Carfilzomib con­tinues to show promising results in multiple myeloma according to four studies presented in a poster session yesterday at the 2010 American Society of Hematology annual meeting in Orlando.

Carfilzomib ^[1] (Kyprolis ^[2]), developed by Onyx Pharmaceuticals, is a new drug that is cur­rently being in­ves­ti­gated as a potential treat­ment for multiple myeloma. It belongs to the same class of drugs as Velcade ^[3] (bor­tez­o­mib). However it works slightly differently by binding to different proteins than Velcade.

Recent research has indicated that car­filz­o­mib is effective for patients with re­lapsed or refractory (resistant) myeloma who have received multiple prior treat­ments or have an advanced stage of disease (see related Beacon ^[4] news).

"The car­filz­o­mib posters con­firm without a doubt that we have an active new drug for the treat­ment of myeloma," said Dr. S. Vincent Rajkumar of the Mayo Clinic, who is not involved in the devel­op­ment of car­filz­o­mib. "We are hopeful that the drug will be granted accelerated approval. Carfilzomib also has the possible added benefit of a lower neu­rop­athy rate."

The four studies presented yesterday showed results for specific patient groups treated with car­filz­o­mib.

Single-Agent Carfilzomib In Patients Without Prior Velcade Treatment

In the Phase 2 trial PX-171-004, researchers evaluated the activity of car­filz­o­mib in re­lapsed/refractory myeloma patients who received one to three prior treat­ments.

In a sub-analysis, the researchers in­ves­ti­gated car­filz­o­mib’s effects in 110 patients participating in the study who had not pre­vi­ously been treated with Velcade.

The researchers found that single-agent car­filz­o­mib induced high response rates in these patients.

Many of the 110 patients had multiple existing illnesses: 53 per­cent had mild neu­rop­athy (pain and tingling in the legs, feet, hands, and arms), 30 per­cent had kidney dysfunction, and 17 per­cent had diabetes. Many of these patients were also considered to have high-risk myeloma due to certain chromosomal ab­nor­mal­i­ties.

The patients were treated with 20 mg/m² of car­filz­o­mib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for a maximum of 12 cycles. In some patients, the dosage of car­filz­o­mib was increased to 27 mg/m² after the first cycle. All patients also received 4 mg of dexamethasone ^[5] (Decadron) in the first cycle only.

Researchers found that of 110 patients who had not received prior Velcade treat­ment, 48 per­cent responded to car­filz­o­mib treat­ment. For patients who received the increased dosage of car­filz­o­mib fol­low­ing cycle 1, the over­all response rate was 54 per­cent.

The most common mild to mod­er­ate treat­ment-related side effects were fatigue (61 per­cent), nausea (43 per­cent), low red blood cell count (39 per­cent), shortness of breath (36 per­cent), cough (34 per­cent), headache (31 per­cent), low platelet count (30 per­cent), and upper res­pira­tory in­fec­tions (30 per­cent). None of the 110 patients dis­con­tinued treat­ment due to periph­eral neu­rop­athy.

Single-Agent Carfilzomib In Patients With Chromosomal Abnormalities

In a sub-analysis of a different Phase 2 trial (PX-171-0030A1), researchers evaluated the effect of chromosomal ab­nor­mal­i­ties on the response rates of re­lapsed/refractory myeloma patients who received single-agent car­filz­o­mib .

The researchers found that the presence of unfavorable chromosomal ab­nor­mal­i­ties did not significantly impact that activity of single-agent car­filz­o­mib in re­lapsed/refractory myeloma patients.

Previous research has indicated that certain chromosomal ab­nor­mal­i­ties are asso­ci­ated with a poorer prognosis for myeloma.

The 266 patients participating in the study had received a median of five prior treat­ments with a median of 13 different anti-myeloma drugs. Nearly all of the patients had been pre­vi­ously treated with Velcade. One third of the patients (31 per­cent) had at least one unfavorable chromosomal ab­nor­mal­ity

The patients were treated with 20 mg/m² of car­filz­o­mib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for a maximum of 12 cycles. After the first cycle, the dosage of car­filz­o­mib was increased to 27 mg/m².

Of the patients with at unfavorable chromosomal ab­nor­mal­i­ties, 28 per­cent responded to treat­ment compared to 24 per­cent of patients with favorable or no ab­nor­mal­i­ties.

Response lasted a similar length of time for both groups: 6 months in patients with unfavorable chromosomal ab­nor­mal­i­ties and 8 months for the remaining patients.

Long-Term Treatment With Single-Agent Carfilzomib

In the trial PX-171-010, researchers evaluated the effect of treating re­lapsed/refractory patients with single-agent car­filz­o­mib for extended periods of time. The trial was an extension study of four Phase 1 and 2 clinical trials that examined the activity of single agent car­filz­o­mib.

In order to be eligible for the extension study, patients must have completed the maximum 12 cycles of treat­ment in the first clinical trial.

The 59 participating patients con­tinued to receive the same dose as in the pre­vi­ous trials (20 mg/m² of car­filz­o­mib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle; in some trials, the car­filz­o­mib dose was escalated to 27 mg/m²). Additionally, one patient con­tinued to receive 4 mg of dexa­meth­a­sone daily.

Researchers found that 24 patients (60 per­cent) are still being treated with car­filz­o­mib with no apparent cumulative side effects. So far, 12 patients have completed over 18 months of car­filz­o­mib treat­ment. The longest treat­ment period was 27 months. Sixteen patients dis­con­tinued treat­ment because of disease pro­gres­sion.

Based on these results, researchers concluded that patients could be treated with car­filz­o­mib for extended periods of time without treat­ment-related side effects.

Safety Analysis of Single-Agent Carfilzomib

In a fourth analysis, researchers evaluated the safety of single-agent car­filz­o­mib in re­lapsed/refractory myeloma from the results of three Phase 2 clinical trials.

Researchers found that car­filz­o­mib was well tolerated in all four analyzed trials. They pointed out in particular that the low levels of neu­rop­athy asso­ci­ated with car­filz­o­mib make it a promising treat­ment for patients with pre-existing neu­rop­athy.

The patients were treated with 20 mg/m² of car­filz­o­mib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle for a maximum of 12 cycles. In three studies, the dosage of car­filz­o­mib was increased to 27 mg/m² after the first cycle in well-tolerated cases. In one study, patients also received low-dose dexa­meth­a­sone.

The most common treat­ment-related side effects were fatigue, low red blood cell counts, nausea, shortness of breath, and low platelet counts. Only 4 per­cent of patients experienced periph­eral neu­rop­athy.

Researchers observed several serious side effects that are most likely treat­ment-related: pneu­monia (3.5 per­cent), congestive heart failure (2.5 per­cent), acute kidney failure (1.7 per­cent), fever (1.2 per­cent), and shortness of breath (1 per­cent).

For more in­­for­ma­tion about the four above studies, please refer to abstract 1938 ^[6] (PX-171-004), abstract 1942 ^[7] (PX-171-003-A1), abstract 1953 ^[8] (PX-171-010), and abstract 1954 ^[9] (Safety Analysis) on the ASH annual meeting website.