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Carfilzomib Shows Promise In Both Newly Diagnosed and Relapsed/Refractory Multiple Myeloma Patients (ASH 2010)

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Published: Dec 20, 2010 4:36 pm

Carfilzomib is well tolerated and highly active in both newly diagnosed multiple myeloma patients as well as relapsed and treatment-resistant patients, according to the results of two recent clinical trials that were presented at the American Society of Hematology 2010 annual meeting in Orlando earlier this month.

These results further underscore carfilzomib’s activity in multiple myeloma.  Several studies with promising results were also reported in poster sessions during the annual meeting (see related Beacon news).

Like Velcade (bortezomib), carfilzomib (Kyprolis), which is being developed by Onyx Pharmaceuticals, is a proteasome inhibitor.  It prevents the break down of important proteins in cancerous cells, thereby causing cell death.

Carfilzomib, Revlimid, Dexamethasone Combination In Newly Diagnosed Multiple Myeloma

Dr. Andrzej Jakubowiak of the University of Michigan presented the results of a Phase 1/2 clinical trial investigating the safety and activity of carfilzomib in combination with Revlimid (lenalidomide) and dexamethasone (Decadron) for newly diagnosed multiple myeloma patients.

“We hypothesize that the carfilzomib, Revlimid, dexamethasone combination has potential for even higher activity in newly diagnosed myeloma [than in relapsed/refractory myeloma]. It could produce higher complete response/near complete response rates than currently available regimens,” explained Dr. Jakubowiak at the start of his talk.

To date, researchers have enrolled 24 patients in the trial.  Patients were placed into one of three treatment groups receiving 20 mg/m2, 27 mg/m2, or 36 mg/m2 of carfilzomib to determine the maximum tolerated dose.  Carfilzomib was administered intravenously on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.

All treatment groups received Revlimid, 25 mg orally on days 1-21, and low-dose dexamethasone orally once per week. After completion of eight cycles, patients received 28-day maintenance cycles with Carfilzomib on days 1, 2, 15, and 16; Revlimid on days 1-21; and dexamethasone weekly at the doses tolerated at the end of eight cycles.

After four months of treatment, 95 percent of patients achieved a partial response or better, with 55 percent of patients achieving a complete or near complete response.

According to Dr. Jakubowiak, response to treatment was rapid, with 89 percent of patients achieving partial responses after one cycle.  He added that all patients showed improvement in responses with continued treatment.  After eight cycles, all patients achieved at least a partial response with 67 percent of patients achieving a complete response or near complete response.

At a follow-up time of six months, no patients experienced disease progression, and all patients were still alive.

According to Dr. Jakubowiak, side effects were mostly mild and included low white blood cell, red blood cell, and platelet counts, which were reversible.  Other side effects included blood clots, fatigue, mood swings, and blood sugar elevations.  Of note, clinically significant peripheral neuropathy (pain and tingling in extremities) as a result of carfilzomib was not observed, even after prolonged treatment.

“It’s still early, but these response rates appear to compare favorably to the current best regimens in newly diagnosed myeloma. Importantly, the regimen is by-and-large well tolerated, allowing for extended treatment,” concluded Dr. Jakubowiak.

He added that the results of this study provide additional support for the evaluation of the combination treatment in newly diagnosed multiple myeloma.  A Phase 3 trial will be comparing the carfilzomib, Revlimid, dexamethasone combination with Revlimid and dexamethasone alone in patients with relapsed multiple myeloma.

The results were well received by physicians in attendance at the meeting.  During the question and answer session following the talk, several people expressed that the results were “wonderful” and “encouraging.”  Another attendee said that these were unprecedented complete response rates.

Single Agent Carfilzomib For Relapsed/Refractory Multiple Myeloma

Dr. David Siegel from the Hackensack University Medical Center in New Jersey presented the results of a Phase 2b trial investigating the safety and efficacy of carfilzomib as a single agent in patients with relapsed multiple myeloma whose disease was refractory to their last treatment regimen.

The study enrolled 266 patients who had received two or more prior therapies including Velcade and either thalidomide (Thalomid) or Revlimid as well as an alkylating agent, such as melphalan (Alkeran). According to Dr. Siegel, the patients were heavily pretreated with a median of four prior therapies.

Patients received carfilzomib at 20 mg/m2 on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle.  After the first cycle, the dose was increased to 27 mg/m2 on the same schedule for up to 12 cycles.

A total of 24 percent of patients achieved a partial response or better. Dr. Siegel added that 10 percent of patients achieved a minimal response.

“The reason I point out the 10 percent of minimal responders,” explained Dr. Siegel, “is that the duration of response was 8.3 months, and this 8.3 months was maintained in both the partial response or better population and the minimal response or better population.”

Dr. Siegel pointed out that the number of prior therapies, plasma involvement in the bone marrow, unfavorable chromosomal abnormalities, and pre-existing peripheral neuropathy were not predictive of response to carfilzomib.

For patients who were refractory to Velcade in their last line of therapy, 19 percent of patients achieved a partial response or better, which according to Dr. Siegel is similar to the overall patient population in the study.

Among patients with unfavorable chromosomal abnormalities, 28 percent responded to treatment.

The median progression-free survival was 3.7 months, and 32 percent of patients achieved stable disease for at least six weeks.

The median overall survival was 15.5 months. Median overall survival for responding patients has not yet been reached, though researchers predict based on current data that it will exceed 19 months.

The most common severe side effects included low platelet counts (27 percent), low red blood cell counts (22 percent), and low white blood cell counts (10 percent), which Dr. Siegel described as surprisingly low.

Despite the fact that 77 percent of patients had mild to moderate peripheral neuropathy prior to enrolling in the trial, new onset peripheral neuropathy resulting from carfilzomib treatment was rare, with severe cases presenting in less than one percent of participants.

Eighty-two percent of patients discontinued therapy, mostly due to progression of disease. However, Dr. Siegel pointed out that none of the patients discontinued therapy due to emerging peripheral neuropathy.

Nine percent of patients died while on the study, half due to disease progression.

“Carfilzomib is a very well tolerated drug in an extremely heavily pretreated patient population at very low incidence of peripheral neuropathy,” concluded Dr. Siegel.

For more information, please see abstracts 862 (carfilzomib, Revlimid, dexamethasone combination) and 985 (single-agent carfilzomib) on the American Society of Hematology annual meeting website as well as the Onyx press release (single-agent carfilzomib).

Photo by José Goulão on Flickr – some rights reserved.
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