Emerging protein kinase inhibitors for the treatment of multiple myeloma

ABSTRACT

Introduction: Significant advances have been made during the last two decades in terms of new therapeutic options but also of innovative approaches to diagnosis and management of multiple myeloma (MM). While patient survival has been significantly prolonged, most patients relapse. Including the milestone approval of the first kinase inhibitor imatinib mesylate for CML in 2001, 48 small molecule protein kinase (PK) inhibitors have entered clinical practice until now. However, no PK inhibitor has been approved for MM therapy yet.

Areas covered: This review article summarizes up-to-date knowledge on the pathophysiologic role of PKs in MM. Derived small molecules targeting receptor tyrosine kinases (RTKs), the Ras/Raf/MEK/MAPK- pathway, the PI3K/Akt/mTOR- pathway as well as Bruton tyrosine kinase (BTK), Aurora kinases (AURK), and cyclin-dependent kinases (CDKs) are most promising. Preclinical as well as early clinical data focusing on these molecules will be presented and critically reviewed.

Expert opinion: Current MM therapy is directed against general vulnerabilities. Novel therapeutic strategies, inhibition of PKs in particular, are directed to target tumor-specific driver aberrations such as genetic abnormalities and microenvironment-driven deregulations. Results of ongoing Precision Medicine trials with PK inhibitors alone or in combination with other agents are eagerly awaited and hold the promise of once more improving MM patient outcome.

KEYWORDS:

• Multiple myeloma
• protein kinase
• cell cycle kinase
• targeted therapy
• precision medicine
• small molecule inhibitors

Declaration of interest

S Vallet has received speaker’s honoraria from Pfizer and MSD and consultancy fees from Roche Pharmaceuticals. K Podar has received speaker’s honoraria from Celgene, Amgen Inc. and Janssen Pharmaceuticals, consultancy fees from Celgene, Takeda and Janssen Pharmaceuticals, and research support from Roche Pharmaceuticals. 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.

Many preeminent investigators around the world significantly contributed to our existing knowledge on the pathophysiologic role of kinases in MM during the last years. Due to journal guidelines, we had to restrict the list of references. We apologize to all those colleagues whose important primary work was not mentioned in this review article.

Additional information

Funding

This paper was funded by FTI-Call Land NÖ/WST3-F-5031298/002-2018.