While such drugs as thalidomide ^[1] (Thalomid), Revlimid ^[2] (lenalidomide), and Velcade ^[3] (bortezomib) have been approved to treat multiple myeloma, the disease remains incurable. New studies are targeting different mechanisms of multiple myeloma in order to create better therapies. A recent paper published in "Lancet Oncology" examines drugs that target different biological mechanisms in multiple myeloma. This article will be the first of three articles discussing these new drugs for myeloma.

Multiple myeloma, like other cancers, is caused by a harmful proliferation of cells that can spread throughout the body. While healthy body cells understand signals to self-destruct if they encode an error, myeloma cells continue to replicate regardless of growth inhibitory signals. Researchers have begun to understand this complex mechanism and have developed new drugs to block different steps in the process.

All cells, including myeloma cells, have surface receptors. These receptors are proteins to which different molecules bind in order to elicit a cellular response, such as proliferation, differentiation, or cell death.

Targeting Cell Death Mechanisms

Scientists found that TRAIL (receptors on the cell surface that induce cell death) can be activated by either binding a molecule (ligand) to the receptor or by activating the receptor through the use of antibodies.

Studies of the ligand-binding procedure with TRAIL show potential in fighting against myeloma in human cells and also in isolated patient samples. Additionally, the ligand-binding technique showed anti-myeloma activity in mice.

Antibodies have also shown potential. Scientists used patient samples and multiple myeloma cell lines, which are cells maintained in the laboratory for testing,to test antibodies against TRAIL and found that the antibodies induced cell death. It may be possible to use this therapy alone or in combination with existing therapies. One such antibody therapy called mapatumumab is already in clinical trials with Velcade.

Targeting Over Expressed TK Receptors

Another target for anti-cancer drugs are TK receptors, which are over expressed in cancer. TK receptors encourage cell proliferation and discourage cell death. Two drugs, Gleevec (imatinib) and Sprycel (dasatinib), act on these receptors.

Sprycel was tested on cells and in patients. In cells, Sprycel worked well when combined with other established myeloma drugs such as dexamethasone ^[4], Velcade, and melphalan ^[5] (Alkeran). It also delayed the growth of myeloma tumors. In patients, Sprycel stabilized four out of 13 patients with relapsed multiple myeloma.

Gleevec was only tested on cells. Studies showed that it was able to prevent growth of multiple myeloma cells and it also worked well when combined with conventional anti-myeloma agents.

About 15 percent of multiple myeloma patients have the chromosomal translocation t(4;14). A chromosomal translocation occurs when a small piece of one chromosome switches with another piece on another chromosome. In myeloma patients, this translocation can mean an adverse prognosis.

Two drugs have been studied on cells with this translocation. One drug, dovitinib, was found to stop cell growth and induce cell death. Another drug, AB1010, was studied in 19 patients with the translocation. Cancer progressed in all patients, but when dexamethasone was added, three patients responded positively. One of the three patients achieved near complete remission.

Other TK receptor inhibitor drugs that have been responsive with combination therapy are pazopanib and Avastin (bevacizumab). Avastin was tested with Revlimid and dexamethasone in 10 patients and seven were partially responsive to treatment.

Additionally, research findings for a new triple combination therapy have shown positive results. Scientists used IGF-1R TK inhibitors, which caused the cell cycle to stop and cell death to occur in multiple myeloma cells from patients. IGF-1R TK inhibitors also improved the effects of anti-myeloma agents. When used with dexamethasone and Velcade, the IGF-1R TK inhibitors substantially inhibited cell growth. Clinical studies have not been done with this combination.

Antibodies Against Surface Antigens

One of the most important receptors in blood plasma cells is the interleukin-6 receptor. When this receptor binds to its corresponding molecule, interleukin-6, it promotes plasma cell proliferation, discourages cell death, and causes multi-drug resistance.

While antibodies against the interleukin-6 receptor have worked poorly, combination therapy with Velcade showed some potential. Of the six patients treated with the antibody against interleukin-6 receptor, three had partial responses and two had unconfirmed partial responses.

Another antibody, anti-CD40, acts on the protein CD40 to cause cell death and toxicity in the cell. The protein CD40 is expressed in cells that have a high proliferation rate. By using antibodies, scientists are trying to block the expression of CD40, thereby decreasing cell proliferation. In clinical trials with 32 myeloma patients, this antibody was not very effective. Currently, researchers are trying a higher dose of the antibody in combination with Velcade in relapsed patients.

Researchers continue to work at understanding mechanisms of multiple myeloma in order to provide breakthrough treatments.

For more information, see the entire article in Lancet Oncology ^[6] journal.