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Preclinical Study Identifies Promising Drug Combo For Multiple Myeloma

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A new preclinical study has identified a promising drug combination for the treatment of multiple myeloma (MM). The study, published in Haematologica, focused on the combined use of the chemotherapy drug azacitidine (also known as 5-azacytidine) with the BCL-2 inhibitor venetoclax (Venclexta), which works by blocking a protein called BCL-2 that helps cancer cells survive.

The findings suggest that utilizing these drugs together could improve the response of MM cells that do not depend on BCL-2 for their survival.

According to the National Cancer Institute, BCL-2 is a protein that helps control whether a cell lives or dies by blocking apoptosis, a type of cell death. When the BCL-2 protein is made or expressed in high amounts, it may stop the cancer cells from dying.

The new study was conducted by a team of researchers at the RCSI University of Medicine and Health Sciences and the Beaumont RCSI Cancer Centre in Dublin.

“Our aim was to widen the patient population that may respond to venetoclax treatment,” research lead Triona Ni Chonghaile, Ph.D., associate professor of physiology and medical physics at RCSI University, told MHE in an email interview.

She explained that only approximately 20% of patients with MM are currently sensitive to venetoclax, including those with a genetic change called a t(11;14) translocation or high expression of BCL-2.

More specifically, the study aimed “to identify epigenetic modifiers that would induce BCL-2 dependence in MM cell lines and enhance the sensitivity to the BCL-2 antagonist venetoclax,” Ni Chonghaile stated.

“We carried out an epigenetic modifier screen in two MM cell lines that did not rely on BCL-2 for survival. One of the lead hits…was 5-azacytidine,” she explained. “As 5-azacytidine is already FDA-approved in combination with venetoclax for acute myelogenous leukemia, we were excited about this result.”

“To the best of our knowledge this [drug] combination had not been previously tested in MM,” Ni Chonghaile said.

Next, the researchers assessed the drug combination in a panel of MM cell lines.

“We demonstrated that the combination was effective irrespective of cytogenetics and prior treatments in the primary CD138+ cells ex vivo,” Ni Chonghaile said.

This means that the two drugs seemed to work effectively across samples from cancer patients at various stages, including those who had undergone prior chemotherapy treatment.

“Our preclinical work sets the stage for assessing safety and efficacy of the combination in a clinical trial in MM,” she added.

Clinical trials will be an important next step to learn if this combination treatment may be a beneficial and tolerable approach, particularly for older adults and those who haven’t responded well to previous therapies.

The research was supported by funding from the Leukemia Research Foundation, Breakthrough Cancer Research, and AbbVie.

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