A recent paper published in Lancet Oncology examines drugs that target biological mechanisms in multiple myeloma. This article is the second of three articles discussing new drugs for myeloma treatment.

Researchers have begun to understand the multi-step process by which myeloma occurs. Key features of this process are signaling pathways, which take information from outside of the cell and from within the cell to create a cascading reaction. While signaling pathways are a part of all cells, they are problematic if not regulated.

Studies have shown that a pathway involving the NFkB receptor is mutated in up to 80 percent of multiple myeloma patients. NFkB receptors are involved in cell proliferation. Preclinical studies have shown that drugs inhibiting NFkB activation have anti-myeloma activity. Velcade (bortezomib) also targets this pathway, and this drug has been correlated with reduced NFkB activity.

Another signaling pathway found to be associated with the adverse prognosis of multiple myeloma is the RAS pathway. Malfunctions in the RAS pathway often lead to abnormal cell proliferation and malignant transformations in cells. While the drug Zarnestra (tipifarnib) inhibits a part of this pathway and seems attractive, phase 2 clinical trials have been unsuccessful. However, Zarnestra has shown some potential when used in combination with Velcade. Further studies are still needed.

A different combination therapy using a P38 MAPK inhibitor (SCIOS-469) with Velcade also showed potential. However, it is possible that the results might be due to Velcade alone.

The P38 pathway controls cell proliferation and cell death. Of the 28 patients who took SCIOS-469 in the phase 2 clinical trial, only 24 percent stabilized. When SCIOS-469 was used in combination with Velcade, nine of the 34 patients achieved a partial response, two showed a minor response, and three stabilized.

Perifosine is a drug that causes cell death. It works by preventing AKT, an enzyme which is responsible for regulating cellular survival, from keeping the cell alive. When perifosine was used in clinical trials with dexamethasone, 15 of the 31 patients stabilized. In studies where perifosine was used with Velcade or with Revlimid (lenalidomide), positive responses to the treatment were seen.

With perifosine and Velcade therapy, 33 percent responded positively. Perifosine and Revlimid therapy led to a 66 percent positive response.

For more information about new myeloma therapies targeting cell signaling pathways, see the entire article in The Lancet Oncology journal.