Predicting Risk of Progression in Relapsed Multiple Myeloma Using Minimal Residual Disease Status and Focal Lesion Assessment with PET-CT
Authors: Baker David , Bimali Milan , Carrillo Luis , Sachedina Archana , Alapat Daisy , Hoque Md shadiqul , Kottarathara Mathew , Parikh Richa , Erra Amani , Mitma Angel , Mathur Pankaj , Tricot Guido , Thanendrarajan Sharmilan , Zangari Maurizio , van Rhee Frits , Schinke Carolina D. 
Published: February 2021

Introduction - Despite improvement in Multiple Myeloma (MM) therapy, most patients will eventually experience disease relapse. The course of relapsed MM can be quite heterogeneous with some patients achieving long-term disease control while others experience rapid successive relapses with short survival. Other than genetic features, there is currently a lack of prognostic markers to guide intensity and duration of therapy in relapsed MM. In the present study, we elucidate the prognostic value of minimal residual disease (MRD) and focal lesion assessment by PET-CT in relapsed patients.
Methods- We investigated 120 MM patients that were diagnosed between 2000-2016 and treated on our Total Therapy (TT) 2-6 protocols, which incorporated multi-agent chemotherapy and tandem transplantation. All 120 patients had achieved a complete remission (CR) after TT and relapsed subsequently after a median of 5 years (0.9-18). Focal lesions were assessed with PET-CT in 112 patients at diagnosis and relapse. Other features investigated included gene expression analysis (GEP) defined by the UAMS GEP70 at diagnosis and relapse (n=75) and FISH at diagnosis (n=84). Once treatment for relapsed disease was initiated, response to therapy, including sequential measurement of MRD by conventional 8 color flow cytometry with a sensitivity of 10-5 was assessed at least every 6-12 months. MM therapy after progression was directed by the treating physician and consisted mostly of combination therapy of a Proteasome Inhibitor with an IMiD and Dexamethasone (62%) or a Daratumumab combination (25%) or other (13%).
Results- Median age at first progression was 65 years and median follow up time was post-relapse was 19 months (range 2.2-65 months). High risk FISH features, including deletion 17p, 1q amplification, t(4;14) and t(14;16) were present in 29% (25/84) of the patients, but were limited in predicting worse PFS post-relapse (p=0.3) and OS (p= 0.5); 75 patients had GEP performed at diagnosis and relapse showing a significant increase (p&lt;0.01) of GEP70 defined high risk at relapse (36%, 26/75) compared to diagnosis (13%, 10/75). GEP70 defined high risk at relapse was significantly predictive of worse PFS (9 months vs 26 months; p=&lt;0.01) and OS (22 months for vs not reached for GEP70 low risk; p&lt;0.01). Focal lesions by PET-CT were found in 45% (50/111) of patients at relapse, 70% (35/50) of those had also focal lesions present at diagnosis. Similar to focal lesion assessment at diagnosis, the presence of at least 3 PET avid focal lesions at relapse confers worse PFS (Median PFS: 12 vs 25 months; p=0.1) and OS (median OS: 25 vs 52 months; p=0.05), albeit the results did not quite reach significance. Response assessment after initiation of treatment was as following: 51% (61/119) patients achieved a CR/sCR, 19% (23/119) achieved a VGPR, 14% (17/119) achieved a PR and 16% (19/119) achieved less than a PR. The achievement of MRD negativity (38%, n= 46/120) was a significant predictor of better PFS (NR vs 15 months; p=&lt;0.01) and OS (NR vs 45 months, p=&lt;0.01). Median time to the achievement of MRD negativity was 12.8 months (range: 1.9 to 36 months). Cox regression model showed that GEP70 defined risk (p&lt;0.01, p&lt;0.01), MRD assessment (p=0.02, p&lt;0.01), age at progression (p=0.02, p&lt;0.01) and the presence of at least 3 focal lesions by PET-CT (p=0.07, p&lt;0.01) were most prognostic for worse PFS and OS in relapsed MM respectively. Time from initial diagnosis to first disease progression had a significant prognostic impact on PFS after first relapse (p=0.04), but not OS (p=0.35).
Conclusion- Current clinical practice for relapsed MM incorporates mainly cytogenetic features that on their own seem to have limited predictive value. Our study suggests that risk classification and prognostication of relapsed MM can be significantly improved by using GEP and focal lesion assessment. Furthermore, achievement of MRD negativity should be the goal in relapsed MM therapy to improve clinical outcome.

Disclosures
van Rhee: EUSA: Consultancy; CDCN: Consultancy; Karyopharm: Consultancy; Adaptive Biotech: Consultancy; Takeda: Consultancy.