scholarly journals High-risk multiple myeloma: how to treat at diagnosis and relapse?

Hematology ◽  
2021 ◽  
Vol 2021 (1) ◽  
pp. 30-36
Author(s):  
María-Victoria Mateos ◽  
Borja Puertas Martínez ◽  
Verónica González-Calle
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Poor Prognosis ◽  
Proteasome Inhibitors ◽  
Past Century ◽  
The Past ◽  
Baseline Factors ◽  
Novel Therapeutic Strategies ◽  
Improvement In Survival

Abstract Patients with multiple myeloma have experienced a great improvement in survival over the past century because of the introduction of novel therapeutic strategies. However, a subgroup of patients with poorer outcomes than expected is considered high risk and identified by the presence of patient- and disease-based factors such as frailty, extramedullary disease, cytogenetic abnormalities, or even relapses occurring earlier than expected according to the baseline factors. Although the management of patients with high-risk features is not well established because of the lack of specific trials in this subgroup of patients and because of their underrepresentation in the clinical trials, treatment should be planned on 2 pillars: (1) poor prognosis with the presence of high-risk features can be at least improved or even abrogated by achieving a deep and sustained response over time, and (2) this can most likely be obtained through using the best therapeutic options and in a response-adapted way. Some clinical trials that have been planned or are ongoing include only patients with high-risk features, using the most effective therapies (proteasome inhibitors, immunomodulatory drugs, and anti-CD38 monoclonal antibodies) as well as chimeric antigen receptor T cells and T-cell engagers that will unravel what the best therapeutic approach will be to overcome the poor prognosis of the presence of high-risk features.

scholarly journals DARATUMUMAB FOR THE TREATMENT OF MULTIPLE MYELOMA

2017 ◽  
pp. 94-102
Author(s):  
V. V. Ryzhko ◽  
M. L. Kanaeva
Keyword(s):  
Multiple Myeloma ◽  
Clinical Practice ◽  
Human Monoclonal Antibody ◽  
Proteasome Inhibitors ◽  
Published Data ◽  
Immunomodulatory Drugs ◽  
Combination Therapies ◽  
The Past ◽  
Excellent Safety Profile ◽  
Improvement In Survival

The use of proteasome inhibitors and immunomodulatory drugs in the clinical practice has contributed to the significant improvement in survival for patients with multiple myeloma over the past decades. Alongside this, due to the recurrent course of the disease, there is a need to introduce new classes of drugs to clinical practice. In 2015,  the FDA (USA) approved two monoclonal  antibodies  for use  in  patients  with  relapsed  multiple  myeloma,  and  immunotherapy has  rapidly become indispensable  in the management of such patients. The article presents an analysis of the published data regarding the mechanism of action, safety and clinical efficacy of daratumumab, a human monoclonal antibody that targets CD38 tumor protein, for the  treatment  of patients  with multiple  myeloma. In Russia, daratumumab is registered  (RU LP-004367  of 07.07.2017) and is indicated as monotherapy for patients with relapsed or refractory multiple myeloma, who have received prior therapies, incuding proteasome  inhibitors and immunomodulatory drugs. Daratumumab demonstrated  an excellent safety profile. In the context of daratumumab therapy, the moderate-grade infusion-related reactions occurring mostly during the  first infusion  are the  main adverse  events.  Daratumumab-based combination  therapies  are currently under active evaluation in patients with relapsed and newly diagnosed myeloma.

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.

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.

scholarly journals What Is New in the Treatment of Smoldering Multiple Myeloma?

2021 ◽  
Vol 10 (3) ◽  
pp. 421
Author(s):  
Niccolo’ Bolli ◽  
Nicola Sgherza ◽  
Paola Curci ◽  
Rita Rizzi ◽  
Vanda Strafella ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Early Treatment ◽  
Individual Case ◽  
Symptomatic Disease ◽  
Plasma Cell Neoplasm ◽  
Smoldering Multiple Myeloma ◽  
Wide Range ◽  
Critical Issues

Smoldering multiple myeloma (SMM), an asymptomatic plasma cell neoplasm, is currently diagnosed according to the updated IMWG criteria, which reflect an intermediate tumor mass between monoclonal gammopathy of undetermined significance (MGUS) and active MM. However, SMM is a heterogeneous entity and individual case may go from an “MGUS-like” behavior to “early MM” with rapid transformation into symptomatic disease. This wide range of clinical outcomes poses challenges for prognostication and management of individual patients. However, initial studies showed a benefit in terms of progression or even survival for early treatment of high-risk SMM patients. While outside of clinical trials the conventional approach to SMM generally remains that of close observation, these studies raised the question of whether early treatment should be offered in high-risk patients, prompting evaluation of several different therapeutic approaches with different goals. While delay of progression to MM with a non-toxic treatment is clearly achievable by early treatment, a convincing survival benefit still needs to be proven by independent studies. Furthermore, if SMM is to be considered less biologically complex than MM, early treatment may offer the chance of cure that is currently not within reach of any active MM treatment. In this paper, we present updated results of completed or ongoing clinical trials in SMM treatment, highlighting areas of uncertainty and critical issues that will need to be addressed in the near future before the “watch and wait” paradigm in SMM is abandoned in favor of early treatment.

scholarly journals The role of idecabtagene vicleucel in patients with heavily pretreated refractory multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110196
Author(s):  
Albert Oriol ◽  
Laura Abril ◽  
Anna Torrent ◽  
Gladys Ibarra ◽  
Josep-Maria Ribera
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Safety Profile ◽  
Proteasome Inhibitors ◽  
Clinical Development ◽  
Phase Iii ◽  
Acceptable Safety Profile ◽  
Refractory Multiple Myeloma ◽  
High Risk Patients ◽  
Risk Patients

The development of several treatment options over the last 2 decades has led to a notable improvement in the survival of patients with multiple myeloma. Despite these advances, the disease remains incurable for most patients. Moreover, standard combinations of alkylating agents, immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies targeting CD38 and corticoids are exhausted relatively fast in a proportion of high-risk patients. Such high-risk patients account for over 20% of cases and currently represent a major unmet medical need. The challenge of drug resistance requires the development of highly active new agents with a radically different mechanism of action. Several immunotherapeutic modalities, including antibody–drug conjugates and T-cell engagers, appear to be promising choices for patients who develop resistance to standard combinations. Chimeric antigen-receptor-modified T cells (CAR-Ts) targeting B-cell maturation antigen have demonstrated encouraging efficacy and an acceptable safety profile compared with alternative options. Multiple CAR-Ts are in early stages of clinical development, but the first phase III trials with CAR-Ts are ongoing for two of them. After the recent publication of the results of a phase II trial confirming a notable efficacy and acceptable safety profile, idecabtagene vicleucel is the first CAR-T to gain regulatory US Food and Drug Administration approval to treat refractory multiple myeloma patients who have already been exposed to antibodies against CD38, proteasome inhibitors, and immunomodulatory agents and who are refractory to the last therapy. Here, we will discuss the preclinical and clinical development of idecabtagene vicleucel and its future role in the changing treatment landscape of relapsed and refractory multiple myeloma.

How I Treat High-risk Multiple Myeloma

Blood ◽  
2021 ◽  
Author(s):  
Elena Zamagni ◽  
Simona Barbato ◽  
Michele Cavo
Keyword(s):  
Quality Of Life ◽  
Risk Factors ◽  
Multiple Myeloma ◽  
Clinical Trials ◽  
High Risk ◽  
Tumor Biology ◽  
Treatment Strategies ◽  
Specific Drug ◽  
Improve Quality

Survival of multiple myeloma (MM) has significantly improved over the last decade; however, a composed group of patients (15-20%), named high-risk (HR) MM, still experience reduced survival. Both tumor biology and suboptimal/absent responses to therapy may underlie HR definition and a clear uniform identification of risk factors is crucial for a proper management of these patients. In biologic-HRMM, MRD negativity attainment and sustain, inside and outside BM, should be the primary goal and therapy should be adapted in patients with frailty to reduce toxicity and improve quality of life. MM treatment has traditionally been tailored on age and more recently frailty or comorbidities, but very rarely on the biology of the disease, mainly because of the lack of a clear benefit derived from a specific drug/combination, inhomogeneity in HR definition and lack of data coming from prospective, properly designed clinical trials. Some attempts have been successfully made recently in this direction. In this review, we are discussing the current different definitions of HR and the need for a consensus, the results of available trials in HR patients and the way through risk-adapted treatment strategies. For this purpose, we are proposing several clinical cases of difficult-to-treat patients throughout different treatment phases.

Transjugular Intrahepatic Portosystemic Shunts in High-Risk Patients

2020 ◽  
Vol 04 (02) ◽  
pp. 148-156
Author(s):  
David S. Shin ◽  
Hong Vo ◽  
Guy Johnson ◽  
Raimund Pichler ◽  
Scott W. Biggins
Keyword(s):  
High Risk ◽  
Cardiac Disease ◽  
Poor Prognosis ◽  
Hepatic Malignancy ◽  
Safety And Efficacy ◽  
End Stage Liver Disease ◽  
The Past ◽  
Portosystemic Shunts ◽  
Risk Patients ◽  
End Stage

AbstractCirrhosis with complications of portal hypertension portends a poor prognosis. Transjugular intrahepatic portosystemic shunts (TIPS) can successfully treat some of these complications in select patients. While the safety and efficacy of TIPS have improved significantly over the past decade, certain patients are categorized as high-risk based on various demographic, laboratory, and comorbid factors. Herein, we provide an in-depth review of TIPS in these settings, including high model for end-stage liver disease score, hepatic malignancy, advanced age, cardiac disease, renal dysfunction, and pregnancy, and discuss their impact on patient selection and procedural considerations.

scholarly journals Selinexor in relapsed/refractory multiple myeloma

2020 ◽  
Vol 11 ◽  
pp. 204062072093062 ◽  
Author(s):  
Joshua Richter ◽  
Deepu Madduri ◽  
Shambavi Richard ◽  
Ajai Chari
Keyword(s):  
Multiple Myeloma ◽  
Hematologic Malignancy ◽  
Proteasome Inhibitors ◽  
Significant Activity ◽  
Combination Drug ◽  
Drug Dosing ◽  
The Past ◽  
Fda Approval ◽  
Drug Choice ◽  
Combination Regimens

Multiple myeloma (MM) represents an incurable hematologic malignancy. Despite significant advances over the past decade, with the advent of multiple new classes of anti-myeloma agents, including immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies, patients ultimately relapse. Selinexor is a first-in-class exportin-1 inhibitor with activity in these multiply relapsed and refractory patients. Although the current Food and Drug Administration (FDA) approval is for the doublet of Selinexor in combination with dexamethasone, ongoing clinical trials are evaluating a number of combination regimens. These triplet and quadruplet, selinexor-based, regimens are showing significant activity in “triple-class” refractory patients. With appropriate combination drug choice, drug dosing, and supportive measures, patients with previously no viable options for therapy, now have multiple potential regimens to control their disease.

Global Approaches in Myeloma: Critical Trials That May Change Practice

2018 ◽  
pp. 656-661 ◽  
Author(s):  
Philippe Moreau ◽  
Cyrille Touzeau
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Therapeutic Strategies ◽  
New Drugs ◽  
High Dose ◽  
High Dose Therapy ◽  
The Past ◽  
Induced Changes ◽  
The Impact ◽  
Specific Section

The treatment of multiple myeloma (MM) has changed dramatically in the past decade with the introduction of new drugs into therapeutic strategies both in the frontline and relapse settings. With the availability of at least six different classes of agents that can be combined in doublet, triplet, or even quadruplet regimens and used together with high-dose therapy and autologous stem cell transplantation, the choice of the optimal strategy at diagnosis and at relapse represents a challenge for physicians. Also problematic is the lack of trials addressing questions, such as sequencing or the duration of maintenance. This review will focus on the results of recent clinical trials both in the frontline and relapse settings that have induced changes in clinical practice and will discuss the impact of important ongoing trials. A specific section will discuss therapeutic strategies when new drugs are not available.

Risk Stratification and Targets in Multiple Myeloma: From Genomics to the Bedside

2018 ◽  
pp. 675-680 ◽  
Author(s):  
Aurore Perrot ◽  
Jill Corre ◽  
Hervé Avet-Loiseau
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Plasma Cells ◽  
Mechanisms Of Action ◽  
The Past ◽  
Novel Drugs ◽  
Genetic Abnormalities ◽  
Frequent Mutations ◽  
Risk Patients ◽  
First Relapse

In the past 15 years, significant improvements in overall survival have been observed in multiple myeloma (MM), mainly due to the availability of novel drugs with variable mechanisms of action. However, these improvements do not benefit all patients, and some of them, defined as high risk, still display short survival. The most important risk factors are the genetic abnormalities present in the malignant plasma cells. The most important high-risk features are the del(17p), the del(1p32), the t(4;14), and 1q gains. Assessing these markers is mandatory at diagnosis and at least at first relapse, since it has been clearly shown that the lenalidomide-dexamethasone combination is not efficient in these high-risk patients. In contrast, a triplet combination adding a proteasome inhibitor or a monoclonal antibody to the lenalidomide-dexamethasone backbone clearly improves the survival. Another way to improve the outcome would be to specifically target genetic abnormalities with specific inhibitors. The sequencing of more than 1,000 MM exomes revealed again a huge heterogeneity. The most frequent mutations involve the KRAS and NRAS genes (20%–25% each). However, to date, no good RAS-inhibitors are clinically available, preventing targeted therapy. The only drugable target is the V600E BRAF mutation. Unfortunately, this specific mutation is present in only 3% of the patients. Finally, it has been recently reported a specific efficiency of the BCL2-inhibitor venetoclax in patients with the t(11;14) translocation, which is found in 20% of the patients.

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