Steroid-free Venclexta combo shows promise in myeloma cells

Adding 5-aza to Venclexta could benefit broader group of myeloma patients

Lindsey Shapiro, PhD avatar

by Lindsey Shapiro, PhD |

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Combining the cancer therapy Venclexta (venetoclax) with a molecule called 5-azacytidine (5-aza) increased the former’s ability to kill lab-grown cancer cells derived from a range of different multiple myeloma patients regardless of their disease stage, a study showed.

While Venclexta is known to benefit only myeloma patients with a specific genetic variant or with high levels of the cell survival protein BCL2, the addition of 5-aza made cells from patients with other genetic backgrounds more sensitive to the treatment.

Researchers believe the addition of 5-aza to Venclexta — a combination already used for treating another type of blood cancer in elderly patients — might enable the cancer therapy to benefit a broader group of myeloma patients.

“This research is a significant step in identifying more effective treatment options for multiple myeloma,” Tríona Ní­ Chonghaile, PhD, associate professor at the Royal College of Surgeons in Ireland (RCSI) and the study’s senior author, said in a university press release. “It shows the benefits of re-evaluating existing treatments in new contexts to expand their potential.”

Adding dexamethasone, a steroid commonly used in myeloma treatment, to the treatment duo did not increase its therapeutic efficacy, further suggesting that this steroid-sparing combo may hold promise in myeloma.

“Our next goal is to test for efficacy and safety for multiple myeloma in a clinical trial setting to bring us closer to offering a new treatment strategy for patients,” said Siobhán Glavey, PhD, clinician-scientist at RCSI and a study author.

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The study, “Steroid-free combination of 5-azacytidine and venetoclax for the treatment of multiple myeloma,” was published in Haematologica.

Sold as Venclyxto in Europe, Venclexta is an oral therapy approved for certain blood cancers, including acute myeloid leukemia, but it does not have regulatory clearance for treating multiple myeloma.

It works by suppressing the activity of BCL-2, a protein that certain cancer cells come to depend on for survival. BCL-2 helps the cells avoid a cell death pathway called apoptosis, and by blocking it, Venclexta allows apoptosis to occur.

Around 20% of multiple myeloma patients carry a genetic abnormality called t(11;14) that caan result in BCL-2 overproduction. Latest Phase 3 clinical trial data showed certain signs of efficacy in patients with this genetic mutation.

Yet, not all patients have myeloma cells that depend on BCL-2 to survive, and as such, these aren’t expected to respond as well to Venclexta.

Now, scientists wanted to find ways of boosting Venclexta’s efficacy for that group to make it of broader benefit. They were particularly interested in epigenetic modifiers that can induce a state of BCL-2 dependence in cancer cells, making them more vulnerable to Venclexta.

Epigenetic modifiers are molecules that add chemical tags to DNA to alter gene activity without changing the genetic sequence.

The team performed a screen of epigenetic modifiers that might be able to do this, evaluating whether they enhanced Venclexta’s cancer-killing abilities in lab-grown myeloma cells that were not BCL-2 dependent to begin with.

Results showed that 5-aza, a known epigenetic modifier, boosted Venclexta’s myeloma-killing abilities in several types of myeloma cells, even in those where Venclexta alone had little to no efficacy.

The treatment duo also effectively killed myeloma cells isolated from patients regardless of the stage of myeloma, including those at a high risk of disease progression and who previously received multiple lines of therapies.

Mechanistically, 5-aza appeared to promote the production of NOXA, a protein involved in apoptosis via a signaling pathway called the integrated stress response. This left the cells more sensitive to Venclexta treatment.

Steroid treatments such as dexamethasone are commonly added to myeloma treatment regimens. Adding dexamethasone to the Venclexta/5-aza combo did not significantly increase myeloma cell death, but did lead to significantly increased death of certain immune cells that play a role in fighting cancer.

“This data would suggest that a steroid has little therapeutic benefit, as it did not enhance the [multiple myeloma] cell killing, but it may enhance the killing of immune cells, potentially limiting immune cells’ capacity to kill tumor cells,” the researchers wrote.

Altogether, the findings suggest that the Venclexta/5-aza combo regimen may be beneficial to a broad range of multiple myeloma patients irrespective of t(11;14) mutation status and disease stage, and that the duo should be used without steroids.

The study was funded by the Leukemia Research Foundation, Breakthrough Cancer Research, and AbbVie, which markets Venclexta.