Post Hoc Analysis of Pooled PERSEUS and GRIFFIN Data Support D-VRd in Transplant-Eligible Myeloma

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The addition of daratumumab (Darzalex) to bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd) induction/consolidation and lenalidomide maintenance resulted in a progression-free survival (PFS) benefit vs VRd followed by lenalidomide alone in transplant-eligible patients with newly diagnosed multiple myeloma who were at least 65 years of age or older, according to a post hoc analysis of pooled data from the phase 3 PERSEUS (NCT03710603) and phase 2 GRIFFIN (NCT02874742) studies presented during the 51st Annual EBMT Meeting.1

At a median follow-up of 47.5 months for PERSEUS and 49.6 months for GRIFFIN, the median PFS was not reached in the D-VRd (n = 122) or the VRd (n = 115) arm. In this pooled intention-to-treat population, D-VRd was noted to have resulted in a 44% reduction in the risk of disease progression or death compared with VRd (HR, 0.56; 95% CI, 0.31-1.01; P = .05). The estimated PFS rates at 48 months in the respective arms were 79.1% and 71.6%.

A higher response rate was also observed with D-VRd vs VRd, with respective complete response (CR) or better rates of 82.8% and 67.0% (odds ratio [OR], 2.37; 95% CI, 1.28-4.39; P = .005); the stringent CR rates in the respective arms were 59.0% and 49.6% (OR, 1.49; 95% CI, 0.88-2.53; P = .14). Broken down further, in the D-VRd arm, the CR rate was 23.8%, the very good partial response (VGPR) rate was 10.7%, and the partial response (PR) rate was 1.6%; 4.9% of patients had stable disease (SD), progressive disease (PD), or were not evaluable (NE). In the VRd arm, the CR rate was 17.4%, the VGPR rate was 19.1%, and the PR rate was 9.6%; 4.3% had SD, PD, or were NE.

A higher overall minimal residual disease (MRD) negativity rate (10-5) was observed in the D-VRd arm vs the VRd arm, at 66.4% and 41.7%, respectively (OR, 2.75; 95% CI, 1.61-4.71; P = .0002). A higher sustained MRD negativity rate of at least 12 months was also observed with D-VRd vs VRd, at 52.5% and 26.1%, respectively (OR, 3.20; 95% CI, 1.83-5.58; P < .0001).

“The limited PFS benefit previously seen in PERSEUS in patients aged 65 years or older was due to a contribution of several factors, including a small number of events, imbalances in cytogenetic risk, and censoring of PFS events,” Roberto Mina, MD, of University of Torino and Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino, in Torino, Italy, and colleagues, wrote in a poster of the data. “After pooling data for patients aged 65 years or older from both PERSEUS and GRIFFIN to perform a more robust analysis and correct for the above imbalances, the addition of daratumumab to both VRd induction/consolidation and [lenalidomide] maintenance led to a PFS benefit vs VRd followed by [lenalidomide] alone.”

Setting the Stage for the Pooled Analysis

The PERSEUS and GRIFFIN trials enrolled patients with newly diagnosed multiple myeloma who were between the ages of 18 years and 70 years and were candidates for high-dose therapy and autologous stem cell transplant (ASCT).

They were randomly assigned 1:1 to receive D-VRd or VRd. In both studies, participants were administered 4 induction cycles of VRd and 2 post-ASCT consolidation cycles of VRd followed by lenalidomide maintenance. For PERSEUS, treatment cycles were comprised of 28 days; for GRIFFIN, treatment cycles were comprised of 21 days. Those in the D-VRd arm for PERSEUS and GRIFFIN also received subcutaneous daratumumab, which was co-formulated with recombinant human hyaluronidase, or intravenous daratumumab, respectively.

Data from both studies showed that D-VRd followed by daratumumab/lenalidomide maintenance improved PFS and led to deeper response and MRD negativity rates vs VRd followed by lenalidomide alone.

“Older adults are at a higher risk of poor prognosis and are a population of particular interest,” the study authors wrote. An unstratified subgroup analysis of PERSEUS revealed that the hazard ratio (HR) for PFS in the subset of patients aged 65 years or older was 0.97 per computerized algorithm and 0.87 per independent review committee assessment. The PFS benefit in this subset was hypothesized to be due to the small number of PFS events, a cytogenetic risk imbalance between treatment groups (high risk: D-VRd, 25.5%; VRd, 19.5%), and an imbalance in censoring patients for PFS after 2 or more missing consecutive disease evaluations (censored events: D-VRd, 0; VRd, 3) which could have impacted the HRs for PFS in favor of the VRd arm.

By increasing sample size, the authors of the post hoc pooled analysis sought to offer a more robust analysis that would provide a better picture of the impact of adding daratumumab to VRd in this particular subset of patients with transplant-eligible, newly diagnosed multiple myeloma.

Unpacking the Pooled Analysis

For the post hoc analysis, investigators analyzed PFS, response rates by International Myeloma Working Group criteria, MRD negativity rates, sustained MRD negativity rates, stem cell mobilization, ASCT rates, and safety.

To do this, they pooled data on patients aged 65 years or older who were included in the primary analysis of PERSEUS and final analysis of GRIFFIN. Notably, this subset accounted for 25.5% of those enrolled in PERSEUS (D-VRd; n = 94/355; VRd, n = 87/354) and 27.1% of those included in GRIFFIN (D-VRd, n = 28/104; VRd, n = 28/103). They estimated PFS by utilizing the Kaplan-Meier method. To compare response and MRD negativity rates, authors leveraged a Mantel-Haenszel estimate of the common OR, which was stratified by International Staging System (ISS) disease stage and cytogenetic risk.

In the pooled intention-to-treat population, the median patient age was 67 years (range, 65-70) in the D-VRd and VRd arms. More than half of patients were male (D-VRd, 62.3%; VRd, 58.3%) and had an ECOG performance status of 0 (54.1%; 57.9%); most patients had an ISS disease stage of I (41.8%; 33.9%) and standard cytogenetic risk (73.9%; 79.8%).

The median duration of treatment in the D-VRd and VRd arms was 37.4 months (range, 0.5-52.5) and 32.6 months (range, 0.1-53.0), respectively. The median relative dose intensities were similar between the arms for bortezomib (D-VRd, 92.9%; VRd, 93.5%) and dexamethasone (95.5%; 100%), but were slightly lower in the D-VRd arm for lenalidomide (75.5%; 87.7%). In the D-VRd arm, the median relative dose intensity for daratumumab was 99.7%. Moreover, discontinuation rates were also comparable for bortezomib and dexamethasone between the arms; the discontinuation rate was higher in the D-VRd arm vs VRd arm for lenalidomide, at 23.3% and 17.5%, respectively.

Stem Cell Mobilization and Transplant Insights

Most patients aged 65 years or older who received at least 1 dose of D-VRd (n = 120) or VRd (n = 114) and were included in the pooled safety population underwent stem cell mobilization (93.3% vs 84.2%). “Median number of CD34-positive cells collected was sufficient for ASCT in both treatment groups,” the authors wrote. “Only 2 patients in the D-VRd group and 1 patient in the VRd group had less than 2 x 106 kg CD34-positive stem cells collected.” Moreover, similar proportions of patients in the D-VRd and VRd arms went on to undergo ASCT (86.7% vs 82.5%).

Safety Spotlight

The overall toxicity profile of D-VRd in this patient subset was noted to be generally comparable to that of all pooled patients irrespective of age. No new safety concerns were cited. In this subgroup, grade 3 or 4 treatment-emergent adverse effects (TEAEs) were reported in 94.2% of those in the D-VRd arm and 86.8% of those in the VRd arm. The most common TEAEs reported in these respective arms were neutropenia or febrile neutropenia (59.2% vs 43.0%), thrombocytopenia (38.3% vs 19.3%), diarrhea (14.2% vs 10.5%), and pneumonitis (10.8% vs 6.1%).

Serious TEAEs were experienced by 67.5% of those in the D-VRd arm vs 52.6% of those in the VRd arm. The most common serious TEAEs reported in the respective arms were pneumonia (12.5% vs 7.9%), febrile neutropenia (6.7% vs 4.4%), pyrexia (6.7% vs 1.8%), diarrhea (5.8% vs 3.5%), and sepsis (5.0% vs 2.6%). Fatal TEAEs occurred in 5.0% of those in the D-VRd arm and 3.5% of those in the VRd arm. TEAEs led to the discontinuation of at least 1 study drug for 40.8% of those in the D-VRd arm and 45.6% of those in the VRd arm.

Take-Home Message

“The post hoc analysis of pooled data from the phase 3 PERSEUS and phase 2 GRIFFIN studies supports D-VRd followed by [daratumumab/lenalidomide] maintenance as standard of care and highlights the benefit of daratumumab during induction, consolidation, and maintenance for all transplant-eligible patients with [newly diagnosed multiple myeloma, irrespective of age,” the study authors concluded.

Reference

Mina R, Rodriguez-Otero P, Voorhees PM, et al. Daratumumab plus bortezomib, lenalidomide, and dexamethasone in transplant-eligible patients with multiple myeloma: a pooled analysis of patients aged ≥65 years from the PERSEUS and GRIFFIN studies. Presented at: 51st Annual EBMT Meeting; March 30-April 2, 2025; Florence, Italy. Abstract A353.