scholarly journals A Review on Therapeutic strategies of Relapsed and Refractory Multiple Myeloma

2021 ◽  
Author(s):  
Dattatreya Mukherjee
Keyword(s):  
Multiple Myeloma ◽  
Current Practice ◽  
Treatment Options ◽  
Therapeutic Strategies ◽  
Effective Technique ◽  
Free Survival ◽  
Immune Modulators ◽  
Multiple Mechanism ◽  
Deacetylase Inhibitor ◽  
Treatment Prognosis

Improvement in treatment options in multiple myeloma (MM) makes the survival rate intodouble during recent years but most of the patient eventually relapses. The treatment of relapseand refracting MM is still now very complex. At the time of relapse, the use of alternative drugsis the current practice. Using Protease inhibitors like Bortezomib and immune-modulators likethalidomide gives a satisfactory treatment prognosis in MM. Now many new options areavailable like second and third generation protease inhibitor like carfilzomib and ixazomib, theimmune-modulator like lenalidomide, pomalidomide, the monoclonal antibody likedaratumumab, elotuzumab, Histone Deacetylase inhibitor, Kinesin Spindle inhibitor and NF-kB,MAPK, AKT inhibitors. Daratumumab, targeting CD38, has multiple mechanism of action likemodulation immunosuppressive bone marrow micro-environment. Daratuzumab has a goodprogression free survival when it is given with lenalidomide/ dexamethasone orbortezomib/dexamethsone. Autologous stem cell transplantation (ASCT) is important treatmentin relapsing and refracting MM. Donor lymphocytic infusion is a new and effective technique inthe treatment of relapsing and refracting MM. The advancement in the treatment of relapsed andrefractory MM has been discussed in this article. The final goal should be finding a balancebetween efficacy, toxicity and cost.

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.

scholarly journals Lenalidomide in Relapsed and Refractory Multiple Myeloma

2020 ◽  
Author(s):  
Dattatreya Mukherjee
Keyword(s):  
Multiple Myeloma ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Good Prognosis ◽  
Front Line ◽  
Hematological Disease ◽  
Disease Treatment ◽  
Free Survival ◽  
Refractory Case ◽  
Alternative Drugs

Improvement in the treatment options in multiple myeloma(MM) makes the survival rate into double during recent years but most of the patient eventually relapses. At the time of relapses, the use of alternative drugs is the current practice. Lenalidomide is an immuno-modulators and it is one of the most versatile drug which is used in several Hematological disease treatment including MM. Several clinical trials have shown a better progression free survival(PFS) and overall survival(OS) with Lenalidomide based regimens. In Pollux study, the regimen with Daratuzumab with Lenalidomide and dexamethasone has shown much better OS and PFS than only Lenalidomide and Dexamethasone. But Some times patients are refractive to Lenalidomides. In that case Pomalidomide or bortezomib based regimen is used. Although Lenalidomide is one of the most promising drug to treat both first line and Relapse-refractory case of MM. Hemato oncology is a challenging topic and its correlated with personalized medicine this days. Different clinical trial are going on with different regimen. In some patient some regimen is showing good result and in some other regimen is giving good prognosis. So its always tough to tell which is the best regimen. In this article we will focus on use of Lenalidomide based regimes and we will see the median OS and median PFS of all these Lenalidomide based regimen. Althrough there is a good room for research on Len refractive cases and personalized treatment in multiple myeloma in both front line and relapsed and refractory cases.

scholarly journals Daratumumab plus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma

Blood ◽  
2019 ◽  
Vol 134 (5) ◽  
pp. 421-431 ◽  
Author(s):  
Ajai Chari ◽  
Joaquín Martinez-Lopez ◽  
María-Victoria Mateos ◽  
Joan Bladé ◽  
Lotfi Benboubker ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Common Grade ◽  
Frontline Treatment ◽  
Phase 1B ◽  
Immunomodulatory Drug ◽  
Grade 3

Abstract Patients with relapsed or refractory multiple myeloma (RRMM) have limited treatment options and poor survival outcomes. The increasing adoption of lenalidomide-based therapy for frontline treatment of multiple myeloma has resulted in a need for effective regimens for lenalidomide-refractory patients. This phase 1b study evaluated daratumumab plus carfilzomib and dexamethasone (D-Kd) in patients with RRMM after 1 to 3 prior lines of therapy, including bortezomib and an immunomodulatory drug; lenalidomide-refractory patients were eligible. Carfilzomib- and daratumumab-naïve patients (n = 85) received carfilzomib weekly on days 1, 8, and 15 of each 28-day cycle (20 mg/m2 initial dose, escalated to 70 mg/m2 thereafter) and dexamethasone (40 mg/wk). Of these, 10 patients received the first daratumumab dose as a single infusion (16 mg/kg, day 1 cycle 1), and 75 patients received a split first dose (8 mg/kg, days 1-2 cycle 1). Subsequent dosing was per the approved schedule for daratumumab. Patients received a median of 2 (range, 1-4) prior lines of therapy; 60% were lenalidomide refractory. The most common grade 3/4 treatment-emergent adverse events were thrombocytopenia (31%), lymphopenia (24%), anemia (21%), and neutropenia (21%). Infusion-related reactions were observed in 60% and 43% of single and split first-dose patients, respectively. Overall response rate was 84% (79% in lenalidomide-refractory patients). Median progression-free survival (PFS) was not reached; 12-month PFS rates were 74% for all treated patients and 65% for lenalidomide-refractory patients. D-Kd was well tolerated with low neutropenia rates, and it demonstrated deep responses and encouraging PFS, including in patients refractory to lenalidomide. The trial was registered at www.clinicaltrials.gov as #NCT01998971.

scholarly journals Systematic Literature Review and Network Meta-Analysis of Treatments for Relapsed/Refractory Multiple Myeloma Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2144-2144
Author(s):  
Chrissy H. Y. Van Beurden-Tan ◽  
Margreet Franken ◽  
Hedwig Blommestein ◽  
Carin A. Uyl-De Groot ◽  
Pieter Sonneveld
Keyword(s):  
Multiple Myeloma ◽  
Research Funding ◽  
Meta Analysis ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Relative Efficacy ◽  
Advisory Committees ◽  
Free Survival ◽  
Refractory Multiple Myeloma ◽  
Risk Of Progression

Abstract INTRODUCTION Since the year 2000 fifteen new treatment options came to market for relapsed/refractory multiple myeloma (RRMM) after a long period in which dexamethasone has been the only treatment option. Direct comparisons are, however, lacking which makes it extremely difficult to evaluate the relative added value of each drug. Our aim was to synthesize all efficacy evidence enabling a comparison of all treatments. METHODS We performed a systematic literature review to identify all publically available phase 3 randomized controlled trials (RCTs) using EMBASE®, MEDLINE®, MEDLINE® in-process, Cochrane Central Register of Controlled Clinical Trials and the website www.clinical-trials.gov. Additionally, two abstracts from international hematology congresses (ASCO and EHA 2016) were added to our search to present the most up-to-date overview. A conventional network meta-analysis (NMA) based on progression-free survival (PFS) outcomes allowed a comparison of all available treatment options using a Bayesian fixed effect NMA programmed in WinBUGS. The oldest treatment, dexamethasone, was used as reference treatment. Additionally, results regarding bortezomib-dexamethasone versus lenalidomide-dexamethasone are presented because these were the two most commonly used comparators. RESULTS Seventeen RCTs were identified including sixteen treatment options: dexamethasone (Dex), oblimersen-dexamethasone (OblDex), thalidomide/thalidomide-dexamethasone (Thal/ThalDex), bortezomib/bortezomib-dexamethasone (Bor/BorDex), lenalidomide-dexamethasone (LenDex), pegylated doxorubicin-bortezomib (PeglDoxBor), bortezomib-thalidomide-dexamethasone (BorThalDex), vorinostat-bortezomib (VorinoBor), panobinostat-bortezomib-dexamethasone (PanoBorDex), carfilzomib-lenalidomide-dexamethasone (CarLenDex), pomalidomide-dexamethasone (PomDex), elotuzumab-lenalidomide-dexamethasone (EloLenDex), carfilzomib-dexamethasone (CarDex), ixazomib-lenalidomide-dexamethasone (IxaLenDex), daratumumab-lenalidomide-dexamethasone (DaraLenDex) and daratumumab-bortezomib-dexamethasone (DaraBorDex). To include all trials within one framework, we assumed: i) the relative efficacy of Bor versus Dex and BorDex versus Dex is the same, ii) the relative efficacy of Thal versus Dex and ThalDex versus Dex is the same, iii) time to progression (TTP) can be used as proxy for PFS in case of missing hazard ratios (HRs) and 95% confidence intervals of PFS, and iv) no difference in efficacy due to dosage scheme (100 versus 200 versus 400 mg Thal) and administration method (intravenous versus subcutaneous Bor). Figure 1 presents the NMA results. The treatments are sorted according to their rank. The figure also presents the probability of being the best treatment, HRs and 95% credible intervals (CrIs) versus Dex. Fourteen out of sixteen treatments were significantly better than Dex (HRs ranged from 0.13 to 0.76). Only OblDex ranked lower; the HR was, however, not significantly different (HR: 1.08; 95% CrI: 0.79 - 1.45). Eleven treatments reduced the risk of progression or death with more than 50%. DaraLenDex was identified as the best treatment because it was the most favorable in terms of i) HR (0.13; 95% CrI: 0.09 - 0.19), and ii) probability of being best (99% of the simulations). DaraLenDex reduced the risk of progression or death with 87% versus Dex, 80% versus Bor/BorDex and 63% versus LenDex. LenDex performed better than Bor/BorDex in ranking (7th versus 13th) as well as in HR (0.53, 95% CrI: 0.39 - 0.71). CONCLUSIONS Our NMA included all available RRMM treatments and identified DaraLenDex as being most effective. NMAs become increasingly important because they provide a complete overview of each treatment's relative efficacy in case of missing head-to-head comparisons. Figure 1. Relapsed/refractory multiple myeloma treatments' network meta-analysis results of progression-free survival outcomes Figure 1. Relapsed/refractory multiple myeloma treatments' network meta-analysis results of progression-free survival outcomes Disclosures Blommestein: BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Sonneveld:Amgen: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Takeda: Consultancy, Honoraria.

scholarly journals Sequencing of nontransplant treatments in multiple myeloma patients with active disease

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 495-503 ◽  
Author(s):  
Andrew J. Yee ◽  
Noopur S. Raje
Keyword(s):  
Multiple Myeloma ◽  
Treatment Options ◽  
Proteasome Inhibitors ◽  
Autologous Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Depth Of Response ◽  
Deacetylase Inhibitor ◽  
Core Components ◽  
High Dose Melphalan

AbstractThe approval of several different classes of drugs in recent years has resulted in a dramatic expansion of treatment options for multiple myeloma patients, improving both survival and quality of life. Lenalidomide and bortezomib are now core components of treatment both at time of diagnosis and at relapse. Next-generation immunomodulatory drugs, like pomalidomide, and newer proteasome inhibitors like carfilzomib and ixazomib are available for use at relapse. Drugs with novel mechanisms of action such as the histone deacetylase inhibitor panobinostat and the monoclonal antibodies targeting SLAMF7 (elotuzumab) and CD38 (daratumumab) are significant steps forward. Recent clinical trials describing novel combinations of these drugs have demonstrated unprecedented improvements in efficacy while maintaining tolerability. All of these options provide not only a challenge for choice of therapy, but also the opportunity to aim for increasing depth of response. This chapter will describe an approach on how to sequence and incorporate these therapies, focusing on patients where high-dose melphalan and autologous stem cell transplant are deferred or not applicable.

Új lehetőségek a refrakter és relabált Hodgkin-lymphomás betegek kezelésében

2015 ◽  
Vol 156 (45) ◽  
pp. 1824-1833 ◽  
Author(s):  
Árpád Illés ◽  
Ádám Jóna ◽  
Zsófia Simon ◽  
Miklós Udvardy ◽  
Zsófia Miltényi
Keyword(s):  
Stem Cell ◽  
Hodgkin Lymphoma ◽  
Treatment Options ◽  
Survival Rates ◽  
Relapse Free Survival ◽  
Term Survival ◽  
Free Survival ◽  
Novel Treatment ◽  
Refractory Hodgkin Lymphoma

Introduction: Hodgkin lymphoma is a curable lymphoma with an 80–90% long-term survival, however, 30% of the patients develop relapse. Only half of relapsed patients can be cured with autologous stem cell transplantation. Aim: The aim of the authors was to analyze survival rates and incidence of relapses among Hodgkin lymphoma patients who were treated between January 1, 1980 and December 31, 2014. Novel therapeutic options are also summarized. Method: Retrospective analysis of data was performed. Results: A total of 715 patients were treated (382 men and 333 women; median age at the time of diagnosis was 38 years). During the studied period the frequency of relapsed patients was reduced from 24.87% to 8.04%. The numbers of autologous stem cell transplantations was increased among refracter/relapsed patients, and 75% of the patients underwent transplantation since 2000. The 5-year overall survival improved significantly (between 1980 and 1989 64.4%, between 1990 and 1999 82.4%, between 2000 and 2009 88.4%, and between 2010 and 2014 87.1%). Relapse-free survival did not change significantly. Conclusions: During the study period treatment outcomes improved. For relapsed/refractory Hodgkin lymphoma patients novel treatment options may offer better chance for cure. Orv. Hetil., 2015, 156(45), 1824–1833.

Stew in its Own Juice: Protein Homeostasis Machinery Inhibition Reduces Cell Viability in Multiple Myeloma Cell Lines

2019 ◽  
Vol 19 (2) ◽  
pp. 112-119 ◽  
Author(s):  
Mariana B. de Oliveira ◽  
Luiz F.G. Sanson ◽  
Angela I.P. Eugenio ◽  
Rebecca S.S. Barbosa-Dantas ◽  
Gisele W.B. Colleoni
Keyword(s):  
Multiple Myeloma ◽  
Cell Death ◽  
Cell Viability ◽  
Cell Lines ◽  
Treatment Options ◽  
Compensatory Mechanism ◽  
Protein Homeostasis ◽  
Protein Response ◽  
Rpmi 8226

Introduction:Multiple myeloma (MM) cells accumulate in the bone marrow and produce enormous quantities of immunoglobulins, causing endoplasmatic reticulum stress and activation of protein handling machinery, such as heat shock protein response, autophagy and unfolded protein response (UPR).Methods:We evaluated cell lines viability after treatment with bortezomib (B) in combination with HSP70 (VER-15508) and autophagy (SBI-0206965) or UPR (STF- 083010) inhibitors.Results:For RPMI-8226, after 72 hours of treatment with B+VER+STF or B+VER+SBI, we observed 15% of viable cells, but treatment with B alone was better (90% of cell death). For U266, treatment with B+VER+STF or with B+VER+SBI for 72 hours resulted in 20% of cell viability and both treatments were better than treatment with B alone (40% of cell death). After both triplet combinations, RPMI-8226 and U266 presented the overexpression of XBP-1 UPR protein, suggesting that it is acting as a compensatory mechanism, in an attempt of the cell to handle the otherwise lethal large amount of immunoglobulin overload.Conclusion:Our in vitro results provide additional evidence that combinations of protein homeostasis inhibitors might be explored as treatment options for MM.

scholarly journals Role of the Pharmacist in Managing Treatment-Resistant Depression: A Focus on Ketamine

Pharmacy ◽  
2021 ◽  
Vol 9 (3) ◽  
pp. 118
Author(s):  
Linda Xing Yu Liu ◽  
Marina Golts ◽  
Virginia Fernandes
Keyword(s):  
Current Practice ◽  
Quality Care ◽  
Treatment Options ◽  
Critical Role ◽  
Transitions Of Care ◽  
Treatment Resistant Depression ◽  
Treatment Resistant ◽  
Resistant Depression ◽  
Multiple Treatments ◽  
The Impact

The impact of depression is well described in the literature, and it is most prominent in patients who have trialed multiple treatments. Treatment-resistant depression (TRD) is particularly debilitating, and it is associated with significant morbidity and mortality. Despite this, there seems to be therapeutic inertia in adopting novel therapies in current practice. Ketamine is an N-methyl-D-aspartate receptor antagonist and anesthetic agent which has recently been shown to be effective in the management of TRD when administered intravenously or intranasally. The treatments, however, are not easily accessible due to restrictions in prescribing and dispensing, high costs, and the slow uptake of evidence-based practice involving ketamine within the Canadian healthcare system. Given the limited treatment options for TRD, novel approaches should be considered and adopted into practice, and facilitated by a multi-disciplinary approach. Pharmacists play a critical role in ensuring access to quality care. This includes dissemination of evidence supporting pharmacological treatments and facilitating translation into current practice. Pharmacists are uniquely positioned to collaborate with prescribers and assess novel treatment options, such as ketamine, address modifiable barriers to treatment, and triage access to medications during transitions of care. Extending the reach of these novel psychiatric treatments in both tertiary and primary care settings creates an emerging role for pharmacists in the collaborative effort to better manage treatment-resistant depression.

scholarly journals Bevacizumab plus capecitabine as later-line treatment for patients with metastatic colorectal cancer refractory to irinotecan, oxaliplatin, and fluoropyrimidines

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Yeong Hak Bang ◽  
Jeong Eun Kim ◽  
Ji Sung Lee ◽  
Sun Young Kim ◽  
Kyu-Pyo Kim ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Median Overall Survival ◽  
Treatment Options ◽  
Multivariable Analysis ◽  
Progression Free Survival ◽  
Line Treatment ◽  
Free Survival ◽  
Medical Need ◽  
Significant Disease

AbstractThere is an unmet medical need for later-line treatment options for patients with metastatic colorectal cancer (mCRC). Considering that, beyond progression, co-treatment with bevacizumab and cytotoxic chemotherapy showed less toxicity and a significant disease control rate, we aimed to evaluate the efficacy of capecitabine and bevacizumab. This single-center retrospective study included 157 patients between May 2011 and February 2018, who received bevacizumab plus capecitabine as later-line chemotherapy after progressing with irinotecan, oxaliplatin, and fluoropyrimidines. The study treatment consisted of bevacizumab 7.5 mg/kg on day 1 and capecitabine 1,250 mg/m2 orally (PO) twice daily on day 1 to 14, repeated every 3 weeks. The primary endpoint was progression-free survival (PFS). The median PFS was 4.6 months (95% confidence interval [CI] 3.9–5.3). The median overall survival (OS) was 9.7 months (95% CI 8.3–11.1). The overall response rate was 14% (22/157). Patients who had not received prior targeted agents showed better survival outcomes in the multivariable analysis of OS (hazard ratio [HR] = 0.59, 95% CI 0.43–0.82, P = 0.002) and PFS (HR = 0.61, 95% CI 0.43–0.85, P = 0.004). Bevacizumab plus capecitabine could be a considerably efficacious option for patients with mCRC refractory to prior standard treatments.

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.

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