Final results from the PLEIADES and EQUULEUS trials: Daratumumab, carfilzomib, and dexamethasone in RRMM

Daratumumab, carfilzomib, and dexamethasone (D-Kd) is an approved standard combination regimen for the treatment of adult patients with relapsed/refractory multiple myeloma (RRMM).¹ Positive results from the phase III CANDOR trial (NCT03158688) led to the U.S. Food and Drug Administration (FDA) approval of D-Kd with intravenous (IV) daratumumab plus twice weekly carfilzomib (56 mg/m²) following one to three prior lines of therapies.^1,2 The updated efficacy and safety data were reported on the Multiple Myeloma Hub here.

When carfilzomib (70 mg/m²) is administered once weekly, it offers a more convenient regimen for patients with RRMM, exhibiting promising responses with both subcutaneous (SC) and IV daratumumab in the initial analyses of the phase II PLEIADES (NCT03412565) and phase Ib EQUULEUS (NCT01998971) trials, respectively. These preliminary data resulted in the U.S. FDA approval of once weekly carfilzomib with both SC and IV daratumumab. Herein, we report the final analysis of both trials published by Moreau et al.¹ in the Blood Cancer Journal.

Results from the PLEIADES and EQUULEUS trials¹

Overall, D-Kd was administered to 66 patients in the PLEIADES trial following one prior line of lenalidomide-based therapy and to 85 patients in EQUULEUS after one to three previous lines of therapy. The median prior lines of therapy were one and two for PLEIADES and EQUULEUS, respectively; baseline characteristics for the two studies are summarized in Table 1.

Table 1. Selected baseline characteristics for the PLEIADES and EQUULEUS trials*

Updated efficacy

PLEIADES

The following results were observed at the median follow-up of 12.4 months in the PLEIADES trial:

• The overall response rate (ORR) was 84.8% in the total cohort and 84.1% in the lenalidomide-refractory cohort.

• The ORR was 75% and 82.1% in the high-risk versus standard-risk cytogenetic cohorts, respectively.
• Median duration of response (DoR) was not reached; the 9-month DoR was 85.4%
• Progression-free survival (PFS) and overall survival (OS) were not assessed.

EQUULEUS

In the EQUULEUS trial, at the median follow-up of 23.7 months, the median DoR was 27.5 months, with a 9-month DoR of 88.3%, and median OS was not reached, with a 24-month OS of 71.2%. The following was observed for the overall population versus lenalidomide-refractory cohorts:

• The ORR was 81.2% vs 74.5%, respectively.

• The median PFS was 25.7 months vs 22.3 months, respectively.
• The 24-month PFS was 52.7% vs 46.9%, respectively.

Updated safety results in PLEIADES and EQUULEUS

Any grade treatment-emergent adverse events (TEAEs) occurred in all patients within the PLEIADES and EQUULEUS trials, with Grade 3–4 TEAEs reported in 74.2% and 78.8% of patients in PLEIADES and EQUULEUS, respectively. The most common any grade and Grade 3–4 hematologic and nonhematologic TEAEs in both trials are reported in Table 2.

Table 2. Any grade (≥25%) and Grade 3–4 (≥5%) TEAEs in the PLEIADES and EQUULEUS trials*

Additional adverse events reported in the PLEIADES and EQUULEUS trials are shown in Table 3.

Table 3. Specific TEAEs in the PLEIADES and EQUULEUS trials*

Recommended dosing regimens of D-Kd in adult patients with RRMM^1,3,4

The recommended dosage regimens for IV or SC daratumumab, the two-dosing (50 mg/m² twice weekly or 70 mg/m² once weekly) carfilzomib schema, and dexamethasone when administered in combination are presented in Figure 1.

Figure 1. Dosing schedule for the D-Kd regimen in RRMM* 

IV, intravenous; Q2W, every two weeks; Q4W, every four weeks; QW, weekly; SC, subcutaneous.
*Data from Moreau, et al.¹ and U.S. Food and Drug Administration.^3,4
†Based on 28-day cycles.

Conclusion

In the longer follow-up analyses of PLEIADES and EQUULEUS, D-Kd regimens were efficacious and well-tolerated in patients with RRMM both in the all-treated and lenalidomide-refractory cohorts. Despite the small sample sizes, these final data further support the use of D-Kd as a standard treatment regimen in RRMM.