Daratumumab Regimen Yields Durable MRD-Negativity in Newly Diagnosed Multiple Myeloma

CASSIOPEIA trial

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Follow-up data from the phase 3 CASSIOPEIA trial (NCT02541383) revealed that durable minimal residual disease (MRD) negativity occurred when patients with newly diagnosed multiple myeloma received induction/consolidation therapy with daratumumab (Darzalex) plus bortezomib (Velcade), thalidomide (Thalomid), and dexamethasone (D-VTd) followed by daratumumab maintenance vs VTd plus observation as maintenance.¹

Findings from the 21st IMS Annual Meeting showed that D-VTd (n = 543) was associated with improved overall MRD-negativity rates (10^-5) at 34.6% vs 23.1% with VTd (n = 542) in the post-induction phase (OR, 1.76; P <.0001) and 63.7% vs 43.7%, respectively, in the post-consolidation phase (OR, 2.26; P <.0001). The rates for VTd were 23.1% and 43.7%, respectively.

Additionally, MRD sample compliance rates with the daratumumab regimen were greater than 90% in the induction/consolidation phase, approximately 80% during the maintenance phase, and was about 60% during the follow-up phase. There was a strong positive correlation between multiparameter flow cytometry and next-generation sequencing in the intention-to-treat (ITT) population, noted lead study author Jill Corre, PharmD, PhD, in a presentation during the meeting.

“Daratumumab-based induction/consolidation and maintenance resulted in the deepest and most durable MRD negativity, leading to superior progression-free survival [PFS] outcomes, including in patients with high-risk cytogenetic abnormalities,” said Corre, of the Centre Hospitalier Universitaire de Toulouse in Toulouse, France.

In the open-label, 2-arm, multicenter CASSIOPEIA trial, patients with newly diagnosed multiple myeloma were randomized to receive either D-VTd or VTd in the induction and consolidation phases. Patients who achieved a partial response or better were then randomized again to receive daratumumab monotherapy or be observed during the maintenance phase. MRD was assessed at post-induction, post-consolidation, and at 6, 12, and 24 months in the maintenance phase. In the follow-up phase, MRD is also being assessed at 1, 2, and 3 years. Corre noted that more patients who were randomized to D-VTd underwent second randomization to maintenance vs VTd at 84.3% vs 79.0%, respectively.

To be eligible for enrollment, patients had to have previously untreated multiple myeloma eligible for high-dose chemotherapy and autologous stem cell transplantation, and have an ECOG performance status of 0 to 2.² Those with primary amyloidosis, plasma cell leukemia, or smoldering multiple myeloma were excluded from the study.

The coprimary end points were stringent complete response after consolidation therapy and PFS after maintenance therapy. Secondary end points included PFS, time to progression, and overall survival.

Prior CASSIOPEIA results established D-VTd as standard of care for patients with transplant-eligible newly diagnosed multiple myeloma.³ At the 2024 European Hematology Congress, data showed that the median PFS was not reached (NR) with the addition of maintenance daratumumab vs 72.1 months with observation (HR, 0.76; 95% CI, 0.58-1.00; P = .0480). The 6-year PFS rates were 60.3% vs 50.5%, respectively.⁴

At the IMS meeting, Corre reported on the MRD negativity depth and durability at an 80.1-month median follow-up.

Additional findings showed that patients who achieved MRD negativity post induction did have improved PFS outcomes. The 72-month PFS rate in those who were MRD negative was 67.2% vs 35.0% who were MRD positive; the median PFS were not reached and 50.0 months, respectively (HR, 0.40; P <.0001).

When examined further in the induction/consolidation phases, those who were MRD negative and received D-VTd as induction/consolidation had a median PFS that was NR vs 77.0 months in those who received VTd and were MRD negative (HR, 0.40; P <.0001). Those on D-TVd who were MRD positive had a median PFS of 54.1 months vs 45.3 months of those who received VTd and were MRD positive (HR, 0.74; P = .0018). The 72-month PFS rates were 76.9%, 52.9%, 39.7%, and 30.8%, respectively.

In the maintenance and follow-up phases, investigators analyzed the overall MRD-negativity rates between 10^-5 and 10^-6. In the D-VTd/daratumumab arm of the maintenance population (n = 229), the MRD 10^-6 rate was 60.7% compared with 52.0% with D-VTd/observation (n = 229; OR, 1.55; P = .0365). In the VTD/daratumumab maintenance (n = 213) and VTd/observation arms (n = 215), the MRD 10^-6 rates were 48.4% and 30.7%, respectively (OR, 2.41; P <.0001), demonstrating that daratumumab maintenance increased MRD-negativity rates and the depth of MRD negativity, irrespective of induction or consolidation treatment choice.

In the landmark PFS analysis from second randomization by post-consolidation MRD status in the maintenance population, the median PFS in those with daratumumab maintenance and were MRD negative was NR and was 66.2 months in those who were MRD positive. In those who received observation as maintenance, the median PFS was 78.1 months and 36.6 months in those who were MRD negative and positive, respectively. The 72-month PFS rates were 72.1%, 52.0%, 47.3%, and 26.2%, respectively. The HR in the MRD-negative groups was 0.54 favoring daratumumab (P = .0007) vs 0.48 in the MRD-positive groups (P <.0001).

Maintenance daratumumab also led to consistently higher MRD-negativity rates within each induction/consolidation group across the 6-month, 1-year, and 2-year time points, Corre noted. This also included sustained MRD-negativity rates compared with observation, which also comprised 3-year sustained MRD negativity, within the induction/consolidation groups.

Daratumumab improved PFS and rates of MRD negativity regardless of cytogenetic risk status. In the ITT population for patients with standard-risk disease, D-VTd had an MRD-negativity rate (10-5) of 66.1% vs 45.8% in patients who received VTd (OR, 2.30; P <.0001). For patients with high-risk disease, the MRD-negativity rate was 62.2% in patients who received D-VTd and 47.7% in the VTd group (OR, 1.81; P = .0595).

This was similar in the maintenance population; the MRD (10-6) rates were 52.0% and 42.0% with daratumumab and observation, respectively, in those with standard-risk disease (OR, 1.49; P = .0060). For those with high-risk disease, the rates were 73.7% and 40.0%, respectively (OR, 4.20; P = .0002).

Disclosures: Corre disclosed advisory board roles with Sanofi and Bristol Myers Squibb; consulting roles with Janssen, Sanofi, Bristol Myers Squibb, Pfizer, and Adaptive; research support from Sanofi and Bristol Myers Squibb; and travel support from Janssen, Sanofi, Bristol Myers Squibb, and Pfizer.

References

1. Corre J, Vincent L, Moreau P, et al. Daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) and DARA maintenance in transplant-eligible newly diagnosed multiple myeloma (NDMM): CASSIOPEIA minimal residual disease (MRD) update. Presented at: 21st International Myeloma Society Annual Meeting & Exposition; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA-47.
2. A study to evaluate daratumumab in transplant eligible participants with previously untreated multiple myeloma (CASSIOPEIA). ClinicalTrials.gov. Updated December 7, 2020. Accessed September 25, 2024. https://tinyurl.com/eehdjs45
3. Moreau P, Hulin C, Perrot A, et al. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): an open-label, randomised, phase 3 trial. Lancet Oncol. 2021;22(10):1378-1390. doi:10.1016/S1470-2045(21)00428-9
4. Moreau P, Hulin C, Perrot A. Daratumumab (dara) + bortezomib/thalidomide/dexamethasone (D-VTd) followed by dara maintenance in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): >6-year update of CASSIOPEIA. Presented at: 2024 European Hematology Association Congress; June 14-17, 2024; Madrid, Spain. Abstract S204.