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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA055819-18
Application #
8555166
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Project Start
2000-06-05
Project End
2014-08-31
Budget Start
2012-09-11
Budget End
2013-08-31
Support Year
18
Fiscal Year
2012
Total Cost
$420,634
Indirect Cost
$130,395
Name
University of Arkansas for Medical Sciences
Department
Type
DUNS #
122452563
City
Little Rock
State
AR
Country
United States
Zip Code
72205
Mikulasova, Aneta; Wardell, Christopher P; Murison, Alexander et al. (2017) The spectrum of somatic mutations in monoclonal gammopathy of undetermined significance indicates a less complex genomic landscape than that in multiple myeloma. Haematologica 102:1617-1625
Rasche, Leo; Weinhold, Niels; Morgan, Gareth J et al. (2017) Immunologic approaches for the treatment of multiple myeloma. Cancer Treat Rev 55:190-199
Rasche, L; Chavan, S S; Stephens, O W et al. (2017) Spatial genomic heterogeneity in multiple myeloma revealed by multi-region sequencing. Nat Commun 8:268
Went, M; Sud, A; Law, P J et al. (2017) Assessing the effect of obesity-related traits on multiple myeloma using a Mendelian randomisation approach. Blood Cancer J 7:e573
Schinke, Carolina; Hoering, Antje; Wang, Hongwei et al. (2017) The prognostic value of the depth of response in multiple myeloma depends on the time of assessment, risk status and molecular subtype. Haematologica 102:e313-e316
Chavan, S S; He, J; Tytarenko, R et al. (2017) Bi-allelic inactivation is more prevalent at relapse in multiple myeloma, identifying RB1 as an independent prognostic marker. Blood Cancer J 7:e535
Sawyer, J R; Tian, E; Shaughnessy Jr, J D et al. (2017) Hyperhaploidy is a novel high-risk cytogenetic subgroup in multiple myeloma. Leukemia 31:637-644
Mohan, Meera; Samant, Rohan S; Yoon, Donghoon et al. (2017) Extensive Remineralization of Large Pelvic Lytic Lesions Following Total Therapy Treatment in Patients With Multiple Myeloma. J Bone Miner Res 32:1261-1266
Rasche, Leo; Angtuaco, Edgardo; McDonald, James E et al. (2017) Low expression of hexokinase-2 is associated with false-negative FDG-positron emission tomography in multiple myeloma. Blood 130:30-34
Stein, Caleb K; Pawlyn, Charlotte; Chavan, Shweta et al. (2017) The varied distribution and impact of RAS codon and other key DNA alterations across the translocation cyclin D subgroups in multiple myeloma. Oncotarget 8:27854-27867

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