MRD By Flow Cytometry and FDG-PET/CT for the Post-Induction Response Assessment in Patients with Multiple Myeloma Treated in the Phase 3 GMMG HD7 Study

Introduction: Minimal residual disease (MRD) in the bone marrow (BM), assessed by flow cytometry or next-generation sequencing, is considered the gold standard for evaluating the depth of treatment response in patients with multiple myeloma and is a known prognostic factor for long-term survival outcomes. However, this method has limitations due to the uneven distribution of myeloma cells in the BM. FDG-PET/CT can non-invasively assess the overall disease burden and, due to its ability to reliably differentiate metabolically active from inactive lesions, it is considered the appropriate imaging method for treatment response evaluation. This study aimed to compare the post-induction MRD status by next-generation flow cytometry and treatment response in FDG-PET/CT assessed by the IMPeTUs criteria in patients with newly diagnosed transplant-eligible multiple myeloma (NDTEMM).

Methods: The GMMG HD7 is an ongoing, randomized, active-controlled, phase 3 trial, which investigates the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with NDTEMM. 72 patients were enrolled in this imaging substudy. All patients underwent FDG PET/CT at baseline and after induction and had data on MRD status assessed by next-generation flow cytometry (cut-off 1x10^-5) post-induction. PET/CT data analysis was conducted using the IMPeTUs criteria, which consider, among others, BM metabolic status according to the 5-point Deauville score (DS), as well as the number and metabolic activity of focal lesions (FL) and paramedullary disease (PMD). We defined PET negativity as FDG uptake equal or lower than the liver background (DS < 4) as previously described.

Results: Baseline characteristics were as follows: 40%, 43% and 11% of the patients were classified as R-ISS Stage I, II and III, respectively. In 6% of the cases the R-ISS stage could not be classified. FL and BM with a DS ≥ 4 were present in 64% and 51%, whereas metabolically active PMD was observed in 34% of the patients. After induction, MRD negativity by flow cytometry was achieved in 32 out of 72 of the cases (44%). MRD rates were similar to those of the entire HD7 cohort, where 42% of the patients were MRD negative after induction. Post-induction results according to IMPeTUs showed that FL and BM remained positive (DS ≥ 4) only in 19% and 4% of the patients; PMD persisted in 4% of the study cohort. PET negativity in all three IMPeTUs criteria parameters was achieved by 53% of the patients. The overall concordance of post induction PET und MRD status in the BM was 53% (38% both negative, 15% both positive). In 39% of the cases, MRD was positive, whereas PET was negative. Respectively, in 8% patients, MRD was negative, while PET was positive.

Conclusion: The results of this study demonstrate moderate levels of concordance between PET and MRD status post-induction. This is at odds with previous findings from other study groups that have shown higher concordance rates between PET and MRD status, and may be attributed to the smaller cohort size and short follow-up period. Patients seem to achieve PET negativity at a higher degree than MRD negativity, likely due to the high sensitivity of MRD assessment in the BM on a molecular level. This underscores the complementary role of FDG-PET/CT in assessing treatment response in multiple myeloma. While MRD status remains the gold standard, PET/CT provides valuable additional information on a whole-body level, particularly in identifying early treatment responses. As long-term outcomes become available, our group will further analyse how PET/CT and MRD status impact long-term survival and disease management. This study highlights the need for integrating both MRD and PET/CT assessments to refine treatment strategies and improve patient outcomes in multiple myeloma.