Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE

Abstract

In patients with transplant-ineligible newly diagnosed multiple myeloma (NDMM), daratumumab reduced the risk of disease progression or death by 44% in MAIA (daratumumab/lenalidomide/dexamethasone [D-Rd]) and 58% in ALCYONE (daratumumab/bortezomib/melphalan/prednisone [D-VMP]). Minimal residual disease (MRD) is a sensitive measure of disease and response to therapy. MRD-negativity status and durability were assessed in MAIA and ALCYONE. MRD assessments using next-generation sequencing (10-5) occurred for patients achieving complete response (CR) or better and after at least CR at 12, 18, 24, and 30 months from the first dose. Progression-free survival (PFS) by MRD status and sustained MRD negativity lasting ≥6 and ≥12 months were analyzed in the intent-to-treat population and among patients achieving at least CR. In MAIA (D-Rd, n = 368; lenalidomide and dexamethasone [Rd], n = 369) and ALCYONE (D-VMP, n = 350; bortezomib/melphalan/prednisone [VMP], n = 356), the median duration of follow-up was 36.4 and 40.1 months, respectively. MRD-negative status and sustained MRD negativity lasting ≥6 and ≥12 months were associated with improved PFS, regardless of treatment group. However, daratumumab-based therapy improved rates of MRD negativity lasting ≥6 months (D-Rd, 14.9% vs Rd, 4.3%; D-VMP, 15.7% vs VMP, 4.5%) and ≥12 months (D-Rd, 10.9% vs Rd, 2.4%; D-VMP, 14.0% vs VMP, 2.8%), both of which translated to improved PFS vs control groups. In a pooled analysis, patients who were MRD negative had improved PFS vs patients who were MRD positive. Patients with NDMM who achieved MRD-negative status or sustained MRD negativity had deep remission and improved clinical outcomes. These trials were registered at www.clinicaltrials.gov as #NCT02252172 (MAIA) and #NCT02195479 (ALCYONE).

Graphical abstract

Figure 1.

PFS based on MRD status (10⁻⁵) in MAIA and ALCYONE. Kaplan-Meier estimates of PFS by MRD status among patients in the ITT populations. MRD was assessed at a threshold of 1 tumor cell per 10⁵ white blood cells. Red lines show MRD-negative patient populations and blue lines show MRD-positive patient populations (D-Rd/Rd shown for MAIA [A]; D-VMP/VMP for ALCYONE [B]).

Figure 2.

PFS based on sustained MRD negativity (10⁻⁵; ≥12 months) in MAIA, ALCYONE, and in both studies pooled. Kaplan-Meier estimates of PFS by sustained MRD negativity lasting ≥12 months among patients in the ITT populations. MRD status was assessed at a threshold of 1 tumor cell per 10⁵ white blood cells. Red lines show MRD-negative patient populations and blue lines show MRD-positive patient populations (D-Rd/Rd shown for MAIA [A]; D-VMP/VMP for ALCYONE [B]; and D-Rd/Rd/D-VMP/VMP for all studies combined [C]).

Figure 3.

PFS by MRD status (10⁻⁵) among all patients in MAIA and ALCYONE and in the pooled daratumumab-based combination groups vs control groups. Kaplan-Meier estimates of PFS based on MRD negativity in the ITT populations. MRD negativity was assessed at a threshold of 1 tumor cell per 10⁵ white blood cells. (A) The red line shows patients who achieved MRD negativity at any time since randomization; the blue line shows patients who were MRD positive. (B) Red lines show regimens containing daratumumab (D-Rd and D-VMP); blue lines show standard of care regimens (Rd and VMP). A total of 5 patients who achieved a best response of VGPR were also MRD negative (all from the D-VMP arm of ALCYONE). Dara, daratumumab; VGPR, very good partial response.