CEPHEUS: Sub-Q Daratumumab With VRd Improves MRD Negativity, PFS in Myeloma if Transplant Deferred

Patients newly diagnosed with multiple myeloma must decide whether to pursue a bone marrow transplant, if they are eligible. But if they defer this option, the anti-CD38 antibody daratumumab (Darzalex Faspro, Johnson & Johnson), given subcutaneously with a standard backbone combination, offers superior results in both progression-free survival (PFS) and in bone marrow tests to detect cancer cells.¹

Those are the findings of the CEPHEUS trial, presented Friday at the International Myeloma Society 21st Annual Meeting & Exposition, taking place in Rio de Janiero, Brazil. The ongoing CEPHEUS trial (NCT03652064), is a phase 3, multicenter, randomized, open-label study that has enrolled 396 patients in 13 countries. It compares the efficacy and safety of daratumumab plus bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) vs VRd in patients with newly diagnosed multiple myeloma who are either ineligible for a transplant or who defer transplant as their initial treatment.

CEPHEUS’ primary end point is the minimal residual disease (MRD) at the 10^-5 sensitivity threshold; this measure uses highly sensitive testing to see if there are cancer cells in the bone marrow. Secondary end points include PFS, complete response (CR) rate, MRD-negative rate at 1 year, durable MRD negativity, and overall response rate. Overall survival (OS) measures were reported and favored D-VRd, but data were not yet mature.

Saad Z. Usmani, MD, MBA | Image credit: MSKCC

Results answer a question that remained following the MAIA trial, comparing daratumumab plus lenalidomide (Revlimid) and dexamethasone (D-Rd) with Rd alone in untreated myeloma, which had shown that giving daratumumab with another version of backbone therapy offered a median OS of 7.5 years in transplant-ineligible patients.²

“The addition of daratumumab to VRd improved the depth of response in terms of MRD negativity being overall at 10^-5 or 10^-6, as well as sustained MRD negativity at 10^-5 defined by more than 12 months,” said Saad Z. Usmani, MD, MBA, of Memorial Sloan Kettering Cancer Center and the lead investigator for CEPHEUS. “The risk of disease progression or death was lower in D-VRd.

“CEPHEUS complements MAIA or D-Rd in supporting a daratumumab-based induction therapy for transplant ineligible or transplant deferred patients,” Usmani said.

The trial broke ground in a few ways: It’s among the first trials to measure MRD negativity as the primary end point, and the regimen’s sponsors will head to FDA after its Oncologic Drug Advisory Committee (ODAC) voted unanimously in April to use MRD-negativity CR as an end point for accelerated approval.

But because the trial began years before the ODAC vote, investigators also accumulated enough PFS events to show these data to regulators, Usmani said in response to a question.

IMS President Philippe Moreau, MD, of University Hospital of Nantes, France, in introducing the abstract, said if CEPHEUS continued the trend seen in recent multiple myeloma trials, involving triplet and quadruplet combinations, "We will have the confirmation that quadruplet is here, probably, to stay.”

Moreau said the reason the myeloma field needs better regimens is that too many patients are lost after the first relapse. “So, the best treatment upfront for elderly patients is very important,” he said.

However, Usmani cautioned that a patient’s level of frailty was a consideration when deciding a regimen, and in fact, CEPHEUS did not enroll overly frail patients in the study.

Methods and Results

Patients had to be at least 18 years of age with transplant-ineligible or transplant-deferred multiple myeloma to enroll. All received eight 21-day cycles of VRd, followed by 28-day cycles of Rd until disease progression.

The patients were randomized to D-VRd received subcutaneous daratumumab, which was given weekly in cycles 1-2, every 3 weeks for cycles 3-8, and every 4 weeks after that until disease progression.

Results were as follows:

• 197 patients were in the D-VRd group and 198 were in the Rd group.
• Median age was 70 years, with a range of 31 to 80 years.
• 28.1% had International Staging System stage III disease; 13.2% had high-risk cytogenetics.
• At a median follow-up of 58.7 months, the overall MRD-negativity rate was 60.7% for D-VRd vs 39.4% for VRd (OR, 2.37; 95% CI, 1.58-3.55; P < .0001).
• PFS was significantly improved with D-VRd vs VRd (HR, 0.57; 95% CI, 0.41-0.79; P = .0005). Median PFS was not reached for D-VRd vs 52.6 months for VRd; estimated 54-month PFS rates were 68.1% vs 49.5%, favoring D-VRd.
• The CR rate was 81.2% vs 61.6%, favoring D-VRd, (P < .0001).
• Sustained MRD-negativity rate was 48.7% vs 26.3%, also favoring D-VRd (P < .0001).
• Patients taking daratumumab were able to stay on treatment longer, for a median duration of 22 more months (56.3 months vs 34.3 months).

OS was trending in favor of D-VRd (HR 0.85; 95% CI, 0.58-1.24). After a sensitivity analysis to censoring deaths due to COVID-19, which was at its peak during enrollment, HR was 0.69 (95% CI, 0.45-1.05) favoring D-VRd. Data are not mature.

Data presented at IMS did not include results by race. In response to a question about results for Black and Latino patients, Usmani said, “This is on our docket of analyses to perform and report on in the future.”

References

1. Usmani S. Daratumumab + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: Results of the phase 3 CEPHEUS study. Presented at: International Myeloma Society 21st Annual Meeting & Exposition; Rio de Janiero, Brazil; September 27, 2024. Abstract OA – 63.
2. Facon T, Kumar S, Plesner T, Orlowski R, et al. for the MAIA trial investigators.Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104-2115. DOI: 10.1056/NEJMoa1817249