How Might Daratumumab Approval Influence Frontline Multiple Myeloma Care?

In a conversation with CancerNetwork^®, Saad Z. Usmani, MD, MBA, FACP, FASCO, discussed the potential ramifications of the FDA approval of subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro) plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) for transplant-ineligible populations with newly diagnosed multiple myeloma (NDMM). In January 2026, the agency approved the regimen based on findings from the phase 3 CEPHEUS trial (NCT03652064).

Findings from the CEPHEUS trial showed that the novel daratumumab regimen improved progression-free survival compared with VRd alone (HR, 0.60; 95% CI, 0.41-0.88; P = .0078). Additionally, minimal residual disease (MRD) negativity occurred in 52.3% of the daratumumab arm and 34.8% of the VRd alone arm (P = .0005).

Usmani detailed considerations for sequencing the newly approved frontline regimen with other therapies, emphasizing the strategy of achieving an initial response as soon as possible before reducing the frequency of dosing in the maintenance setting. Looking ahead, he described how regulatory decisions like this might signal a shift away from a continuous therapy model towards more fixed-duration approaches, which may allow patients to undergo treatment for 2 to 3 years rather than indefinitely.

Usmani is a myeloma specialist, cellular therapist, and chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center. He is also a member of the International Myeloma Foundation’s Scientific Advisory Board.

CancerNetwork: How do efficacy and safety findings from the CEPHEUS trial support the approval of subcutaneous daratumumab plus VRd for this NDMM population?

Usmani: The CEPHEUS clinical trial was based on proving 2 important points: if we can get to a good depth of response with this treatment approach, and whether it will give better remission periods. It met both those benchmarks. From a safety standpoint, with anti-CD38 monoclonal antibodies, we’ve noticed a higher chance of infections, but that did not affect the survival outcomes for patients. Otherwise, we’ve known about the safety profile for frontline treatments; we did not encounter any new kind of [adverse] effects here, and that’s what led to the approval of this combination for the transplant-ineligible patient population.

How do you see daratumumab plus VRd being sequenced with other therapeutic options or strategies in the treatment of patients with multiple myeloma?

The frontline treatment approaches, now, for most patients would be a quadruplet regimen, unless we have [patients who are] frail. The idea is that [in] the initial part of treatment for the first 4 or 6 months, we try to get patients into a deeper response quicker, while managing the [adverse] effects from the treatments. From that perspective, that exposure to the quadruplet is for a fixed duration of time. Then, patients move on to a maintenance period where they’re getting less frequent treatments and [fewer] drugs.

From a treatment schema standpoint, that would be important. If we can get a majority of patients into good remissions that last for 4 or 5 plus years, for any patients being diagnosed in 2026, we’re essentially pushing off any potential chances of disease coming back to 2032 or 2033. By that time, we are going to have [better] treatment options for our patients if the disease comes back. That’s the goal: kick that can of the disease, the likelihood of [it] coming back, as [far] down the line as possible.

Looking ahead, what other anticipated developments in multiple myeloma have the potential to shift clinical practice?

We have several exciting T-cell–redirecting therapies called bispecifics and trispecifics [along with] CAR T-cell therapies that are making their way into the earlier relapse and frontline treatment [settings]. That will also shift the landscape of how we approach treatment. Another very important aspect of all the progress we’ve made in myeloma is with the continuous therapy model, which means that patients continue to get treatment for as long as it’s working and if they can tolerate it without significant [adverse] effects. But we’ll eventually be able to, I imagine in the next few years, stop treatment early based on sustained MRD results. We would be able to define the duration of treatment; [for example], patients would probably need to be treated for 2 or 3 years. That would be ideal.

Reference

FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for newly diagnosed multiple myeloma. News release. FDA. January 27, 2026. Accessed February 10, 2026. https://tinyurl.com/47r6r8xf