PERSEUS: Primary efficacy and safety results

Bortezomib, lenalidomide, and dexamethasone (VRd) induction followed by autologous stem cell transplantation, VRd consolidation, and lenalidomide maintenance is currently considered the standard of care for patients with transplant-eligible newly diagnosed multiple myeloma (NDMM). However, new treatment directions are needed to further increase the depth of response and long-term disease control.

Daratumumab, a CD38 monoclonal antibody, is currently approved for use in several treatment regimens aimed at both transplant-eligible and non-transplant-eligible NDMM. Recently, the phase II GRIFFIN study (NCT02874742) investigated the addition of daratumumab to VRd induction and consolidation with lenalidomide maintenance for transplant-eligible NDMM. Results showed a greater depth of response and longer progression-free survival (PFS) compared with VRd and lenalidomide alone.

The randomized phase III PERSEUS trial (NCT03710603) subsequently investigated daratumumab in combination with VRd and lenalidomide compared with VRd and lenalidomide alone in patients with transplant-eligible NDMM. The primary results of the study were recently presented at the 65th American Society of Hematology (ASH) Annual Meeting and Exposition by Sonneveld. We summarize the key points below.

Study design¹

• Open label, multicenter, randomized trial
• Across 14 countries and 115 sites
• January 19, 2019 to January 3, 2020
• Patient eligibility criteria:
  • Age 18–70 years
  • Confirmed diagnosis of NDMM
  • Eligible for high-dose therapy and autologous stem cell transplantation
  • Eastern Cooperative Oncology Group performance-scale score 0–2

• The full study design is shown in Figure 1

d, dexamethasone; DARA, daratumumab; D-VRd, daratumumab + bortezomib + lenalidomide + dexamethasone; MRD, measurable residual disease; PD, progressive disease; PO, oral; R, lenalidomide; SC, subcutaneous; V, bortezomib; VRd, bortezomib + lenalidomide + dexamethasone.
*Adapted from Sonneveld.¹

• The primary study endpoint was PFS
• The key secondary study endpoints were complete response (CR) or better, overall survival, and negative measurable residual disease (MRD) with CR or better

Results¹

• In total, 709 patients were enrolled and randomized 1:1.
  • There were 355 patients in the daratumumab + VRd (D-VRd) group
  • The VRd group included 354 patients
• Patient characteristics at baseline were balanced between the two treatment groups (Table 1).
• Overall, 89.7% of patients treated with D-VRd underwent transplantation compared with 87% of patients treated with VRd.

Table 1. Baseline patient characteristics*

CRAB, calcium renal anemia bone; D-VRd, daratumumab + bortezomib + lenalidomide + dexamethasone; ECOG PS, European Cooperative Oncology Group performance scale; ISS, International Staging System; MM, multiple myeloma; VRd, bortezomib + lenalidomide + dexamethasone. *Adapted from Sonneveld.1
Characteristic, % (unless otherwise stated)	D-VRd (n = 355)	VRd (n = 354)
Median age, years	61.0	59.0
Male	59.4	57.9
ECOG PS score
0	62.3	65.0
1	32.1	30.5
2	5.4	4.5
3	0.3	0
ISS stage
I	52.4	50.4
II	32.1	35.4
III	15.5	14.2
Cytogenetic profile
Standard risk	74.4	75.1
Intermediate risk	4.2	2.8
High risk	21.4	22.0
MM diagnosis
CRAB criteria only	35.3	32.1
Biomarkers of malignancy only	14.7	18.5
CRAB criteria and biomarkers of               malignancy	50.0	49.4

Efficacy

• The median follow-up was 47.5 months
• Both PFS and achieving a CR or better were significantly higher in patients treated with D-VRd vs VRd (Figure 2)

CR, complete response; D-VRd, daratumumab + bortezomib + lenalidomide + dexamethasone; PFS, progression-free survival; VRd, bortezomib + lenalidomide + dexamethasone.
*Adapted from Sonneveld.¹

• Patients treated with D-VRd experienced a 58% reduction in the risk of progression/death compared with patients treated with VRd (hazard ratio, 0.42).
• The rates of overall negative MRD at a sensitivity of 10⁻⁵, 10⁻⁶, and sustained negative MRD at 12 months are shown in Figure 3.
• In total, 64% of patients discontinued daratumumab maintenance after achieving sustained negative MRD.

D-VRd, daratumumab + bortezomib + lenalidomide + dexamethasone; MRD, measurable residual disease; VRd, bortezomib + lenalidomide + dexamethasone.
*Adapted from Sonneveld.¹

 Safety

• The most common Grade 3–4 adverse events (AEs) experienced by ≥10% of patients in either treatment group are shown in Figure 4.
• Overall, 9.1% of patients in the D-VRd group experienced an adverse event that led to treatment discontinuation vs 22.5% of patients in the VRd group

AE, adverse event; D-VRd, daratumumab + bortezomib + lenalidomide + dexamethasone; VRd, bortezomib + lenalidomide + dexamethasone.
*Adapted from Sonneveld.¹

 Conclusion

These results, in combination with those of the GRIFFIN and CASSIOPEIA (NCT02541383) trials highlight a significant and meaningful clinical benefit in depth of response, PFS, and MRD negativity with D-VRd together with daratumumab and lenalidomide maintenance. The risk-benefit profile was also favorable. Together, these results demonstrate the potential of this regimen as a standard-of-care treatment for transplant-eligible patients with NDMM.