scholarly journals New Insights into Therapeutic Targets in Myeloma

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 184-190 ◽  
Author(s):  
Kenneth C. Anderson
Keyword(s):  
Rapid Evolution ◽  
Proteasome Inhibitors ◽  
Complete Response ◽  
Patient Stratification ◽  
Immunomodulatory Drugs ◽  
Combination Therapies ◽  
Number Of Patients ◽  
Treatment Paradigm ◽  
Novel Targets ◽  
And Personalized Medicine

Abstract Patient outcome in multiple myeloma (MM) has been remarkably improved due to the use of combination therapies including proteasome inhibitors and immunomodulatory drugs, which target the tumor in its BM microenvironment. Ongoing efforts to improve the treatment paradigm even further include using oncogenomics to better characterize molecular pathogenesis and to develop refined patient stratification and personalized medicine in MM; using models of MM in its BM milieu to identify novel targets and to validate next-generation therapeutics directed at these targets; developing immune-based therapies including mAbs, immunotoxins targeting MM cells and cytokines, and novel vaccine strategies; and using functional oncogenomics to inform the design of novel combination therapies. With continued rapid evolution of progress in these areas, MM will be a chronic illness with sustained complete response in a significant number of patients.

scholarly journals New Insights into Therapeutic Targets in Myeloma

Hematology ◽  
2011 ◽  
Vol 2011 (1) ◽  
pp. 184-190 ◽  
Author(s):  
Kenneth C. Anderson
Keyword(s):  
Rapid Evolution ◽  
Proteasome Inhibitors ◽  
Complete Response ◽  
Patient Stratification ◽  
Immunomodulatory Drugs ◽  
Combination Therapies ◽  
Number Of Patients ◽  
Treatment Paradigm ◽  
Novel Targets ◽  
And Personalized Medicine

Patient outcome in multiple myeloma (MM) has been remarkably improved due to the use of combination therapies including proteasome inhibitors and immunomodulatory drugs, which target the tumor in its BM microenvironment. Ongoing efforts to improve the treatment paradigm even further include using oncogenomics to better characterize molecular pathogenesis and to develop refined patient stratification and personalized medicine in MM; using models of MM in its BM milieu to identify novel targets and to validate next-generation therapeutics directed at these targets; developing immune-based therapies including mAbs, immunotoxins targeting MM cells and cytokines, and novel vaccine strategies; and using functional oncogenomics to inform the design of novel combination therapies. With continued rapid evolution of progress in these areas, MM will be a chronic illness with sustained complete response in a significant number of patients.

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 Brain Complete Response to Cabozantinib prior to Radiation Therapy in Metastatic Renal Cell Carcinoma

2019 ◽  
Vol 2019 ◽  
pp. 1-4 ◽  
Author(s):  
An Uche ◽  
Chad Sila ◽  
Tad Tanoura ◽  
James Yeh ◽  
Neil Bhowmick ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Radiation Therapy ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Kinase Inhibitor ◽  
Complete Response ◽  
Heavily Pretreated ◽  
Treatment Paradigm ◽  
Endothelial Growth Factor

Cabozantinib represents an established vascular endothelial growth factor- (VEGF-) tyrosine kinase inhibitor (TKI) in the treatment paradigm of metastatic renal cell carcinoma (mRCC). Its activity in mRCC patients with brain metastases (BMs) has been largely underreported in prospective clinical trials. We present the unique case of a heavily pretreated mRCC patient with BMs who achieved a brain complete response to cabozantinib prior to receiving radiation therapy. We end with a literature review and discussion of the biologic rationale and growing evidence supporting the intracranial activity of cabozantinib.

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.

scholarly journals Combination of subtherapeutic anti-TNF dose with dasatinib restores clinical and molecular arthritogenic profiles better than standard anti-TNF treatment

2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Lydia Ntari ◽  
Christoforos Nikolaou ◽  
Ksanthi Kranidioti ◽  
Dimitra Papadopoulou ◽  
Eleni Christodoulou-Vafeiadou ◽  
...  
Keyword(s):  
Gene Expression ◽  
Therapeutic Effect ◽  
Expression Analysis ◽  
Mode Of Action ◽  
Gene Expression Analysis ◽  
Kinase Inhibitors ◽  
High Dose ◽  
Dependent Manner ◽  
Combination Therapies ◽  
Number Of Patients

Abstract Background New medications for Rheumatoid Arthritis (RA) have emerged in the last decades, including Disease Modifying Antirheumatic Drugs (DMARDs) and biologics. However, there is no known cure, since a significant proportion of patients remain or become non-responders to current therapies. The development of new mode-of-action treatment schemes involving combination therapies could prove successful for the treatment of a greater number of RA patients. Methods We investigated the effect of the Tyrosine Kinase inhibitors (TKIs) dasatinib and bosutinib, on the human TNF-dependent Tg197 arthritis mouse model. The inhibitors were administered either as a monotherapy or in combination with a subtherapeutic dose of anti-hTNF biologics and their therapeutic effect was assessed clinically, histopathologically as well as via gene expression analysis and was compared to that of an efficient TNF monotherapy. Results Dasatinib and, to a lesser extent, bosutinib inhibited the production of TNF and proinflammatory chemokines from arthritogenic synovial fibroblasts. Dasatinib, but not bosutinib, also ameliorated significantly and in a dose-dependent manner both the clinical and histopathological signs of Tg197 arthritis. Combination of dasatinib with a subtherapeutic dose of anti-hTNF biologic agents, resulted in a synergistic inhibitory effect abolishing all arthritis symptoms. Gene expression analysis of whole joint tissue of Tg197 mice revealed that the combination of dasatinib with a low subtherapeutic dose of Infliximab most efficiently restores the pathogenic gene expression profile to that of the healthy state compared to either treatment administered as a monotherapy. Conclusion Our findings show that dasatinib exhibits a therapeutic effect in TNF-driven arthritis and can act in synergy with a subtherapeutic anti-hTNF dose to effectively treat the clinical and histopathological signs of the pathology. The combination of dasatinib and anti-hTNF exhibits a distinct mode of action in restoring the arthritogenic gene signature to that of a healthy profile. Potential clinical applications of combination therapies with kinase inhibitors and anti-TNF agents may provide an interesting alternative to high-dose anti-hTNF monotherapy and increase the number of patients responding to treatment.

scholarly journals How shall we treat locally advanced triple negative breast cancer?

F1000Research ◽  
2020 ◽  
Vol 8 ◽  
pp. 1649
Author(s):  
Paulo Luz ◽  
David Dias ◽  
Ana Fortuna ◽  
Luis Bretes ◽  
Beatriz Gosalbez
Keyword(s):  
Breast Cancer ◽  
Triple Negative Breast Cancer ◽  
Triple Negative ◽  
Locally Advanced ◽  
Surrogate Marker ◽  
Metastatic Breast ◽  
Complete Response ◽  
Number Of Patients ◽  
Her 2 ◽  
Near Future

Triple negative breast cancer (TNBC) has been shown to respond to neoadjuvant chemotherapy (NACT). It has been established that achieving pathological complete response (pCR) for certain aggressive subtypes of breast cancer, including HER-2 (over-expressed) and TNBC, provides an important surrogate marker for predicting long-term clinical response and survival outcomes. How to increase the number of patients that achieve pCR remains challenging. Platinum-based NACT seems to be part of the solution and capecitabine, an active drug in metastatic breast cancer, but not a standard one in earlier stages may have found its place in the adjuvant setting. In the near future immunotherapy can play a role in early TNBC

Isatuximab plus carfilzomib and dexamethasone in east Asian patients with relapsed multiple myeloma: IKEMA subgroup analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e20015-e20015
Author(s):  
Kihyun Kim ◽  
Chang Ki Min ◽  
Youngil Koh ◽  
Kenichi Ishizawa ◽  
Sung-Hyun Kim ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Disease Progression ◽  
Residual Disease ◽  
East Asian ◽  
Progression Free Survival ◽  
Complete Response ◽  
Efficacy And Safety ◽  
Asian Patients ◽  
Number Of Patients ◽  
East Asian Patients

e20015 Background: The Phase 3 IKEMA study (NCT03275285) demonstrated that isatuximab (Isa) plus carfilzomib and dexamethasone (Kd) significantly improved progression-free survival (PFS) compared with Kd in patients (pts) with relapsed multiple myeloma (RMM) (hazard ratio [HR] 0.53; 99% confidence interval [CI] 0.32–0.89; P= 0.0007). We evaluated the efficacy and safety of Isa-Kd in the East Asian patients (19 Japanese, 27 Korean). Methods: RMM pts who received 1-3 prior lines of therapy were stratified to receive Isa-Kd or Kd. Isa-Kd arm received Isa (10 mg/kg intravenously) weekly for 4 weeks, then every 2 weeks. Both arms received K (20 mg/m2 days 1-2, 56 mg/m2 thereafter) twice-weekly for 3 of 4 weeks, and d (20 mg) twice-weekly. Treatment continued until disease progression or unacceptable adverse events (AE). The primary endpoint was prolongation of PFS. Key secondary endpoints included; very good partial response or better (≥VGPR), complete response (CR) rate and minimal residual disease negativity (MRD–) rate. Results: East Asian pts (25 Isa-Kd, 21 Kd) were randomized. Pt characteristics were similar in the East Asian subgroup compared with the intent to treat (ITT) population (N = 302). Median age (Isa-Kd 64.0 [range 45–83] years vs Kd 60.0 [range 33–73] years); median prior lines Isa-Kd 2.0 (range 1–3) vs Kd 1.0 (range 1–3); refractory to lenalidomide 16.0% Isa-Kd vs 47.6% Kd; refractory to PI 20.0% Isa-Kd vs 33.3% Kd; high-risk cytogenetics 48.0% Isa-Kd vs 42.9% Kd. After a median follow-up of 20.7 months, the addition of Isa to Kd improved ≥VGPR, CR and MRD– rates (Table). The HR 0.64 (95%CI: 0.231-1.764) for disease progression or death favored Isa-Kd. Grade ≥3 AEs were observed in 79.2% Isa-Kd vs 55.0% Kd pts, serious TEAEs in 45.8% Isa-Kd vs 50.0% Kd; TEAEs leading to treatment discontinuation were lower in the Isa-Kd group (4.2% Isa-Kd vs 10.0% Kd). Overall, 64.0% Isa-Kd vs 42.9% Kd pts were still receiving treatment. Conclusions: Efficacy and safety results of Isa-Kd in East Asian pts are consistent with the results of the overall IKEMA population, in which significantly better efficacy (PFS, CR, ≥VGPR and MRD– rate) was reported in favor of Isa-Kd without an increase in the number of patients with serious TEAEs or discontinuations. Isa-Kd is a potential treatment option for East Asian pts with RMM. Clinical trial information: NCT03275285. [Table: see text]

scholarly journals Analysis of HLA-G expression in renal tissue in lupus nephritis: a pilot study

Lupus ◽  
2019 ◽  
Vol 28 (9) ◽  
pp. 1091-1100
Author(s):  
V Foschi ◽  
D Bortolotti ◽  
A F Doyle ◽  
V Stratigou ◽  
L Stephens ◽  
...  
Keyword(s):  
Lupus Nephritis ◽  
Juxtaglomerular Apparatus ◽  
Complete Response ◽  
Renal Tissue ◽  
Response To Treatment ◽  
Induction Phase ◽  
Glomerular Epithelial Cells ◽  
Number Of Patients ◽  
Renal Biopsies ◽  
Infiltrating Cells

Background The study aimed to investigate whether HLA-G antigen is expressed in the kidneys of patients affected by lupus nephritis (LN) and whether its detection in renal biopsies could be adopted as a marker of treatment response and prognosis. Methods Thirty renal biopsies from patients with LN were selected and analyzed through immunohistochemistry. Laboratory and clinical data were retrospectively collected at baseline, 6 and 12 months and at the latest clinical appointment. A number of patients (63.3%) were treated with rituximab (RTX) +/− methylprednisolone in the induction phase. The expression of HLA-G in glomeruli, tubules and infiltrating cells was examined and compared between lupus patients who achieved either complete or partial renal response and those who did not respond to treatment. Results HLA-G staining was observed in the glomeruli of 20 of 30 samples from patients with LN. The expression of the antigen was detected in podocytes, along glomerular capillary walls, on parietal glomerular epithelial cells and within the juxtaglomerular apparatus. Seventy per cent of patients whose glomeruli expressed HLA-G achieved partial or complete response at 6 months and 75% at the latest available follow up compared with 30% and 40%, respectively, of those who did not show any expression. The pattern of staining in tubules and infiltrating cells was highly variable precluding any clinical correlation. Conclusion This study demonstrates that HLA-G is expressed in renal tissue in LN. Our retrospective data suggest that its expression could correlate with response to treatment.

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