CEPHEUS Study Results Show Efficacy of Daratumumab-Based Quadruplet, Triplet Therapeutic Approaches

In an interview with Pharmacy Times, Saad Usmani, MD, MBA, discussed the CEPHEUS results being presented during the International Myeloma Society 2024 Annual Meeting, happening September 25 through 29 in Rio de Janeiro, Brazil. Usmani said not only did the CEPHEUS trial highlight the importance of minimal residual disease (MRD) as a study end point, but the results emphasize the potential of daratumumab (Darzalex; Johnson & Johnson)-based quadruplet and triplet therapeutic approaches.

Q: What does the daratumumab plus bortezomib, lenalidomide, and dexamethasone (VRd) treatment regimen offer that previous treatment options have not?

Saad Usmani, MD, MBA: The idea of adding subcutaneous daratumumab to VRD as part of induction therapy and maintenance therapy for transplant-ineligible newly diagnosed patients is to see if we can deepen the responses and improve the survival outcomes for patients.

Q: Can you give an overview of the CEPHEUS trial’s design, including its primary and secondary end points?

Usmani: The CEPHEUS clinical trial is a randomized phase 3 study examining the role of adding subcutaneous daratumumab to VRd in patients who are either transplant-ineligible or have deferred their transplant in the newly diagnosed setting. The study builds on the prior success of VRd as an induction therapy for this patient population, along with DRd—or daratumumab, lenalidomide, and dexamethasone—as a result of the MAIA clinical trial. So, this phase 3 trial randomized 395 patients to either VRd or daratumumab plus VRd as an induction. And then maintenance in the standard of care arm then continued with Rd, and it was DRd in the experimental arm. The primary end point was overall MRD negativity rate and secondary end points included progression free survival, sustained MRD negativity for more than 12 months, [complete responses] or better rate, as well as overall survival.

Q: What findings do you have so far with regard to minimal residual disease?

Usmani: The study methods’ primary endpoint of MRD negativity overall, MRD negativity at 105 using next-generation sequencing, being about 61% in the dara-VRd arm, compared to 39.4% in the VRd arm, so significantly increasing the overall MRD negativity rate by approximately 20-odd percent.

Q: Are there any significant findings related to secondary end points?

Usmani: The study also met the progression-free survival (PFS) endpoint. The median PFS in the dara-VRd arm after 58.7 months of follow up was not reached, whereas it was 52.6 months in the VRd arm and a hazard ratio of 0.57, with a p-value of 0.0005. So, this is, perhaps, the other important end point that was reached for this clinical trial.

Q: How might the findings from CEPHEUS impact pharmacists’ counseling and management of patients with myeloma?

Usmani: Based on this particular trial, the idea of using daratumumab-based quadruplets or triplets as standard of care for transplant ineligible or deferred patients is, you know, a standard of care approach. Now, I think quadruplets, especially, have made a mark in the field and so, as our pharmacist colleagues counsel patients, I think improving depth of response and that helping translate into better PFS is a very important measure for our newly diagnosed patients in this setting.

Q: Is there anything you’d like to add?

Usmani: So, the general consensus about induction therapy in the field, based on all these randomized phase 3 trials that are incorporating, CD38 monoclonal antibodies into the front line setting, is that they're safe to give, they’re efficacious, and they are helping us improve outcomes for our patients.