The overall objective of this program project is to understand MM growth in the context of its interaction with the bone marrow microenvironment (ME) in order to translate and exploit this knowledge into smarter MM growth control in patients. A concerted effort by a team of basic and clinical scientists is aimed at further overcoming the tremendous obstacles posed by MM's extensive genetic heterogeneity. We hypothesize that MM subjugates various ME components, perhaps in a MM subtypespecific manner, and that such MM-induced ME imprints may become an irreversible force contributing to MM's defiance of cure. In light of our theme of growth control in MM, toward achieving cure in an increasingly higher proportion of patients, investigators of 4 projects and 5 cores will continue to collaborate in a highly integrated and synergistic fashion. Project 1 plans to achieve better growth control via risk-based treatment strategies in an effort to reduce treatment-related toxicities in low-risk disease while accelerating outcome improvement in high-risk disease. Translational work will interrogate the MM-ME interaction and elucidate, through examination of serial gene expression profiling (GEP) samples, how this interaction affects growth control. Project 2 postulates to achieve better growth control in the relapsed setting by optimizing the clinical activity of haplo-identical NK cells via combination therapy with bortezomib and CS1 antibody. Basic research will examine the antimyeloma activity of human NK cells activated/expanded with K562 cells transfected with membrane-bound interleukin-15 (IL-15) and the co-stimulatory molecule 4-1BBL, in combination with bortezomib and CS1 Ab, in a murine model. Projects 3 and 4 deal with the role of bone, disease in MM pathogenesis. Project 3 will focus on fundamental observations relevant to DKK1 suppression of Wnt/beta-catenin signaling and the interaction of beta-catenin/cadherin cell adhesion with focal lesions, osteolytic bone disease, and MM dissemination to extramedullary disease, in an effort to harness the molecular MM-ME interaction therapeutically pertinent to MM pathogenesis, allowing us to investigate growth control via another avenue (by reduction of tumor cell adhesion). Project 4 will shed light on the biological mechanisms by which osteoblasts and osteoclasts affect myeloma cell growth and dissemination. By unraveling the consequences of altered activities of osteoclasts and osteoblasts on MM dissemination, and understanding the mechanisms involved, novel therapeutic interventions for MM can be developed. This work will be accomplished with access to 5 shared resource cores.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-J (M1))
Program Officer
Merritt, William D
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Arkansas for Medical Sciences
Other Clinical Sciences
Schools of Medicine
Little Rock
United States
Zip Code
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

Showing the most recent 10 out of 284 publications