Minimal Residual Disease (MRD) Status and Its Impact on Clinical Outcome Is Highly Variable in Multiple Myeloma and Dependent on Molecular Subgroups Defined By Gene Expression Profiling (GEP)
Authors: Thanendrarajan Sharmilan , Farmer Phil , Bailey Clyde , Schinke Carolina , Al Hadidi Samer , Zangari Maurizio , Rogers Stephanie , Williams Anne , Zhan Fenghuang , Shaughnessy, Jr John D , Patel Tanvi H. , Trikannad Anup Kumar , Shrestha Asis , Naqvi Syed , Cheema Hira Imad , Shrivastava Trilok , Karri Manozna , Bachu Ramya , van Rhee Frits 
Published: December 2024

Introduction:
MRD status has a significant impact on the clinical outcome of patients with multiple myeloma. Achieving sustaining MRD-negative status is considered prognostically relevant for multiple myeloma patients and is highly associated with improved survival. However, the clinical impact of MRD-positive patients and non-sustaining MRD negative patients have not been explored in detail. In this study, we investigate the clinical impact of achieving MRD-positive, sustaining MRD-negative and non-sustaining MRD negative status in multiple myeloma patients after prior treatment depending on their genetic risk profile using gene expression profile (GEP) including seven molecular subgroups (CD-1, CD-2, HY, LB, MF, MS ,PR). In our previous studies we have demonstrated that patients in the HY, CD-1, CD-2 and LB molecular subgroups defined by GEP had superior event free and overall survival compared to the PR, MS and MF molecular subgroup patients differentiating between low-risk and high-risk patients.
Methods:
We included in this single-center retrospective study newly diagnosed multiple myeloma patients after induction chemotherapy and first melphalan based autologous stem cell transplantation (ASCT) with a least two serial 8-color MRD flow cytometry tests with sensitivity at 10-5 within a 1- year window after 2 years of ASCT with available gene expression profile data. Multiple myeloma patients who had two or more serial MRD-negative tests in that time frame were considered as sustaining MRD-negative (SMRD-N) patients, patients without any MRD-negative status at all were considered positive (MRD-P), and patients with at least one MRD-negative test were considered non-sustaining negative (NSMRD-N).
Results:
In our study, we identified 331 MRD-P (35.5%),223 NSMRD-N (23.9%), and 378 SMRD-N (40.6%) multiple myeloma patients with 932 patients in total. The median predicted overall survival rate was 6.54 years in the MRD-P group, 11.39 years in the NSMRD-N group and not reached yet in the SMRD-N group (p&lt;0.0001). According to our GEP data, all 932 myeloma patients were assigned to different molecular subgroups, as following: HY: 321 (34.4%), CD-2: 173 (18.6%), PR: 118 (12.7%), LB: 107 (11.5%), MS: 88 (9.4%), CD-1: 64% (6.9%), MF: 61 (6.6%). The most frequently noticed MRD status is SMRD-N, as seen in the CD-1, MS, LB, PR, and HY molecular subgroup (7.4, 11.1%, 11.4%, 12.7%, 39.7%, n=28-150). In the MF and CD-2 molecular subgroups the most commonly noticed MRD status is MRD-P with 41% (n=25) and 46.2% (n=80), respectively. NSMRD-N was the least frequently observed MRD status in all molecular subgroups (7.2 - 34.1%, n=16-76), except CD-1 molecular subgroup with equal findings between MRD-P and NSMRD-N at 5.5% and 8.1% (n=both 18). The worst predicted overall survival for the SMRD-N patients is observed in CD-1 molecular subgroup with a median overall survival of 10.5 years, compared to other groups where it is not reached yet. In the MRD-Pmyeloma patients, there is a significant separation of the clinical outcome between different genetic molecular subgroups. While myeloma MRD-P patients in the PR and MF molecular subgroup have inferior predicted overall survival with a median predicted overall survival with 3.58 and 4.61 years, respectively, myeloma patients in the MS, LB, HY, CD-2, and CD1 molecular subgroup have a relatively better outcome with median predicted overall survival between 6.0 years - not reached yet (p&lt;0.0001). Patients with NSMRD-N status reveal significant differences in clinical outcome. While the 7.5 year predicted overall survival is superior in myeloma patients with CD-2, CD-1, HY molecular subgroup with 81%, myeloma patients in the LB, MS and MF molecular reveal an intermediate predicted overall survival rate with 62% and worse clinical outcome is noticed in the PR molecular subgroup with 38%. (p=0.0002%).
Conclusion:
The MRD status has significant impact on the clinical outcome in multiple myeloma patients. SMRD-N, NS-MRD-N and MRD-P patients have very distinct and specific clinical outcomes depending on their risk profile defined by GEP.