Daratumumab Quadruplet Improves Outcomes in Transplant-Ineligible Myeloma
Saad Z. Usmani, MD, MBA, FACP, FASCO, discusses the CEPHEUS trial results and impact on frontline treatment in transplant-ineligible patients with newly diagnosed multiple myeloma.
The phase 3 CEPHEUS trial (NCT03652064) demonstrated that adding subcutaneous daratumumab and hyaluronidase-fihj (Darzalex Faspro) to bortezomib, lenalidomide, and dexamethasone (VRd) significantly improved treatment outcomes for patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for or deferred autologous stem cell transplant (ASCT).1
Findings from the study were presented at the 21st International Myeloma Society Annual Meeting. The quadruplet regimen achieved a 60.9% rate of minimal residual disease (MRD) negativity compared with 39.4% with VRd alone at a 10-5 sensitivity (odds ratio [OR], 2.37; P < .0001). Complete response (CR) or better rates also favored the daratumumab arm (81.2% vs 61.6%; OR, 2.73; P < .0001).
The trial randomly assigned patients to receive either the daratumumab quadruplet or VRd alone. Daratumumab was given weekly for the first two 21-day cycles, every 3 weeks during cycles 3 to 8, and monthly in maintenance. Both groups followed a VRd induction regimen, with lenalidomide and dexamethasone maintenance for the control arm.
Overall, MRD-negativity rate with a CR or better served as the trial’s primary end point. The secondary end points of sustained MRD negativity and progression-free survival also improved with the daratumumab regimen.
In an interview with Targeted OncologyTM, Saad Z. Usmani, MD, MBA, FACP, FASCO, chief of the myeloma service at Memorial Sloan Kettering Cancer Center, discusses the results and the trial’s impact on frontline treatment in transplant-ineligible patients with newly diagnosed multiple myeloma.
Microscopic, photorealistic image of myeloma cells - Generated with Adobe Firefly
Targeted Oncology: Can you provide an overview of the CEPHEUS trial?
Usmani: CEPHEUS is a phase 3 clinical trial comparing daratumumab subcutaneously along with VRd as induction [vs] VRd [alone] in patients with newly diagnosed multiple myeloma who are either transplant ineligible or have deferred stem cell transplant, and the primary end point of this trial was achieving MRD negativity.
What were the main characteristics of the patients in the study? How does this reflect the real-world population?
The study enrolled a total of 395 patients in 1:1 randomization. The median age of the patients was 70 years and 55 or more percent were 70 years or older. The patients primarily made up intermediate, fit, transplant ineligible, or transplant deferred patients, and the transplant deferred patients made up about 27% of the population. In terms of high-risk features, the ISS stage III was seen in 28% of the patients, and high-risk cytogenetics in about 13% of the patients. So, the treatment arms were fairly well balanced.
What were the efficacy results from the study?
The study met its primary end point in terms of overall MRD-negativity rate at 10-5, showing about 61% compared [with] 39% on the standard-of-care arm. There is an overall increase of approximately 20% in MRD-negativity in [complete response] or better patients, and then sustained MRD negativity was also superior at the 12-month mark, 48.7% vs 26.3%. At a median follow-up of 58.7 months, the median PFS has not been reached in the [daratumumab plus] VRd arm, whereas in the VRd arm, it is 52.6 months. At month 54, the PFS rates [are] 68.1% vs 49.5% and the hazard ratio is 0.57, and it is statistically significant. These are exciting results and they further cement the place of quadruplet induction treatment for multiple myeloma in the frontline setting.
What were the most common or critical adverse effects observed in the study?
Hematologic [adverse events] typically are the most common ones that we observe in patients with newly diagnosed multiple myeloma, and there was, overall, a higher proportion of patients with those [adverse] effects in the daratumumab-containing arm compared with the VRd alone arm. But the duration of treatment on the [daratumumab] VRd arm was also almost 2 years longer than VRd, so you have to kind of take that into account. The infections were the other feature. But again, in terms of the upper respiratory tract infections that were grade 3 or higher, those numbers were similar in the study. So was peripheral sensory neuropathy.
How do these results impact treatment options for patients who are ineligible for stem cell transplants?
These results do signify that adding daratumumab to VRd for this patient population, improves the depth of response in terms of overall MRD negativity, sustained MRD negativity, and then the PFS benefit is in favor of the [daratumumab] plus VRd arm as well. The overall survival appears to be showing a trend in favor of the experimental arm, despite the fact that the study actually enrolled during the height of the COVID pandemic. This complements the use of daratumumab as a quadruplet for this patient population in the frontline setting.
Are there any challenges in applying the VRd regimen in community oncology settings? If so, how could that be addressed?
Daratumumab has been now utilized in the community for almost a decade. I think it started mostly in the relapse stage and then subsequently in the frontline stage with the MAIA clinical trial [NCT02252172]. So, our community colleagues are used to using daratumumab. The subcutaneous formulation utilized in the CEPHEUS trial is very easy to administer in the clinic and so that will make the regimen utility quite convenient for both patients as well as community doctors.
How do the findings from this trial shape the future of multiple myeloma treatment?
I think quadruplet induction regimens are becoming the mainstay or standard of care for newly diagnosed patients, whether they are transplant eligible or ineligible. And the CEPHEUS trial results complement the use of daratumumab that was already demonstrated to show better survival outcomes in the MAIA clinical trial and now, with the quadruplet regimen in this space for the transplant ineligible patients.
