The emerging role of carfilzomib combination therapy in the management of multiple myeloma

Abstract

Carfilzomib is a proteasome inhibitor that selectively and irreversibly binds to its target, resulting in sustained inhibition absent of off-target effects relative to bortezomib. Single-agent carfilzomib has produced robust and durable responses in clinical trials and it has been approved in the US for treating relapsed and refractory multiple myeloma (MM). Due to its favorable safety profile, carfilzomib is particularly suitable for use in combination strategies. Promising data have been reported from studies that investigated the use of carfilzomib in combination with immunomodulators, alkylating agents, glucocorticoids, histone deacetylase inhibitors and kinesin spindle protein inhibitors. Ongoing pivotal randomized Phase III studies are investigating the efficacy and safety of carfilzomib combinations in patients with relapsed MM and transplant ineligible patients.

Keywords::

• carfilzomib
• drug combinations
• multiple myeloma
• newly diagnosed
• relapsed/refractory

Financial & competing interests disclosure

P Moreau has served on advisory boards for Onyx Pharmaceuticals. Financial support for the preparation of this manuscript was supplied by Onyx Pharmaceuticals. The author has 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.

Medical writing assistance (funded by Onyx Pharmaceuticals) was provided by T Spurway on behalf of Prism Ideas Ltd.

Key issues

• There are several benefits of using combination therapies to treat patients with multiple myeloma (MM), including the potential to overcome resistance, the stimulation of synergistic apoptotic mechanisms and the enhanced susceptibility of myeloma cells to combination therapies.

• Clinical factors that need to be taken into account when selecting drug combinations for the treatment of MM include the mechanism of action of each agent, the potential for drug resistance pathways and the possibility of drug interactions and toxicities.

• Clinical studies have demonstrated that the proteasome inhibitor (PI) bortezomib can be used effectively as part of a doublet, triplet or quadruplet drug combination to treat patients with relapsed and/or refractory MM (RRMM) or newly diagnosed MM (NDMM).

• The PI carfilzomib has several pharmacological advantages over bortezomib:

  • – Carfilzomib irreversibly binds to the β5 subunit of the 26S proteasome, whereas bortezomib is a reversible inhibitor.

  • – Carfilzomib does not cause neurodegeneration and does not inhibit non-proteasome, serine protease targets.

  • – Carfilzomib has greater anti-tumor activity than bortezomib and can overcome resistance to conventional therapeutic agents.

• Single-agent carfilzomib has rapid, durable anti-tumor activity and an acceptable tolerability profile in heavily pre-treated patients with RRMM. The US FDA has approved the use of single-agent carfilzomib for treating patients with relapsed and refractory MM.

• Numerous studies have shown that carfilzomib is an effective and well-tolerated therapeutic when used as part of the following combination regimens:

  • – Doublet, triplet or quadruplet combinations in patients with RRMM.

  • – Triplet combinations in patients with relapsed or progressive MM.

  • – Triplet or quadruplet combinations in patients with NDMM.

  • – As a replacement to bortezomib in patients with MM, who are refractory to bortezomib-containing regimens.