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

Data from the phase 3 PERSEUS trial (NCT03710603) showed that subcutaneous (SC) daratumumab (Darzalex; Janssen Biotech) in combination with VRd (bortezomib [Velcade; Takeda Pharmaceuticals], lenalidomide [Revlimid; Bristol Myers Squibb], dexamethasone) in transplant-eligible patients with newly diagnosed multiple myeloma (NDMM) significantly improved progressionfree survival (PFS), Pieter Sonneveld, MD, PhD, explained during a late-breaking abstract presentation at the 65th American Society of Hematology Annual Meeting & Exposition in San Diego, California. Sonneveld, professor of hematology at Erasmus Medical Center Cancer Institute in Rotterdam, Netherlands, and Erasmus University Rotterdam, explained further that SC daratumumab 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

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In 2020, Sonneveld explained there were an estimated 176,404 individuals worldwide diagnosed with MM, with approximately 117,077 patients dying from MM in the same year. Although novel treatments have improved outcomes, MM remains incurable.¹

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

Currently, daratumumab in combination with VTd (bortezomib, thalidomide [Thalomid; Bristol-Myers Squibb], dexamethasone) is approved for transplanteligible patients with NDMM, and this quadruplet therapy has shown clinical benefit compared with 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 patients younger [than] 60 years, the standard treatment is induction therapy [and] 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 daratumumab combined with VRd (D-VRd) for induction and consolidation therapy followed by daratumumab plus lenalidomide maintenance. The 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 daratumumab for induction, for consolidation, and for the maintenance treatment,” Sonneveld said. “[Also, daratumumab] given subcutaneously is new. There have been studies in latestage myeloma and early-stage smaller studies that use daratumumab by intravenous administration. But this is subcutaneous, which makes life easier for patients.”¹

To build on the research conducted in GRIFFIN, Sonneveld explained that PERSEUS evaluated SC daratumumab in combination with VRd induction and consolidation therapy followed by daratumumab 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 daratumumab plus lenalidomide, if patients continued the treatment for 2 years and were in complete response, they were allowed to stop the daratumumab administration. In fact, approximately two-thirds of patients reached this stage, so they could stop daratumumab, and they were followed by MRD analysis and response criteria to see whether 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 < .0001) and MRD negativity (75.2% vs 47.5%; P < .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 daratumumab, and at the moment, fewer than 10 patients had to restart daratumumab,” Sonneveld said.¹

The primary end point of PERSEUS is PFS, with key secondary end points including CR or better rate, MRD negativity rate (10-5 threshold as determined by clonoSEQ assay), and OS. In total, 709 patients were randomly assigned to each treatment arm, either D-VRd (n = 355) or VRd (n = 354). The median age of patients was 60 years (range, 31-70). Additionally, 14.8% of patients had International Staging System (ISS) stage III disease and 21.7% had high cytogenetic risk (t[4;14], t[14;16], or del[17p]).^1,2

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

Additionally, 64% of patients (207 of 322) receiving maintenance in the D-VRd group discontinued daratumumab 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 daratumumab 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 [sensitivity] to the treatment and [achievement of] the MRD-negative state. This is important for the well-being 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. Furthermore, 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 < .0001 [crossing the prespecified stopping boundary of P = .0126]). Furthermore, 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 with VRd across clinically relevant subgroups, including in patients with ISS stage III disease and patients with high cytogenetic risk.²

“[PFS] was clearly superior with the addition of daratumumab 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. Furthermore, OS data were immature, with 78 deaths in the study (34 in the D-VRd arm [9.6%] and 44 in the VRd arm [12.4%]). Because of the period of the study, 7 deaths also occurred due to COVID-19 (4 in the D-VRd arm and 3 in the VRd arm).^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% of patients in the D-VRd arm vs 49.3% of patients in the VRd arm. Additionally, TEAEs resulted 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, it was consistent with the already known safety profiles for VRd alone and for [SC daratumumab] alone, so the treatment was very well tolerated,” Sonneveld said.¹

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

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

References

1. Sonneveld P. Late-breaking abstracts. Presented at: 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA.

2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. 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. Abstract presented at: 65th American Society of Hematology Annual Meeting & Exposition; December 9-12, 2023; San Diego, CA. Abstract LBA-1. https://ash.confex.com/ash/2023/webprogram/Paper191911.html