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Thalidomide Analogs Active Against Multiple Myeloma

Thalidomide Analogs Active Against Multiple Myeloma

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

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

Biological Basis

"These results support previously reported data and demonstrate growing evidence for direct activity of the IMiDs against human multiple myeloma cells," said Kenneth C. Anderson, MD, professor of medicine in the department of adult oncology at the Dana-Farber Cancer Institute and Harvard Medical School. "The results from these studies provide the framework for a new biologically based treatment paradigm, using these agents either alone or in combination with conventional therapies, to achieve improved outcome in this disease."

The IMiDs are structural analogs of thalidomide that have significantly greater immunomodulatory activity in vitro but do not demonstrate teratogenicity in animal models. In addition, in a phase I healthy human volunteer trial, they did not produce the sedative effect associated with thalidomide. These compounds have been reported to enhance T-cell proliferation and interleukin (IL)-2 production. The IMiDs have also been shown to be potent inhibitors of inflammatory cytokines (eg, tumor necrosis factor-alpha and IL-1-beta), while stimulating the anti-inflammatory cytokine IL-10.

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

 
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