Emerging drugs for the treatment of Waldenström macroglobulinemia.

INTRODUCTION: Waldenström's Macroglobulinemia (WM) is an indolent lymphoma with uniquely distinct and heterogenous clinical and genomic profiles. Clonal lymphoplasmacytic cells secrete monoclonal IgM. More than 90% of patients harbor a mutation in MYD88 gene, leading to the constitutive activation of downstream pathways, involving BTK-mediated signaling. The use of BTK inhibitors has changed the treatment landscape of WM and has paved the way for new approaches to therapy.

AREAS COVERED: WM is an orphan disease and ibrutinib is the only FDA/EMA approved agent. Currently established agent combinations will be reviewed with a focus on emerging therapeutic options. These include second generation inhibitors, agents that target other molecules in the BCR signaling pathway, CXCR4 inhibitors, proteasome inhibitors and anti-CD38 antibodies. The current research goal is to establish a combination that can induce deep and durable responses with minimal associated toxicity. In addition, agents that can overcome ibrutinib resistance or act in a synergistic manner with BTKi are under investigation.

EXPERT OPINION: The optimal therapeutic approach for WM patients is not currently established. The question of whether a combinatory (or synergistic) regimen to overcome resistance and allow for fixed- duration treatment will allow for deep/durable responses is being addressed in ongoing clinical trials.