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.

Autologous Stem-Cell Transplantation for Multiple Myeloma in the Era of Novel Therapies

2020 ◽  
Vol 16 (2) ◽  
pp. 56-66 ◽  
Author(s):  
Ricardo D. Parrondo ◽  
Sikander Ailawadhi ◽  
Taimur Sher ◽  
Asher A. Chanan-Khan ◽  
Vivek Roy
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Residual Disease ◽  
Proteasome Inhibitors ◽  
Novel Therapies ◽  
Immunomodulatory Agents

Despite the evolution of the therapeutic arsenal for the treatment of multiple myeloma (MM) over the past decade, autologous stem-cell transplantation (ASCT) remains an integral part of the treatment of patients with both newly diagnosed and relapsed MM. The advent of novel therapies, such as immunomodulatory agents, proteasome inhibitors, and monoclonal antibodies, has led to unprecedented levels of deep hematologic responses. Nonetheless, studies show that ASCT has an additive effect leading to additional deepening of responses. As the therapeutic agents for MM continue to evolve, the timing, duration, and sequence of their use in combination with ASCT will be crucial to understand to obtain the deepest response and survival benefit for patients with MM. This review aims to discuss the role of ASCT for the management of MM, with a particular focus on the role of ASCT in the context of novel therapies and minimal residual disease.

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 relapsed and/or refractory multiple myeloma

2020 ◽  
Vol 12 (s1) ◽  
Author(s):  
Hans C. Lee ◽  
Claudio Cerchione
Keyword(s):  
Multiple Myeloma ◽  
Nuclear Export ◽  
Histone Deacetylase Inhibitors ◽  
Alkylating Agents ◽  
Treatment Options ◽  
Unmet Need ◽  
Proteasome Inhibitors ◽  
Antibody Drug Conjugate ◽  
Refractory Multiple Myeloma ◽  
Therapeutic Landscape

The expanding therapeutic landscape of relapsed and/or refractory multiple myeloma (RRMM) has contributed to significant improvements in patient outcomes. These have included combinations of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (mAbs), histone deacetylase inhibitors, and/or alkylating agents. More recently, the approval of the first-in-class nuclear export inhibitor selinexor and the first-in-class B-cell maturation antigen (BCMA) antibody-drug conjugate (ADC) belantamab mafodotin has helped address the current unmet need in patients refractory to PI, IMiD, and anti-CD38 mAb directed therapy, otherwise known as triple class refractory myeloma. With the growing number of treatment options in the RRMM therapeutic landscape, the choice and sequencing of drugs and combinations has become increasingly complex. In this review we discuss our approach and considerations in the treatment of both early and late RRRM based on best available data and our clinical experience.

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 Targets and New Agents in High-Risk Multiple Myeloma

2016 ◽  
pp. e431-e441 ◽  
Author(s):  
Ajay K. Nooka ◽  
Sagar Lonial
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Personalized Medicine ◽  
Residual Disease ◽  
Proteasome Inhibitors ◽  
New Agents ◽  
Immunomodulatory Agents ◽  
Single Drug ◽  
Sequencing Studies ◽  
Minimal Residual

Advances in the treatment of multiple myeloma have resulted in dramatic improvements in outcomes for patients. The newly emerging profiling of mutations emerging as a consequence of large prospective sequencing studies such as the CoMMpass Study or other efforts from European investigators are not further helping to define the place and role for personalized medicine in myeloma. While mutations such as NRAS, KRAS, and BRAF do occur in myeloma, it is not clear that targeting them as a single drug strategy will result in meaningful responses or durations of response. Personalized medicine in multiple myeloma at this time likely entails the use of risk-based approaches for maintenance therapy, the use of current biology-based treatments such as proteasome inhibitors, and immunomodulatory agents, with an eye towards the use of mutation-specific treatments in the setting of minimal residual disease or in concert with biology-based treatments overall.

Real-world treatment patterns in relapsed/refractory multiple myeloma: Clinical and economic outcomes in patients treated with pomalidomide or daratumumab

2021 ◽  
pp. 107815522199553
Author(s):  
Joshua Richter ◽  
Vamshi Ruthwik Anupindi ◽  
Jason Yeaw ◽  
Suneel Kudaravalli ◽  
Stojan Zavisic ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Real World ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Economic Outcomes ◽  
Office Visits ◽  
Refractory Multiple Myeloma ◽  
Kaplan Meier ◽  
Real World Evidence ◽  
New Treatment

Introduction Real-world evidence on later line treatment of relapsed/refractory multiple myeloma (RRMM) is sparse. We evaluated clinical outcomes among RRMM patients in the 1-year following treatment with pomalidomide or daratumumab and compared economic outcomes between RRMM patients and non-MM patients. Patient and Methods Adult patients with ≥1 claim of pomalidomide or daratumumab were identified between January 2012 and February 2018 using IQVIA PharMetrics® Plus US claims database. Patients were required to have a diagnosis or treatment for MM and a claim of any immunomodulatory drugs and proteasome inhibitors before the index date. Mean time to new therapy, overall survival (OS) using Kaplan-Meier curve and adverse events (AEs) were reported over the 1-year post-index period. RRMM patients were also matched to a non-MM comparator cohort and economic outcomes were compared between the two cohorts. Results 289 RRMM patients were matched to 1,445 patients without MM. Most prevalent hematological AE was anemia (72.0%) and non-hematological AE was infections (75.4%). Mean (SD) time to a new treatment was 4.7 (5.3) months and median OS was 14.6 months. RRMM patients had significantly higher hospitalizations and physician office visits (Both P < .0001) compared to non-MM patients. Adjusting for baseline characteristics, patients with RRMM had 4.9 times (95% CI 3.8-6.4, P < .0001) the total healthcare costs compared with patients without MM. The major driver of total costs among RRMM patients was pharmacy costs (67.3%). Conclusion RRMM patients showed a high frequency of AEs, low OS, and a substantial economic burden suggesting need for effective treatment options.

Third-Generation and Investigational Cephalosporins: I. Structure-Activity Relationships and Pharmacokinetic Review

1983 ◽  
Vol 17 (7-8) ◽  
pp. 507-515 ◽  
Author(s):  
Pamela Garzone ◽  
James Lyon ◽  
Victor L. Yu
Keyword(s):  
Classification Scheme ◽  
Third Generation ◽  
Serum Concentrations ◽  
New Agents ◽  
The Third ◽  
Structure Activity ◽  
Pharmacokinetic Properties ◽  
Fluid Penetration ◽  
Third Generation Cephalosporins ◽  
Antibacterial Spectrum

The structure-relationships and pharmacokinetic properties of the new second- and third-generation cephalosporins are reviewed. The new second-generation cephalosporins include ceforanide, cefotiam, and cefuroxime. The third-generation cephalosporins include cefmenoxime, cefoperazone, cefotaxime, cefsulodin, ceftazidime, ceftizoxime, ceftriaxone, and moxalactam. These new cephalosporins are semisynthetic analogs with different chemical substitutions on a 7-aminocephalosporanic nucleus. As a result of these chemical modifications, improvements in the antibacterial spectrum as well as pharmacokinetic properties have occurred. In general, the new cephalosporins have longer half-lives, higher and prolonged serum concentrations, and increased cerebrospinal fluid penetration. Selected cephalosporins also have increased biliary tract concentrations. A classification scheme for these new agents, based on generation and susceptibility to Pseudomonas aeruginosa, is presented.

Relapsed Multiple Myeloma

Hematology ◽  
2010 ◽  
Vol 2010 (1) ◽  
pp. 303-309 ◽  
Author(s):  
Sagar Lonial
Keyword(s):  
Multiple Myeloma ◽  
Clinical Trials ◽  
Phase 1 ◽  
Treatment Options ◽  
Single Agent ◽  
Great Promise ◽  
New Agents ◽  
Ongoing Work ◽  
The Many

Abstract Advances in treatment options for patients with multiple myeloma have made a significant impact on the overall survival of patients and have helped achieve levels of response and duration of remission previously not achievable with standard chemotherapy-based approaches. These improvements are due, in large part, to the development of the novel agents thalidomide, bortezomib, and lenalidomide, each of which has substantial single-agent activity. In addition, a large number of second-generation agents are also in clinical development, such that the repertoire of available treatment options continues to expand. To better interpret clinical trials performed in the relapsed setting, it is important that definitions of relapse categories are used to help better pinpoint the specific benefit for a given therapy, especially in the combination therapy setting as it aids in determining if ongoing work should be continued or abandoned for a given new agent. Insights from preclinical modeling and in vitro work have identified several new combinations, new targets and second- or third-generation versions of existing targets that hold great promise in the setting of relapsed myeloma. Combinations of thalidomide, bortezomib, and lenalidomide with conventional agents or among each other have resulted in enhanced response rates and efficacy. Clinical trials of agents such as carfilzomib, pomalidomide, vorinostat, panobinostat, and elotuzomab are just a few of the many exciting new compounds that are being tested in phase 1 and phase 2 clinical trials for relapsed patients. Further clinical and translational testing are critical to better understanding how best to combine these new agents, as well as identifying patient populations that may best benefit from treatment with these developing new agents.

scholarly journals Monoclonal Antibody Therapies in Multiple Myeloma: A Challenge to Develop Novel Targets

2019 ◽  
Vol 2019 ◽  
pp. 1-10 ◽  
Author(s):  
Hiroko Nishida ◽  
Taketo Yamada
Keyword(s):  
Multiple Myeloma ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Novel Agents ◽  
Current Status ◽  
Antibody Drug Conjugate ◽  
The Past ◽  
Deacetylase Inhibitor ◽  
Car T ◽  
Immune Therapies

The treatment options in multiple myeloma (MM) has changed dramatically over the past decade with the development of novel agents such as proteasome inhibitors (PIs); bortezomib and immunomodulatory drugs (IMiDs); thalidomide, and lenalidomide which revealed high efficacy and improvement of overall survival (OS) in MM patients. However, despite these progresses, most patients relapse and become eventually refractory to these therapies. Thus, the development of novel, targeted immunotherapies has been pursued aggressively. Recently, next-generation PIs; carfilzomib and ixazomib, IMiD; pomalidomide, histone deacetylase inhibitor (HDADi); panobinostat and monoclonal antibodies (MoAbs); and elotuzumab and daratumumab have emerged, and especially, combination of mAbs plus novel agents has led to dramatic improvements in the outcome of MM patients. The field of immune therapies has been accelerating in the treatment of hematological malignancies and has also taken center stage in MM. This review focuses on an overview of current status of novel MoAb therapy including bispecific T-cell engager (BiTE) antibody (BsAb), antibody-drug conjugate (ADC), and chimeric antigen receptor (CAR) T cells, in relapsed or refractory MM (RRMM). Lastly, investigational novel MoAb-based therapy to overcome immunotherapy resistance in MM is shown.

Second Autologous Stem Cell Transplant (ASCT) as Salvage Therapy for Relapsed Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1170-1170
Author(s):  
Rebecca L. Olin ◽  
David L. Porter ◽  
Selina M. Luger ◽  
Stephen J. Schuster ◽  
Donald Tsai ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplant ◽  
Treatment Options ◽  
Univariate Analysis ◽  
Complete Response ◽  
Autologous Stem Cell Transplant ◽  
Response To Therapy ◽  
Cell Transplant ◽  
Significant Difference

Abstract Introduction: Autologous stem cell transplant (ASCT) as part of initial therapy has been shown to prolong survival of patients with multiple myeloma, with some achieving durable complete remission. However, the majority of patients ultimately relapse after ASCT and require salvage treatment. Options for the treatment of such patients have increased significantly over recent years, including not only novel chemotherapeutic and biological agents but also additional ASCTs. We performed a retrospective analysis of our experience with salvage ASCT for multiple myeloma to determine which clinical variables influence outcome. Methods: Between October 1992 and February 2005, we performed 342 ASCTs for multiple myeloma. Twenty-six of these were salvage transplants for relapsed disease after prior ASCT, and all were included in the analysis. Patients who received two planned (tandem) ASCTs were not included. Results: The median age at diagnosis was 47 (range 25–66), and median ISS and DS stages at diagnosis were 1 and 2, respectively. The initial ASCT was melphalan-based in 21/26; six (23%) achieved a complete response (CR) to the initial transplant, and fifteen (58%) achieved a partial response (PR). The median event-free survival (EFS) after the initial transplant was 19.5 months (range 2–60). The median time between initial and salvage ASCT was 2.6 years (range 0.3–7.6). Twenty-two patients (85%) received non-transplant therapy between ASCTs, and the median number of lines of therapy prior to salvage ASCT was 3. At the time of salvage ASCT, the median age was 52.5 (range 28–69). Fourteen patients received melphalan alone, eight received melphalan/TBI, and four received other regimens. Eleven patients (42%) achieved a response to therapy (1 CR, 10 PR). One patient (4%) died of transplant-related toxicity. The median follow-up after salvage ASCT is 12 months (range 0.2–58). Median EFS is 9 months, and median overall survival (OS) is 36 months. The 2-year EFS is 14%, and 2-year OS is 52%. On univariate analysis, both response to and EFS after initial transplant significantly predict improved EFS after salvage transplant (p=0.0008 and p=0.0065 respectively). Both also predict improved OS (p=0.03 and 0.0005 respectively). A greater than 12 month interval between first and second transplant also correlated with OS (p=0.04). There was no significant difference in EFS or OS by preparative regimen. Interestingly, type of response to the salvage transplant (CR/PR or less than PR) did not predict improved EFS or OS. Conclusion: This study suggests that salvage ASCT after relapse from initial ASCT is a feasible therapy for patients with heavily treated multiple myeloma, particularly those with a prolonged response to the first transplant.

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