Clonal competition with alternating dominance in multiple myeloma

Keats, Jonathan J.; Chesi, Marta; Egan, Jan B.; Garbitt, Victoria M.; Palmer, Stephen; Braggio, Esteban; Wier, Scott Van; Blackburn, Patrick R.; Baker, Angela; Dispenzieri, Angela; Kumar, Shaji; Rajkumar, S. Vincent; Carpten, John D.; Barrett, Michael T.; Fonseca, Rafaël; Stewart, A. Keith; Bergsagel, P. Leif

doi:10.1182/blood-2012-01-405985

Cited by 575 publications

(492 citation statements)

References 28 publications

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“…The existence of these dominant behaviours exhibited by the u 1 or u 2 populations are consistent with the principle of competitive exclusion of clonal sub-populations in heterogeneous tumours (Egan Keats et al, 2012;Leith et al, 1989). In Fisher et al (2013) the authors interpreted the experimental data, which showed suppression and reappearance of cancer clones in myeloma patients (Keats et al, 2012) and chronic lymphocytic leukaemia patients (Schuh et al, 2012), by suggesting that two subclones can exist in a dynamic equilibrium. While all these experimental studies record the survival/suppression of tumour clones in various cancers, they do not offer a mechanistic explanation for the factors that could lead to these behaviours.…”

Section: Conclusion and Discussionmentioning

confidence: 78%

“…In this study, we will investigate the role of cancer mutation on the possibility of clonal competition with alternating dominance or even competitive exclusion between two cancer cell sub-populations (as discussed before, these types of competition have been observed experimentally (Leith et al, 1989;Keats et al, 2012;Schuh et al, 2012)). To this end, we will introduce a nonlocal model for cell-cell and cell-matrix adhesion for two populations of cells (this model is a generalization of the models in Armstrong et al (2006); Gerisch & Chaplain (2008); Painter et al (2015)).…”

Section: Introductionmentioning

confidence: 99%

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Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

Buono

Eftimie

2016

Springer Proceedings in Mathematics &Amp; Statistics

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[Date] Cells adhere to each other and to the extracellular matrix (ECM) through protein molecules on the surface of the cells. The breaking and forming of adhesive bonds, a process critical in cancer invasion and metastasis, can be influenced by the mutation of cancer cells. In this paper, we develop a nonlocal mathematical model describing cancer cell invasion and movement as a result of integrin-controlled cell-cell adhesion and cell-matrix adhesion, for two cancer cell populations with different levels of mutation. The partial differential equations for cell dynamics are coupled with ordinary differential equations describing the extracellular matrix (ECM) degradation and the production and decay of integrins. We use this model to investigate the role of cancer mutation on the possibility of cancer clonal competition with alternating dominance, or even competitive exclusion (phenomena observed experimentally). We discuss different possible cell aggregation patterns, as well as travelling wave patterns. In regard to the travelling waves, we investigate the effect of cancer mutation rate on the speed of cancer invasion.

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Section: Conclusion and Discussionmentioning

confidence: 78%

Section: Introductionmentioning

confidence: 99%

Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

Buono

Eftimie

2016

Springer Proceedings in Mathematics &Amp; Statistics

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“…11,[36][37][38] Furthermore, recent evidence for clonal competition with alternating dominance of tumour subclones during disease progression suggests that the presence of genetic features at diagnosis may not allow conclusions to be made about their presence or absence at a later time during the disease course. [39][40][41] The database also fails to provide stringent information about treatment with novel agents. However, given that patients transplanted in the years 2004-2008 had the same outcome as patients transplanted in 1999-2003 (Supplementary Table 1), novel treatment modalities are unlikely to have had a major impact.…”

Section: Discussionmentioning

confidence: 99%

Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation

Auner

Szydlo

Biezen

et al. 2013

Bone Marrow Transplant

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Outcomes and prognostic factors of reduced intensity-conditioned allo-SCT (RIC allo-SCT) for multiple myeloma (MM) relapsing or progressing after prior autologous (auto)-SCT are not well defined. We performed an analysis of 413 MM patients who received a related or unrelated RIC allo-SCT for the treatment of relapse/progression after prior auto-SCT. Median age at RIC allo-SCT was 54.1 years, and 44.6% of patients had undergone two or more prior auto-SCTs. Median OS and PFS from the time of RIC allo-SCT for the entire population were 24.7 and 9.6 months, respectively. Cumulative non-relapse mortality (NRM) at 1 year was 21.5%. In multivariate analysis, CMV seronegativity of both patient and donor was associated with significantly better PFS, OS and NRM. Patient-donor gender mismatch was associated with better PFS, fewer than two prior auto-SCT was associated with better OS, and shorter time from the first auto-SCT to the RIC allo-SCT was associated with lower NRM. The results of this study identify patient and donor CMV seronegativity as the key prognostic factor for outcome after RIC allo-SCT for MM relapsing or progressing after prior auto-SCT.

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“…3 The clinical heterogeneity of MM is due to the coexistence of different myeloma clones with various mutation patterns and subsequent biological and clinical behaviors. According to a Darwinian evolutionary model, the sequence in which therapies are performed may induce different biological responses in the different clones, with the eradication of an indolent clone and the growth of a more aggressive one.…”

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confidence: 99%

Management of older adults with multiple myeloma

Palumbo¹,

Mina²

2013

Blood Reviews

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Two-thirds of patients with multiple myeloma are aged 65 years or more and the prevalence of multiple myeloma in elderly patients is expected to rise in the next future. Patients older than 65 years are usually considered ineligible for transplantation. The introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, combined with conventional chemotherapy, has radically changed the treatment paradigm of elderly patients and improved outcome. A sequential approach, consisting of an induction regimen associated with a high rate of complete response, followed by consolidation/maintenance therapy, induces a profound cytoreduction and delays relapse, thus improving survival. Novel agents associated with reduced-intensity autologous transplant showed to be safe and effective in fit elderly patients. Patients older than 75 years or vulnerable ones are more susceptible to adverse events that negatively affect treatment adherence and outcome. In this setting, less toxic regimens and appropriate dose reductions should be adopted. Here we provide an overview of novel agent-based treatment strategies for elderly patients with multiple myeloma.

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Clonal competition with alternating dominance in multiple myeloma

Cited by 575 publications

References 28 publications

Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

Lyapunov–Schmidt and Centre Manifold Reduction Methods for Nonlocal PDEs Modelling Animal Aggregations

Reduced intensity-conditioned allogeneic stem cell transplantation for multiple myeloma relapsing or progressing after autologous transplantation: a study by the European Group for Blood and Marrow Transplantation

Management of older adults with multiple myeloma

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