Mature plasma cells comprise the majority of tumor cells in multiple myeloma (MM), but we recently reported that these cells have little to no clonogenic growth potential either in vitro or in vivo. Instead, we found that MM growth was driven by clonally related memory B cells that are capable of recapitulating disease in immunodeficient mice and are relatively resistant to standard anti-MM therapies. These functional properties suggest that these clonotypic B cells are MM cancer stem cells (CSC) and play a central role in disease relapse and progression. However, it is unclear whether our laboratory findings apply to the pathogenesis of the disease since little data exists in MM or any human malignancy that CSCs are actually clinically relevant. Proof that the changes in the frequency and/or persistence of CSCs are associated with clinical outcomes or that the targeting and inhibition of CSCs improves survival rates would provide the strongest evidence for their clinical relevance and promote their further study. To this end, we have developed laboratory assays that are capable of serially quantifying MM CSCs over the course of treatment and our early data suggest that changes in MM CSC frequency are associated with progression free survival. We have also identified MM CSC targeting strategies based on their expression of CD20 and enhanced telomerase activity and have initiated pilot clinical trials utilizing the anti-CD20 antibody rituximab and the novel telomerase inhibitor imetelstat. Although clinical activity was limited in these early phase trials, results from our correlative studies have provided important insights regarding anti-CD20 and telomerase inhibitor based approaches in MM and allowed us to modify these approaches. The overall goal of this project is to determine whether or not MM CSCs are clinically relevant, and we believe that our previous studies now place us in an ideal position to address this question by both correlating their frequency with clinical outcomes and determining the clinical impact of novel CSC-targeting strategies. These findings may have important implications for both MM and the CSC field in general, and we propose to: 1). Examine the relationship between MM CSC frequency and clinical outcomes in patients treated with state of the therapies;2). Determine the effects of B cell directed radioimmunotherapy in MM;and 3). Determine the activity of telomerase inhibition in MM.

Public Health Relevance

Virtually all patients with multiple myeloma will relapse and die from their disease. Our previous findings suggest that cancer stem cells possess functional properties implicating a central role in relapse. Therefore, we will determine whether these cells actually play a clinical role in the disease.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA174951-01A1
Application #
8628225
Study Section
Clinical Oncology Study Section (CONC)
Program Officer
Merritt, William D
Project Start
2014-05-01
Project End
2019-04-30
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
1
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Garfall, Alfred L; Stadtmauer, Edward A; Hwang, Wei-Ting et al. (2018) Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma. JCI Insight 3:
Ghosh, Nilanjan; Ye, Xiaobu; Tsai, Hua-Ling et al. (2017) Allogeneic Blood or Marrow Transplantation with Post-Transplantation Cyclophosphamide as Graft-versus-Host Disease Prophylaxis in Multiple Myeloma. Biol Blood Marrow Transplant 23:1903-1909
Rich, Jeremy N; Matsui, William H; Chang, Jenny C (2016) Cancer stem cells: A nuanced perspective. Medicine (Baltimore) 95:S26-8
Gocke, Christian B; McMillan, Ross; Wang, Qiuju et al. (2016) IQGAP1 Scaffold-MAP Kinase Interactions Enhance Multiple Myeloma Clonogenic Growth and Self-Renewal. Mol Cancer Ther 15:2733-2739
Meads, M B; Fang, B; Mathews, L et al. (2016) Targeting PYK2 mediates microenvironment-specific cell death in multiple myeloma. Oncogene 35:2723-34
Lombardi, Lindsey R; Kanakry, Christopher G; Zahurak, Marianna et al. (2016) Therapeutic drug monitoring for either oral or intravenous busulfan when combined with pre- and post-transplantation cyclophosphamide. Leuk Lymphoma 57:666-75
Alonso, Salvador; Hernandez, Daniela; Chang, Yu-Ting et al. (2016) Hedgehog and retinoid signaling alters multiple myeloma microenvironment and generates bortezomib resistance. J Clin Invest 126:4460-4468
Kasamon, Yvette L; BolaƱos-Meade, Javier; Prince, Gabrielle T et al. (2015) Outcomes of Nonmyeloablative HLA-Haploidentical Blood or Marrow Transplantation With High-Dose Post-Transplantation Cyclophosphamide in Older Adults. J Clin Oncol 33:3152-61
McCurdy, Shannon R; Kanakry, Jennifer A; Showel, Margaret M et al. (2015) Risk-stratified outcomes of nonmyeloablative HLA-haploidentical BMT with high-dose posttransplantation cyclophosphamide. Blood 125:3024-31
Xian, Lingling; Huff, Carol Ann; Resar, Linda M S (2015) IBRUTinib: BRUTe force against bortezomib-resistant myeloma cells. Cell Cycle 14:1349-50

Showing the most recent 10 out of 16 publications