EMA Receives Indication Extension Application for D-VRd in Newly Diagnosed, Transplant-Eligible Multiple Myeloma

The European Medicines Agency (EMA) has received a type II variation application seeking approval for an indication extension of subcutaneous daratumumab (Darzalex) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) for the treatment of adult patients with newly diagnosed multiple myeloma who are eligible for autologous stem cell transplant (ASCT).¹

The submission was supported by updated findings from the phase 3 PERSEUS trial (NCT03710603)which were presented at the 2023 ASH Annual Meeting and simultaneously published in The New England Journal of Medicine. Data showed that the 4-year progression-free survival (PFS) rate at a median follow-up of 47.5 months was 84.3% with D-VRd vs 67.7% with VRd, resulting in a 58% reduction in the risk of disease progression or death when patients were treated with the D-VRd regimen (HR, 0.42; 95% CI, 0.30-0.59; P <.001).^1,2

Furthermore, the rate of complete response (CR) or better with D-VRd was 87.9% vs 70.1% with VRd (P <.001), and the rates of stringent CR (sCR) and CR were 69.3% and 18.6%, respectively, with D-VRd vs 44.6% and 25.4% with VRd.²

“Despite significant advances, multiple myeloma remains an incurable disease affecting more than 35,000 people each year in Europe alone,” Edmond Chan, MBChB, MD (Res), EMEA Therapeutic Area Lead Haematology, Johnson & Johnson Innovative Medicine, stated in a press release.¹ “We know response to first-line therapy is vital to improve patients’ long-term outcomes, which is why we are proud of today’s submission and the potential of this daratumumab subcutaneous-based, quadruplet therapy to achieve deep and durable responses in patients with newly diagnosed multiple myeloma.”

Multiple myeloma currently is an incurable disease. In the European Union, over 35,000 patients were diagnosed with the disease in 2022 and more than 22,700 died, representing an area with high clinical need.

PERSEUS is an ongoing, randomized, open-label trial that enrolled patients between the ages of 18 and 70 years with newly diagnosed, transplant-eligible multiple myeloma and an ECOG performance status of 2 or less. Additional enrollment criteria include 10% or more monoclonal plasma cells in the bone marrow or presence of a biopsy proven plasmacytoma; measurable disease; and adequate bone marrow, renal, and liver function.³

Exclusion criteria for patients included treatment with prior or current systemic therapy or SCT; grade 2 or higher peripheral neuropathy or neuropathic pain; a prior or concurrent invasive malignancy; radiation therapy within 14 days of randomization; plasmapheresis within 28 days of randomization; meningeal involvement of multiple myeloma; chronic obstructive pulmonary disease with a forced expiratory volume in 1 second; and moderate or severe asthma.³

Eligible patients received either subcutaneous daratumumab combined with VRd induction and consolidation therapy followed by daratumumab and lenalidomide maintenance therapy (n = 355) or VRd induction and consolidation therapy and lenalidomide maintenance therapy alone (n = 354). Patients in the D-VRd arm had a median age of 61.0 years (range, 32-70) and those in the VRd arm had a median age of 59.0 years (range, 31-70).²

The primary end point of the trial was PFS, and key secondary end points included the rate of CR or better, minimal residual disease (MRD)–negative status in patients who achieved a CR or better, and overall survival.²

Treatment with D-VRd also led to higher rates of MRD negativity compared with the control arm. Of the patients treated on the D-VRd arm, 64% in the maintenance phase discontinued treatment after achieving a CR or better and sustained MRD negativity for at least 12 months following 2 years of maintenance per the trial protocol.¹

The overall safety profile of D-VRd followed by daratumumab and lenalidomide maintenance therapy aligned with the known safety profiles for subcutaneous daratumumab, VRd, and lenalidomide.

“The impressive results from the PERSEUS study highlight the potential of this daratumumab subcutaneous-based regimen to transform patient outcomes and provide an effective therapy option in newly diagnosed, transplant-eligible multiple myeloma,” Craig Tendler, MD, vice president of Clinical Development, Diagnostics, and Global Medical Affairs at Johnson & Johnson Innovative Medicine, stated in the press release.1 “We are committed to advancing innovative regimens, such as D-VRd, as we strive towards the elimination of this complex disease. We now look forward to working with the EMA on the review of this submission.”

References

1. Johnson & Johnson submits application to the European Medicines Agency for Darzalex (daratumumab)-based quadruplet therapy for the treatment of patients with transplant-eligible, newly diagnosed multiple myeloma. News release. Johnson & Johnson. March 6, 2024. Accessed March 6, 2024. https://www.globenewswire.com/news-release/2024/03/06/2841454/0/en/Johnson-Johnson-submits-application-to-the-European-Medicines-Agency-for-DARZALEX-daratumumab-based-quadruplet-therapy-for-the-treatment-of-patients-with-transplant-eligible-newly-.html
2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054
3. Daratumumab, velcade (bortezomib), lenalidomide and dexamethasone compared to velcade, lenalidomide and dexamethasone in subjects with previously untreated multiple myeloma (Perseus). ClinicalTrials.gov. Updated September 27, 2022. Accessed March 6, 2024. https://www.clinicaltrials.gov/study/NCT03710603