Thalidomide Analogs Active Against Multiple Myeloma

Laboratory studies evaluating the activity ofCelgene’s immunomodulatory drugs (IMiDs) on multiple myeloma cells suggest that these agents may be beneficial in the treatmentof multiple myeloma. Researchers from the Dana-Farber Cancer Institute andHarvard Medical School presented data on the IMiDs at the 42^nd annual meeting ofthe American Society of Hematology.

The data demonstrate a dose-dependent effect of IMiDs onmultiple myeloma cells and show their impact at the molecular level on multiplemyeloma cell growth. In addition, the IMiDs were found to have direct antitumoreffects, including enhancement of multiple myeloma cell death (apoptosis) andcell-cycle arrest. These compounds were also synergistic with other antimyelomaagents in some of the cell lines studied.

Biological Basis

"These results support previously reported data anddemonstrate growing evidence for direct activity of the IMiDs against humanmultiple myeloma cells," said Kenneth C. Anderson, MD, professor ofmedicine in the department of adult oncology at the Dana-Farber Cancer Instituteand Harvard Medical School. "The results from these studies provide theframework for a new biologically based treatment paradigm, using these agentseither alone or in combination with conventional therapies, to achieve improvedoutcome in this disease."

The IMiDs are structural analogs of thalidomide that havesignificantly greater immunomodulatory activity in vitro but do not demonstrateteratogenicity in animal models. In addition, in a phase I healthy humanvolunteer trial, they did not produce the sedative effect associated withthalidomide. These compounds have been reported to enhance T-cell proliferationand interleukin (IL)-2 production. The IMiDs have also been shown to be potentinhibitors of inflammatory cytokines (eg, tumor necrosis factor-alpha andIL-1-beta), while stimulating the anti-inflammatory cytokine IL-10.

According to David I. Stirling, PhD, chief scientific officer ofCelgene Corporation and one of the researchers involved in these studies,"these findings support our basic understanding of the biological activityof these compounds as well as the scientific rationale for initiating phase I/IIclinical development with our lead IMiD in myeloma patients." The leadcompound, currently in clinical trials in myeloma patients, was selected basedon the overall activity demonstrated in these and other test systems, as well ason the toxicologic and pharmacologic properties of the compounds.