Subcutaneous Daratumumab Plus VRd Significantly Improved PFS, Increased Depth of Response in Patients With Newly Diagnosed Multiple Myeloma

Data from the phase 3 PERSEUS trial (NCT03710603) showed that subcutaneous daratumumab (Darzalex, Janssen Biotech; DARA SC) in combination with bortezomib (Velcade; Takeda Pharmaceutical Company Limited), lenalidomide (Revlimid; Bristol Myers Squibb), and dexamethasone (VRd) in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) significantly improved progression-free survival (PFS), explained Pieter Sonneveld, MD, PhD, during a late-breaking abstract presentation at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition. Sonneveld, professor of hematology at Erasmus MC Cancer Institute and Erasmus University Rotterdam in Netherlands, explained further that DARA SC combined with VRd also increased depth of response in complete response (CR) or better and minimal residual disease (MRD) negativity, with consistent PFS benefit shown across clinically relevant subgroups.^1,2

In 2020, Sonneveld explained that there was an estimated 176,404 people worldwide diagnosed with multiple myeloma (MM), with approximately 117,077 patients dying from MM in that same year. Although novel treatments have improved outcomes, MM remains incurable.¹

Although novel treatments have improved outcomes, MM remains incurable. Image Credit: © David A Litman - stock.adobe.com

During the PERSEUS trial, investigators compared the quadruplet therapy combination of DARA plus VRd followed by DARA plus lenalidomide maintenance vs the triplet therapy combination of VRd followed by lenalidomide maintenance.²

Currently, DARA in combination with bortezomib, thalidomide (Thalomid, Bristol Myers Squibb) and dexamethasone (VTd) is approved for transplant-eligible patients with NDMM, and this quadruplet therapy has shown clinical benefit compared to VTd alone. VRd induction followed by autologous stem cell transplant (ASCT), VRd consolidation, and lenalidomide maintenance is also considered a standard of care for transplant-eligible patients with NDMM, Sonneveld explained.^1,2

“For younger patients up to 60 years of age, the standard treatment is induction therapy, then [ASCT],” Sonneveld said during the presentation. “This has been the standard for a long time, and it includes lenalidomide maintenance after the [ASCT].”¹

In the phase 2 GRIFFIN study (NCT02874742), investigators assessed intravenous DARA combined with VRd (D-VRd) for induction and consolidation therapy, followed by DARA plus lenalidomide maintenance. The phase 2 trial results showed improved depth of response and PFS vs VRd induction and consolidation therapy and lenalidomide maintenance in transplant-eligible patients with NDMM after more than 4 years of follow-up.^1,2

“For the PERSEUS study, we tried to improve on the standard treatment by adding DARA for induction, for consolidation, and for the maintenance treatment,” Sonneveld said. “[Also, DARA] given subcutaneously is new. There have been studies in late stage myeloma and also in early stage smaller studies that use DARA by intravenous administration. But this is subcutaneous, which makes life easier for patients.”¹

To build on the research conducted in the GRIFFIN study, Sonneveld explained that the phase 3 PERSEUS study evaluated DARA SC in combination with VRd induction and consolidation therapy followed by DARA plus lenalidomide maintenance in comparison with VRd for induction and consolidation therapy, with lenalidomide maintenance in transplant-eligible patients with NDMM. The results showed deep and durable MRD negativity with D-VRd.^1,2

“We used a 4 week schedule rather than a 3 week schedule for these D-VRd treatments,” Sonneveld said. “For the maintenance treatment of DARA plus lenalidomide, if patients continue the treatment for 2 years and they were in complete response, they were allowed to stop the DARA administration. In fact, approximately two-thirds of patients reached this stage so they could stop DARA, and they were followed by MRD analysis and response criteria to see if the disease remained MRD negative.”¹

During the study, the MRD–negativity rate was defined as the proportion of patients who achieved MRD negativity and CR or better at any time. The results showed that overall rates of CR (87.9% vs 70.1%; P <0.0001) and MRD negativity (75.2% vs 47.5%; P <0.0001) were significantly higher with D-VRd vs VRd.^1,2

“The follow up is too short to be able to report on this extensively, but two-thirds of patients were able to stop DARA, and, at the moment, less than 10 patients had to restart DARA,” Sonneveld said.¹

The primary endpoint of the PERSEUS trial is PFS, with key secondary endpoints including CR or better rate, MRD–negativity rate (10–5 threshold; clonoSEQ), and OS. In total, 709 patients were randomized into each treatment arm, either D-VRd (n=355) or VRd (n=354). The median (range) age of patients was 60 (31-70) years. Additionally, 14.8% of patients had ISS stage 3 disease, and 21.7% had high cytogenetic risk (t[4;14], t[14;16], or del[17p]).^1,2

“In many trials, MRD is, let’s say, the hype of the day, but we think it's more than the hype of the day. It really represents a deep state of responsiveness. So [MRD] was very extensively analyzed in this trial,” Sonneveld said. “You can see there's a big difference [in MRD] between those 2 treatments.”¹

Additionally, 64% (207/322) of patients receiving maintenance in the D-VRd group discontinued DARA after achieving sustained MRD negativity in accordance with the trial protocol. In the VRd arm, only 29.7% of patients reached this point of sustained MRD negativity. According to Sonneveld, sustained MRD negativity is very important as a treatment outcome.^1,2

“Sustained MRD negativity for more than 12 months was one of the criteria for stopping [DARA] in the maintenance phase. You can see that there’s a huge difference [in sustained MRD negativity] between the 2 treatment arms,” Sonneveld said. “This is a very important finding because it means that the treatment exposure of the patients is reduced over time, if they have demonstrated to be sensitive to the treatment and to achieve the MRD negative state. This is important for the wellbeing of patients and for quality of life. We think this will have a major impact on the choice of treatment for this group of patients.”¹

At clinical cutoff, 314 patients had completed all 4 induction and 2 consolidation cycles, with 309 patients in the D-VRd arm and 299 patients in the VRd arm. Further, 294 patients had undergone ASCT, with 322 patients in the D-VRd arm and 300 patients in the VRd arm starting maintenance therapy.^1,2

At a median follow-up of 47.5 months, investigators observed that PFS had significantly improved in the D-VRd arm vs the VRd arm (HR, 0.42; 95% CI, 0.30-0.59; P <0.0001 [crossing the prespecified stopping boundary of 0.0126]). Further, although median PFS was not reached in either arm, with estimated 48-month PFS rates at 84.3% for D-VRd and 67.7% for VRd, prespecified subgroup analyses showed a consistent improvement in PFS with D-VRd compared to VRd across clinically relevant subgroups, including in patients with ISS stage 3 disease and patients with high cytogenetic risk.²

“[PFS] was clearly superior with the addition of DARA to VRd,” Sonneveld said. “You can see here the [HR] is 0.42, and this is unprecedented in this kind of phase 3 trial in [MM].”¹

Additionally, Sonneveld noted that with an estimated 4 year PFS of 84.3% in the D-VRd arm vs 67.7% in the VRd arm, there was a 58% reduction of the risk of progression. Further, OS data were immature, with 78 deaths on study (D-VRd, 34 [9.6%]; VRd, 44 [12.4%]). Because of the period of the study, 7 deaths also occurred due to COVID-19 (D-VRd, 4; VRd, 3).^1,2

Furthermore, the most frequent (≥10%) grade 3 or 4 treatment-emergent adverse events (TEAEs) during the trial for the D-VRd vs VRd arms were neutropenia (62.1% vs 51.0%, respectively), thrombocytopenia (29.1% vs 17.3%, respectively), diarrhea (10.5% vs 7.8%, respectively), pneumonia (10.5% vs 6.1%, respectively), and febrile neutropenia (9.4% vs 10.1%, respectively). Serious TEAEs occurred in 57.0% of patients in the D-VRd arm vs 49.3% of patients in the VRd arm. Additionally, TEAEs resulting in treatment discontinuation in 8.8% of patients in the D-VRd arm vs 21.3% of patients in the VRd arm.²

“For the safety profile, I can tell you, it was consistent with the already known safety profiles for VRd alone, and for [DARA SC] alone, so the treatment was very well tolerated,” Sonneveld said.¹

Sonneveld explained that the clinical consequence of these results is the patient performs well and has a very good response in terms of MRD negativity and was able to discontinue DARA in this trial.¹

“We think this is going to be the standard treatment in the coming [sic] years, at least in Europe,” Sonneveld said. “This trial was performed in many European countries and in Australia. In Europe for sure, [this trial] will set the stage as the standard treatment for patients, and hopefully also in the United States.”¹

REFERENCES

1. Sonneveld P. Late-Breaking Abstracts. Presented at: 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.
2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. LBA-1 Phase 3 Randomized Study of Daratumumab (DARA) + Bortezomib, Lenalidomide, and Dexamethasone (VRd) Versus Vrd Alone in Patients (Pts) with Newly Diagnosed Multiple Myeloma (NDMM) Who Are Eligible for Autologous Stem Cell Transplantation (ASCT): Primary Results of the Perseus Trial. 2023. Accessed December 11, 2023. https://ash.confex.com/ash/2023/webprogram/Paper191911.html