This week’s news of interim results from the ENDEAVOR trial, a head-to-head comparison of “real world” schedules of Kyprolis versus Velcade, reveals an impressive benefit of carfilzomib over bortezomib in relapsed myeloma. Indeed, the 929-patient phase III trial showed progression-free survival (PFS) of 18.7 months for Kyprolis versus 9.4 months for Velcade—basically a doubling of PFS or remission duration.

In the ENDEAVOR trial, Kyprolis was given in the usual schedule of two IV infusions per week for three out of four weeks, with dose escalation to 56 mg/m2. Velcade was also given according to the standard schedule, with subcutaneous (versus IV) administration allowed at the discretion of the investigator. (Sub-Q administration occurred more than 75 percent of the time.)

The results in this large trial follow on the heels of the impressive results in the 792-patient ASPIRE trial, which showed the superiority of Kyprolis plus Revlimid/Dexamethasone (Rd) over Rd alone. A head-to-head comparison of Kyprolis versus Velcade in the frontline setting is ongoing in a trial by the Eastern Cooperative Oncology Group (ECOG). Impressive results with the Kyprolis/Rd combination in the high-risk smoldering myeloma (HR - SMM) setting were presented at the 2014 Annual Meeting of the American Society of Hematology (ASH).

A strong case is emerging to place Kyprolis within the treatment paradigm for myeloma. One must applaud Onyx/Amgen for the direct comparison trials, which allow assessment of both efficacy and toxicity (concerns over which hampered panobinostat’s initial approval in 2014). In the case of Kyprolis, although there are some increased toxicities versus Velcade—including cardiac and renal issues as well as dyspnea and hypertension—these certainly do not preclude use of the drug with normal cautions. Although oral formulations of both Kyprolis and Velcade are in development, it seems their primary role will be in the ongoing therapy or maintenance settings.

Kyprolis is already under review by the FDA in the one-to-three relapse setting based upon the ASPIRE trial results. Future reviews will likely consider the other settings in which Kyprolis can add value—from HR-SMM, frontline, and early relapse to the already approved relapsed/refractory situation. The increases in both depth and length of remissions are definitely important. The twice-weekly IV schedule is a challenge for patients and there is much interest in the ongoing once-weekly schedule study results.

Full data from the ENDEAVOR trial will be submitted for presentation at the 2015 American Society of Clinical Oncology (ASCO) Annual Meeting. In the meantime, this important emerging option is great news for patients. As always, it takes time to determine the best new treatment paradigm—but head-to-head comparison data help considerably. Stay tuned for what will be many updates to come.

Image of Dr. Brian G.M. DurieDr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.

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