scholarly journals Introductory Chapter: Oral Selinexor, a Selective Inhibitor of Nuclear Export in the Treatment of Patients with Multiple Myeloma Refractory to Proteasome Inhibitors, Immunomodulatory Agents and Monoclonal Antibodies

2021 ◽  
Author(s):  
Ota Fuchs
Keyword(s):  
Multiple Myeloma ◽  
Monoclonal Antibodies ◽  
Nuclear Export ◽  
Proteasome Inhibitors ◽  
Selective Inhibitor ◽  
Immunomodulatory Agents

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.

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 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 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 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 Once weekly selinexor, carfilzomib and dexamethasone in carfilzomib non-refractory multiple myeloma patients

2021 ◽  
Author(s):  
Cristina Gasparetto ◽  
Gary J. Schiller ◽  
Sascha A. Tuchman ◽  
Natalie S. Callander ◽  
Muhamed Baljevic ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Overall Response Rate ◽  
Response Rate ◽  
Proteasome Inhibitors ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Free Survival ◽  
Grade 3 ◽  
Dose Modifications

Abstract Background Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM). Methods The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m2) + dexamethasone (40 mg) (XKd) once weekly (QW) was evaluated in patients with relapsed refractory MM (RRMM) not refractory to carfilzomib. Results Thirty-two patients, median prior therapies 4 (range, 1–8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m2, and dexamethasone 40 mg, all QW. The overall response rate was 78% including 14 (44%) ≥ very good partial responses. Median progression-free survival was 15 months. Conclusions Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

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