine for thousands of years. For the treatment of malaria, natural products were used until the development of synthetic drugs, and most of the currently available anti-malarial drugs have been derived based on the compounds from these traditional medicinal plants. The current chapter tries to briefly indicate the emerging resistance against anti-malarial drugs and to discuss the recent research on natural products that have been evaluated for anti-malarial activity. Rigorous evaluation of the efficacy and safety of traditional medicines is required along with identification of active constituents in order to develop new drugs with novel mechanisms of action.

scholarly journals New drugs and novel mechanisms of action in multiple myeloma in 2013: a report from the International Myeloma Working Group (IMWG)

Leukemia ◽  
2013 ◽  
Vol 28 (3) ◽  
pp. 525-542 ◽  
Author(s):  
E M Ocio ◽  
◽  
P G Richardson ◽  
S V Rajkumar ◽  
A Palumbo ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Working Group ◽  
Mechanisms Of Action ◽  
New Drugs ◽  
International Myeloma Working Group

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 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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