Bortezomib, lenalidomide, and dexamethasone (VRd) ± daratumumab (DARA) in patients (pts) with transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): A multicenter, randomized, phase III study (PERSEUS).

Abstract

TPS8055 Background: DARA, a human, CD38-targeting, IgGκ monoclonal antibody, is approved in many countries for use as monotherapy in relapsed/refractory MM (RRMM), and in combination with standard-of-care regimens in RRMM and transplant-ineligible NDMM. Given the initial safety and efficacy observed with DARA plus VRd (D-VRd) in the safety run-in cohort of the ongoing phase 2 GRIFFIN study in TE NDMM pts, the phase 3 PERSEUS study will evaluate the efficacy and safety of D-VRd versus VRd alone in TE NDMM. Methods: This is an ongoing multicenter, open-label, randomized phase 3 study of D-VRd versus VRd alone in TE NDMM pts. Approximately 690 pts across Europe will be stratified by ISS stage and cytogenetic risk (high risk defined as presence of del17p, t[4;14], or t[14;16]) and randomized in a 1:1 ratio. All pts will receive VRd (V: 1.3 mg/m2 SC Days 1, 4, 8, 11; R: 25 mg PO Days 1-21; d: 40 mg PO Days 1-4, 9-12) for 4 pre-transplant induction and 2 post-transplant consolidation cycles (all 28-d cycles), followed by R (10 mg PO Days 1-28) maintenance until progressive disease (PD). Pts in the DARA group will also receive subcutaneous DARA (1,800 mg co-formulated with recombinant human hyaluronidase PH20 [rHuPH20; Halozyme]) QW in Cycles 1-2, Q2W in Cycles 3-6, and Q4W in maintenance Cycles 7+ until PD. After induction, pts will undergo melphalan 200 mg/m2 conditioning and autologous stem cell transplantation (ASCT). Pts in the DARA group who achieve sustained minimal residual disease (MRD) negativity (10–5 threshold; assessed by NGS) for 12 months after ≥24 months of maintenance will stop DARA but continue R maintenance until PD; upon loss of CR or MRD-negative status, pts will restart DARA treatment. All pts will receive preinfusion medications. The primary endpoint is progression-free survival (PFS). Secondary endpoints include MRD-negative rate, overall response rate, PFS on next line of therapy, overall survival, time to and duration of response, health-related quality of life, pharmacokinetics, immunogenicity, stem cell yield after mobilization, time to engraftment post-ASCT, and safety. Clinical trial information: NCT03710603.

Monoclonal Antibodies to Treat Multiple Myeloma: A Dream Come True

“…Although there were more cases of neutropenia (41.4% vs. 21.6%), thrombocytopenia (16.2% vs. 8.8%) and infections (90.9% vs. 61.8%) in the daratumumab group, the rate of treatment discontinuation was 15.2% in the Dara-VRd arm vs. 20.6% in the VRd arm. The ongoing phase III trial PERSEUS is evaluating the efficacy of daratumumab combined with VRd in the induction and consolidation phases and with lenalidomide in the maintenance phase [65].…”

Multiple myeloma: Role of autologous transplantation

“…Among all, the introduction of carfilzomib and daratumumab in the first line, the addition of busulfan to melphalan and the ixazomib maintenance seem to be incorporated in the clinical practice in the near future. Tailoring of maintenance therapy based on the MRD status is another challenge that is being addressed in ongoing studies, such as the PERSEUS clinical trial [87]. Apart from highly effective therapies resulting in "functional cure", the optimization of the abovementioned ASCT components also lies in the establishment of a favourable safety profile by further minimizing morbidity and mortality and, ideally, performing ASCT in an outpatient setting [88].…”

Consolidation with carfilzomib, lenalidomide, and dexamethasone (KRd) following ASCT results in high rates of minimal residual disease negativity and improves bone metabolism, in the absence of bisphosphonates, among newly diagnosed patients with multiple myeloma

“…Importantly, a major eligibility criterion in our study pertained to the MRD status after ASCT. There are several ongoing trials that use the MRD status as their primary endpoint or formulate the consolidation/ maintenance therapeutic strategy based on the MRD status, such as the PERSEUS and the MASTER trials 11,12 . The primary results of the MASTER trial are encouraging, as none of the 27 MRD-negative patients who have entered the observation phase have relapsed during a short-term median follow-up of 5 months.…”