Emerging treatment option for myeloma presented at hematology meeting

CURE invited Diane Gambill, PhD, a CURE advisory board member, to share her thoughts on advancements in myeloma highlighted at the 2011 annual meeting of the American Society of Hematology.

I have blogged about the 'next generation' proteasome inhibitor carfilzomib and will likely have a chance to do so again as this interesting class of drugs expands.

The proteasome inhibitors are a favorite of mine because they target a very interesting complex of proteins inside cells that was discovered in the 1990s. The proteasome helps the cell get rid of proteins that are made incorrectly or that get damaged once they are already made. Since myeloma cells grow rapidly and are actively making lots of proteins, they accumulate damaged proteins more quickly than normal cells. If cells cannot get rid of damaged proteins, they will die.

This explains, at least in part, why the proteasome inhibitor currently available in the clinic, Velcade (bortezomib), is effective in treating myeloma. Velcade and the immunomodulator Revlimid (lenalidomide) have become standard therapies for myeloma; unfortunately, not all myeloma cells are killed by standard treatments. Some myeloma cells are naturally resistant to treatment (referred to as treatment refractory) while others become resistant during treatment. Several studies are under way or completed that suggest carfilzomib might be active in myeloma that is refractory to treatment or becomes resistant during the course of treatment.

Two phase 2 trials have been conducted to study the efficacy of single-agent carfilzomib in treatment refractory or resistant myeloma. The PS0-171-003-A1 trial was reported at ASCO in 2011 [Proteasome inhibitors in myeloma: The next generation] and showed that 24% of patients who had previously received Velcade or Revlimid responded to carfilzomib. These responses were long lasting and there was a relatively low incidence of adverse events, including peripheral neuropathy (1% grade 3/4). Grade 3/4 peripheral neuropathy, which is considered moderate to severe neuropathy, occurs in about 8% of patients treated with Velcade for relapsed/refractory myeloma.

The second phase 2 trial with final results reported at ASH 2011, PX-171-004, showed similar results. This trial examined response to carfilzomib in patients who had relapsed or refractory disease but had not previously received Velcade. The response rates in this trial ranged from 42% to 52% depending on the dose of carfilzomib (20 mg/m2 or 27 mg/m2) with the higher response rate achieved with the higher dose. Responses were durable with a median time to disease progression of 8.3 months and 13.1 months at the low and high dose, respectively. This is an important result because the majority of patients had previously received an average of two prior therapies including Revlimid and/or stem cell transplant. The safety profile was similar to that seen in the PX-171-003-A1 trial.

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