A new drug called perifosine, when given in combination with other drugs, has been shown to be effective against relapsed or refractory multiple myeloma. Several perifosine studies were presented at the American Society for Hematology (ASH) meeting this year.

Perifosine prevents the growth of myeloma cells by inhibiting the pathway of Akt, a key signaling protein that regulates cellular survival. Perifosine also promotes apoptosis, or programmed cell death, by activating a specific protein pathway called the JNK pathway.

Perifosine first demonstrated clinical activity when combined with another drug, dexamethasone. In the two studies described here, perifosine was given in combination with dexamethasone and Revlimid (lenalidomide) or with dexamethasone and Velcade (bortezomib).

In a Phase 1 trial presented on Monday, Dr. Andrzej Jakubowiak sought to explore the effects of perifosine given in conjunction with Revlimid. While Revlimid alone works actively against multiple myeloma, it displays enhanced effects when combined with dexamethasone. This study was designed to determine the effects of the perifosine-dexamethasone-Revlimid (peri-dex-Rev) combination.

Thirty patients completed the study, and the overall response rate to the combination of drugs was 50 percent. As of August 2008, the average time until myeloma progression was 31 weeks in patients who showed at least a partial response, and 23 weeks for all patients. Common side effects included fatigue, anemia (low levels of hemoglobin), hypophosphatemia (abnormally low levels of phosphate in the blood), thrombocytopenia (abnormally low levels of blood platelets which help regulate the formation of blood clots), and neutropenia (abnormally low levels of neutrophil, a type of white blood cell).

A set of Phase 1 and 2 studies led by Dr. Paul Richardson explored the perifosine-dexamethasone-Velcade (peri-dex-Vel) combination in a patient population that was previously treated with, and resistant to, Velcade. Combinations without dexamethasone were also tested. The results were presented at the ASH meeting on Tuesday.

A total of 76 patients participated in the two trials. Together, the peri-dex-Vel and peri-Vel combinations had an overall response rate of 40 percent. As of August 2008, the average time until progression in patients with at least a partial response to the drug was 34 weeks. Common side effects included upper respiratory infection, proteinuria (excess of serum proteins in urine), leukopenia (low levels of leukocytes, a type of white blood cell), hyponatremia (low sodium levels in the plasma), anemia, neutropenia, lymphopenia (low levels of lymphocytes, a type of white blood cell), and thrombocytopenia.

Because these combinations involving perifosine and Velcade were shown to be active in a patient population resistant to Velcade, these results are encouraging. Further clinical trials are planned.

For more information, see abstracts 3691 (peri-dex-Rev combination) and 870 (peri-dex-Vel combination) from the ASH meeting.