A secondary analysis of the TOURMALINE-MM2 trial (NCT01850524) found that greater depth of treatment response was associated with longer progression-free survival (PFS) and duration of response (DOR) among patients with newly diagnosed multiple myeloma (NDMM) who were ineligible for autologous stem cell transplantation (ASCT).
The study, published in the journal eJHaem, also found that patients who had a later best confirmed response to therapy demonstrated longer PFS and DOR compared with patients who experienced an early best confirmed response within 4 months of therapy initiation.
The double-blind, phase 3 TOURMALINE-MM2 trial enrolled patients with NDMM who were ineligible for ASCT and randomized them to receive either ixazomib-lenalidomide-dexamethasone (IRd) or placebo-Rd. A total of 351 patients were part of the IRd cohort, while 354 received placebo-Rd. Patients treated with IRd showed clinically meaningful improvements in PFS in the trial, although the difference was not statistically significant, the authors noted.
In the secondary analysis, study authors aimed to determine the impact of the quality of response and response kinetics on long-term treatment outcomes. PFS and DOR were examined by response depth as well as the length of time to best confirmed response. Those with a best confirmed response of 0-4 months were considered early responders (n = 424), and patients who experienced a best confirmed response later than 4 months after treatment were considered late responders (n = 281).
Among the overall population of 705 patients, 20% experienced complete response (CR) or stringent CR (sCR), 35% experienced a very good partial response (VGPR), 26% had a partial response (PR), 10% showed stable disease (SD), and 3% had progressive disease (PD).
Experiencing a deeper response to therapy was associated with longer median PFS and DOR. The median PFS was not reached among patients with CR, was 37.2 months in patients with VGPR, and 16.4 months in those who experienced PR. The median DOR was not reached, 42.6 months, and 15.4 months among patients with CR, VGPR, and PR, respectively.
In patients who had a PFS (n = 511) or DOR (n = 484) of at least 6 months and showed at least a PR, those who responded late to treatment with IRd or placebo-Rd had prolonged PFS compared with early responders. The median PFS among late responders to IRd was 59.7 months vs 17.9 months in early responders; in those treated with placebo-Rd, median PFS was 56.6 among late responders vs 12.4 months in early responders.
The median DOR was not reached in late responders to IRd and was 20.9 months in early responders. Among patients treated with placebo-Rd, the median DOR was 58.2 months in late responders and 11.7 months in early responders.
In multivariable analyses by Cox proportional hazards modeling, late response to therapy was associated with prolonged PFS after adjusting for covariates (HR, 0.31; 95% CI, 0.21-0.46; P < .001). In a predictive model using multivariable analysis, late response to treatment was independently associated with prolonged PFS (HR, 0.31; 95% CI, 0.21-0.44; P = .001).
The study was exploratory and the findings require further confirmation, marking one limitation, the authors noted. However, previously reported findings support the notion that deeper and later responses may lead to improved outcomes. Further analyses of studies on other classes of multiple myeloma drugs are needed to determine whether treatment with other therapies shows similar outcomes, the authors noted.
Still, the findings showed that late responders to both IRd and placebo-Rd treatment experienced significantly better outcomes compared with early responders.
“Our findings thus indicate that a slow response to therapy may be a powerful prognostic factor and highlight that slowness of response to treatment with a [proteasome inhibitor]-[immunomodulatory drug]-steroid combination is not a negative predictor of outcome in NDMM,” the authors concluded.
Richardson PG, Facon T, Venner CP, et al. Late versus early response and depth of response are associated with improved outcomes in patients with newly diagnosed multiple myeloma enrolled in the TOURMALINE-MM2 trial. eJHaem. Published online August 3, 2023. doi:10.1002/jha2.759