Peripheral residual disease activity assessment by MALDI-TOF mass spectrometry in patients with newly-diagnosed multiple myeloma in the GMMG-HD7 study

Abstract Background A broad spectrum of methods is used for the evaluation of disease activity and minimal residual disease (MRD) in multiple myeloma (MM), including minimally-invasive blood tests and invasive bone marrow analyses to asses residual disease. Mass spectrometry (MS) is a highly sensitive, emerging method to isotype and measure M-protein levels in the peripheral blood, holding the potential for less invasive assessment of therapy response and monitoring of peripheral residual disease (PRD). Herein, we present PRD data from the phase 3 randomized German-speaking Myeloma Multicenter Group (GMMG) HD7 trial (NCT03617731). Methods Serum samples (n = 3154) from 622 patients (pts) at major timepoints (baseline, post induction [IND], post [last] autologous stem cell transplant [ASCT], at 12 months from start of maintenance [MT12], at EOS and [suspected] progressive disease) treated within the GMMG-HD7 trial (Isa-RVd vs. RVd induction followed by randomization into Isa-R vs. R maintenance) were included for analysis, comprising pts with both intact Ig (n = 505) and light chain type (n = 117) MM. The samples were blinded for analysis using the EXENT® Analyzer combining automated IgG/IgA/IgM and total light chains (κ/λ) immune-purification and MALDI-TOF MS analysis to isotype, quantify and track monoclonal immunoglobulins. Results were screened for plausibility, matched to isotype by immunofixation at baseline, and manually reviewed in case of inconsistencies. Landmark analyses were performed post IND, ASCT, and MT12. As MS assessments of light chain type MM were non-inferior to assessments by immunofixation, qualitative assessments of monoclonal light chain persistence were also included in this analysis. Progression free survival (PFS) was measured as the time from the respective landmark until progressive disease or death from any cause, whichever occurred first. For analyses evaluating continued negative MRD (using next generation flow cytometry at a sensitivity of 10-5) from the bone marrow, and continued negative PRD, continued negativity was assessed from IND until ASCT. PFS was estimated using the Kaplan-Meier method, while Hazard ratios and corresponding 95% confidence intervals were obtained using a multivariable Cox regression model adjusted for relevant covariates (treatment arm, age, sex, Revised International Staging System for MM [R-ISS]). Results Post IND, post ASCT, and MT12 22%, 49%, and 79% of pts were PRD-. PRD negativity showed significant prognostic value for PFS (IND HR 0.38, 95% CI 0.23–0.66; p < 0.001 / ASCT HR 0.43, 95% CI 0.29–0.65; p < 0.001 / MT12 HR 0.26, 95% CI 0.15–0.46; p < 0.001). Similar to previously published reports (e.g., Puig et al. 2024; Kubicki et al. 2024; Mai et al. 2023; Claveau et al. 2022), prognostic impact of PRD by MS was most pronounced at later timepoints. When combined with paired bone marrow MRD, the PRD/MRD double-negative pts showed significantly better PFS compared to the double-positive pts (IND HR 0.21, 95% CI 0.11–0.42; p < 0.001; ASCT HR 0.26, 95% CI 0.16–0.43; p < 0.001; MT12 HR 0.09, 95% CI 0.04–0.19; p < 0.001). Compared to double-positive pts, pts with either only PRD- or MRD- status had a similar PFS (e.g., MT12 (PRD+/MRD-): HR 0.11, 95% CI 0.04–0.34; p < 0.001; MT12 (PRD-/MRD+): HR 0.12, 95% CI 0.01–0.97; p = 0.047). Continued PRD- or MRD- status was associated with significantly improved PFS as compared to non-continued PRD- or MRD- status (PRD-/MRD- continued vs. non-continued: HR 0.43/0.33, 95% CI 0.23–0.81/0.21–0.52; p = 0.009/< 0.001). In-depth comparisons of PRD course show significantly improved PFS for continued PRD- vs. PRD+ pts (HR 0.34, 95% CI 0.18–0.65; p = 0.001), and PRD positive-to-negative vs. continued PRD+ pts (HR 0.44, 95% CI 0.27–0.73; p = 0.001). Conclusion The results from the phase 3 GMMG-HD7 trial underscore the significant prognostic value of PRD assessment for newly-diagnosed MM, especially during later timepoints. Association with simultaneous bone marrow MRD assessment demonstrates the utility of PRD as a minimally-invasive option for disease monitoring. Positive PRD results gained significant prognostic value when confirmed by a positive MRD measurement and vice versa. Continued PRD response showed similar prognostic impact as established continued MRD from the bone marrow, highlighting the potential value of MS PRD tracking as an emerging modality for long-term follow-up in pts with newly-diagnosed MM.