scholarly journals High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

2019 ◽  
Vol 8 (7) ◽  
pp. 997 ◽  
Author(s):  
Antonio Giovanni Solimando ◽  
Matteo Claudio Da Vià ◽  
Sebastiano Cicco ◽  
Patrizia Leone ◽  
Giuseppe Di Lernia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Risk Profile ◽  
Biological Knowledge ◽  
Great Efficacy ◽  
Comprehensive Understanding ◽  
Angiogenic Therapy ◽  
Risk Profiling ◽  
Molecular Determinants ◽  
Druggable Targets

Multiple myeloma (MM) is a genetically heterogeneous disease that includes a subgroup of 10–15% of patients facing dismal survival despite the most intensive treatment. Despite improvements in biological knowledge, MM is still an incurable neoplasia, and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. The aim of this review is to provide an integrated clinical and biological overview of high-risk MM, discussing novel therapeutic perspectives, targeting the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug-resistance can foster a better tailored clinical management of the high-risk profile and therapy-refractoriness. Among the current clinical difficulties in MM, patients’ management by manipulating the tumor niche represents a major challenge. The angiogenesis and the stromal infiltrate constitute pivotal mechanisms of a mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy, but variable and unpredictable responses in high-risk MM. The comprehensive understanding of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Here, we provide a broad outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better select candidates for dual immune/vasculogenesis targeting.

scholarly journals High-Risk Multiple Myeloma: Integrated Clinical and Omics Approach Dissects the Neoplastic Clone and the Tumor Microenvironment

2019 ◽  
Author(s):  
Antonio Giovanni Solimando ◽  
Matteo Claudio Da Vià ◽  
Sebastiano Cicco ◽  
Patrizia Leone ◽  
Giuseppe Di Lernia ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Clinical Management ◽  
The Novel ◽  
Great Efficacy ◽  
Angiogenic Therapy ◽  
Risk Profiling ◽  
Comprehensive Knowledge ◽  
Molecular Determinants ◽  
Druggable Targets

Multiple myeloma (MM) is a genetically heterogenous disease that includes a subgroup of 10-15% of patients facing dismal survival despite most intensive treatment. The aim of this review article is to provide an integrated clinical and biological overview on the high-risk MM discussing the novel therapeutic perspectives aimed to target the neoplastic clone and its microenvironment. The dissection of the molecular determinants of the aggressive phenotypes and drug resistance can foster a better tailored clinical management of high-risk profile and refractoriness to therapy. Among the current clinical difficulties in MM, patient’s management manipulating the tumor niche represents a major challenge given the limited knowledge about the MM-milieu interaction. The angiogenesis and bystander infiltrate constitute pivotal mechanisms of mutual collaboration between MM and the non-tumoral counterpart. Immuno-modulatory and anti-angiogenic therapy hold great efficacy but variable and unpredictable responses in high-risk MM. Therefore, it would be worth to better select the population and the MM stage that could profit to a dual immune/vasculogenesis targeting. The comprehensive knowledge of the genetic heterogeneity and MM high-risk ecosystem enforce a systematic bench-to-bedside approach. Despite significant improvements in the biology knowledge, MM is still a chronic and incurable neoplasia and therapeutic options able to overcome the relapsing/refractory behavior represent an unmet clinical need. Here, we corroborate previous biological findings providing a synthetic outlook of novel druggable targets. We also summarize the existing multi-omics-based risk profiling tools, in order to better personalize the patient-oriented clinical management.

scholarly journals Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma

Blood ◽  
2016 ◽  
Vol 128 (9) ◽  
pp. 1174-1180 ◽  
Author(s):  
Hervé Avet-Loiseau ◽  
Rafael Fonseca ◽  
David Siegel ◽  
Meletios A. Dimopoulos ◽  
Ivan Špička ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Poor Prognosis ◽  
Progression Free Survival ◽  
Risk Profile ◽  
Risk Status ◽  
Free Survival ◽  
The Poor ◽  
Key Points ◽  
Risk Patients

Key Points KRd has a favorable benefit-risk profile compared with Rd, regardless of baseline cytogenetic risk status, in patients with relapsed MM. KRd improves but does not abrogate the poor prognosis associated with high-risk cytogenetics in patients with relapsed MM.

scholarly journals A Peri-Implant Disease Risk Score for Patients with Dental Implants: Validation and the Influence of the Interval between Maintenance Appointments

2019 ◽  
Vol 8 (2) ◽  
pp. 252 ◽  
Author(s):  
Miguel de Araújo Nobre ◽  
Francisco Salvado ◽  
Paulo Nogueira ◽  
Evangelista Rocha ◽  
Peter Ilg ◽  
...  
Keyword(s):  
High Risk ◽  
Risk Score ◽  
Disease Risk ◽  
Disease Incidence ◽  
Risk Groups ◽  
Risk Profile ◽  
Moderate Risk ◽  
C Statistic ◽  
Disease Risk Score ◽  
Very High

Background: There is a need for tools that provide prediction of peri-implant disease. The purpose of this study was to validate a risk score for peri-implant disease and to assess the influence of the recall regimen in disease incidence based on a five-year retrospective cohort. Methods: Three hundred and fifty-three patients with 1238 implants were observed. A risk score was calculated from eight predictors and risk groups were established. Relative risk (RR) was estimated using logistic regression, and the c-statistic was calculated. The effect/impact of the recall regimen (≤ six months; > six months) on the incidence of peri-implant disease was evaluated for a subset of cases and matched controls. The RR and the proportional attributable risk (PAR) were estimated. Results: At baseline, patients fell into the following risk profiles: low-risk (n = 102, 28.9%), moderate-risk (n = 68, 19.3%), high-risk (n = 77, 21.8%), and very high-risk (n = 106, 30%). The incidence of peri-implant disease over five years was 24.1% (n = 85 patients). The RR for the risk groups was 5.52 (c-statistic = 0.858). The RR for a longer recall regimen was 1.06, corresponding to a PAR of 5.87%. Conclusions: The risk score for estimating peri-implant disease was validated and showed very good performance. Maintenance appointments of < six months or > six months did not influence the incidence of peri-implant disease when considering the matching of cases and controls by risk profile.

scholarly journals MUKnine OPTIMUM protocol: a screening study to identify high-risk patients with multiple myeloma suitable for novel treatment approaches combined with a phase II study evaluating optimised combination of biological therapy in newly diagnosed high-risk multiple myeloma and plasma cell leukaemia

BMJ Open ◽  
2021 ◽  
Vol 11 (3) ◽  
pp. e046225
Author(s):  
Sarah Brown ◽  
Debbie Sherratt ◽  
Samantha Hinsley ◽  
Louise Flanagan ◽  
Sadie Roberts ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
High Risk ◽  
Plasma Cell ◽  
Phase Ii ◽  
Whole Body ◽  
Cell Leukaemia ◽  
High Dose ◽  
Newly Diagnosed ◽  
Genetic Changes ◽  
Novel Treatment

IntroductionMultiple myeloma (MM) is a plasma cell tumour with over 5800 new cases each year in the UK. The introduction of biological therapies has improved outcomes for the majority of patients with MM, but in approximately 20% of patients the tumour is characterised by genetic changes which confer a significantly poorer prognosis, generally termed high-risk (HR) MM. It is important to diagnose these genetic changes early and identify more effective first-line treatment options for these patients.Methods and analysisThe Myeloma UK nine OPTIMUM trial (MUKnine) evaluates novel treatment strategies for patients with HRMM. Patients with suspected or newly diagnosed MM, fit for intensive therapy, are offered participation in a tumour genetic screening protocol (MUKnine a), with primary endpoint proportion of patients with molecular screening performed within 8 weeks. Patients identified as molecularly HR are invited into the phase II, single-arm, multicentre trial (MUKnine b) investigating an intensive treatment schedule comprising bortezomib, lenalidomide, daratumumab, low-dose cyclophosphamide and dexamethasone, with single high-dose melphalan and autologous stem cell transplantation (ASCT) followed by combination consolidation and maintenance therapy. MUKnine b primary endpoints are minimal residual disease (MRD) at day 100 post-ASCT and progression-free survival. Secondary endpoints include response, safety and quality of life. The trial uses a Bayesian decision rule to determine if this treatment strategy is sufficiently active for further study. Patients identified as not having HR disease receive standard treatment and are followed up in a cohort study. Exploratory studies include longitudinal whole-body diffusion-weighted MRI for imaging MRD testing.Ethics and disseminationEthics approval London South East Research Ethics Committee (Ref: 17/LO/0022, 17/LO/0023). Results of studies will be submitted for publication in a peer-reviewed journal.Trial registration numberISRCTN16847817, May 2017; Pre-results.

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