The treatment landscape for multiple myeloma is evolving with the increased use of monoclonal antibodies in newly diagnosed patients. DARZALEX has established a strong position compared to its market competitors. In frontline clinical studies for multiple myeloma, DARZALEX has proven successful and is now considered a standard therapy. It has exceeded rivals' expectations in effectiveness and safety, positioning itself to dominate the multiple myeloma market. While both J&J's DARZALEX and Bristol Myers Squibb and AbbVie's EMPLICITI were introduced in the same month, DARZALEX has outpaced EMPLICITI, achieving blockbuster status.

The standard treatment for transplant-eligible patients has been VRd followed by ASCT, VRd consolidation, and lenalidomide maintenance. Phase II results from the GRIFFIN trial previously demonstrated that adding daratumumab to VRd significantly enhanced progression-free survival. The PERSEUS trial, differing from GRIFFIN, was a larger phase III randomized prospective study that included daratumumab in the maintenance phase. The PERSEUS study is being conducted in collaboration with the European Myeloma Network as the sponsor. This trial used subcutaneous daratumumab instead of intravenous, administered it every four weeks to improve tolerability, and allowed for discontinuation of maintenance daratumumab if patients maintained MRD negativity for at least 12 months.

 

The potential for curing newly diagnosed multiple myeloma (NDMM) relies on achieving sustained MRD negativity at a level of 10-6. In the PERSEUS study, 47% of patients treated with D-VRd followed by D-R (daratumumab and lenalidomide) maintenance reached sustained MRD negativity at 10-6 for 12 months, compared to 19% with VRd followed by R (lenalidomide). Among high-risk patients, 58% achieved MRD negativity at 10-6 and 30% maintained it, versus 31% and 14% with VRd followed by R, respectively. During D-R maintenance, MRD negativity at 10-6 increased by 30% compared to 15% with R alone. Additionally, 31% of MRD-positive patients converted to sustained MRD negativity at 10-6 with D-R maintenance, versus 10% with R alone. Furthermore, 64% of patients discontinued DARA after achieving sustained MRD negativity at 10-5.

KOL insights

“We were not surprised to see the difference with the addition of daratumumab, but we were very surprised by the magnitude of the difference between the two arms. For MRD negativity, the large difference favoring D-VRd increased over time, and this was even more evident for MRD at 10−6.” – MD, United States

“Many investigators and clinicians are still unsure if continued use of daratumumab (or another anti-CD38 monoclonal antibody) in maintenance is necessary, and this study did not answer that question. Many of us do not routinely use daratumumab in maintenance, except in high-risk patients. Additional ongoing studies including the SWOG S1803 study and the GMMG-HD7 study will answer that important question.” – MD, United States

Conclusion 

The PERSEUS trial provides significant insights into the treatment of transplant-eligible patients with NDMM. The trial compared the efficacy of D-VRd versus VRd, with a particular focus on MRD negativity rates and PFS. Johnson & Johnson has already filed the sBLA in the US and EU for transplant-eligible patients with NDMM based on the PERSEUS trial. Johnson & Johnson’s emerging competitor Sanofi in Multiple Myeloma also presented data at EHA 2024 in the same setting (phase III GMMG-HD7 study, Abstract Number- #S202). Data from the GMMG-HD7 study suggests that SARCLISA is expected to compete with DARZALEX in this setting. In 2025, based on findings from the phase III GMMG-HD7 study, Sanofi is anticipating possible regulatory filing for SARCLISA-VRd in first-line transplant eligible multiple myeloma patients. In the latter part of 2024, the final data readout is anticipated.  DARZALEX-VRd combo has the benefit of being the first mover in this setting. 

MRD negativity at a sensitivity level of 10-6 indicates an extremely low level of cancer cells remaining after treatment, which is a strong predictor of long-term outcomes in multiple myeloma. The PERSEUS trial found that rates of MRD negativity at this level were approximately doubled with D-VRd compared to VRd. This suggests that the addition of daratumumab to the standard VRd regimen significantly enhances the depth of response.

Furthermore, sustained MRD negativity for at least 12 months was also more common with D-VRd. This sustained response is crucial as it implies ongoing disease control and is associated with better survival outcomes. In high-risk patients who achieved MRD negativity, PFS was notably improved with D-VRd vs. VRd. This finding is particularly important as high-risk patients typically have poorer prognoses and more aggressive disease courses.

The trial also highlighted the benefits of maintenance therapy. Patients who remained MRD positive after initial treatment had improved PFS when maintained on D-R compared to R alone. This indicates that continuous therapy with daratumumab can provide additional disease control even in patients who do not achieve complete MRD negativity.

 

Overall, these data support the use of D-VRd induction followed by D-R maintenance as a new standard of care for transplant-eligible NDMM patients. This regimen not only increases the likelihood of achieving deep remissions but also maintains those responses over time, translating into improved long-term outcomes for patients.