Clinical Value of Peripheral Residual Disease (PRD) and Measurable Residual Disease (MRD) in Newly Diagnosed Elderly Patients in the GEM2017FIT Trial

Introduction: In elderly patients (pts) with multiple myeloma (MM), MRD evaluation by NGF has shown to surpass conventional responses to predict patient outcomes with even a higher clinical impact as compared to younger transplant eligible cases. However, integrating MRD into routine clinical practice in these pts can be particularly challenging due to the need of a bone marrow (BM) aspiration. Our study investigates the clinical value of PRD assessed by mass-spec (MS) and MRD by Next Generation Flow in non-transplant eligible pts included in the GEM2017FIT trial.

Patients and methods: GEM2017FIT is an open-label, randomized, phase 3 trial for fit pts with newly diagnosed MM aged between 65 and 80 years. Fitness was assessed with the GAH scale and eligible pts required ≤42 points. Pts randomly received 18 induction cycles of either VMP-Rd (arm1, control) or KRd (arm 2a) or Dara-KRd in a 1:1:1 ratio; those pts not treated with Dara during induction (arms 1 and 2a) received 4 cycles of consolidation with Dara-Rd. After induction and consolidation, pts were randomized to receive maintenance with Dara-R or observation (after stratification according to the MRD status by NGF). VMP and Rd were administered at conventional doses. In the Kz-based regimens, Kz was given twice weekly at a dose of 36mg/m² during cycles 1-2 and at 56 mg/m² from cycle 3 onwards. Dara was initially planned as iv. but subsequently switched to sc, and always administered with the conventional dose and schedule.

The primary endpoint of the study was the rate of MRD negativity post-induction (sensitivity 10^-5). Secondary endpoints included standard responses, progression-free survival (PFS) and overall survival (OS). Besides, we have used Quantitative Immunoprecipitation Mass Spectrometry with anti IgG/A/M, total k and total l beads to assess PRD post-induction using the EXENT^® Analyzer (The Binding Site, part of Thermo Fisher Scientific).

Results: 230 pts who completed the 18 induction cycles were included in this study and analyzed for the primary endpoint using NGF and MS. Median age was 72 years (64–80), 48% were male, nearly one third had ISS 3 and 12% presented with extramedullary disease.

PRD and MRD status (NGF with a sensitivity of 10^-6) were associated with significant differences in PFS (p<0.0001, HR 0.29 and p<0.0001, HR 0.31, respectively). 79.6% of the results were concordant (25.2% [58/230] NGF+MS+, 54.3% [125/230] NGF-MS-) and 20.4% were discordant (8.7% [20/230] NGF-MS+, 11.7% [27/230] NGF+MS-). Taking NGF results as a reference, the negative and positive predictive values of MS were 82% and 74% (p<0.0001), respectively. When comparing PRD and MRD status (NGF^-5) similar results were observed (p<0.0001, HR 0.29 [and p=0.0004, HR 0.32, respectively).

When pts were stratified based on their GAH scale score, both PRD and MRD status were associated with significantly different PFS. For pts with GAH ≤20, the mPFS was not reached (NR) in the PRD- group compared to the PRD+ group (p=0.0021, HR 0.25), and the same result was observed for MRD (p=0.0074, HR 0.31). For patients with GAH >20, the mPFS was NR in the PRD- group compared to 34 months in the PRD+ group (p=0.0064, HR 0.31), and a similar outcome was observed for MRD (p=0.0044, HR 0.31).

We also studied the value of both PRD and MRD according to the pts' cytogenetic risk. Both PRD and MRD were able to stratify pts with different PFS, with clear significance in standard risk pts (PRD: p=0.0049, HR 0.22; MRD: p=0.0051, HR 0.23) and those with del17/del17p/t(4;14)/t(14;16)/Gain/amp1q/del1p (PRD: p=0.0032, HR 0.33; MRD: p=0.0081, HR 0.38). Combining the cytogenetic risk with PRD or MRD status, we observed that PRD negative and standard risk pts had a very favorable outcome (mPFS NR) compared to PRD positive and high-risk pts (mPFS 34 months; p<0.0001 HR 0.12). The same tendency was observed for MRD- and standard risk pts vs MRD+ and high-risk pts (mPFS NR vs 36 months; p<0.0001; HR 0.12).

Conclusions: In this cohort of non-transplant eligible fit elderly pts with newly diagnosed MM, PRD and MRD assessment showed a significant clinical value in terms of PFS, both in the global cohort as well as in different risk groups based on fragility and cytogenetic risk. These findings suggest that the integration of PRD assessment into routine clinical practice may be beneficial for all elderly pts, independently of their specific risk features.