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

Cells have correction mechanisms that prevent deleterious proteins from aggregating. Blocking either of these systems leads to an accumulation of toxins proteins in the cell and results in cell death.

Heat-shock Protein Inhibitors

One system that responds to misfolded proteins is heat-shock proteins (HSP). Among their other functions, these proteins stabilize survival signaling proteins that are overexpressed in multiple myeloma.

By using HSP inhibitors, misfolded proteins are forced to accumulate in the cell, the cell becomes toxic, and then cell death occurs. Research has shown that HSP inhibitors when used alone and with Velcade ^[1] (bortezomib) have anti-myeloma activity.

In a phase 2 clinical trial, 13 patients treated with HSP inhibitor tanespimycin ^[2] alone had varying degrees of positive responses in 12 patients. Three patients had complete responses, four had partial responses, and five had minor responses.

New ProteasomeAnd Aggresome Inhibitors

Another response to misfolded proteins is elimination of the proteins by the proteasome or the aggresome.

The proteasome inhibitor, Velcade, is already in use and now, other proteasome inhibitors with increased potency and more ease of use are being developed. Carfilzomib is a new group of proteasome inhibitors with more potency.

Two phase 2 clinical trials were done with this compound and both had positive findings. In the first trial, six patients were treated for five days every 14 days, and there was one partial response. In the other trial, 13 patients were treated twice weekly for 3 weeks, and four received a partial response.

Other proteasome inhibitors like NI-0052 and CEP-18770 are also being developed.

Inhibiting another system that disposes misfolded proteins, the aggresome, can also be used to treat multiple myeloma. Although no clinical data exists, blocking the aggresome and proteasome together can increase cytotoxicity and prevent the growth of myeloma cells.

Histone Deacetylase Inhibitors

Some tumors have a decrease in the amount of DNA that is expressed, thereby reducing the expression of genes that prevent tumors from growing. Treating the cells with a histone deacetylase (HDAC) inhibitor causes more genes that prevent tumor growth to be expressed and can lead to cell death in myeloma cells.

HDAC inhibitors with antimyeloma inhibitors have had some positive responses. Seven people were treated with HDAC, Velcade, and dexamethasone ^[3]. Of those, one had a near complete response, three had partial responses, and one had a minor response.

Other Agents

Other agents being used are Aplidin ^[4] (plitidepsin) and arsenic trioxide. Aplidin is derived from a marine tunicate, Aplidium albicans. Arsenic trioxide is the commercial form of arsenic.

Aplidin has been shown to be involved with signaling pathways (such as the P38 pathway) to induce cell death, and has had a synergistic response with some anti-myeloma drugs. Preliminary data of the drug used in 26 patients showed that two patients had partial responses, four had minor responses, and seven stabilized.

Arsenic trioxide has been tried in patients with ascorbic acid, with Velcade and ascorbic acid, and with melphalan ^[5] and ascorbic acid. Of the 65 patients who were treated with arsenic trioxide plus melphalan and ascorbic acid, 31 showed responses. Though it has shown results in relapsed patients, further studies still need to be conducted.

Previous Beacon articles have highlighted new myeloma therapies that target signaling pathways ^[6] and cell-surface receptors ^[7].

For more information about new myeloma therapies, see the entire article in The Lancet Oncology ^[8] journal.