Daratumumab Plus VTd Enhances MRD-Negativity Rates in Transplant-Eligible Myeloma

Herve Avet Loiseau, MD, PhD

Minimal residual disease–negativity rates were significantly higher after utilizing daratumumab plus bortezomib, thalidomide, and dexamethasone (VTd) vs VTd alone in patients with newly diagnosed, transplant-eligible multiple myeloma, according to findings from the phase 3 CASSIOPEIA study that were presented at the 2021 ASH Annual Meeting and Exposition.

Investigators also emphasized that daratumumab maintenance resulted in more robust and durable MRD negativity. Rates of complete response (CR) or greater plus MRD-negativity were higher among patients in the D-VTd arm vs VTd alone arm, respectively, both in terms of post-induction treatment (9.2% vs 5.4%) (odds ratio [OR], 1.79; P = .0150) and consolidation therapy across all subgroups (33.7% vs 19.9%; OR, 2.06; P<.0001). Further, sustained CR of greater plus MRD-negativity rates at 1-year were also higher among patients in the D-VTd arm (50.1%) compared with patients in the VTd alone arm (30.1%; OR, 2.37; P <.0001) At 2 years, the sustained CR or greater plus MRD-negativity rates continued to favor patients in the D-VTd arm (35.5% vs 18.8%; OR, 2.41; P <.0001).

“Longer follow-up is needed to adequately assess the progression-free survival and overall survival benefit of sustained MRD negativity for daratumumab vs observation after D-VTd induction/consolidation,” study presenter, Herve Avet Loiseau, MD, PhD, head of the Laboratory for Genomics in Myeloma at the University Hospital Center of Toulouse, France, said in a presentation on the data.

Key eligibility criteria for both parts 1 and 2 of CASSIOPEIA require that patients be transplant eligible with newly diagnosed disease. Patients also needed to be between the ages of 18 to 65 years with an ECOG performance status ranging from 0 to 2.

A total of 1085 patients were first randomized in part 1 of the study for 4 cycles of pre-transplant induction therapy followed by 2 cycles of post-transplant consolidation therapy in either the D-VTD arm (n = 543) or the VTd alone arm (n = 542). A total of 886 patients who achieved a partial response or better were then randomized a second time in part 2 for post-transplant daratumumab maintenance therapy (n = 442) or observation (n = 444).

Induction/consolidation therapy featured intravenous daratumumab at 16 mg/kg weekly during cycles 1 and 2 with or without bortezomib at 1.3 mg/m2 on days 1, 4, 8, and 11; thalidomide daily at 100 mg; and intravenous dexamethasone at 20 to 40 mg. Maintenance daratumumab was given intravenously at 16 mg/kg weekly at a reduced intensity.

In part 1 of CASSIOPEIA, D-VTd induction therapy prolonged progression-free survival (PFS) and improved depth of response for patients, which included increased rates of stringent complete response (sCR), complete response (CR) or better, and MRD-negativity. In part 2, daratumumab maintenance therapy improved PFS and increased rates of CR or better and MRD-negativity, but only for patients who received VTd induction.

For patients at risk of progression 1 and 2 years after induction, improved PFS was observed among those who achieved 1- (HR, 0.20; P < .0001) or 2-years (HR, 0.08; P < .0001) sustained MRD-negativity over patients who did not achieve MRD-negativity.

Moreover, patients in the D-VTd arm who achieved 1- (HR, 0.20; P = .0001) or 2-years (HR, 0.08; P <.0001) of sustained MRD-negativity saw improvements in PFS vs those who did not regardless of treatment. Additionally, at-risk patients treated with D-VTd who had sustained MRD negativity for 1 to 2 years following post-induction treatment also had improved PFS vs those in the same arm who did not (1-year: HR, 0.20; P <.0001; 2-years: HR, 0.04; P <.0001).

In part 2, daratumumab maintenance therapy (58.6%) significantly improved the MRD-negativity rate over observation (47.1%; OR, 1.80; P = .0001). For patients in the D-VTd arm who received daratumumab maintenance, the rates of MRD-negativity were 64.2% vs 57.6% with observation (OR, 1.43; P = .1037). Conversely, VTd induction and consolidation yielded significantly higher rates of MRD negativity following daratumumab maintenance compared with observation (52.6% vs 35.8%; OR, 2.26; P = .0002).

Although the 1- or 2-year sustained MRD-negativity rates were not statistically significantly different between daratumumab and observation for patients in the D-VTd induction/consolidation arm. Moreover, the 1-year sustained MRD-negativity rate was significantly higher for daratumumab maintenance (35.7%) compared with observation (21.4%) among patients in the VTd alone induction/consolidation arm (OR, 2.22; P = .0006).

Reference

1. Loiseau HA, Sonneveld P, Moreau P, et al. Daratumumab (DARA) with bortezomib, thalidomide, and dexamethasone (VTd) in transplant-eligible patients (Pts) with newly diagnosed multiple myeloma (NDMM): analysis of minimal residual disease (MRD) negativity in Cassiopeia part 1 and part 2. Presented at: 63rdAmerican Society of Hematology Annual Meeting and Exposition; December 11-13, 2021; Virtual. Abstract 82.