Currently in its 10th year of funding, this P01's objective is to achieve durable growth control in multiple myeloma (MM) through highly integrated translational research conducted by clinical and basic scientists. The overall hypothesis will be pursued that various components of the bone marrow microenvironment (ME) contribute to eventual treatment failure by providing (in a MM genotype-specific manner) a plethora of survival and proliferation signals, and that novel therapeutic strategies, coincapacitating MM and ME, will augment growth control. Through a combination of autotransplantsupported high-dose melphalan and therapies that co-target MM and ME, therapeutic strategies will be employed to maximize sustained complete responses. Novel immunotherapeutic approaches are aimed at augmenting autologous host responses via cancer/testis antigen vaccination and employing allogeneic natural killer cells and cytotoxic T lymphocytes. Gene expression profiling (GEP) should improve prognostic models and identify, in concert with Project 4, genes involved in pathogenetic cross talk between MM and ME. Because soluble syndecan-1 has cytokine-trapping properties, studies will determine if blocking heparan sulfate function or its bioavailability may inhibit tumor growth and dissemination. To successfully implement these Projects, 4 Cores are required: A) Admin., Data Mgmt., and Biostatistics; B) Functional Imaging; C) Molecular Genetics; and D) Cell Analysis/Tissue Banking. With access to a large patient population with MM, treated in a hypothesis-driven clinical trial setting with comprehensive follow-up, this P01 will shed light on the molecular and biological mechanisms of disease development/ progression and the current obstacles to sustaining complete remission.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
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Study Section
Subcommittee G - Education (NCI)
Program Officer
Wu, Roy S
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University of Arkansas for Medical Sciences
Schools of Medicine
Little Rock
United States
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Rasche, L; Alapat, D; Kumar, M et al. (2018) Combination of flow cytometry and functional imaging for monitoring of residual disease in myeloma. Leukemia :
Went, Molly; Sud, Amit; Försti, Asta et al. (2018) Identification of multiple risk loci and regulatory mechanisms influencing susceptibility to multiple myeloma. Nat Commun 9:3707
Mehdi, Syed J; Johnson, Sarah K; Epstein, Joshua et al. (2018) Mesenchymal stem cells gene signature in high-risk myeloma bone marrow linked to suppression of distinct IGFBP2-expressing small adipocytes. Br J Haematol :
Rasche, Leo; Angtuaco, Edgardo J; Alpe, Terri L et al. (2018) The presence of large focal lesions is a strong independent prognostic factor in multiple myeloma. Blood 132:59-66
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
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
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
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
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
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

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