FDA Approval Sought for Subcutaneous Daratumumab Plus VRd in Transplant-Ineligible or -Deferred, Newly Diagnosed Myeloma

A supplemental biologics license application (sBLA) has been submitted to the FDA seeking the approval of daratumumab and hyaluronidase-fihj (subcutaneous daratumumab; Darzalex Faspro) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) for the treatment of adult patients with newly diagnosed multiple myeloma for whom autologous stem cell transplant (ASCT) is deferred or those who are ineligible for ASCT.¹

The sBLA is supported by data from the phase 3 CEPHEUS trial (NCT03652064). Findings presented at the 21st IMS Annual Meeting showed that patients treated with D-VRd (n = 197) experienced a minimal residual disease (MRD)–negativity rate (10-5 sensitivity) of 60.9% compared with 39.4% for those given VRd alone (n = 198; odds ratio [OR], 2.37; 95% CI, 1.58-3.55; P < .0001).²

Patients in the D-VRd arm experienced a complete response (CR) or better rate of 81.2% vs 61.6% in the VRd arm (OR, 2.73; 95% CI, 1.71-4.34; P < .0001). The stringent CR, CR, very good partial response (PR), and PR rates in the experimental arm were 65.0%, 16.2%, 11.7%, and 4.1%, respectively. In the control arm, these respective rates were 44.4%, 17.2%, 25.3%, and 6.1%.

If approved, D-VRd would represent the first FDA-approved treatment for patients with newly diagnosed multiple myeloma based on a study using MRD-negativity rate as a primary end point, according to an announcement for Johnson & Johnson.¹

“[Subcutaneous daratumumab]–based therapies continue to be at the forefront of multiple myeloma research. We’re encouraged that the FDA Oncologic Drugs Advisory Committee recently voted in favor of MRD-negativity as an acceptable endpoint in multiple myeloma trials,” Craig Tendler, MD, vice president of Late Clinical Development and Global Medical Affairs, Innovative Medicine, at Johnson & Johnson, stated in a news release. “CEPHEUS is the first registrational study with a primary endpoint of MRD-negativity filed by Johnson & Johnson in multiple myeloma. The data from CEPHEUS add to the body of evidence for [subcutaneous daratumumab] in newly diagnosed multiple myeloma and, together with the results of the [phase 3] PERSEUS study [NCT03710603], demonstrate the potential benefit of this quadruplet regimen for newly diagnosed patients, regardless of transplant eligibility.”

On July 30, 2024, the FDA approved D-VRd for induction and consolidation in patients with newly diagnosed multiple myeloma who are candidates for ASCT, based on findings from PERSEUS.³

CEPHEUS was a phase 3 study that enrolled patients with newly diagnosed multiple myeloma who were ineligible for ASCT or deferred transplant.² An ECOG performance status of 0 to 2 and a frailty score of 0 or 1 were required for enrollment.

Patients were randomly assigned 1:1 to receive 1800 mg of daratumumab once per week during cycles 1 and 2, then once every 3 weeks in cycles 3 to 8, in combination with 1.3 mg/m² of bortezomib on days 1, 4, 8, and 11 of each 21-day cycle, 25 mg of lenalidomide on days 1 to 14 of each cycle, and 20 mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12 of each cycle for 8 cycles; or VRd alone at the same dosing schedule.

In cycle 9 and beyond, patients received either 1800 mg of daratumumab once every 4 weeks plus 25 mg of lenalidomide on days 1 to 21 and 40 mg of dexamethasone on days 1, 8, 15, and 22 of each 28-day cycle; or lenalidomide and dexamethasone alone at the same dosing schedule.

The trial’s primary end point was MRD-negativity rate with a CR or better. Secondary end points consisted of progression-free survival (PFS), the proportion of patients with sustained MRD negativity with a CR or better for at least 12 months, CR or better rate, and overall survival.

Additional data showed the MRD-negativity rate at a 10^-6 sensitivity was 46.2% in the D-VRd arm vs 27.3% in the VRd arm (OR, 2.24; 95% CI, 1.48-3.40; P = .0001). MRD negativity at a 10^-5 sensitivity was sustained for at least 12 months in 48.7% of patients in the D-VRd arm vs 26.3% of those in the VRd arm (OR, 2.63; 95% CI, 1.73-4.00; P < .0001).

The median PFS was not reached in the daratumumab arm vs 52.6 months in the VRd alone arm (HR, 0.57; 95% CI, 0.41-0.79; P = .0005). The 54-month PFS rates were 68.1% and 49.5%, respectively.

OS data were not mature at data cutoff, and no statistically significant difference was observed between the 2 arms. However, a trend favoring D-VRd was observed overall (HR, 0.85; 95% CI, 0.58-1.24) and when censoring for deaths due to COVID-19 (HR, 0.69; 95% CI, 0.45-1.05).

Grade 3/4 treatment-emergent adverse effects (TEAEs) were reported in 92.4% of patients in the D-VRd arm (n = 197) vs 85.6% of those in the VRd arm (n = 195). TEAEs led to the discontinuation of all study drugs in 7.6% treated with D-VRd and 15.9% of those given VRd. Grade 5 non–COVID-19 TEAEs occurred in 10.7% of patients in the experimental arm vs 7.7% of those in the control arm.

The most common any-grade TEAEs included blood and lymphatic disorders (D-VRd, 82.7%; VRd, 64.6%), including neutropenia (55.8%; 39.0%), thrombocytopenia (46.7%; 33.8%), and anemia (37.1%; 31.8%); gastrointestinal disorders (79.7%; 81.5%), including diarrhea (56.9%; 59.0%) and constipation (38.1%; 42.1%); general disorders and administration-site conditions (80.7%; 75.4%), including peripheral edema (42.1%; 39.0%) and fatigue (32.0%; 30.8%); psychiatric disorders (46.2%; 49.2%), including insomnia (32.0%; 32.3%); infections (91.9%; 85.6%), including upper respiratory tract infection (39.6%; 32.8%) and COVID-19 (38.1%; 24.6%); and second primary malignancies (7.6%; 9.2%).

Any-grade peripheral sensory neuropathy was reported in 55.8% of patients in the D-VRd arm vs 61.0% of those in the VRd arm; the respective rates of grade 3/4 peripheral sensory neuropathy were 8.1% and 8.2%.

References

1. Johnson & Johnson files for U.S. FDA approval of Darzalex Faspro-based quadruplet regimen for newly diagnosed multiple myeloma patients for whom transplant is not planned. News release. Johnson & Johnson. September 30, 2024. Accessed September 30, 2024. https://www.investor.jnj.com/news/news-details/2024/Johnson--Johnson-files-for-U.S.-FDA-approval-of-DARZALEX-FASPRO-based-quadruplet-regimen-for-newly-diagnosed-multiple-myeloma-patients-for-whom-transplant-is-not-planned/default.aspx
2. Usmani SZ, Facon T, Hungaria V, et al. Daratumumab SC + bortezomib/lenalidomide/dexamethasone in patients with transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: results of the phase 3 CEPHEUS study. Presented at: 21st International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-63.
3. FDA approves daratumumab and hyaluronidase-fihj with bortezomib, lenalidomide, and dexamethasone for multiple myeloma. FDA. July 30, 2024. Accessed September 30, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-daratumumab-and-hyaluronidase-fihj-bortezomib-lenalidomide-and-dexamethasone-multiple