Zenbexus Combo Nearly Doubles Deep Responses in Relapsed Myeloma

A three-drug combination built around a newer oral medication helped more people with relapsed or refractory multiple myeloma reach a deep remission, with no detectable disease, than a commonly used standard treatment, according to results from the phase 3 EXCALIBER-RRMM trial.

The combination includes Zenbexus (iberdomide), Darzalex Faspro (daratumumab and hyaluronidase-fihj) and dexamethasone. It was compared with Darzalex Faspro, Velcade (bortezomib) and dexamethasone. The findings were presented at the 23rd Annual International Myeloma Society Meeting & Exposition and published in The Lancet Oncology.

Relapsed multiple myeloma means the cancer has come back after treatment. Refractory means it stopped responding to a treatment. The Zenbexus combination received accelerated approval from the Food and Drug Administration (FDA) in August 2026 for people with relapsed or refractory multiple myeloma, based on data from this trial.

Zenbexus belongs to a newer class of drugs called CELMoDs, or cereblon E3 ligase modulators. These medications are related to immunomodulatory drugs such as Revlimid (lenalidomide), and they work by helping the body break down proteins that myeloma cells rely on to survive.

How well did Zenbexus work in relapsed multiple myeloma?

After a median follow-up of 15.7 months, 41.1% of people who received the Zenbexus combination reached a measurable residual disease (MRD)–negative complete response, compared with 20.7% of those who received the Velcade combination.

A complete response means tests no longer show signs of myeloma. MRD-negative takes that a step further: using highly sensitive lab testing, doctors could not find even a tiny number of remaining myeloma cells in the bone marrow. In this trial, the test could detect as few as one myeloma cell among 100,000 cells.

This matters because reaching MRD negativity is strongly linked to people living longer without their cancer getting worse and living longer overall. The FDA recognizes MRD-negative complete response as a measure that can support accelerated approval.

Among people who reached a complete response or better, 89.5% (85 of 95) in the Zenbexus group were MRD negative, compared with 83% (44 of 53) in the Velcade group. The benefit held across different groups of patients, including people who had previously taken Revlimid, whose myeloma had stopped responding to Revlimid or who had taken Revlimid in their most recent treatment.

Other response results also favored the Zenbexus combination:

• Overall response rate (the cancer shrank at least partially): 88.9% with the Zenbexus combination vs. 76.1% with the Velcade combination
• Complete response or better: 45.9% vs. 24.9%
• Very good partial response or better: 74.4% vs. 61.5%

Researchers are still evaluating the trial's second main goal, progression-free survival, which measures how long people live without their cancer growing or spreading.

Dr. Sagar Lonial, lead study investigator and chief medical officer of Winship Cancer Institute of Emory University, said in his presentation of the data that the improvement in MRD-negative complete responses was significant and consistent across many patient groups. He added that the combination represents "a new standard of care in the context of an early first relapse."

Who was included in the EXCALIBER-RRMM trial?

The trial enrolled people with multiple myeloma that had progressed after one or two prior lines of therapy. Participants' myeloma could not be refractory to anti-CD38 antibodies, the drug class that includes Darzalex Faspro.

The MRD analysis included 207 people who received the Zenbexus combination and 213 who received the Velcade combination. The median age was 68 in the Zenbexus group and 67 in the Velcade group. About two-thirds of participants had received one prior line of therapy, and roughly 90% had previously taken an immunomodulatory drug.

People in the Zenbexus group took Zenbexus as a pill once a day on days 1 through 21 of each 28-day cycle, along with Darzalex Faspro given as an injection under the skin and dexamethasone, a steroid. The first stage of the trial tested different doses to find the best balance of benefit and side effects, and researchers selected a 1-mg dose of Zenbexus.

EXCALIBER-RRMM is the first randomized phase 3 study in relapsed or refractory multiple myeloma to use both MRD-negative complete response and progression-free survival as its main goals.

What side effects did people experience with Zenbexus?

Severe (grade 3 or 4) side effects occurred in 91.7% of people who received the Zenbexus combination and 70.1% of those who received the Velcade combination. Researchers noted the side effects were consistent with what is already known about CELMoDs and Darzalex Faspro with dexamethasone.

The most common severe side effect with the Zenbexus combination was neutropenia, a drop in a type of white blood cell that helps fight infection. It occurred in 84.3% of people in the Zenbexus group vs. 11.3% in the Velcade group. Most people in the Zenbexus group (82.4%) received growth factor medications that help the body make more white blood cells. Neutropenia was mostly managed by pausing treatment (51.5%) or lowering the dose (13.2%), and only 1% of people stopped Zenbexus because of it.

Some side effects were less common with the Zenbexus combination:

• Severe thrombocytopenia (low platelets, which help blood clot): 12.7% with the Zenbexus combination vs. 44.1% with the Velcade combination
• Peripheral sensory neuropathy (nerve damage that can cause numbness, tingling or pain, often in the hands and feet): 12.3% vs. 42.6%

Infections of any severity occurred in 78.9% of the Zenbexus group and 69.6% of the Velcade group, and most were grade 3 or lower. Fatal infections were similar between the groups (2% vs. 1.5%).

Blood clots in the veins occurred in 5.9% of people in the Zenbexus group and 3.9% in the Velcade group. Everyone in the Zenbexus group was required to take medication to prevent blood clots, and no severe clotting events were reported in that group.

Deaths occurred in 11.1% of the Zenbexus group and 15.5% of the Velcade group, mostly due to the myeloma getting worse.

People with multiple myeloma who have questions about whether this combination may be right for them should talk with their care team.

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