Evaluation of Sustained Minimal Residual Disease Negativity With Daratumumab-Combination Regimens in Relapsed and/or Refractory Multiple Myeloma: Analysis of POLLUX and CASTOR

Abstract

PURPOSE In relapsed and/or refractory multiple myeloma, daratumumab reduced the risk of progression or death by > 60% in POLLUX (daratumumab/lenalidomide/dexamethasone [D-Rd]) and CASTOR (daratumumab/bortezomib/dexamethasone [D-Vd]). Minimal residual disease (MRD) is a sensitive measure of disease control. Sustained MRD negativity and outcomes were evaluated in these studies. METHODS MRD was assessed via next-generation sequencing (10−5) at suspected complete response (CR), 3 and 6 months following confirmed CR (POLLUX), 6 and 12 months following the first dose (CASTOR), and every 12 months post-CR in both studies. Sustained MRD negativity (≥ 6 or ≥ 12 months) was evaluated in the intention-to-treat (ITT) and ≥ CR populations. RESULTS The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the ITT population, MRD-negativity rates were 32.5% versus 6.7% for D-Rd versus lenalidomide and dexamethasone (Rd) and 15.1% versus 1.6% for D-Vd versus bortezomib and dexamethasone (Vd; both P < .0001). Higher MRD negativity rates were achieved in ≥ CR patients in POLLUX (D-Rd, 57.4%; Rd, 29.2%; P = .0001) and CASTOR (D-Vd, 52.8%; Vd, 17.4%; P = .0035). More patients in the ITT population achieved sustained MRD negativity ≥ 6 months with D-Rd versus Rd (20.3% v 2.1%; P < .0001) and D-Vd versus Vd (10.4% v 1.2%; P < .0001), and ≥ 12 months with D-Rd versus Rd (16.1% v 1.4%; P < .0001) and D-Vd versus Vd (6.8% v 0%). Similar results for sustained MRD negativity were observed among ≥ CR patients. More patients in the daratumumab-containing arms achieved MRD negativity and sustained MRD negativity, which were associated with prolonged progression-free survival. CONCLUSION Daratumumab-based combinations induce higher rates of sustained MRD negativity versus standard of care, which are associated with durable remissions and prolonged clinical outcomes.

CD38-Directed Therapies for Management of Multiple Myeloma

“… 16 MRD negativity was 15.1% in the DVd arm as compared to 1.6% in the Vd arm. 17 This study is relevant in the United States as DVd is both effective and safe for patients who relapse on lenalidomide based maintenance therapy with prior exposure but not refractoriness to PIs. Patients with lenalidomide and bortezomib refractory multiple myeloma present a highly refractory group of patients with limited options.…”

Persistent bone marrow minimal residual disease as a “high‐risk” disease feature in multiple myeloma

“…The SARS-CoV-2 infection and vaccination have raised concerns in complement mediated hemolytic anemias (i.e., paroxysmal nocturnal hemoglobinuria, PNH, and cold agglutinin disease, CAD), particularly if on treatment with complement inhibitors. [1][2][3] Among complement amplifying triggers (infections, traumas, and surgery 4,5 ) an emerging causative agent may be represented by SARS-CoV-2 vaccines. In PNH patients on complement inhibitors, pharmacodynamic breakthrough hemolysis (BTH) has been defined as hemolysis reactivation with hemoglobin drop due to increased complement activity.…”

Minimal Residual Disease in Multiple Myeloma: Something Old, Something New

“…Using the ongoing POLLUX and CASTOR studies in relapsed/refractory patients, an exploratory analysis has found that "Sustained MRD negativity" (defined as the maintenance of MRD negativity in bone marrow confirmed ≥ 6 or ≥12 months apart) is associated with improved PFS compared with patients who obtain MRD-negative status but not MRD dura- In addition, new relevant definitions are emerging regarding MM MRD. Using the ongoing POLLUX and CASTOR studies in relapsed/refractory patients, an exploratory analysis has found that "Sustained MRD negativity" (defined as the maintenance of MRD negativity in bone marrow confirmed ≥ 6 or ≥12 months apart) is associated with improved PFS compared with patients who obtain MRD-negative status but not MRD durability [95].…”