Research Abstract

I currently serve as the Director of the Bing Center for Waldenstrom's Macroglobulinemia at the DFCI. The Bing Center cares for over 1,200 patients a year with WM, and IgM related disorders. Most patients seen in the Bing Center enter studies evaluating the genetic basis, pathogenesis and treatment of WM. A registry of patients and families funded through the International Waldenstrom’s Macroglobulinemia Foundation has recruited over 1000 patients and family members to study the genetic basis and predispositions for WM. The use of whole genome sequencing (WGS) has been used by us to define the genomic landscape of WM. Using paired normal/tumor tumor samples, we identified and validated highly recurring MYD88 (L265P) and CXCR4 WHIM-like somatic mutations. The discovery of MYD88 L265P somatic mutation which is present in 95% of WM patients has permitted the differentiation of WM from overlapping B-cell disorders, including marginal zone lymphoma and IgM myeloma. The feasibility for the diagnostic and response assessment potential for MYD88 L265P peripheral blood testing in WM was also demonstrated by my laboratory. In as well, my laboratory has worked on MYD88 L265P signaling in WM including and has shown the activation of IRAK 1/4/TRAF6/NFKB and defined for the first time signaling through Bruton’s tyrosine kinase (BTK). These findings led to a clinical trial in WM patients using the BTK inhibitor ibrutinib which has shown remarkable activity in relapsed/refractory WM patients, and led to the first breakthrough designation in oncology by the U.S. FDA, and subsequent approval of ibrutinib by the FDA and EMA for the treatment of WM. Our current efforts are now focused on defining the role of other recurring mutations in WM that are observed at lower frequencies, but which may still have important impact on pathogenesis and treatment (e.g. ARID1A, CD79A/B, and TP53), and gene loss in pathways that impact critical growth regulatory functions (e.g. HIVEP2, TNFAIP3). Transcriptomic and epigenomic analysis is also being undertaken, with the goal of developing a highly integrated genomic profile for MYD88 mutated and unmutated WM disease. My laboratory has also undertaken efforts to develop inhibitors of MYD88 signaling. Kinase inhibitors that target IRAK1 and HCK were developed as part of these efforts with Nathanael Gray’s group at Harvard Medical School, while a stapled peptide approach to disabling MYDDosome signaling is being pursued with Loren Walensky’s group at the Dana Farber Cancer Institute. The signaling pathway associated with the CXCR4 WHIM-like mutations which are present in 40% of WM patients has also been a focus of my laboratory. We showed that CXCR4-WHIM like mutations activate AKT and ERK, and block ibrutinib activity in vivo, and also associated with ibrutinib resistance in WM patients. Use of CXCR4 inhibitors in vitro block ibrutinib resistance, and a clinical trial with the CXCR4 inhibitor ulocuplomab is being initiated in WM. In addition to my clinical and laboratory activities, I also chair the Waldenstrom’s Macroglobulinemia Clinical Trials Group (WMCTG) and have conducted clinical studies focused on identifying novel agents for the primary and salvage therapy of WM. Many of the agents included in these trials were validated for their activity in WM by preclinical studies in my laboratory, and include monoclonal antibodies (rituximab, alemtuzumab), nucleoside analogue (fludarabine), bifunctional alkylator (bendamustine), immunomodulating agents (thalidomide, lenalidomide, pomalidomide), as well as proteasome (bortezomib, MLN4924, carfilzomib), phosphodiesterase (sildenafil), HMG-CoA reductase (simvastatin), c-kit (imatinib mesylate), MTOR (everolimus), BCR (ibrutinib, Avila 292) and BCL2 (ABT-199) inhibitors. These trials have resulted in the identification of many active treatments for WM patients, and identified specific risks in WM patients such as the rituximab-related IgM flare, disease transformation from nucleoside analogues, erythroid suppression by lenalidomide, late immune mediated thrombocytopenia by alemtuzumab, and IgM discordance by everolimus. These discoveries greatly impacted the standard of care for both primary and salvage therapy of WM, led to the first approval ever of an agent for the treatment of WM in the U.S. and Europe, and were incorporated into published International Consensus and National Comprehensive Cancer Network (NCCN) guidelines for WM patient management, as well as in many journal and textbook publications.