Carfilzomib

Abstract

IntroductionProteasome inhibition is highly effective treatment for multiple myeloma (MM), Waldenström macroglobulinemia, low-grade nonHodgkin lymphomas, and primary amyloidosis. 1 Almost 10 years ago, the US Food and Drug Administration (FDA) approved the dipeptidyl boronic acid derivative proteasome inhibitor bortezomib (BTZ) for the treatment of refractory MM and subsequently frontline therapy for MM, thus opening the door to a new era of improved MM therapy. Indeed, disease-free and overall survival for most MM patients has been significantly extended. Nevertheless primary or secondary BTZ resistance 2 is common, and treatment is often limited by BTZ-induced, dose-limiting side effects, mostly consequent to peripheral neuropathy. 3 Although less frequent BTZ administration at lower doses and using subcutaneous delivery 4,5 may contribute to a lowered BTZ neuropathy incidence and severity without seemingly compromising efficacy, new proteasome inhibitors-the "second generation"-have now been developed and are aimed at being potentially more efficacious and less toxic. The FDA recently granted accelerated approval for carfilzomib (CFZ) injection for the treatment of patients with MM who have received at least 2 prior therapies, including BTZ and an immunomodulatory agent, and who have demonstrated disease progression on or within 60 days of the completion of last therapy. This spotlight review focuses on the data leading to drug approval and provides helpful management tips for treating physicians. Ubiquitin-proteasome pathway inhibition in MM treatmentProteasomes are present in all eukaryotic cells. 6,7 They degrade proteins 8,9 and influence a multitude of cellular processes, [10][11][12][13][14][15][16] including proliferation and DNA repair. [17][18][19] Proteasome inhibition leads to an unfolded protein stress response by accumulation of misfolded proteins in the cell, 20-22 inhibits NF-B, 23 and thus induces cell-cycle arrest 24,25 and apoptosis. [26][27][28] The (malignant) plasma cell in particular is susceptible to proteasome inhibition, even to small changes, 29 because of its inherent function in Ab production. 22,[30][31][32] The proteasomeThe constitutive 26S proteasome consists of protein-recognizing 19S regulatory particles and a 20S proteolytic core 33 that carries 3 protein-specific 29 catalytic sites: the chymotrypsin, trypsin, and caspase-like sites. 34,35 Blocking the chymotrypsin-like site is most effective in cellular growth inhibition in vitro, but coinhibition of other proteasome subunits further increases overall growth retardation. [35][36][37][38] Unique immunoproteasomes exist in cells of immune or hematopoietic origin, where the catalytic sites differ from the constitutive proteasomes. 36 These play an important role in generating antigens for MHC class I presentation. 39 Both constitutive and immunoproteasomes are expressed in MM cells and are targeted by the available inhibitors BTZ and CFZ. It has not been fully elucidated whether the anticancer effects depend on inhibition o...

PI3KCA plays a major role in multiple myeloma and its inhibition with BYL719 decreases proliferation, synergizes with other therapies and overcomes stroma-induced resistance

“…Moreover, the combination of the drugs induced apoptosis and cleavage of caspase-3, caspase-9 and PARP more than each of the drugs alone. Carfilzomib is an emerging therapy which was recently approved for the treatment of MM (Kortuem & Stewart, 2013). Previous studies showed that some bortezomib-resistant cell lines (Kuhn et al, 2009) and patients (Vij et al, 2012) were responsive to carfilzomib.…”

European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma

“…[1][2][3] The introduction of novel agents, thalidomide, lenalidomide, bortezomib, but also the availability of various others, such as 3rd-generation immunomodulatory drugs (IMiDs; pomalidomide), novel proteasome inhibitors, including carfilzomib, ixazomib and oprozomib, antibodies, such as elotuzumab (target: CS1), daratumumab and SAR650984 (CD38), siltuximab (IL-6), tabalumab (BAFF), denosumab (RANKL), romosozumab (sclerostin), Bruton tyrosine kinase, heat shock protein inhibitors and other innovative phase I/II agents have changed or will alter the therapeutic scenario in several ways. [4][5][6][7] Moreover, cereblon (CRBN) has been identified as a possible biomarker for the assessment of clinical efficacy of IMiDs, although this is still a subject of controversy and CRBN testing needs to be standardized. 8,9 The predictive role of CRBN was assessed in the HOVON/GMMG trial, where higher CRBN expression was associated with better survival and clinical efficacy of thalidomide.…”

When Cyborgs meet: building communities of cooperating wearable agents

“…Wireless connectivity is achieved through a Metricom wireless modem or a Lucent WaveLAN adapter. The hardware is described in more detail in [1,2,9,10].…”

“…Among the first systems were several designed at Carnegie-Mellon University [8,12,17]. Similar systems have been built and evaluated at the University of Washington [3,4] and by our own research group [1,2,10]. While [3] is one of the few systems designed for co-located collaboration, it is still a sophisticated, yet traditional videoconference system intended for visual and audio communication.…”

“…Most of them are wearable videoconference systems [1,2,3,4,8,10,12,17], while others aim at establishing personal relationships between users [5]. For example, our own Proem system [9] enables two or more users to exchange personal user profiles in real-time during face-to-face encounters with the goal to identify shared interests.…”