D-VRd Extends PFS in Newly Diagnosed Multiple Myeloma Subgroups

Meletios A. Dimopoulos, MD

Patients with newly diagnosed multiple myeloma who received induction and consolidation therapy with subcutaneous daratumumab (Darzalex) in combination with bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (D-VRd) with daratumumab and lenalidomide maintenance experienced prolonged progression-free survival (PFS) and higher rates of minimal residual disease (MRD) negativity compared with those treated with bortezomib plus lenalidomide and dexamethasone (VRd) across subgroups, according to findings from a cytogenetic risk analysis of the phase 3 PERSEUS trial (NCT03710603).

Data presented during the 2024 International Myeloma Society Annual Meeting demonstrated that the median PFS was not evaluable (NE) across all major subgroups who received D-VRd in the intent-to-treat population. Specifically, those with revised standard risk were brought to attention, experiencing a 71% reduction in the risk of disease progression or death with D-VRd vs VRd (HR, 0.29; 95% CI, 0.15-0.56; P = .0001). Of note, PFS was favored with D-VRd followed by daratumumab/lenalidomide maintenance.

“The PERSEUS regimen demonstrates improved MRD negativity and PFS outcomes in patients with high-risk cytogenetics, including gain (1q21) and with 2 or more high-risk cytogenetic abnormalities,” Meletios A. Dimopoulos, MD, professor and chairman of the Department of Clinical Therapeutics at the National and Kapodistrian University of Athens School of Medicine, in Greece, said during the presentation.

Overall, 709 patients were randomly assigned 1:1 to the VRd (n = 354) or D-VRd (n = 355) arms. During induction, bortezomib was given at 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11; plus, lenalidomide at 25 mg orally on days 1 to 21; dexamethasone at 40 mg orally or intravenously on days 1 to 4 and 9 to 12; and daratumumab at 1800 mg subcutaneously every week during cycles 1 to 2 and every 2 weeks during cycles 3 to 4. Patients then went to single transplant and received consolidation therapy with matched dosing.

During maintenance, the VRd group was given lenalidomide at 10 mg orally on days 1 to 28 until disease progression. The D-VRd group was given daratumumab at 1800 mg subcutaneously every 4 weeks plus lenalidomide at 10 mg orally on days 1 to 28. If patients were MRD-positive, they continued to D-R until progression. If patients were MRD-negative, they stopped daratumumab and continued lenalidomide. Daratumumab was restarted when there was a confirmed loss of complete response (CR) without progressive disease or recurrence of MRD.

The primary end point was PFS. Secondary end points included overall CR or better rate, overall MRD-negativity rate, and overall survival.

R2-International Staging System (ISS) disease states were assessed. Between both arms, among patients with low (HR, 0.42; 95% CI, 0.16-1.11), low-intermediate (HR, 0.29; 95% CI, 0.14-0.57), intermediate-high (HR, 0.46; 95% CI, 0.29-0.75), and high disease stage (HR, 0.63; 95% CI, 0.25-1.61), the median PFS was NE in both the D-VRd vs the VRd arms, but the hazard ratios favored D-VRd.

Dimopoulos noted that when daratumumab was added, the PFS was extended despite R2-ISS disease stage, and there was a more pronounced benefit for those with stage II and III disease.

The analysis then went through various subgroups based on MRD negativity at 10-5, with outcomes generally favoring D-VRd followed by D-R. MRD negativity at 10-5 with a CR or better in the D-VRd and VRd arms, respectively, was highlighted in patients with standard-risk (77.3% vs 48.1%; OR, 3.67; 95% CI, 2.52-5.33), high-risk (68.4% vs 47.4%; OR, 2.40; 95% CI, 1.24-4.63), revised standard-risk (75.3% vs 47.3%; OR, 3.39; 2.14-5.37), and revised high-risk disease (73.1% vs 49.3%; OR, 2.79; 95% CI, 1.68-4.62).

The subgroup analysis also looked at sustained MRD negativity at 10-5for 12 months, which evaluated patients with standard-risk (69.3% vs 31.2%; OR, 4.98; 95% CI, 3.45-7.20), high-risk (48.7% vs 25.6%; OR, 2.75; 95% CI, 1.40-5.42), revised standard-risk (66.1% vs 31.7%; OR, 4.19; 95% CI, 2.67-6.59), and revised high-risk disease (59.2% vs 27.7%; OR, 3.79; 95% CI, 2.30-6.26). These were evaluated in the D-VRd and VRd arms, respectively.

The rate of MRD negativity at 10-6 with CR or better was evaluated across different cytogenetic risk statuses. Between both arms, analysis was conducted for standard-risk (67.0% vs 33.1%; OR, 4.12; 95% CI, 2.87-5.91), high-risk (57.9% vs 30.8%; OR, 3.09; 95% CI, 1.60-6.00), revised standard-risk (66.1% vs 33.5%; OR, 3.86; 95% CI, 2.47-6.05), and revised high-risk disease (63.1% vs 32.4%; OR, 3.56; 95% CI, 2.17-5.84).

Investigators assessed rates of CR or better and MRD negativity at 10-5 for patietnts with R2-ISS low (79.3% vs 48.7%; OR, 4.11; 95% CI, 2.30-7.35), low-intermediate (75.7% vs 46.2%; OR, 3.62; 95% CI, 2.03-6.45), intermediate-high (73.1% vs 47.8%; OR, 2.97; 95% CI,1.70-5.21), and high disease (60.0% vs 47.4%; OR, 1.67; 95% CI, 0.47-5.93).

Similarly, results were assessed with R2-ISS for sustained MRD negativity at 10-5 for 12 months or more in the D-VRd and VRd arms, respectively. Stages evaluated were low (70.7% vs 33.3%; OR, 4.82; 95% CI, 2.76-8.43), low-intermediate (68.5% vs 25.5%; OR, 6.35; 95% CI, 3.51-11.49), intermediate-high (58.3% vs 31.3%; OR, 3.07; 95% CI, 1.77-5.32), and high (45.0% vs 21.1%; OR, 3.07; 95% CI, 0.75-12.59).

Analysis for MRD negativity at 10-6 with CR or better between the D-VRd and VRd arms included patients with R2-ISS low (67.2% vs 32.5%; OR, 4.27; 95% CI, 2.46-7.41), low-intermediate (68.5% vs 29.2%; OR, 5.25; 95% CI, 2.94-9.38), intermediate-high (60.2% vs 34.8%; 95% CI, 2.83; 95% CI, 1.65-1.88), and high disease (60.0% vs 31.6%; OR, 3.25; 95% CI, 0.87-12.14).

For those with sustained MRD negativity at 10-6 for 12 or more months, the analysis rates included RS-ISS low (50.0% vs 21.1%; OR, 3.75; 95% CI, 2.10-6.69), low-intermediate (50.5% vs 17.0%; OR, 4.98; 95% CI, 2.65-9.34), intermediate-high (43.5% vs 19.1%; OR, 3.26; 95% CI, 1.79-5.94), and high disease (35.0% vs 10.5%; 95% CI, 4.58; 95% CI, 0.81-25.80).

Reference

Dimopoulos MA, Sonneveld P, Rodriguez-Otero P, et al. Daratumumab (DARA)/bortezomib/lenalidomide/ dexamethasone (D-VRd) with D-R maintenance (maint) in transplant-eligible (TE) newly diagnosed myeloma (NDMM): PERSEUS cytogenetic risk analysis. Presented at the 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio De Janeiro, Brazil. Abstract OA-48.