Late Relapsing Multiple Myeloma ≥ 10 Years after Treatment on Total Therapy Protocols Are Associated with Good Outcome
Authors: Mohan Meera , Kendrick Samantha , Pandey Yadav , Parikh Richa , Farmer Phil , Kottarathara Mathew , Hoque Shadiqul , Mitma Angel , Thanendrarajan Sharmilan , Schinke Carolina D. , Tricot Guido , Zangari Maurizio , van Rhee Frits 
Published: November 2020

Introduction
Novel agents are incorporated into a backbone of multi-agent chemotherapy and tandem transplantation in successive Total Therapy (TT) protocols for multiple myeloma (MM) patients. The TT protocols extend the duration of remission with a significant proportion of patients achieving long-term disease control. However, a small percentage of patients have documented late relapse and we theorize that these relapses are indolent with overall good clinical outcome. While even a late relapse is seemingly an undesirable outcome, defining the clinical implications is imperative to understanding the impact on long-term prognosis and management.
Methods
Our MM database was interrogated to identify patients that presented with relapsing disease ≥ 10 years from diagnosis and were treated on TT protocols. All patients had myeloma markers every 2 to 3 months and bone marrows with either PET-CT or MRI at least once a year. In the group of patients with documented relapse, we obtained the pattern of relapse, clinical and laboratory markers, cytogenetics, FISH, gene expression profile (GEP), bone marrow (BM) minimal residual disease (MRD), imaging (PET-CT and MRI, use of salvage transplant, and response assessment including best response to treatment. Patterns of relapses were evaluated based on elevated serum myeloma markers, BM plasmacytosis and presence of macrofocal relapse/extramedullary disease. Clinical relapses were classified based on the International Myeloma Working Group criteria. Indolent relapse was defined as a biochemical relapse with a rising M-protein or free light chains, less than 30% bone marrow plasmacytosis involvement, absence of focal lesion on imaging and of CRAB criteria, low riskGEP70 signature at relapse or no abnormal metaphase cytogenetics.
Results
A total of 2055 patients were enrolled and treated on successive TT protocols (TT1 to TT7) of which 658 patients had ≥10 years follow up from initial study enrollment. Among these 658 patients, 8% (53/658) had a clinical relapse ≥ 10 years from diagnosis. The median time to clinical relapse was 11. 8 years (range, 9.8 - 17.6). Median age at the time of relapse was 67.7 years with 28% being females.
Gene expression profiling showed that 45% (24/53) belonged to the molecular CD2 and LB subgroups. The most common pattern of relapse is with BM plasmacytosis in 49% (26/53) with 36% (19/53) presenting with CRAB clinical features. Focal lesions by MRI and/or CT-PET were present in 35.8% (19/53). Overall, 56.6% (30/53) of patients had indolent relapses; of these 9 and 7 belonged to the CD2 and LB molecular subgroups, respectively. BM MRD assessment by 8-color flow cytometry was available in 17 patients and MRD positivity preceded clinical relapse by a median 17.9 months (range: 0 - 60.8). Forty-one patients required treatment for disease relapse with 11 patients managed expectantly without treatment. While most patients (73.1%, 30/41) received initial treatment with either PI/IMiD/PI IMiD combinations, 8 patients later underwent salvage ASCT. A response of ≥ VGPR was attained in 70% (31/47) of the treated patients with the large majority (87%) achieving a sCR/CR. The overall survival from relapse at 5 years was 73.3% (95% CI: 55.0% to 85.1%). A total of 14/53 patients died during follow-up;7 patients died to progressive disease; 6 of these 7 presented with focal lesions detected on imaging and had an aggressive relapse. Three patients died to treatment related complications, 1 had an unrelated pneumonia, the cause of death was indeterminate in 2 and unknown in 1. Overall, in these 14 patients, median time to death from initial diagnosis was 15.4 years (range: 11.8 - 18.0) and a median time to death from relapse was 3.2 years (range: 0.3 - 6.0).
Conclusions
Late relapses (&gt;10 years) in MM are a rare event occurring in 8% of long-term survivors and accounting for 2.6% of all patients treated on the TT protocols. Intriguingly, most patients with late relapsing MM belong to the GEP subtype LB and CD2 and accounted for 51% of the indolent relapses. These findings have clinical implications and emphasizes the importance of extended and close follow-up even in patients with prolonged clinical remission.

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