FDA approves oral therapy Zenbexus for adults with hard-to-treat myeloma
New 'breakthrough' treatment option welcomed by cancer community
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The U.S. Food and Drug Administration (FDA) has granted conditional approval to iberdomide, an oral medication to be used in combination with an antibody-based therapy and a prescription steroid, to treat adults with hard-to-manage multiple myeloma.
Bristol Myers Squibb (BMS), iberdomide’s developer, will sell the newly approved therapy under the brand name Zenbexus, according to a company press release announcing the FDA’s decision. Importantly, because of certain safety risks tied to its use, Zenbexus will only be available in the U.S. through a specialized program required by the FDA.
The authorized treatment combo uses Zenbexus with the approved therapy Darzalex Faspro (daratumumab and hyaluronidase-fihj) and the corticosteroid dexamethasone. It’s specifically indicated for myeloma that has failed to respond or come back following at least one previous line of treatment, including a proteasome inhibitor and an immunomodulatory agent.
“The FDA approval of [Zenbexus] marks the anticipated arrival of a new therapeutic class for relapsed or refractory [treatment-resistant] multiple myeloma and has the potential to make a meaningful difference for patients,” said Sagar Lonial, MD, chief medical officer of the Winship Cancer Institute of Emory University.
Accelerated approval allows a medication to be commercially available based on early clinical evidence that it will likely benefit patients. As a condition of this type of approval, BMS will be required to conduct additional tests aimed at definitively proving clinical benefit, with full approval contingent on the results.
The FDA’s decision comes about six months after BMS filed for the therapy’s approval in the U.S. The application was granted priority review, shortening the review period from the standard 10 months to six months. Zenbexus had also received breakthrough therapy and orphan drug designations, which are meant to accelerate a therapy’s development and regulatory review.
The decision was welcomed by members of the myeloma community.
“This approval represents an important step forward by expanding treatment options for patients facing their first relapse,” said Heather Cooper Ortner, president and CEO of the International Myeloma Foundation. “Every new option gives patients and their healthcare teams additional choices as treatment needs evolve, as well as renewed hope for the future.”
FDA approval based on strong trial data
Myeloma is a form of blood cancer in which certain immune cells grow out of control in the bone marrow, the spongy insides of bones. Zenbexus belongs to a novel class of anticancer therapies known as cereblon E3 ligase modulators (CELMoDs), which are designed to break down proteins that myeloma cells need to survive.
Taken as an oral capsule once daily for 21 days of a 28-day treatment cycle, Zenbexus is the first CELMoD therapy to win FDA approval, the developer noted.
“[The] approval of Zenbexus represents meaningful progress for patients living with multiple myeloma and underscores the power of our targeted protein degradation platform, particularly our CELMoD programs,” said Cristian Massacesi, MD, chief medical officer and head of development at BMS. “As the first approved CELMoD, ZENBEXUS marks the arrival of a new treatment class and is an important milestone in our efforts to expand what is possible for patients with multiple myeloma.”
Zenbexus’s accelerated approval was based mainly on data from an ongoing global Phase 3 clinical trial called EXCALIBER-RRMM (NCT04975997). The study enrolled more than 800 people with myeloma whose disease had either failed to respond to, or come back after, one or two previous lines of treatment.
All participants received Darzalex Faspro and dexamethasone, in combination with either Zenbexus or an approved myeloma therapy called bortezomib (sold as Velcade and generics).
After 16 months of follow-up, data showed that patients given the Zenbexus regimen had significantly higher rates of minimal residual disease negativity (41% vs. 21%), meeting one of the trial’s main goals.
This meant that more patients given Zenbexus did not have any detectable cancer cells following treatment, an outcome that is predictive of better long-term survival without disease progression.
“The strong results observed with the CELMoD-based combination within a familiar triplet approach creates the potential for a new treatment foundation in multiple myeloma,” said Lonial, who served as lead investigator for the EXCALIBER-RRMM trial.
Certain safety risks noted on Zenbexus label
The safety profile of the Zenbexus-based combination treatment was generally consistent with the known profile of each individual drug, according to the researchers.
The most commonly reported adverse events were upper respiratory tract infection, fatigue, musculoskeletal pain, pneumonia, diarrhea, constipation, and rash. Motor problems, sleep issues, low antibody levels, and COVID-19 also commonly occurred among patients on the regimen.
Zenbexus’ prescribing label also carries a boxed warning — the FDA’s most stringent safety warning — noting that the therapy may cause problematic blood clots, which can disrupt blood flow and lead to complications such as heart attack or stroke.
The boxed warning also notes that Zenbexus can damage a developing fetus and pass into semen. As such, the therapy should not be used in pregnancy, and both women with potential to become pregnant and men should utilize effective forms of contraception while taking Zenbexus and for at least a month after stopping the treatment.
Given the safety issues, Zenbexus is only available through a Risk Evaluation and Mitigation Strategy, which is an FDA-mandated program for therapies that pose serious potential risks.
“We believe this is only the beginning,” Massacesi said. “This approval validates years of scientific research and strengthens our confidence in the potential of this approach as we continue to advance our innovative pipeline on behalf of patients with significant unmet needs.”
A combination treatment based on another BMS CELMoD, mezigdomide, is now under review by the FDA, with a decision expected next year.
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