Pharmacodynamics and pharmacokinetics of proteasome inhibitors for the treatment of multiple myeloma

ABSTRACT

Introduction: Multiple myeloma (MM) is the second most commonly diagnosed hematologic malignancy and has an increasing incidence and prevalence globally, and proteasome inhibitors (PIs) form the backbone of some of our most effective regimens for all phases of this disease in fit and frail patients.

Areas covered: Strong understanding of the proteasome complex is increasingly important as the rapid development of new PIs and innovative myeloma therapies complicate the use of old and new combination regimens. We focus herein on the pharmacodynamics and pharmacokinetics of the approved PIs and others in development, including their safety and efficacy in corresponding clinical studies.

Expert opinion: Advancements such as the first oral PI, ixazomib, with a more convenient route of administration and improved toxicity profile led to an improved quality of life, patient compliance, and all-oral combination regimens which are efficacious for long-term management of standard and high-risk MM. Novel pan-PIs, such as marizomib, hold the promise of superior clinical activity due to irreversible targeting of all multicatalytic proteinase complex subunits. Development of clinically validated biomarkers of PI sensitivity/resistance is required to inform utilization of the most optimal and effective, rationally targeted PI treatments for all MM patients.

KEYWORDS:

• Myeloma
• pharmacodynamics
• pharmacokinetics
• proteasome inhibitors

Article highlights

• Proteasome inhibitors (PIs) with regulatory approvals include bortezomib, carfilzomib, and ixazomib, while others, such as marizomib and oprozimib also show promise.

• Due to a significantly lower rate of peripheral neuropathy of any grade, subcutaneous versus intravenous delivery of bortezomib is considered a preferred standard of practice.

• Carfilzomib has the potential for superior potency and efficacy with decreased neuropathy, but cardiovascular adverse events may be increased and require careful patient monitoring.

• In the setting of renal failure, bortezomib or carfilzomib do not require dose adjustment while ixazomib does, and all three drugs need dose adjustment in patients with hepatic impairment.

• No validated biomarkers of PI sensitivity and/or resistance have been prospectively confirmed, though recent gene expression signature approaches in this area show promise.

• PIs remain cornerstone agents in the treatment of all phases of multiple myeloma, including newly approved ‘quadruplet’ regimens that incorporate immunotherapies.

This box summarizes the key points contained in the article.

Declaration of interest

M Baljevic has served on advisory boards for Amgen, Inc., which markets carfilzomib, Takeda Pharmaceutical Company, which markets bortezomib and ixazomib, and has served in an advisory capacity to Karyopharm Therapeutics and Cardinal Health. RZ Orlowski has served on advisory boards for Amgen, Inc., Celgene Corporation, GSK Biologicals, Ionis Pharmaceuticals, Inc., Juno Therapeutics, Kite Pharma, Legend Biotech, Molecular Partners, Servier, and Takeda Pharmaceutical Company, and received research funding from BioTheryX. 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 funded by the National Cancer Institute [P50 CA142509, R01s CA184464 and 194264, and U10 CA032102], the Leukemia & Lymphoma Society [SCOR-12206-17], and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation through support to RZ Orlowski.