Federal regulators have approved a new oral drug for multiple myeloma that patients can take as early as their first relapse, opening a treatment class that has not previously been available for the disease.
The Food and Drug Administration granted accelerated approval on August 13 to iberdomide, sold by Bristol Myers Squibb as Zenbexus, in combination with daratumumab and hyaluronidase-fihj and dexamethasone. The combination is for adults with multiple myeloma who have already received at least one prior line of therapy that included both a proteasome inhibitor and an immunomodulatory agent.
For a household living with myeloma, the practical meaning is narrower than the word approval suggests. This is not a cure, nor is it a first-line treatment. It is an additional option at the point when the disease has returned, the moment when the number of remaining choices begins to feel finite to patients and families.
A New Drug Class Enters at First Relapse
Iberdomide is the first cereblon E3 ligase modulator, or CELMoD, approved for multiple myeloma. The class works by recruiting a cellular protein-degradation system to degrade proteins that myeloma cells depend on, an approach related to but distinct from older immunomodulatory drugs already used in the treatment of this disease.
The FDA approval notice describes the dosing. Iberdomide is taken by mouth at 1 mg once daily, with or without food, on days 1 through 21 of a 28-day cycle. Daratumumab and hyaluronidase-FHJ, marketed as Darzalex Faspro, is given as an injection under the skin at 1800 mg on a schedule that starts weekly and becomes less frequent over successive cycles. Dexamethasone is taken orally at 20 mg or 40 mg on days 1, 8, 15, and 22. Treatment continues until the disease progresses or toxicity becomes unacceptable.
The application was granted priority review, and iberdomide had previously received breakthrough therapy and orphan drug designations. The review was conducted under Project Orbis, an FDA program that allows concurrent submission and review with international regulators. For this application, the agency worked with Switzerland's Swissmedic.
Multiple myeloma is a cancer of plasma cells in the bone marrow. It is generally treatable but not curable, and most patients relapse. Each relapse tends to be harder to control than the one before, because the disease acquires resistance to drugs already used. That is why an approval that lands at first relapse rather than after four or five failed regimens is meaningful to the people who track this field.
Reading an Approval Built on a Surrogate Measure
The evidence behind the decision needs to be stated plainly, because accelerated approval means something specific.
Efficacy was evaluated in EXCALIBER-RRMM, a phase 3, two-stage, multicenter, randomized, open-label trial in adults with relapsed or refractory myeloma who had received one or two prior lines of therapy. A total of 939 patients were randomized across both stages. The first stage randomized 279 patients to three iberdome dose levels or the comparator, and the 1 mg daily dose was selected based on safety, efficacy, and pharmacokinetics, in accordance with the trade coverage of the approval. The second stage randomized 660 patients. The comparison arm received daratumumab and hyaluronidase-fihj with bortezomib and dexamethasone.
The major efficacy measure supporting the approval was minimal residual disease-negative complete response at any time, a laboratory measure of how thoroughly the cancer has been cleared from the bone marrow. In the primary efficacy population of the first 420 patients randomized, 207 to the iberdomide combination and 213 to the comparator, that rate was 41 percent versus 21 percent, a statistically significant difference at a median follow up of 16 months. As reported on the trial results, this is the first approval in relapsed or refractory myeloma based on that endpoint.
Doubling the rate of a deep laboratory response is not the same as living longer. Minimal residual disease negativity is considered predictive of improved progression-free survival, but progression-free survival was the trial's other primary endpoint, and that analysis is still maturing. Continued approval may be contingent on verification and description of clinical benefit in a confirmatory trial.
Two limits on how far the result travels are worth stating. Patients whose disease was refractory to a prior anti-CD38 monoclonal antibody or to prior bortezomib were excluded from the trial. Because daratumumab is itself an anti-CD38 antibody, that exclusion means the combination was not tested in a group of patients who commonly experience later relapse.
Sagar Lonial, MD, lead investigator of EXCALIBER-RRMM and chief medical officer of the Winship Cancer Institute at Emory University, said in the manufacturer's announcement that the approval marks the arrival of "a new therapeutic class" for relapsed or refractory myeloma. That comment came through the company, which is relevant context for readers weighing it.
Questions Worth Bringing to an Oncology Appointment
Patients and caregivers considering this option have a specific set of questions, and none of them should be answered by a news article.
The prescribing information carries boxed warnings for embryo-fetal toxicity and for serious venous and arterial thromboembolism, along with warnings and precautions for neutropenia, infections, and second primary malignancies. Because of the embryo-fetal toxicity risk, the drug is available only through a restricted distribution program, a risk evaluation and mitigation strategy that imposes specific requirements on patients and prescribers. Anyone starting it will need to understand what that program requires before the first dose, and patient guidance from the myeloma nonprofit HealthTree covers the same ground in plainer language.
Reasonable questions include whether this combination fits the specific disease characteristics and prior treatment history, which side effects warrant a call to the clinic rather than waiting for the next visit, how the treatment schedule will affect work and caregiving, and what the plan is if the disease progresses on this regimen.
Cost and access are separate from the question of approval. A newly approved oncology drug typically takes time to appear in insurer formularies and in the treatment pathways used by health systems, and coverage for a combination regimen can differ from that of its individual components. The company has said it offers patient support programs for eligible patients once the drug is commercially available. Patients can also ask the treating practice about foundation copay assistance for myeloma and about whether prior authorization will be required. Medicare beneficiaries taking an oral cancer drug should ask specifically how it will be billed, because that determines out-of-pocket exposure.
No one should stop, start, or change a myeloma regimen based on an approval announcement. Treatment sequencing in this disease is individualized, and the option that is right at a given relapse depends on what has already been used and how the disease responded.
What happens next sits with the confirmatory data. Time-to-event outcomes from EXCALIBER-RRMM, including progression-free survival and overall survival, continue to mature, and those results will determine whether the accelerated approval converts to full approval. MedicalDaily will report the confirmatory findings and any changes to the approved indication.
Key Questions Answered
What was approved? Iberdomide, sold as Zenbexus, in combination with daratumumab and hyaluronidase-fihj and dexamethasone, for adults with multiple myeloma who have had at least one prior line of therapy including a proteasome inhibitor and an immunomodulatory agent.
Why is it called first in class? It is the first cereblon E3 ligase modulator, or CELMoD, approved for multiple myeloma.
What did the trial show? In the primary efficacy population, 41 percent of patients on the iberdomide combination reached minimal residual disease-negative complete response at any time, compared with 21 percent on the comparator regimen.
Does it help people live longer? That has not been established. Progression-free survival was a second primary endpoint, and those data are still maturing. Continued approval may depend on confirming clinical benefit.
What are the main safety warnings? Boxed warnings for embryo-fetal toxicity and for serious venous and arterial thromboembolism, plus warnings for neutropenia, infections, and second primary malignancies. Access runs through a restricted distribution program.
Who was not studied? Patients whose disease was refractory to a prior anti-CD38 antibody or to prior bortezomib were excluded from the trial.
Should a patient ask to switch to it? Not based on a news report. Treatment sequencing in myeloma is individualized, and the decision belongs to the treating oncology team.
