Project 3: Early Detection and Prevention of Multiple Myeloma Progression
Multiple myeloma is a malignant plasma cell neoplasm leading to anemia, hypercalcemia, renal insufficiency and bone lesions. It is preceded by a common benign monoclonal plasma cell expansion called monoclonal gammopathy of undetermined significance (MGUS) that shares the same initiating events seen in multiple myeloma, including recurrent immunoglobulin gene translocations and hyperdiploidy. There is a third clinical entity in between these two conditions, called smoldering multiple myeloma, in which there has been more extensive plasma cell expansion than in MGUS, but in which the malignant features of multiple myeloma are not seen.
This research project is focused on using genetics to more precisely demarcate benign plasma cells from malignant plasma cells and develop a pathogenetic definition of multiple myeloma.
We hypothesize that an accumulation of secondary genetic events marks the progression from a benign to 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 multiple myeloma cases and in less than 5% of MGUS cases. We postulate that individually or in combination they can be used to define malignant plasma cells.
There is also increasing evidence for a role of the tumor microenvironment in progression of smoldering multiple myeloma, and recently 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 patients with MGUS, smoldering multiple myeloma and multiple myeloma, and correlate these with the clinical course. We validate our findings using an independent cohort of patients with smoldering multiple myeloma enrolled in prospective randomized clinical trials.
Ultimately, we hope that a genetic definition allows for both the early detection and prompt treatment of multiple myeloma, resulting in the prevention of the malignant consequences of multiple myeloma and in prolonged survival for patients.