Emerging drugs for the treatment of Waldenström macroglobulinemia

ABSTRACT

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.

KEYWORDS:

• BTK inhibitors
• CXCR4
• MYD88
• CXCR4 inhibitors
• Waldenström’s macroglobulinemia

Article highlights

• Waldenström’s macroglobulinemia remains to date an incurable, orphan disease

• Given the rarity of WM and its indolent course, which requires long follow-up, robust clinical trial data has been limited and few randomized clinical trials have been conducted to date.

• Understanding disease biology and the genomic landscape of the disease are key to the development of new, active and safe agents and predicting response depth and kinetics for each patient.

• More than 90% of patients harbor a mutation in MYD88 gene, leading to the constitutive activation of downstream pathways, involving BTK-mediated signaling .

• The treatment landscape has been changed with the introduction of BTK inhibitors and ibrutinib (the only EMA/FDA approved drug for the disease), the first-in-class drug has changed paved the way for new treatment approaches.

• Emerging drugs for the treatment of the disease 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 develop a non-genotoxic, fixed duration treatment, which can achieve prolonged disease control.

• In the future the optimal therapeutic strategy will most likely be adopted to some extent to the mutational status of the patient. At the same time an optimal treatment combination could potentially allow treating the WM patient beyond that.

Declaration of interest

E Kastritis has received honoraria/personal fees from Amgen, Genesis Pharma, Janssen, Takeda and Prothena and research grants from Amgen and Janssen. MAD has received honoraria/personal fees from Amgen, BMS, Celgene, GSK, Janssen, Takeda. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.