Failure to Achieve Sustained Imaging MRD Negativity Assessed By Diffusion-Weighted Whole-Body MRI (DW-MRI) Is Associated with Adverse Prognosis in Newly Diagnosed Multiple Myeloma Patients Treated with Autologous Stem Cell Transplantation Followed By Maintenance Therapy

Introduction: sustained minimal residual disease (MRD) negativity assessed by bone marrow (BM) techniques is emerging as a surrogate biomarker of patients' outcome in Multiple Myeloma (MM). Moreover, spatial genomic heterogeneity that characterizes MM patients explains the persistence of residual disease within and outside the BM in patients with hematological complete response. Therefore the combined evaluation of BM MRD and functional imaging assessment is required to examine MM eradication. Diffusion-weighted whole-body MRI (DW-MRI) is increasingly used in the management of MM patients, but few data are available regarding the predictive information obtainable from this technique. The Myeloma Response Assessment and Diagnosis System (MY-RADS) recommendations have established criteria for Response Assessment Category (RAC) with a 5 point scale defining complete imaging response (i.e. RAC 1) or some residual-progressive disease after treatment (i.e. RAC 2-5). We performed DW-MRI in MM patients after autologous stem cell transplantation (ASCT) and at 1 year during maintenance therapy in order to evaluate the predictive information of sustained imaging MRD negativity on outcome.

Patients and methods: We analyzed the outcome of 70 newly diagnosed consecutive MM patients (median age 60 years) diagnosed at our institution from January 2015 to December 2020 receiving maintenance therapy after ASCT. Patients underwent DW-MRI evaluation according to MY-RADS criteria at day +100 after ASCT, before maintenance, and after 1 year with the aim of monitoring imaging MRD. BM samples were collected for MRD assessment by 8-color FCM (sensitivity 10-5) at day +100 after ASCT and after 1 year. We focused on sustained 1-year DW-MRI negativity according to RAC response, and its predictive role at that timepoint on progression free survival (PFS) and overall survival (OS); PFS of second line treatment was also evaluated. In patients with available 1-year BM MRD evaluations, concordance between BM and DW-MRI results was calculated and the level of agreement was expressed by Cohen's kappa statistics.

Results: Out of 70 patients, 28 (40%) were ISS stage 3 and 16 (23%) showed high risk cytogenetics. Patients were treated with the following induction regimens: VTD 55, VRD 5, Dara-VRD 7, KRD 2, KCD 1. Single ASCT with MEL200 conditioning was performed in 40 patients (57%), whereas 30 patients (43%) received double ASCT. Subsequent maintenance was performed with lenalidomide (60 patients, 86%) or daratumumab-lenalidomide (10 patients, 14%). Response rates after ASCT were PR 8%, VGPR 22%, CR 54% and sCR 16%. After a median follow of 42 months, no difference in PFS and OS was observed according to ISS stage, whereas superior PFS and OS were observed for patients with standard risk cytogenetics, compared to patients with high risk profile: median PFS 50.6 vs 36,2 months, p 0,002, HR 0,33 (95% CI 0,12-0,83); 3-year OS 94% vs 78%, p 0,04, HR 0,27 (95% CI 0,06-1,23). Imaging MRD negativity (RAC1) before maintenance was observed in 41 patients (58%), whereas long term 1 year imaging MRD negativity during maintenance was observed in 53 patients (76%). The 17 (24%) patients with imaging residual disease (RAC ≥2) at 1 year showed a worse prognosis both in terms of PFS and OS (RAC 1 vs RAC ≥2: median PFS NR vs 28,4 months, p <0,0001, HR 0,11 - 95% CI: 0,03-0,33; 3-year OS 100% vs 81%, p < 0,0002, HR 0,15 (95% CI: 0,03-0,78). This subgroup of lenalidomide refractory patients received the following second line treatment: DVD (6), KD reinduction followed by ASCT (6), KPD (1), PVD (2); suboptimal median PFS of 13 months was observed. BM MRD at 1-year timepoint was available in 32 patients and was negative in 29 (90%) cases. Concordance between 1-year DW-MRI and BM FCM results was high (85%, kappa 0,46: 8% both positive, 77% both negative). Of note, the 2 patients with negative BM and positive imaging MRD at 1 year developed aggressive extramedullary relapse, one with CNS disease.

Conclusion: Sustained imaging MRD negativity assessed by DW-MRI has strong predictive relevance for survival in newly diagnosed MM patients on maintenance therapy after ASCT. Moreover, given the high rates of CR seen in patients with MM with novel effective treatment combinations, the detection of imaging residual disease during lenalidomide-based maintenance can help the physician to early identify patients with a high risk of relapse and poor response to second line treatments.

Belotti:Celgene: Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Roccaro:Amgen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Research Funding; Fondazione AIRC: Research Funding; Transcan2/Era-NET/FRRB: Research Funding. Rossi:Janssen: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees. Tucci:Gentili: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Kiowa Kyrin: Honoraria; Takeda: Honoraria; MSD: Honoraria; Janssen: Membership on an entity's Board of Directors or advisory committees.