Daratumumab-Based Triplets Translate to Improved MRD-Negative Remissions in Myeloma

Herve Avet-Loiseau, MD, PhD

Daratumumab (Darzalex) plus lenalidomide (Revlimid) and dexamethasone (D-Rd), or plus bortezomib (Velcade) and dexamethasone (D-Vd) each led to higher rates of minimal residual disease (MRD) negativity compared with lenalidomide plus dexamethasone (Rd) or bortezomib plus dexamethasone (Vd) alone in patients with relapsed/refractory multiple myeloma who were enrolled in the phase 3 POLLUX and CASTOR trials, translating to prolonged, durable remissions, according to an exploratory analysis published in the Journal of Clinical Oncology.

The median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR. In the intention-to-treat (ITT) population in POLLUX, the MRD-negativity rate was 32.5% with D-Rd vs 6.7% with Rd. In the ITT population in CASTOR, the MRD-negativity rate was 15.1% with D-Vd vs 1.6% with Vd (both P < .0001).

“Daratumumab-based combinations induce higher rates of sustained MRD negativity vs

standard of care, which are associated with durable remissions and prolonged clinical outcomes,” Herve Avet-Loiseau, MD, PhD, lead study author, and head of the Laboratory for Genomics in Myeloma at the University Hospital Center of Toulouse, France, and co-authors wrote in the publication.

Findings from the primary analyses of the POLLUX and CASTOR trials demonstrated that the addition of daratumumab to Rd and Vd each led to approximately a 60% reduction in the risk of progression or death in patients with relapsed/refractory multiple myeloma.

Given that MRD can be used to measure disease control, investigators evaluated the rates of sustained MRD negativity and outcomes in patients enrolled in the POLLUX and CASTOR trials.

In total, 569 patients in POLLUX (D-Rd, n = 286; Rd, n = 283) and 498 patients in CASTOR (D-Vd, n = 251; Vd, n = 247) were randomized to the daratumumab and control groups, respectively.

MRD was evaluated with next-generation sequencing at a sensitivity of 10-5 at suspected complete response (CR), 3 and 6 months after confirmed CR in POLLUX, 6 and 12 months after the first dose was administered in CASTOR, and every 12 months after CR in both studies.

Sustained MRD negativity for at least 6 and no more than 12 months was evaluated in the ITT and at least CR-attaining patient populations.

Additional results demonstrated that higher MRD-negativity rates were achieved in at least CR-attaining 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 for at least 6 months with D-Rd vs Rd (20.3% vs 2.1%; P < .0001) and D-Vd vs Vd (10.4% vs 1.2%; P < .0001), and at least 12 months with D-Rd vs Rd (16.1% vs 1.4%; P < .0001) and D-Vd vs Vd (6.8% vs 0%).

In both trials, fewer daratumumab-treated patients with durable MRD negativity lasting at least 12 months had high cytogenetic risk vs standard cytogenetic risk (POLLUX, 8.8% vs 91.2%, respectively; CASTOR, 33.3% vs 66.7%).

Similar results for sustained MRD negativity were reported among at least CR-attaining patients. More patients in the daratumumab-containing arms achieved MRD negativity and sustained MRD negativity, which were associated with prolonged progression-free survival (PFS).

“Achieving durable MRD negativity may predict long-term outcomes, as durable MRD negativity improves PFS and increases the time between treatment relapses for relapsed/refractory multiple myeloma; this supports the concept that sustained MRD negativity may serve as a surrogate end point for PFS in ongoing and future clinical trials. Prospectively gathered clinical data will be useful in developing future paradigms for MRD analysis as a clinical practice decision tool,” concluded the authors.

Reference

Avet-Loiseau H, San-Miguel J, Casneuf T, et al. Evaluation of sustained minimal residual disease negativity with daratumumab-combination regimens in relapsed and/or refractory multiple myeloma: analysis of POLLUX and CASTOR. J Clin Oncol. 2021;39(10):1139-1149. doi:10.1200/JCO.20.01814