Toward the objective of Growth Control in MM, Project 1 continues its path of translational research based on the concept that control of a malignancy with enornnous genomic instability requires effective interference with redundant escape mechanisms via multi-targeted combination therapy as delivered in Total Therapy (TT). Unprecedented success in gene expression profiling (GEP)-defined low-risk and lack of substantive progress in high-risk MM provided the rationale for adopting a risk-based treatment approach in Aim 1, hypothesizing that overall progress in MM growth control can be accelerated by GEP-defined riskbased therapies. TT4 for low-risk MM emphasizes reduction of morbidity while retaining TT3 efficacy with 4- yr continuous CR estimates of 90%. Appreciating MM re-growth during prolonged treatment recovery phases of TT3 as a mechanism of treatment failure, TT5 for high-risk MM will apply dose-dense but less doseintense therapy to provide quasi-continuous exposure to 8-drug synergistic combinations as a means of avoiding host exhaustion. Translational research emphasizes pharmacogenomic studies into the mechanisms of action of bortezomib and, for the first time, of melphalan, whose synergistic interaction with novel agents will be maximally exploited. Taking full advantage of the enormous repository of protocolspecified serial GEP samples and imaging studies in TT2 and TT3, follow-up over the next 5 years will enable us to test the hypothesis that therapeutic success in TT3 compared with TT2 can be explained in the context of MM-microenvironment (ME) interaction revealed by GEP studies of both MM and the ME.
Aim 2 will interrogate the MM-ME interaction viewed as critical toward disease manifestation, progression, and therapeutic response. We expect to unravel resistance mechanisms due to expansion of primary resistant tumor subpopulations or secondary transformation events with high LDH and human myeloma cell line (HMCL) signatures;derive "cure signatures" for patients in continuous CR for more than 7 yr;identify thalidomide and bortezomib beneficiaries toward future individualized therapy;determine whether drug (bortezomib, melphalan) test-dose?induced GEP alterations provide insight into molecular disease evolution;determine whether reactivation of tumor dormancy at focal lesion sites is responsible for late and unexpected relapses;and elucidate whether and how myeloma cells may uniquely interact, in a molecular subtype-specific fashion, with the ME and thus contribute to disease manifestation and progression events.
This will be the first time in MM clinical trial research that a prognostic tool as powerful as gene expression profiling will be used for selecting patients for two separate risk-based protocols. Toward truly individualized therapies in the future, single institution resources generated during 2 decades of comprehensively conducted and translationally directed therapy will be crucial toward identifying more generally applicable simpler surrogate tools for selecting maximally effective therapies tailored to the individual patient.
|Johnson, Sarah K; Stewart, James P; Bam, Rakesh et al. (2014) CYR61/CCN1 overexpression in the myeloma microenvironment is associated with superior survival and reduced bone disease. Blood 124:2051-60|
|Dhodapkar, Madhav V; Sexton, Rachael; Waheed, Sarah et al. (2014) Clinical, genomic, and imaging predictors of myeloma progression from asymptomatic monoclonal gammopathies (SWOG S0120). Blood 123:78-85|
|Lapteva, Natalia; Szmania, Susann M; van Rhee, Frits et al. (2014) Clinical grade purification and expansion of natural killer cells. Crit Rev Oncog 19:121-32|
|Bam, R; Venkateshaiah, S U; Khan, S et al. (2014) Role of Bruton's tyrosine kinase (BTK) in growth and metastasis of INA6 myeloma cells. Blood Cancer J 4:e234|
|Papanikolaou, X; Rosenbaum, E R; Tyler, L N et al. (2014) Hematopoietic progenitor cell collection after autologous transplant for multiple myeloma: low platelet count predicts for poor collection and sole use of resulting graft enhances risk of myelodysplasia. Leukemia 28:888-93|
|Sawyer, Jeffrey R; Tian, Erming; Heuck, Christoph J et al. (2014) Jumping translocations of 1q12 in multiple myeloma: a novel mechanism for deletion of 17p in cytogenetically defined high-risk disease. Blood 123:2504-12|
|Tian, Erming; Sawyer, Jeffrey R; Heuck, Christoph J et al. (2014) In multiple myeloma, 14q32 translocations are nonrandom chromosomal fusions driving high expression levels of the respective partner genes. Genes Chromosomes Cancer 53:549-57|
|Waheed, Sarah; Mitchell, Alan; Usmani, Saad et al. (2013) Standard and novel imaging methods for multiple myeloma: correlates with prognostic laboratory variables including gene expression profiling data. Haematologica 98:71-8|
|Lamy, Laurence; Ngo, Vu N; Emre, N C Tolga et al. (2013) Control of autophagic cell death by caspase-10 in multiple myeloma. Cancer Cell 23:435-49|
|Sousa, Mirta M L; Zub, Kamila Anna; Aas, Per Arne et al. (2013) An inverse switch in DNA base excision and strand break repair contributes to melphalan resistance in multiple myeloma cells. PLoS One 8:e55493|
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