Addition of Daratumumab to Rd/Vd Heightens MRD Negativity Rates in R/R Myeloma

Over time, the use of combination therapies has improved outcomes for patients with multiple myeloma (MM), but the majority of patients experience relapse, which underscores the need for more treatment options. One idea being considered in today’s research is that minimal residual disease (MRD) negativity and sustained MRD negativity could be a predictive and prognostic end point for clinical outcomes.

High rates of sustained MRD negativity were achieved with daratumumab (Darzalex)-containing combinations compared with the standard-of-care combinations, according to an exploratory analysis of 2 ongoing clinical trials, POLLUX (NCT02076009) and CASTOR (NCT02136134). The sustained MRD negativity in this analysis correlated with durable remissions and prolonged clinical outcomes.¹

Primary Findings

The POLLUX trial evaluated the addition of daratumumab to lenalidomide (Revlimid) and dexamethasone (D-Rd). According to the most recently reported data, the combination prolonged progression-free survival (PFS) in patients with relapsed/refractory MM. The 12-month PFS rate was 83.2% (95% CI, 78.3%-87.2%) in the daratumumab group versus 60.1% (95% CI, 54.0%-65.7%) in the Rd alone group.² In CASTOR, the addition of daratumumab to bortezomib (Velcade) and dexamethasone (D-Vd) also extended PFS in comparison with Vd alone. With the addition of daratumumab, the median PFS was not reached compared with 7.2 months in the control group (HR, 0.39; 95% CI, 0.28-0.53; P < .001). Adding daratumumab also led to a better overall response rate in the study of 82.9% versus 63.2% in the control arm (P < .001).³

According to next-generation sequencing results from the primary analysis of each trial, higher MRD negativity (10-5) rates were achieved with daratumumab-based regimens compared with regimens excluding daratumumab. In the POLLUX trial specifically, the achievement of MRD negativity was 26.2% compared 6.4% in the control arm (P < .0001). Likewise, in the CASTOR trial, MRD negativity was achieved in 11.6% of the daratumumab arm compared with 2.4% of the control arm (P < .0001).¹

Together, POLLUX and CASTOR represent the largest pool of MRD data collected prospectively from patients with relapsed/refractory MM. Both studies are randomized, open-label, multicenter, phase 3 studies. The eligibility criteria for the trials allowed for patients with progressive disease per IMWG criteria who received at least 1 prior line of therapy and had a partial response or better to ≥1 line of previous therapy. In terms of ineligibility, patients who were refractory to lenalidomide could not enroll in the POLLUX study and those refractory to bortezomib or another proteasome inhibitor were ineligible for the CASTOR study.

The 2 studies are evaluating PFS as the primary end point and secondarily assessing tumor response and disease progression. To evaluate MRD status, patients were tested at the time of complete response (CR) and 3 to 6 months following a CR in the POLLUX study and at the time of a CR and 6 to 12 months following a CR, in the CASTOR study.

For the purposes of the exploratory analysis, MRD negativity rate was defined as the number of patients with negative MRD results at any time during treatment. The sensitivity threshold for MRD negativity in the exploratory analysis was 10-5.

Exploratory Findings

The cohort assessed was comprised of 569 patients from the POLLUX study, of whom 286 received the daratumumab regimen and 283 of whom received Rd. The analysis also included 498 patients from the CASTOR, of whom 251 received D-Vd and 247 received Vd. Follow-up was a median duration of 54.8 months (range, 0.0-61.9) for the POLLUX cohort and 50.2 months (range, 0.0-58.6) for the CASTOR cohort.

The results showed a ≥4-fold higher MRD negativity rate (10-5) with the use of daratum`umab-based regimens when compared with controls. In the intention-to-treat (ITT) population of the POLLUX cohort, the MRD negativity rate was 32.5% with D-Rd versus 6.7% with Rd alone (P < .000001). MRD negativity was sustained for ≥6 months in 20.3% of the D-Rd arm versus 2.1% of the Rd alone arm (P < .0001). MRD negativity was sustained for ≥12 months in 16.1% of the D-Rd arm compared with only 1.4% of the Rd arm (P < .0001).

In the CASTOR cohort, the D-Vd arm achieved a 15.1% MRD negativity rate compared with 1.6% in the VD alone arm (P < .000001). MRD negativity was sustained for ≥6 months in 10.4% of the D-Vd arm versus 1.2% of the Vd alone arm (P < .0001), and was sustained for ≥12 months in 6.8% of the D-Vd arm versus none of the Vd arm patients (P < .0001).

Investigators assessed the durability of response to daratumumab-containing regimens in this exploratory analysis. In the POLLUX population, the CR rate was 57.4% with D-Rd versus 29.2% with Rd alone (P = .0001). CRs lasted for ≥6 months in 35.8% of the D-Rd arm compared with 9.2% of the Rd arm (P < .0001). CRs were sustained for 12 months or more in 28.4% of the D-Rd arm versus 6.2% of the Rd arm (P = .0001).

In the CASTOR population, the CR rate observed with the daratumumab-based regimen was 52.8% versus 17.4% with Rd alone (P = .0035). CRs were sustained for ≥6 months for 36.1%

of the D-Vd group compared with 13.0% of the Vd group (P = .0404). CRs lasted for ≥12 months in 23.6% of patients treated with D-Vd compared with none of the patients who received Vd (P = .0098).

Overall, the data showed a lower risk of disease progression or death in patients who achieved MRD negativity compared with those who did not. This finding was consistent with previous research. In addition, deeper responses were observed in patients who had MRD negative status.

_References:

_{1. Avet-Loiseau H, San-Miguel J, Casneuf T, et al. Evaluation of sustained minimal residual disease negativity with daratumumabcombination regimens in relapsed and/or refractory multiple myeloma: analysis of POLLUX and CASTOR. J Clin Oncol. Published online January 29, 2021. doi:10.1200/JCO.20.01814}

_{2. Dimopoulos MA, Priol A, Nahi H, et al; POLLUX Investigators. Daratumumab, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331. doi:10.1056/NEJMoa1607751}

_{3. Palumbo A, Chanan-Khan A, Weisel K, et al; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766. doi:10.1056/NEJMoa1606038}