The road to cure in multiple myeloma

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2503-2503
Author(s):  
Irene M. Ghobrial ◽  
Kenneth C. Anderson
Keyword(s):  
Multiple Myeloma ◽  
Median Survival ◽  
Hematologic Malignancy ◽  
Treatment Strategies ◽  
Molecular Pathogenesis ◽  
Fatal Disease ◽  
The Road ◽  
The Past ◽  
Recent Advances ◽  
New Treatment

For the past several decades, multiple myeloma (MM), the second most common hematologic malignancy, has been considered a fatal disease with a median survival of 5 years. However, recent advances in the understanding of the molecular pathogenesis of MM have led to new treatment strategies.

Molecular pathogenesis of Parkinson disease: insights from genetic studies

2009 ◽  
Vol 11 ◽  
Author(s):  
Thomas Gasser
Keyword(s):  
Parkinson Disease ◽  
Treatment Strategies ◽  
Molecular Pathogenesis ◽  
Direct Role ◽  
Genetic Studies ◽  
Protective Function ◽  
The Past ◽  
The Common ◽  
New Treatment ◽  
Molecular Pathophysiology

Over the past few years, genetic findings have changed our views on the molecular pathogenesis of Parkinson disease (PD), as mutations in a growing number of genes have been found to cause monogenic forms of the disorder. These mutations cause neuronal dysfunction and neurodegeneration either by a toxic gain of function, as in the case of the dominant forms of monogenic PD caused by mutations in the genes for α-synuclein or LRRK2, or by a loss of an intrinsic protective function, as is likely for the recessive PD genes parkin (PRKN), PINK1 and DJ-1. Evidence is emerging that at least some of the pathways uncovered in the rare monogenic forms of PD may play a direct role in the aetiology of the common sporadic disorder and that variants of the respective genes contribute to the risk of developing the disease. These findings will allow the search for new treatment strategies that focus on the underlying molecular pathophysiology, rather than simply on ameliorating symptoms.

scholarly journals Recent advances in acute promyelocytic leukaemia

F1000Research ◽  
2017 ◽  
Vol 6 ◽  
pp. 1273 ◽  
Author(s):  
Chin-Hin Ng ◽  
Wee-Joo Chng
Keyword(s):  
Targeted Therapy ◽  
Acute Promyelocytic Leukaemia ◽  
Fusion Gene ◽  
Promyelocytic Leukaemia ◽  
Fatal Disease ◽  
The Past ◽  
Trans Retinoic Acid ◽  
Recent Advances ◽  
All Trans Retinoic Acid ◽  
New Treatment

Acute promyelocytic leukaemia (APML) is a subtype of leukaemia arising from a distinct reciprocal translocation involving chromosomes 15 and 17, which results in thePML-RARAfusion gene. Over the past three decades, APML has been transformed from a highly fatal disease to a highly curable one. This drastic improvement is because of the introduction of a new treatment strategy with all-trans retinoic acid and, more recently, arsenic trioxide. The revolutionary treatment of APML has also paved the way for a new cancer treatment, which is genetically targeted therapy. In this review, we look into this amazing journey of transformation and provide recent advances in the management of APML.

scholarly journals Towards Molecular Profiling in Multiple Myeloma: A Literature Review and Early Indications of Its Efficacy for Informing Treatment Strategies

2018 ◽  
Vol 19 (7) ◽  
pp. 2087 ◽  
Author(s):  
Wolfgang Willenbacher ◽  
Andreas Seeber ◽  
Normann Steiner ◽  
Ella Willenbacher ◽  
Zoran Gatalica ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Plasma Cells ◽  
Hematologic Malignancy ◽  
Proteasome Inhibitors ◽  
Treatment Strategies ◽  
Gene Mutations ◽  
Molecular Profiling ◽  
Complex Dynamic ◽  
Therapeutic Implications ◽  
The Past

Multiple myeloma (MM), the second most common hematologic malignancy, is characterized by the clonal expansion of plasma cells. Despite dramatic improvements in patients′ survival over the past decade due to advances in therapy exploiting novel molecular targets (immunomodulatory drugs, proteasome inhibitors and monoclonal antibodies), the treatment of relapsed and refractory disease remains challenging. Recent studies confirmed complex, dynamic, and heterogeneous genomic alterations without unifying gene mutations in MM patients. In the current review, we survey recent therapeutic strategies, as well as molecular profiling data on MM, with emphasis on relapsed and refractory cases. A critical appraisal of novel findings and of their potential therapeutic implications will be discussed in detail, along with the author’s own experiences/views.

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.

scholarly journals Influence of metformin on HIF-1 pathway in multiple myeloma

2020 ◽  
Vol 72 (5) ◽  
pp. 1407-1417
Author(s):  
Kinga A. Kocemba-Pilarczyk ◽  
Sonia Trojan ◽  
Barbara Ostrowska ◽  
Małgorzata Lasota ◽  
Paulina Dudzik ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Plasma Cells ◽  
Treatment Strategies ◽  
Annexin V ◽  
Growth And Survival ◽  
Hypoxic Conditions ◽  
New Treatment ◽  
First Time ◽  
Pcr Techniques

Abstract Background Multiple myeloma (MM) is defined as plasma cells malignancy, developing in the bone marrow. At the beginning of the disease, the malignant plasma cells are dependent on bone marrow microenvironment, providing growth and survival factors. Importantly, the recent studies pointed hypoxia as an important factor promoting progression of MM. In particular, hypoxia-triggered HIF-1 signaling was shown to promote chemoresistance, angiogenesis, invasiveness and induction of immature phenotype, suggesting that strategies targeting HIF-1 may contribute to improvement of anti-myeloma therapies. Methods The Western Blot and RT-PCR techniques were applied to analyze the influence of metformin on HIF-1 pathway in MM cells. To evaluate the effect of metformin on the growth of MM cell lines in normoxic and hypoxic conditions the MTT assay was used. The apoptosis induction in metformin treated hypoxic and normoxic cells was verified by Annexin V/PI staining followed by FACS analysis. Results Our results showed, for the first time, that metformin inhibits HIF-1 signaling in MM cells. Moreover, we demonstrated the effect of metformin to be mainly oxygen dependent, since the HIF-1 pathway was not significantly affected by metformin in anoxic conditions as well as after application of hypoxic mimicking compound, CoCl2. Our data also revealed that metformin triggers the growth arrest without inducing apoptosis in either normoxic or hypoxic conditions. Conclusions Taken together, our study indicates metformin as a promising candidate for developing new treatment strategies exploiting HIF-1 signaling inhibition to enhance the overall anti-MM effect of currently used therapies, that may considerably benefit MM patients.

Monoclonal gammopathy of undetermined significance and smoldering multiple myeloma: biological insights and early treatment strategies

Hematology ◽  
2013 ◽  
Vol 2013 (1) ◽  
pp. 478-487 ◽  
Author(s):  
Ola Landgren
Keyword(s):  
Multiple Myeloma ◽  
Patient Outcomes ◽  
Early Treatment ◽  
Monoclonal Gammopathy ◽  
Treatment Strategies ◽  
Precursor State ◽  
The Past ◽  
Smoldering Multiple Myeloma ◽  
Remarkable Progress ◽  
Undetermined Significance

Abstract After decades of virtually no progress, multiple myeloma survival has improved significantly in the past 10 years. Indeed, multiple myeloma has perhaps seen more remarkable progress in treatment and patient outcomes than any other cancer during the last decade. Recent data show that multiple myeloma is consistently preceded by a precursor state (monoclonal gammopathy of undetermined significance [MGUS]/smoldering multiple myeloma [SMM]). This observation provides a framework for prospective studies focusing on transformation from precursor disease to multiple myeloma and for the development of treatment strategies targeting “early myeloma.” This review discusses current biological insights in MGUS/SMM, provides an update on clinical management, and discusses how the integration of novel biological markers, molecular imaging, and clinical monitoring of MGUS/SMM could facilitate the development of early treatment strategies for high-risk SMM (early myeloma) patients in the future.

scholarly journals Targeting NF-κB Signaling for Multiple Myeloma

Cancers ◽  
2020 ◽  
Vol 12 (8) ◽  
pp. 2203 ◽  
Author(s):  
Ada Hang-Heng Wong ◽  
Eun Myoung Shin ◽  
Vinay Tergaonkar ◽  
Wee-Joo Chng
Keyword(s):  
Multiple Myeloma ◽  
Molecular Mechanisms ◽  
Nuclear Factor Kappa B ◽  
Hematologic Malignancy ◽  
Survival Rates ◽  
Nuclear Factor ◽  
The Past ◽  
The World ◽  
Future Drug ◽  
Research Findings

Multiple myeloma (MM) is the second most common hematologic malignancy in the world. Even though survival rates have significantly risen over the past years, MM remains incurable, and is also far from reaching the point of being managed as a chronic disease. This paper reviews the evolution of MM therapies, focusing on anti-MM drugs that target the molecular mechanisms of nuclear factor kappa B (NF-κB) signaling. We also provide our perspectives on contemporary research findings and insights for future drug development.

scholarly journals Modern Myoma Treatment in the Last 20 Years: A Review of the Literature

2018 ◽  
Vol 2018 ◽  
pp. 1-6 ◽  
Author(s):  
Ahmed El-Balat ◽  
Rudy Leon DeWilde ◽  
Iryna Schmeil ◽  
Morva Tahmasbi-Rad ◽  
Sandra Bogdanyova ◽  
...  
Keyword(s):  
Treatment Strategies ◽  
Cellular Level ◽  
Review Of The Literature ◽  
Human Species ◽  
Theoretical Concepts ◽  
Uterine Smooth Muscle ◽  
Healthcare Burden ◽  
The Past ◽  
Life Threatening ◽  
New Treatment

Myomas, also known as fibroids, are a specific characteristic of the human species. No other primates develop fibroids. At a cellular level, myomas are benign hyperplastic lesions of uterine smooth muscle cells. There are interesting theoretical concepts that link the development of myomas in humans with the highly specific process of childbirth from an upright position and the resulting need for greatly increased “expulsive” forces during labor. Myomas might be the price our species pays for our bipedal and highly intelligent existence. Myomas affect, with some variability, all ethnic groups and approximately 50% of all women during their lifetime. While some remain asymptomatic, myomas can cause significant and sometimes life-threatening uterine bleeding, pain, infertility, and, in extreme cases, ureteral obstruction and death. Traditionally, over 50% of all hysterectomies were performed for fibroids, leading to a significant healthcare burden. In this article, we review the developments of the past 20 years with regard to multiple new treatment strategies that have evolved during this time.

scholarly journals Mechanisms of Immune Evasion in Multiple Myeloma: Open Questions and Therapeutic Opportunities

Cancers ◽  
2021 ◽  
Vol 13 (13) ◽  
pp. 3213
Author(s):  
Cirino Botta ◽  
Francesco Mendicino ◽  
Enrica Antonia Martino ◽  
Ernesto Vigna ◽  
Domenica Ronchetti ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Intermediate Phase ◽  
Hematologic Malignancy ◽  
Treatment Strategies ◽  
Current Treatment ◽  
System Control ◽  
Disease Evolution ◽  
Bm Niche ◽  
Open Questions ◽  
Asymptomatic Stage

Multiple myeloma (MM) is the second most common hematologic malignancy, characterized by a multi-step evolutionary path, which starts with an early asymptomatic stage, defined as monoclonal gammopathy of undetermined significance (MGUS) evolving to overt disease in 1% of cases per year, often through an intermediate phase known as “smoldering” MM (sMM). Interestingly, while many genomic alterations (translocation, deletions, mutations) are usually found at early stages, they are not sufficient (alone) to determine disease evolution. The latter, indeed, relies on significant “epigenetic” alterations of different normal cell populations within the bone marrow (BM) niche, including the “evasion” from immune-system control. Additionally, MM cells could “educate” the BM immune microenvironment (BM-IM) towards a pro-inflammatory and immunosuppressive phenotype, which ultimately leads to disease evolution, drug resistance, and patients’ worse outcome. Indeed, it is not a case that the most important drugs for the treatment of MM include immunomodulatory agents (thalidomide, lenalidomide, and pomalidomide) and monoclonal antibodies (daratumumab, isatuximab, and elotuzumab). On these bases, in this review, we describe the most recent advances in the comprehension of the role of the different cells composing the BM-IM, and we discuss the potential molecular targets, which could represent new opportunities to improve current treatment strategies for MM patients.

scholarly journals Second Line Treatment Strategies in Multiple Myeloma: A Referral-Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 819-819
Author(s):  
Sarah Goldman-Mazur ◽  
Alissa Visram ◽  
S Vincent Rajkumar ◽  
Prashant Kapoor ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Board Of Directors ◽  
Research Funding ◽  
Alkylating Agents ◽  
Treatment Strategies ◽  
Line Treatment ◽  
Advisory Committees ◽  
The Past ◽  
Line Therapy ◽  
Over Time

Abstract Background Recommendations for 2 nd line treatment for relapsed multiple myeloma (MM) patients have been changing over the past two decades, given the introduction of novel agents, different side-effect profiles, and attempts at more individualized treatment approaches. We designed this study to characterize how 2 nd line treatment strategies have evolved over the last two decades for MM patients. Methods Patients with MM with at least one relapse treated with a 2 nd line regimen, seen at Mayo Clinic between 2003-2021, were included. To visualize trends in treatment choices we divided the study period into 2-year intervals and for descriptive purpose the period was divided into three 6-year intervals. We used "100% stacked area" charts to show how the constituent parts of the whole have changed over time. The height of each colored stack represents the proportion of patients in that category at a given point in time. Results A total of 1439 patients were included. Patients were diagnosed between 2001 and 2018, the initiation of 2 nd line treatment occurred between June 2003 and February 2021. Median age at diagnosis was 62.7 years (interquartile range, 55.8-69.3), 60.0% were male. International Staging System stage I was present in 23.5% of patients, stage II in 32.9% and stage III in 28.8%. In the 1 st line therapy novel agents were used in 82.8% of cases, regimens based on proteasome inhibitors (PI) in 26.5%, immunomodulatory drugs (IMID) in 42.0% and combination of PI+IMID in 21.1%. Upfront autologous stem cell transplantation (ASCT) was performed in 50.1% of patients, and maintenance after 1 st line was used in 25.2%. For 2 nd line treatment, during 2003-2008 the majority were treated with doublets (70.5%), followed by triplets (14.8%) and salvage ASCT (7.7%) (Figure 1A). Patients were treated with IMID or PI-based therapy (50.7% and 21.8%, respectively); only 3.7% received PI+IMID and 20.1% of patients received alkylating agents/anthracyclines. The most frequently used regimens were lenalidomide-dexamethasone (RD, 32.2%) and bortezomib-dexamethasone (VD, 18.1%, Figure 1B). Between 2009-2014, the use of triplets in 2 nd line increased (43.0%), although doublets were still more common (50.9%). Like previous years, IMID-based therapy was most frequently used (37.3%), however, the use of PI-based therapy increased (36.0%). PI+IMID-based therapy was implemented in 17.9% of patient, and 27.3% received alkylating agents/anthracyclines. Most frequently used regimens included: RD (29.4%), bortezomib-cyclophosphamide-dexamethasone (CYBORD, 17.4%), bortezomib-lenalidomide-dexamethasone (VRD, 13.4%) and VD (13.3%). Finally, during 2015-2021, triplets were most common (68.9%), followed by doublets (23.0%). IMID- and PI+IMID-based therapies were most often implemented (34.2% and 31.1%, respectively), followed by PI-based therapy (26.8%). 28.1% of patients received monoclonal antibodies; only 15.9% received alkylating agents/anthracyclines. Most frequently used regimens include RD (13.8%), carfilzomib-RD (11.6%), daratumumab-RD (9.8%), CYBORD (9.3%), VRD (8.8%), daratumumab-pomalidomide-dexamethasone (5.9%) and daratumumab-VD (5.2%). Median time to next treatment (TTNT) from 2 nd line therapy has improved over the course of the three time periods (p<0.01; Figure 1C): years 2003-2008, 10.4 months; years 2009-2014, 13.2 months; and years 2014-2021, 16.6 months. Similarly, the median overall survival from 1 st relapse has increased over the three intervals: 30.9 months, 48.4 months, and 65.8 months, respectively. Conclusions Over the past two decades, the effectiveness of 2 nd line treatment has improved, reflected by improved TTNT from 2 nd line therapy. With the introduction of new agents in 2012-2015 (carfilzomib, pomalidomide and daratumumab) and favorable results for triplets demonstrated in randomized trials, the triplet therapies started to be used more frequently. Over time, the landscape of 2 nd line therapies has become more diverse, which may reflect a more individualized approach to each patient. Moreover, the large variety of treatment strategies makes comparisons more and more challenging. Figure 1 Figure 1. Disclosures Kapoor: Ichnos Sciences: Research Funding; Karyopharm: Consultancy; BeiGene: Consultancy; Pharmacyclics: Consultancy; Sanofi: Consultancy; Amgen: Research Funding; Cellectar: Consultancy; Regeneron Pharmaceuticals: Research Funding; Glaxo SmithKline: Research Funding; Karyopharm: Research Funding; Sanofi: Research Funding; Takeda: Research Funding; AbbVie: Research Funding. Dispenzieri: Pfizer: Research Funding; Alnylam: Research Funding; Takeda: Research Funding; Oncopeptides: Consultancy; Sorrento Therapeutics: Consultancy; Janssen: Consultancy, Research Funding. Gertz: Akcea Therapeutics, Ambry Genetics, Amgen Inc, Celgene Corporation, Janssen Biotech Inc, Karyopharm Therapeutics, Pfizer Inc (to Institution), Sanofi Genzyme: Honoraria; Aurora Biopharma: Other: Stock option; Akcea Therapeutics, Alnylam Pharmaceuticals Inc, Prothena: Consultancy; AbbVie Inc, Celgene Corporation: Other: Data Safetly & Monitoring; Ionis Pharmaceuticals: Other: Advisory Board. Dingli: Sanofi: Consultancy; Apellis: Consultancy; Novartis: Research Funding; Alexion: Consultancy; Janssen: Consultancy; GSK: Consultancy. Kumar: Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Tenebio: Research Funding; Carsgen: Research Funding; Beigene: Consultancy; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Novartis: Research Funding; Sanofi: Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy.

Sign in / Sign up

Export Citation Format

Share Document