Multiple Myeloma Targeted Therapies - Targeted Cancer Therapy

MULTIPLE MYELOMA KNOWLEDGE CENTER

Targeted Therapies

Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules that are essential for cancer cell survival.

Sample Classes in Development for Multiple Myeloma

BRAF Inhibitors

Some patients with multiple myeloma have a mutation in a pathway called BRAF. This mutation results in unchecked growth of myeloma cells.

Patients with many kinds of cancer may have a specific BRAF mutation called V600E. For example, it is often found in patients with melanoma. A drug called Zelboraf® (vemurafenib, Genentech) has been approved for these melanoma patients, and it has been successful.

Thinking that patients with multiple myeloma who have this mutation may be candidates for this treatment, researchers conducted a small clinical trial. Results showed that one patient responded well to this treatment.

To find out whether the effect of Zelboraf is more widespread, a Phase 2 clinical trial in myeloma is in its early stages. The trial is testing the drug’s effect in patients with the BRAF V600E mutation.

FGFR3 Inhibitors

About 15 percent of patients with multiple myeloma have translocation t(4;14), which is associated with a poor prognosis. A translocation is an abnormality that results when a chromosome or a segment of a chromosome becomes attached or interchanged with another chromosome.

One characteristic of multiple myeloma cells with this abnormality is activation of the receptor RTK tyrosine kinase (RTK) fibroblast growth factor receptor 3 (FGFR3). A drug blocking activation of FGFR3, dovitinib (Novartis), has been studied in a clinical trial.

During a Phase 2 trial — the first clinical trial of this agent conducted by the Multiple Myeloma Research Consortium (MMRC) — 43 patients who had relapsed at least three times were given dovitinib as a single agent. Unfortunately, none of the patients had a significant response to dovitinib regardless of whether they had the translocation or not. However, the drug may prove to be effective when used in combination with other therapies.

Targeted Kinase Inhibitors

Cyclin dependent kinases (CDKs) help regulate the cell cycle. In multiple myeloma, this cycle is not functioning properly. For this reason, CDK inhibitors, which block the activity of CDKs and lead to the death of cancer cells, may be effective in myeloma. The MMRC has been involved in clinical trials testing CDKs.

In a small Phase 1 clinical trial, the CDK inhibitor alvocidib (flavopiridol, Tolero Pharmaceutical) was combined with Velcade® (bortezomib, Takeda Oncology) and evaluated in patients with multiple myeloma who had relapsed. Among 16 patients, two (12 percent) had a complete response, and five (31 percent) showed a partial response.

Another CDK inhibitor, dinaciclib (Merck), was tested as a single agent in a recent clinical trial in 27 patients with multiple myeloma who had relapsed after several rounds of treatment. The confirmed response rate was 11 percent, with two patients achieving a very good partial response and 10 achieving some degree of response or disease stabilization. A Phase 1 clinical trial testing dinaciclib in combination with Velcade and dexamethasone is in its early stages.

An MMRC Phase I clinical trial is testing the CDK inhibitor palbociclib (Pfizer) in combination with Revlimid® (lenalidomide, Celgene) and dexamethasone. Because CDK inhibitors have been shown to enhance proteasome activity, the hope is that the combined action will result in a more robust response.

MEK Inhibitors

Another approach being studied in myeloma is stopping activation of a protein called MEK. Through a complex signaling pathway, this protein helps promote growth of cancer cells. MEK inhibitors block the activity of this protein, resulting in slowed cancer growth.

A National Cancer Institute-sponsored study testing the MEK inhibitor selumetinib (Array BioPharma) in patients with relapsed/refractory disease who have had at least two previous rounds of treatment has just been completed. Results have not yet been published. In the meantime, other researchers are exploring trials with MEK inhibitors in combination with other agents, including conventional chemotherapy.