D-VRd Plus Daratumumab/Lenalidomide Maintenance Yields Favorable PFS Outcomes in High-Risk Myeloma

D-VRd With D-R Maintenance in
Myeloma | Image Credit:© LASZLO -
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D-VRd (daratumumab [Darzalex], bortezomib [Velcade], lenalidomide [Revlimid], and dexamethasone) followed by daratumumab/lenalidomide maintenance generated progression-free survival (PFS) and minimal residual disease (MRD) negativity benefits vs VRd followed by single-agent lenalidomide maintenance in patients with transplant-eligible newly diagnosed multiple myeloma regardless of the presence of high-risk cytogenetic abnormalities, according to findings from an expanded analysis of the phase 3 PERSEUS trial (NCT03710603).1

Findings presented at the 51st Annual EBMT Meeting showed that the PFS outcomes favored the D-VRd arm (n = 355; D-VRd followed by daratumumab/lenalidomide maintenance) over the VRd arm (n = 354; VRd followed by lenalidomide maintenance) across all cytogenetic risk subgroups in the intention-to-treat (ITT) population (n = 709). Across all subgroups, the median PFS was not evaluable (NE) with D-VRd. The median PFS in the VRd arm and the HRs for PFS in each subgroup were as follows (Table 1):

Table 1. Median PFS Across Cytogenetic Risk Subgroups in the ITT Population

The PFS curves based on revised cytogenetic risk criteria in the ITT population showed that patients with revised standard-risk disease who received D-VRd had the highest PFS rate approaching 54 months of follow-up, closely followed by those with revised standard-risk disease in the VRd arm, those with revised high-risk disease in the D-VRd arm, and those with revised high-risk disease in the VRd arm.

“This is the highest advantage that we ever saw [with] new treatments [in patients with newly diagnosed multiple myeloma with high-risk cytogenetics],” Mario Boccadoro, MD, emphasized in the presentation. “It almost abrogated the high-risk, negative features of these patients.”

Boccadoro is a full professor and chief of the Division of Hematology at the Azienda Ospedaliero-Universitaria Città della Salute e della Scienza di Torino in Italy.

Furthermore, daratumumab improved outcomes in patients with gain(1q21) or amp(1q21). The PFS curves based on gain(1q21) or amp(1q21) status showed that patients lacking both abnormalities in the D-VRd arm had the highest PFS rate approaching 54 months of follow-up, closely followed by those lacking both abnormalities in the VRd arm, those with either abnormality irrespective of the presence of other HCRAs in the D-VRd arm, and those with either abnormality irrespective of the presence of other HCRAs in the VRd arm.

Recapping the PERSEUS Trial Design

PERSEUS enrolled patients with transplant-eligible newly diagnosed multiple myeloma between 18 and 70 years of age and an ECOG performance status of 2 or lower.1,2 Patients were randomly assigned 1:1 to receive D-VRd or VRd for 4 28-day cycles in the induction phase. Daratumumab was administered at 1800 mg weekly for cycles 1 and 2 and every 2 weeks for cycles 3 and 4. Bortezomib was given at 1.3 mg/m2 on days 1, 4, 8, and 11. Lenalidomide was administered at 25 mg on days 1 through 21. Dexamethasone was given at 40 mg on days 1 through 4 and 9 through 12.

Following a single transplant, patients continued treatment in their respective arms for two 28-day cycles in the consolidation phase. VRd was administered at the induction phase dose. Daratumumab was administered at 1800 mg every 2 weeks.

During the maintenance phase, which consisted of 28-day cycles, patients in the VRd arm received lenalidomide at 10 mg daily until progressive disease (PD). Patients in the D-VRd arm received daratumumab at 1800 mg every 4 weeks plus lenalidomide at 10 mg daily for at least 2 years. After a minimum of 2 years of daratumumab/lenalidomide maintenance, patients with MRD-positive disease (including those with NE or indeterminate MRD results) continued daratumumab/lenalidomide until PD. Those with MRD-negative disease (defined as a complete response [CR] or better and 12 months of sustained MRD negativity at a sensitivity of 10–5) stopped daratumumab and continued lenalidomide; these patients were permitted to restart daratumumab upon confirmed loss of CR without PD or recurrence of MRD.

PFS served as the trial’s primary end point. Key secondary end points included overall rate of CR or better, overall rate of MRD negativity, and OS.

Cytogenetic risk was centrally assessed by fluorescence in situ hybridization.

Looking Back at the Primary PERSEUS Readout

In the primary analysis of PERSEUS, at a median follow-up of 47.5 months (range, 0-54.4), treatment with D-VRd followed by daratumumab/lenalidomide maintenance resulted in a significant PFS improvement vs VRd followed by lenalidomide maintenance across the ITT population of patients with transplant-eligible newly diagnosed multiple myeloma.2 The estimated 48-month PFS rate was 84.3% (95% CI, 79.5%-88.1%) in the D-VRd arm vs 67.7% (95% CI, 62.2%-72.6%) in the VRd arm (HR, 0.42; 95% CI, 0.30-0.59; P < .001). The rates of sustained MRD negativity at sensitivities of 10–5 and 10–6 were also significantly higher in the D-VRd arm vs the VRd arm.

Delineating Additional Efficacy Data Per Subgroup

Boccadoro noted that the patient demographics and baseline characteristics were well balanced between the 2 arms.1

MRD Negativity Rates at 10–5 Sensitivity

A subgroup analysis of rates of MRD negativity at a sensitivity of 10–5 with a CR or better favored the D-VRd arm across all cytogenetic risk subgroups. The rates of MRD negativity (10–5) with a CR or better in the D-VRd and VRd arms, respectively, were:

• 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 (95% CI, 2.14-5.37)
• Revised high risk: 73.1% vs 49.3%; OR, 2.79 (95% CI, 1.68-4.62)
• Gain(1q21): 69.5% vs 46.5%; OR, 2.62 (95% CI, 1.27-5.41)
• Amp(1q21): 85.7% vs 55.6%; OR, 4.80 (95% CI, 1.38-16.69)
• Gain(1q21) or amp(1q21): 74.7% vs 49.5%; OR, 3.01 (95% CI, 1.63-5.56)
• Isolated gain(1q21): 73.0% vs 48.9%; OR, 2.82 (95% CI, 1.12-7.10)
• Isolated amp(1q21): 94.1% vs 56.5%; OR, 12.31 (95% CI, 1.39-109.10)
• 1 revised HCRA: 75.3% vs 50.0%; OR, 3.04 (95% CI, 1.68-5.51)
• At least 2 revised HCRAs: 66.7% vs 47.4%; OR, 2.22 (95% CI, 0.85-5.83)

Sustained MRD negativity rates at a sensitivity of 10–5 (defined as those lasting at least 12 months) also favored the D-VRd arm across all subgroups:

• Standard risk: D-VRd arm, 69.3% vs VRd arm, 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)
• Revised high risk: 59.2% vs 27.7%; OR, 3.79 (95% CI, 2.30-6.26)
• Gain(1q21): 62.7% vs 29.6%; OR, 4.00 (95% CI, 1.92-8.34)
• Amp(1q21): 71.4% vs 27.8%; OR, 6.50 (95% CI, 2.17-19.48)
• Gain(1q21) or amp(1q21): 65.5% vs 29.0%; OR, 4.66 (95% CI, 2.54-8.56)
• Isolated gain(1q21): 67.6% vs 31.9%; OR, 4.44 (95% CI, 1.77-11.17)
• Isolated amp(1q21): 88.2% vs 26.1%; OR, 21.25 (95% CI, 3.71-121.61)
• 1 revised HCRA: 61.9% vs 28.2%; OR, 4.13 (95% CI, 2.31-7.41)
• At least 2 revised HCRAs: 51.5% vs 26.3%; OR, 2.97 (95% CI, 1.10-8.04)

MRD Negativity Rates at 10–6 Sensitivity

A subgroup analysis of rates of MRD negativity at a sensitivity of 10–6 with a CR or better also favored the D-VRd arm across all cytogenetic risk subgroups:

• Standard risk: D-VRd arm, 67.0% vs VRd arm, 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)
• Revised high risk: 63.1% vs 32.4%; OR, 3.56 (95% CI, 2.17-5.84)
• Gain(1q21): 61.0% vs 31.0%; OR, 3.49 (95% CI, 1.69-7.20)
• Amp(1q21): 75.0% vs 41.7%; OR, 4.20 (95% CI, 1.42-12.39)
• Gain(1q21) or amp(1q21): 65.5% vs 34.6%; OR, 3.59 (95% CI, 1.98-6.52)
• Isolated gain(1q21): 64.9% vs 31.9%; OR, 3.94 (95% CI, 1.58-9.80)
• Isolated amp(1q21): 82.4% vs 39.1%; OR, 7.26 (95% CI, 1.62-32.60)
• 1 revised HCRA: 64.9% vs 31.8%; OR, 3.97 (95% CI, 2.23-7.08)
• At least 2 revised HCRAs: 57.5% vs 34.2%; OR, 2.61 (95% CI, 1.00-6.83)

Sustained MRD negativity rates at a sensitivity of 10–6 (defined as those lasting at least 12 months) also favored the D-VRd arm across all subgroups:

• Standard risk: D-VRd arm, 51.9% vs VRd arm, 20.3%; OR, 4.24 (95% CI, 2.88-6.22)
• High risk: 30.3% vs 14.1%; OR, 2.64 (95% CI, 1.18-5.90)
• Revised standard risk: 50.0% vs 21.0%; OR, 3.77 (95% CI, 2.34-6.07)
• Revised high risk: 42.3% vs 15.5%; OR, 3.99 (95% CI, 2.27-7.01)
• Gain(1q21): 42.4% vs 15.5%; OR, 4.01 (95% CI, 1.76-9.15)
• Amp(1q21): 60.7% vs 16.7%; OR, 7.73 (95% CI, 2.42-24.63)
• Gain(1q21) or amp(1q21): 48.3% vs 15.9%; OR, 4.94 (95% CI, 2.53-9.63)
• Isolated gain(1q21): 51.4% vs 19.1%; OR, 4.46 (95% CI, 1.69-11.77)
• Isolated amp(1q21): 76.5% vs 13.0%; OR, 21.67 (95% CI, 4.15-113.02)
• 1 revised HCRA: 46.4% vs 16.4%; OR, 4.42 (95% CI, 2.32-8.42)
• At least 2 revised HCRAs: 30.3% vs 13.2%; OR, 2.87 (95% CI, 0.87-9.51)

Diving Into the Future

“These results support the use of D-VRd induction/consolidation followed by daratumumab/lenalidomide maintenance as a new standard of care for transplant-eligible patients with newly diagnosed myeloma, regardless of cytogenetic risk status,” Boccadoro concluded.

Disclosures: Boccadoro reported serving as a consultant for Amgen, BeiGene, Bristol Myers Squibb, Ceigene Corporation, GSK, Janssen, Menarini Silicon Biosystems, Regeneron Pharmaceuticals, Sanofi, and Takeda.

References

1. Moreau P, Dimopoulos MA, Sonneveld P, et al. (DARA)/bortezomib/lenalidomide/dexamethasone (D-VRd) with D-R maintenance (maint) in transplant-eligible (TE) newly diagnosed myeloma (NDMM): analysis of PERSEUS based on cytogenetic risk. Presented at: EBMT 51st Annual Meeting; March 30-April 2, 2025. Florence, Italy. Abstract OS14-01.
2. Sonneveld P, Dimopoulos MA, Boccadoro M, et al. Daratumumab, bortezomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2024;390(4):301-313. doi:10.1056/NEJMoa2312054