Abstract: Although the prognosis of multiple myeloma (MM) patients has dramatically improved during recent years, virtually all patients eventually develop relapsed refractory disease. Several new therapeutics have been developed in the last few years, including carfilzomib, a second-generation proteasome inhibitor (PI) that has been approved by the US Food and Drug Administration (FDA) in the setting of relapsed and/or refractory MM, as a single agent with or without dexamethasone, and in combination with lenalidomide in 2012 and 2015, respectively. Other promising combinations with carfilzomib are being investigated. Carfilzomib has shown superiority over the first-generation PI bortezomib on both efficacy and toxicity. In particular, profoundly lower incidence in polyneuropathy compared to bortezomib has been described. However, carfilzomib has a different toxicity profile, with more cardiovascular adverse events. Therefore, caution should be taken with the use of carfilzomib for elderly and cardiovascularly compromised patients. The once-weekly administration of carfilzomib, recently approved by the FDA in combination with dexamethasone, will lead to a lower burden for the patient and caregivers compared to the twice-weekly schemes that were routinely used until recently. This review has a focus on clinical trial data that has led to drug approval, as well as new promising combination studies, and provides advice for treating physicians who are now prescribing this drug to patients.


Keywords: carfilzomib, relapsed, refractory multiple myeloma, proteasome inhibitor


INTRODUCTION

Outcomes for multiple myeloma (MM) patients have improved significantly during recent years, mainly due to the application of high-dose conventional therapy with autologous stem-cell transplantation as a routine procedure for transplant-eligible MM patients, significant improvements in supportive care strategies, and the introduction and widespread use of the immunomodulatory imide drugs (IMiDs) thalidomide and lenalidomide and the proteasome inhibitor (PI) bortezomib.1 However, the majority of patients eventually develop relapsed and refractory disease, and the prognosis of MM patients who have received at least three prior lines of therapy who have become double-refractory to IMiDs (thalidomide or lenalidomide) and PIs (bortezomib) and have been exposed to an alkylating agent is very poor, with event-free survival and overall survival (OS) only 5 and 13 months, respectively.2 Therefore, the development of new therapeutics, especially for this group of patients, is needed.

Proteasome inhibition is a highly effective treatment for MM. Almost 15 years ago, the US Food and Drug Administration (FDA) approved the first PI, bortezomib, for the treatment of relapsed and/or refractory MM (RRMM) and subsequently for frontline MM treatment. The introduction of bortezomib led to improved progression-free survival (PFS) and OS of MM patients.3 Nevertheless, the presence of primary resistance or development of acquired resistance to bortezomib is common, and treatment is often limited by dose-limiting side effects, most often due to peripheral neuropathy (PNP). Although subcutaneous administration instead of intravenous administration decreases the incidence of PNP, ~5%–10% of patients still experience severe PNP. Therefore, second-generation PIs were developed to improve efficacy, combined with a different toxicity profile. Carfilzomib is a new-generation PI, which in contrast to the reversible binding of bortezomib, binds irreversibly and selectively to its target: the chymotrypsin-like activity of the 20S proteasome. In 2012, the FDA approved carfilzomib for the treatment of patients who have received at least two prior therapies, including bortezomib and an immunomodulatory agent, and who have demonstrated disease progression on or within 60 days of the completion of last therapy.4–6

Mechanisms of action

The proteasome is a multienzyme catalytic complex found in the nucleus and cytoplasm of eukaryotic cells that is responsible for degrading or processing intracellular proteins. Ubiquitylation of proteins marks the proteins for proteasomal degradation. Proteasome inhibition leads to accumulation of intracellular proteins, resulting in cell death.7,8

The 20S proteasome consists of 28 protein subunits, in a cylindrical structure, created by four stacked rings. Two of those rings consist of seven α-subunits and two rings consist of seven β-subunits. Proteasome enzymatic activities are performed by three of the seven β-subunits: β1, β2, and β5. These proteasome enzymatic activities have been characterized as chymotrypsin-like. Bortezomib is a slowly reversible inhibitor, targeting the chymotrypsin-like activity of the proteasome. Compared to bortezomib, carfilzomib has greater selectivity for the chymotrypsin-like activity of the proteasome and binds irreversibly. Carfilzomib administration leads to dose-dependent inhibition of the chymotrypsin-like proteasome activity in all tissue, except for the brain. Figure 1 shows the mechanism of proteasome inhibition by carfilzomib.4,9

Carfilzomib selectively inhibits the β5 subunit of the constitutive proteasome (c20S) and LMP7 of the immunoproteasome (i20S). Inhibition of all proteasome subunits leads to cytotoxic effects in hematologic tumor cells, but also to peripheral blood mononuclear cells. When selectively inhibiting β5and LMP7, an antitumor effect is seen, though with minimal toxicity in untransformed cells. With MM cells, inhibition of chymotrypsin-like subunits alone is enough to induce apoptosis by inducing proteasome-substrate accumulation. This might be the reason that MM cells are so sensitive to chymotrypsin-like subunits.10

In contrast to bortezomib, carfilzomib is associated to a lesser extent with treatment-induced PNP. Bortezomib-induced PNP might be explained by a non-proteasome-dependent mechanism, and this drug inhibits also several nonproteasome targets (eg, serine proteases cathepsin G, cathepsin A, rennin, dipeptidyl peptidase II, and HtrA2/Omi). HtrA2/Omi is known to be involved in neuronal survival, and is inhibited by bortezomib, but not by carfilzomib. This may explain why the unselective binding of bortezomib seems to play an important role in the high rates of sensory polyneuropathy associated with this drug.11

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