Sustained MRD Negativity Predictive of Long-term Outcomes in RRMM

Sustained minimal residual disease (MRD) negativity may predict long-term outcomes in relapsed/refractory multiple myeloma (RRMM), a recent analysis of the POLLUX (NCT02076009) and CASTOR (NCT02136134) studies found. In addition, daratumumab-based combinations led to higher rates of sustained MRD negativity compared with the standard of care.

Although patients with multiple myeloma (MM) have had improved response rates due to combination therapies in recent years, the majority relapse and must undergo further therapy. The authors of the new study, which was published in The Journal of Clinical Oncology, assessed sustained MRD negativity and patient outcomes based on data from POLLUX and CASTOR, which represent the largest set of MRD data collected from RRMM patients.

The phase 3 POLLUX study compared daratumumab, lenalidomide, and dexamethasone (D-Rd) with lenalidomide and dexamethasone (Rd) in RRMM. CASTOR, also a phase 3 study, compared daratumumab, bortezomib, and dexamethasone (D-Vd) with bortezomib and dexamethasone (Vd) in RRMM. Overall, 569 patients in POLLUX and 498 in CASTOR were included in the new analysis.

Both studies assessed MRD, a known sensitive measure of disease control, with next-generation sequencing based on the International Myeloma Working Group guidelines, which recommend a sensitivity threshold of 10^-5 (1 tumor cell in 100,000). Patients were assessed at suspected complete response (CR); at 3 and 6 months after confirmed CR in the POLLUX study; at 6 and 12 months after the first dose in the CASTOR study; and every 12 months following CR in both studies.

The combined analysis included 537 patients on daratumumab-containing regimens and 530 patients given the standard of care (Rd or Vd). Researchers assessed MRD in both the intention-to-treat (ITT) population and in patients who achieved complete response or better. Sustained MRD negativity was defined as at least 6 months and at least 12 months. Median follow-up was 54.8 months in POLLUX and 50.2 months in CASTOR.

MRD negativity rates in the ITT population were 32.5% in the D-Rd group and 6.7% in the Rd cohort in the POLLUX study. Patients who achieved CR or better had higher MRD rates, with 57.4% of those patients on the D-Rd regimen and 29.2% on the Rd regimen showing MRD negativity (P = .0001). In the CASTOR study, MRD negativity rates in the ITT population were 15.1% in the D-Vd group vs 1.6% in the Vd group. In the CR or better population, 52.8% of patients on the D-Vd regimen and 17.4% on the Vd regimen achieved MRD negativity (P = .0035).

In both studies, the daratumumab combination treatment saw higher percentages of patients in the ITT and CR or better cohorts achieve sustained MRD negativity compared with the standard of care. In the D-Rd group in POLLUX, 20.3% of patients achieved sustained MRD negativity of at least 6 months vs 2.1% in the Rd cohort (P < .0001). At 12 or more months, combination group patients still had higher rates of sustained negativity (16.1% vs 1.4%; P < .0001).

In CASTOR, the D-Vd and Vd groups achieved 6 months or longer sustained negativity at rates of 10.4% and 1.2%, respectively (P < .0001). More D-Vd patients also achieved sustained MRD negativity for 12 or more months (6.8%) compared with Vd patients (0%).

MRD negativity was also associated with longer progression-free survival (PFS). In patients who achieved sustained MRD negativity for 6 or more months, PFS was prolonged in both studies, regardless of treatment arm. Patients who achieved sustained MRD negativity for 12 or more months on a daratumumab combination regimen also had longer PFS compared with those who were MRD-positive. Overall survival data will be assessed at the end of both studies.

“Achieving durable MRD negativity may predict long-term outcomes, as durable MRD negativity improves PFS and increases the time between treatment relapses for RRMM,” the authors wrote. “This supports the concept that sustained MRD negativity may serve as a surrogate end point for PFS in ongoing and future clinical trials.”

The authors point out that although findings suggest that MRD monitoring may be predictive of long-term outcomes in RRMM, there is no consensus on how or when to use it. “Prospectively gathered clinical data will be useful in developing future paradigms for MRD analysis as a clinical practice decision tool,” they wrote.

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. Published online January 29, 2021. doi:10.1200/JCO.20.01814