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.

Trial registration: ClinicalTrials.gov NCT02136134 NCT02076009.

FIG 1.

PFS based on MRD status (10⁻⁵) in POLLUX (A) and CASTOR (B). Shown are the results of the Kaplan-Meier estimates of PFS among patients in the ITT population based on the absence of MRD at a threshold of one tumor cell per 10⁵ white cells. Blue lines show regimens containing daratumumab; red lines show standard-of-care regimens. D-Rd, daratumumab plus lenalidomide and dexamethasone; D-Vd, daratumumab plus bortezomib and dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; PFS, progression-free survival; Rd, lenalidomide and dexamethasone; Vd, bortezomib and dexamethasone.

FIG 2.

PFS based on sustained MRD negativity (10⁻⁵; ≥ 6 months) in the ITT populations of POLLUX (A) and CASTOR (B). Shown are the results of the Kaplan-Meier estimates of PFS among patients in the ITT population based on sustained MRD negativity ≥ 6 months at a threshold of one tumor cell per 10⁵ white cells. Blue lines show regimens containing daratumumab; red lines show standard-of-care regimens. D-Rd, daratumumab plus lenalidomide and dexamethasone; D-Vd, daratumumab plus bortezomib and dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; PFS, progression-free survival; Rd, lenalidomide and dexamethasone; Vd, bortezomib and dexamethasone.

FIG 3.

PFS based on sustained MRD negativity (10⁻⁵; ≥ 12 months) in the ITT populations of POLLUX (A) and CASTOR (B). Shown are the results of the Kaplan-Meier estimates of PFS among patients in the ITT population based on sustained MRD negativity ≥ 12 months at a threshold of one tumor cell per 10⁵ white cells. Blue lines show regimens containing daratumumab; red lines show standard-of-care regimens. D-Rd, daratumumab plus lenalidomide and dexamethasone; D-Vd, daratumumab plus bortezomib and dexamethasone; ITT, intention-to-treat; MRD, minimal residual disease; PFS, progression-free survival; Rd, lenalidomide and dexamethasone; Vd, bortezomib and dexamethasone.

FIG 4.

PFS by response and MRD status (10⁻⁵) among (A) all patients in POLLUX and CASTOR and (B) in the pooled daratumumab-based combination groups versus control groups. Shown are the results of the Kaplan-Meier estimates of PFS among patients in the ITT population based on the absence of MRD at a threshold of one tumor cell per 10⁵ white cells and on response category (≥ CR, ≤ VGPR). In panel A, blue line shows patients who achieve ≥ CR and MRD negativity at any time since random assignment; red line shows patients who achieve ≤ VGPR or are MRD-positive. In panel B, blue lines show regimens containing daratumumab; red lines show standard-of-care regimens. ≥ CR, complete response or better; D-Rd, daratumumab plus lenalidomide and dexamethasone; D-Vd, daratumumab plus bortezomib and dexamethasone; HR, hazard ratio; ITT, intention-to-treat; MRD, minimal residual disease; PFS, progression-free survival; Rd, lenalidomide and dexamethasone; Vd, bortezomib and dexamethasone; ≤ VGPR, very good partial response or worse.