Bortezomib Plus Hsp90 Inhibitor in Relapsed or Refractory Multiple Myeloma
The heat shock protein 90 (Hsp90) inhibitor KW-2478 combined with bortezomib seems to be tolerated well by patients with relapsed or refractory multiple myeloma, according to a two-part, phase I/II trial. The antimyeloma activity was modest, wrote Jamie Cavenagh, MD, FRCP, FRCPath, of St. Bartholomew’s Hospital (London), and his coauthors in the British Journal of Cancer, but the tolerability of the combination supports “further exploration of alternate dosing schedules and combinations.”
KW-2478 has shown only modest activity as a single agent in the relapsed/refractory myeloma population. But in preclinical studies, it showed synergistic antimyeloma activity with bortezomib.
The antitumor activity continued when bone marrow stromal cells were present. This may mean that KW-2478 plus bortezomib can keep the bone marrow environment from overcoming what normally is its protective effect. Hence, the motivation for this phase I/II study.
The objective response rate in the efficacy evaluable phase I/II population was 39.2%, clinical benefit rate was 51.9%, median progression-free survival was 6.7 months, and median duration of response was 5.5 months. The most frequently observed treatment-related grade 3/4 adverse events were diarrhea, fatigue, neutropenia, nausea, and thrombocytopenia.
Because nearly all multiple myeloma patients eventually become refractory to treatment or relapse, there is a need for new agents that act in a “mechanistically different manner” than other treatments used so far in this therapeutic arena.