Project 3: Early Detection and Prevention of Multiple Myeloma Progression
Developing a pathogenetic definition
Multiple myeloma is a malignant plasma cell neoplasm that leads to anemia, hypercalcemia, renal insufficiency and bone lesions.
Multiple myeloma is preceded by a common benign monoclonal plasma cell expansion called monoclonal gammopathy of undetermined significance (MGUS). MGUS shares the same initiating events seen in multiple myeloma, including recurrent immunoglobulin gene translocations and hyperdiploidy.
In between multiple myeloma and MGUS is a third clinical entity called smoldering multiple myeloma. In this condition, there is more-extensive plasma cell expansion than in MGUS, but the malignant features of multiple myeloma are not seen.
This research project focuses on using genetics to more precisely demarcate benign plasma cells from malignant plasma cells and on developing a pathogenetic definition of multiple myeloma.
Hypothesis
We hypothesize that an accumulation of secondary genetic events marks the progression from a benign state to a malignant state. These events involve a handful of pathways common to many cancers, including MYC/MAX; MAPK (NRAS, KRAS, BRAF, FGFR3, PTPN11, NF1); NFKB (TRAF3, TRAF2, CYLD, BIRC2/3, MAPK3K14); TP53/MDM2; RB1/CDKN2C; and others (DIS3, FAM46C).
One of these pathways is dysregulated in more than 95% of people with multiple myeloma and in less than 5% of people with MGUS. We postulate that individually or in combination, the pathways can be used to define malignant plasma cells.
There also is increasing evidence for a role of the tumor microenvironment in progression of smoldering multiple myeloma. Clonal hematopoiesis has been associated with increased inflammation and more-rapid progression of multiple myeloma.
We use next-generation sequencing to identify clonal hematopoiesis and to characterize the genetic events present in people with MGUS, smoldering multiple myeloma and multiple myeloma. We correlate these data with the clinical course. We validate our findings using an independent cohort of people with smoldering multiple myeloma enrolled in prospective randomized clinical trials.
Toward early detection
Ultimately, we hope that a genetic definition enables early detection and prompt treatment of multiple myeloma, resulting in the prevention of the malignant consequences of multiple myeloma and in prolonged survival.
Project investigators
Project lead (basic): Marta Chesi, Ph.D.
Project co-lead (clinical): Leif Bergsagel, M.D.
Project co-lead (clinical): S. Vincent Rajkumar, M.D.
