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 ^[1] news).

Like Velcade ^[2] (bor­tez­o­mib), carfilzomib ^[3] (Kyprolis ^[4]), which is being developed by Onyx Pharmaceuticals ^[5], 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 ^[6] (lena­lido­mide) and dexamethasone ^[7] (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 ^[8] (Thalomid) or Revlimid as well as an alkylating agent, such as melphalan ^[9] (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 ^[10] (car­filz­o­mib, Revlimid, dexa­meth­a­sone com­bi­na­tion) and 985 ^[11] (single-agent car­filz­o­mib) on the American Society of Hematology annual meeting website as well as the Onyx press release ^[12] (single-agent car­filz­o­mib).