scholarly journals Stratification for RRMM and Risk-Adapted Therapy: Sequencing of Therapies in RRMM

Cancers ◽  
2021 ◽  
Vol 13 (23) ◽  
pp. 5886
Author(s):  
Georg Jeryczynski ◽  
Arnold Bolomsky ◽  
Hermine Agis ◽  
Maria-Theresa Krauth
Keyword(s):  
Multiple Myeloma ◽  
Proteasome Inhibitors ◽  
Patient Specific ◽  
Innovation Implementation ◽  
Drug Classes ◽  
Frontline Treatment ◽  
Specific Factors ◽  
Line Setting ◽  
The Right ◽  
Optimal Treatment Strategy

The treatment landscape for relapsed multiple myeloma (RRMM) has experienced an unprecedented wave of innovation. Implementation of numerous new substances and drug classes with different modes of action is made possible in routine clinical practice. Next generation proteasome inhibitors, monoclonal antibodies, as well as first in class agents such as selinexor and venetoclax have widened the therapeutic spectrum. This has led to an increase in progression-free and overall survival. Consequently, new challenges for treating physicians in choosing the right treatment at the right stage of the disease have been generated. Several trials support the use of novel agents in the frontline treatment of newly diagnosed multiple myeloma. The use of lenalidomide or bortezomib as a backbone in the first-line setting, requires strategies for treatment once these patients relapse and are refractory to these drugs. Despite the variety of options, selecting the optimal treatment strategy is difficult, since multiple factors have to be considered: patient-specific factors such as age and co-morbidities, as well as myeloma/tumor specific factors such as cytogenetics and relapse kinetics. This review intends to summarize the existing data and guidelines regarding the optimal sequencing of treatments of RRMM using already approved agents as well as agents under investigation.

scholarly journals Novel Non-Immunologic Agents for Relapsed and Refractory Multiple Myeloma: A Review Article

Cancers ◽  
2021 ◽  
Vol 13 (20) ◽  
pp. 5210
Author(s):  
Arthur Bobin ◽  
Cécile Gruchet ◽  
Stéphanie Guidez ◽  
Hélène Gardeney ◽  
Laly Nsiala Makunza ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Hdac Inhibitors ◽  
Proteasome Inhibitors ◽  
Curative Therapy ◽  
Refractory Multiple Myeloma ◽  
Novel Treatments ◽  
Treatment Regimens ◽  
Drug Classes

Novel treatments are needed to address the lack of options for patients with relapsed or refractory multiple myeloma. Even though immunotherapy-based treatments have revolutionized the field in recent years, offering new opportunities for patients, there is still no curative therapy. Thus, non-immunologic agents, which have proven effective for decades, are still central to the treatment of multiple myeloma, especially for advanced disease. Building on their efficacy in myeloma, the development of proteasome inhibitors and immunomodulatory drugs has been pursued, and has led to the emergence of a novel generation of agents (e.g., carfilzomib, ixazomib, pomalidomide). The use of alkylating agents is decreasing in most treatment regimens, but melflufen, a peptide-conjugated alkylator with a completely new mechanism of action, offers interesting opportunities. Moreover, with the identification of novel targets, new drug classes have entered the myeloma armamentarium, such as XPO1 inhibitors (selinexor), HDAC inhibitors (panobinostat), and anti-BCL-2 agents (venetoclax). New pathways are still being explored, especially the possibility of a mutation-driven strategy, as biomarkers and targeted treatments are increasing. Though multiple myeloma is still considered incurable, the treatment options are expanding and are progressively becoming more diverse, largely because of the continuous development of non-immunologic agents.

scholarly journals Use of KRD-PACE as Salvage Therapy in Aggressive, Relapsed/Bortezomib-Refractory Extramedullary Multiple Myeloma: A Report of Two Cases and Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-6
Author(s):  
Ricardo D. Parrondo ◽  
Vivek Roy ◽  
Taimur Sher ◽  
Victoria Alegria ◽  
Asher A. Chanan-Khan ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Poor Prognosis ◽  
Proteasome Inhibitors ◽  
Salvage Chemotherapy ◽  
First Line ◽  
Immunomodulatory Agents ◽  
Resistance To Therapy ◽  
Line Setting ◽  
Novel Agent

Extramedullary multiple myeloma is defined by the presence of plasma cell infiltration outside of the bone marrow. It is associated with a poor prognosis and resistance to therapy and is often associated with high-risk cytogenetics. Aggressive relapsed and refractory extramedullary multiple myeloma is often treated with salvage infusional chemotherapy to achieve rapid disease control. Commonly used regimens include DCEP, CVAD, and VTD-PACE. While VTD-PACE contains bortezomib and thalidomide which have potent antimyeloma activity, the advent of novel agent therapy with proteasome inhibitors and immunomodulatory agents being used in the first-line setting has resulted in many patients being refractory to bortezomib by the time they are treated with VTD-PACE. Herein, we discuss two cases of aggressive relapsed, high-risk, bortezomib-refractory extramedullary multiple myeloma treated with KRD-PACE and review the available clinical data on salvage chemotherapy regimens used in relapsed refractory myeloma.

Carfilzomib Induced Tumor Lysis Syndrome and Other Adverse Events

2018 ◽  
Vol 33 (2) ◽  
pp. 213-216 ◽  
Author(s):  
El Bitar Sandy ◽  
Chanudi Weerasinghe ◽  
Terenig Terjanian
Keyword(s):  
Multiple Myeloma ◽  
Targeted Therapy ◽  
Adverse Events ◽  
Safety Profile ◽  
Tumor Lysis Syndrome ◽  
Proteasome Inhibitors ◽  
Second Line ◽  
Rare Occurrence ◽  
Tumor Lysis ◽  
Line Setting

In the area of multiple myeloma (MM) therapy, proteasome inhibitors (PI) have emerged with promising responses both in the first- and second-line setting. Carfilzomib (CFZ) is a second-generation, selective PI approved in 2012 for the treatment of relapsed/refractory multiple myeloma (RRMM) in patients who received 2 prior therapies or have evidence of disease progression within 60 days of completion of last therapy. Its safety profile reported adverse events (AEs) ranging from drug-related AEs (nausea and vomiting), hematologic AEs (neutropenia and thrombocytopenia), and nonhematologic AEs (electrolyte imbalances). As CFZ use is gaining popularity, various hematological, renal, cardiovascular, pulmonary, and neurological toxicities have been reported. We are presenting this case to describe a rare occurrence of tumor lysis syndrome (TLS) with the use of this novel targeted therapy.

scholarly journals Prognostic and Therapeutic Biomarker Developments in Multiple Myeloma

2021 ◽  
Author(s):  
Craig Thomas Wallington-Beddoe ◽  
Rachel Lauris Mynott
Keyword(s):  
Multiple Myeloma ◽  
Patient Management ◽  
New Technologies ◽  
Patient Specific ◽  
Individual Risk ◽  
Novel Therapies ◽  
Therapeutic Approaches ◽  
Insufficient Information ◽  
Drug Classes ◽  
Individual Risk Factors

Abstract New approaches to stratify multiple myeloma patients for informing on prognosis and therapy selection are needed since patients are currently managed in a similar manner regardless of individual risk factors. However, despite new and improved biomarkers for determining the prognosis of patients, there is currently insufficient information to utilise biomarkers to intensify, reduce or altogether change treatment, nor to target patient-specific biology. The ever-increasing number and complexity of drug classes to treat multiple myeloma have improved response rates and so clinically useful biomarkers will need to be relevant in the era of such novel therapies. Therefore, the field of multiple myeloma biomarker development is rapidly progressing, spurred on by new technologies and therapeutic approaches, and underpinned by a deeper understanding of tumour biology with individualised patient management the goal. In this review we describe the main biomarker categories in multiple myeloma and relate these to prognostic and therapeutic applications.

scholarly journals Emerging Therapeutic Strategies to Overcome Drug Resistance in Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1686
Author(s):  
Lorraine N. Davis ◽  
Daniel W. Sherbenou
Keyword(s):  
Multiple Myeloma ◽  
Drug Resistance ◽  
Proteasome Inhibitors ◽  
Cross Resistance ◽  
Multi Drug Resistance ◽  
Immunomodulatory Drugs ◽  
Drug Conjugates ◽  
Plasma Cell Neoplasm ◽  
Drug Classes ◽  
Malignant Plasma Cell

Multiple myeloma is a malignant plasma cell neoplasm that remains incurable and is ultimately fatal when patients acquire multi-drug resistance. Thus, advancing our understanding of the mechanisms behind drug resistance in multi-relapsed patients is critical for developing better strategies to extend their lifespan. Here, we review the understanding of resistance to the three key drug classes approved for multiple myeloma treatment: immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies. We consider how the complex, heterogenous biology of multiple myeloma may influence the acquisition of drug resistance and reflect on the gaps in knowledge where additional research is needed to improve our treatment approaches. Fortunately, many agents are currently being evaluated preclinically and in clinical trials that have the potential to overcome or delay drug resistance, including next-generation immunomodulatory drugs and proteasome inhibitors, novel small molecule drugs, chimeric antigen receptor T cells, antibody-drug conjugates, and bispecific antibodies. For each class, we discuss the potential of these strategies to overcome resistance through modifying agents within each class or new classes without cross-resistance to currently available drugs.

Novel Approaches to Treatment of Double-Refractory Multiple Myeloma

2013 ◽  
pp. e302-e306
Author(s):  
Hans C. Lee ◽  
Jatin J. Shah ◽  
Robert Z. Orlowski
Keyword(s):  
Multiple Myeloma ◽  
Patient Population ◽  
Drug Targets ◽  
Hdac Inhibitors ◽  
Proteasome Inhibitors ◽  
Initial Therapy ◽  
Frequent Use ◽  
Drug Classes ◽  
Recent Phase ◽  
Phase Ii And Iii

Multiple myeloma (MM) refractory to both proteasome inhibitors and immunomodulatory agents (IMiDs; double-refractory myeloma) has a poor prognosis. With the more frequent use of these agents as part of initial therapy, and then in the maintenance setting until disease progression, such drug resistance is an emerging problem of great significance. New therapeutic strategies are clearly needed for this patient population, including the development of more potent agents within existing antimyeloma drug classes, exploration of rational combinations of both novel and conventional drugs, and validation of new myeloma drug targets. Several approaches have shown substantial promise, including use of the second-generation proteasome inhibitor carfilzomib and the third-generation IMiD pomalidomide, which led to the recent regulatory approval of both agents. In addition, the kinesin-spindle protein KSP inhibitor ARRY-520 has shown activity as a first-in-class drug in myeloma therapeutics, whereas the histone deacetylase (HDAC) inhibitors vorinostat and panobinostat have demonstrated efficacy when used in rational combinations. This overview provides a summary of novel agents that have shown activity in double-refractory myeloma in recent phase II and III clinical trials, and a framework for future studies that will help to improve outcomes in this patient population.

scholarly journals Prognostic and predictive biomarker developments in multiple myeloma

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Craig T. Wallington-Beddoe ◽  
Rachel L. Mynott
Keyword(s):  
Multiple Myeloma ◽  
New Technologies ◽  
Predictive Biomarker ◽  
Patient Specific ◽  
Individual Risk ◽  
Therapeutic Approaches ◽  
Disease Characteristics ◽  
Drug Classes ◽  
Therapeutic Decision Making ◽  
Individual Risk Factors

AbstractNew approaches to stratify multiple myeloma patients based on prognosis and therapeutic decision-making, or prediction, are needed since patients are currently managed in a similar manner regardless of individual risk factors or disease characteristics. However, despite new and improved biomarkers for determining the prognosis of patients, there is currently insufficient information to utilise biomarkers to intensify, reduce or altogether change treatment, nor to target patient-specific biology in a so-called predictive manner. The ever-increasing number and complexity of drug classes to treat multiple myeloma have improved response rates and so clinically useful biomarkers will need to be relevant in the era of such novel therapies. Therefore, the field of multiple myeloma biomarker development is rapidly progressing, spurred on by new technologies and therapeutic approaches, and underpinned by a deeper understanding of tumour biology with individualised patient management the goal. In this review, we describe the main biomarker categories in multiple myeloma and relate these to diagnostic, prognostic and predictive applications.

Proteasome inhibitors as therapeutics

2005 ◽  
Vol 41 ◽  
pp. 205-218
Author(s):  
Constantine S. Mitsiades ◽  
Nicholas Mitsiades ◽  
Teru Hideshima ◽  
Paul G. Richardson ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Drug Class ◽  
Proteasome Inhibitors ◽  
Cell Cycle Regulators ◽  
Current State ◽  
Intracellular Mechanism ◽  
Ubiquitin Proteasome ◽  
Proteasome Pathway ◽  
Hodgkin's Lymphomas ◽  
Clinical Research Data

The ubiquitin–proteasome pathway is a principle intracellular mechanism for controlled protein degradation and has recently emerged as an attractive target for anticancer therapies, because of the pleiotropic cell-cycle regulators and modulators of apoptosis that are controlled by proteasome function. In this chapter, we review the current state of the field of proteasome inhibitors and their prototypic member, bortezomib, which was recently approved by the U.S. Food and Drug Administration for the treatment of advanced multiple myeloma. Particular emphasis is placed on the pre-clinical research data that became the basis for eventual clinical applications of proteasome inhibitors, an overview of the clinical development of this exciting drug class in multiple myeloma, and a appraisal of possible uses in other haematological malignancies, such non-Hodgkin's lymphomas.

The massive nodular cutaneous and soft tissues lesions of the right shoulder and the arm as the extramedullary manifestation of the advanced stage of multiple myeloma

Oncoreview ◽  
2017 ◽  
Vol 7 (4) ◽  
pp. 180-183
Author(s):  
Arkadiusz Drobiecki ◽  
Marcin Pasiarski ◽  
Agnieszka Stelmach-Gołdyś ◽  
Bartosz Garus
Keyword(s):  
Multiple Myeloma ◽  
Soft Tissues ◽  
Advanced Stage ◽  
The Right

scholarly journals Boosting Immunity against Multiple Myeloma

Cancers ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1221
Author(s):  
Raquel Lopes ◽  
Bruna Velosa Ferreira ◽  
Joana Caetano ◽  
Filipa Barahona ◽  
Emilie Arnault Carneiro ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Proteasome Inhibitors ◽  
Treatment Strategies ◽  
Complete Response ◽  
Drug Conjugates ◽  
Incurable Disease ◽  
Car T ◽  
Patient’S Outcome ◽  
The Impact

Despite the improvement of patient’s outcome obtained by the current use of immunomodulatory drugs, proteasome inhibitors or anti-CD38 monoclonal antibodies, multiple myeloma (MM) remains an incurable disease. More recently, the testing in clinical trials of novel drugs such as anti-BCMA CAR-T cells, antibody–drug conjugates or bispecific antibodies broadened the possibility of improving patients’ survival. However, thus far, these treatment strategies have not been able to steadily eliminate all malignant cells, and the aim has been to induce a long-term complete response with minimal residual disease (MRD)-negative status. In this sense, approaches that target not only myeloma cells but also the surrounding microenvironment are promising strategies to achieve a sustained MRD negativity with prolonged survival. This review provides an overview of current and future strategies used for immunomodulation of MM focusing on the impact on bone marrow (BM) immunome.

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