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Proteasome inhibitors in myeloma: The next generation


CURE invited Diane Gambill, PhD, a CURE advisory board member, to share her thoughts on some of the myeloma studies highlighted at the 2011 annual meeting of the American Society of Clinical Oncology. The FDA approval of the first proteasome inhibitor, Velcade (bortezomib), in 2003 ushered in a new era in the treatment of multiple myeloma. Unfortunately, one consequence of introducing a new drug is the inevitable emergence of resistance. Cancer cells have a dismaying ability to quickly "learn" how to defend themselves against new anticancer agents almost as quickly as they can be introduced into the clinic. Help for emerging resistance might be on the way. As is often the case, a successful therapeutic agent generates interest in developing the next generation of similar drugs, each developed with a goal of improving on the first generation. Toward that end, the next generation of proteasome inhibitors is currently in clinical development.Carfilzomib inhibits the activity of the proteasome in a slightly different way than Velcade; thus, it is postulated that carfilzomib might work in patients whose myeloma has become resistant to Velcade. At this year's meeting of the American Society for Clinical Oncology, several phase 2 trials testing this notion were presented.In one study (PX-171-003-A1), carfilzomib was given as a single agent in 266 patients with myeloma that had received Velcade and Revlimid (lenalidomide) as previous treatments either separate lines of treatment or in combination. Results were promising with a 24% overall response rate including 1 complete response and 13 very good partial responses. The most frequent grade 3/4 toxicities (considered moderate to severe) were anemia (63%), thrombocytopenia (77%), neutropenia (29%) and fatigue (20%). The incidence of grade 3/4 peripheral neuropathy, which is often associated with myeloma and can be a dose-limiting side effect of intravenous Velcade (see note below about new data with subcutaneous administration of Velcade), was low at 1.1% (3 patients). The most notable result, however, was that responses jmappear to be durable. This might be due in part to fewer patients discontinuing therapy due to toxicity, the so-called dose-response effect. Although the data are not yet mature, median overall survival was 15.6 months in all patients and 20.7 months in patients with a response.Currently available options for patients with relapsed and/or refractory myeloma include Revlimid with low-dose Decadron (dexamethasone) or Velcade with Decadron. A second phase 2 trial presented at this year's meeting addressed the question of whether adding carfilzomib to Revlimid and low-dose Decadron was safe and effective. In this study (PX-181-006), 52 patients were treated with the combination of three drugs. This trial enrolled patients who were less heavily pretreated than the 003-A1 study (at least two prior therapies) and prior Velcade or Revlimid were not required but 75% of the patients had received prior Velcade and 62% had received prior Revlimid. This trial resulted in an overall response rate of 78%, which included 12 complete responses and 9 very good partial responses. The most frequent grade 3/4 toxicities were anemia (13%), thrombocytopenia (12%), neutropenia (17%), fatigue (12%) and diarrhea (6%). Keeping in mind that phase 2 trial results need confirmation in randomized clinical trials, we await the results of phase 3 trials in relapsed/refractory myeloma. The FOCUS trial is currently under way to determine how carfilzomib compares wtih best supportive care, and the ASPIRE study has already enrolled 144 patients to assess the relative efficacy of Revlimid plus low-dose Decadron with or without carfilzomib. Completion dates for these trials are scheduled for spring of 2012. The current choices for treatment of myeloma include several effective agents developed over the past decade. Will carfilzomib be next? Several other agents are in late-stage clinical trials for relapsed and/or refractory myeloma including the monoclonal antibody elotuzumab, a third proteasome inhibitor (NPI-0052), and a host of other early-phase compounds. In terms of proteasome inhibitors, it is also worth nothing that a recent publication in the medical journal Lancet Oncology showed, in a randomized clinical trial, that subcutaneous administration in patients with relapsed myeloma was generally safer than intravenous administration with significantly less grade 3 or 4 peripheral neuropathy.

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