Development of a New Risk Stratification System for Patients with Newly Diagnosed Multiple Myeloma Using R-ISS and 18F-FDG PET/CT
Authors: Cho Hee Jeong , Kim Juhyung , Lee Jung Min , Baek Dong Won , Jung Sung-Hoon , Yoon Sang Eun , Park Sung-Soo , Kim Do Young , Shin Ho-Jin , Mun Yeung-Chul , Yi Jun Ho , Kim Hyo Jung , Kim Da Jung , Lee Ho Sup , Bae Sung Hwa , Sohn Sang Kyun , Min Chang-Ki , Kim Kihyun , Lee Je-Jung , Lee Yoo Jin , Jo Jae-Cheol , Moon Joon Ho 
Published: November 2021

Abstract
Background
A high number of focal lesions (FL) detected using PET/CT at diagnosis were found to be associated with adverse prognosis along with Revised International Staging System (R-ISS). In present study, we combined R-ISS with FL using PET/CT to design a reliable and easily applicable risk stratification system in patients with newly diagnosed MM (NDMM).
Methods
In training cohort, the data of 380 patients with NDMM who underwent 18F-fluorodeoxyglucose (18F-FDG) PET/CT upon diagnosis from 10 hospitals of the Korean Multiple Myeloma Working Party were retrospectively analyzed. All patients were classified by R-ISS and were treated by frontline therapy with proteasome inhibitors (PI) and/or immunomodulatory drugs (IMiD). The K-adaptive partitioning algorithm was adopted to develop the new risk groups with homogeneous survival. Sixty-seven patients in external validation cohort were additionally collected to confirm reproducibility of the new risk groups.
Results
In the training cohort, 199 patients (52.4%) showed FL &gt; 3 using PET/CT at diagnosis. R-ISS stages I, II, and III were 78 patients (20.5%), 230 (60.5%), and 72 (18.9%), respectively. The combined R-ISS with PET/CT newly allocated NDMM patients into four groups: R-ISS/PET stage I (n=30; R-ISS I with FL≤3), stage II (n=149; R-ISS I with FL&gt;3 and R-ISS II with FL≤3), stage III (n=166; R-ISS II with FL&gt;3 and R-ISS III with FL≤3), and stage IV (n=35; R-ISS III with FL&gt;3). The new R-ISS/PET showed significantly pronounced survival differences according to stages. Two-year overall survival (OS) rates were 96.6%, 89.5%, 75.0%, and 57.9% (p &lt; 0.001), and 2-year progression-free survival (PFS) rates were 86.9%, 65.1%, 41.9%, and 15.2% (p &lt; 0.001) in stages I, II, III, and IV, respectively. The prognostic role of the R-ISS/PET for survival outcomes was also confirmed in different subgroups classified by transplant eligibility and by types of treatments. In the external validation cohort, the new R-ISS/PET was successfully implemented. Two-year OS rates for were 100%, 89.9%, 82.6%, and 42.0% for R-ISS/PET I, II, III, and IV, respectively (p = 0.001). PFS rates at 2 years for each R-ISS/PET were 100%, 74.5%, 57.9%, and 25.6%, respectively (p = 0.004). In the multivariate Cox analysis for survival outcome, R-ISS/PET was a significant factor and could predict long-term outcomes with regard to OS: stage II vs. I (HR 2.50, p = 0.215), (ii) stage III vs. I (HR 5.11, p = 0.025), and (iii) stage IV vs. I (HR 10.3, p = 0.003) and PFS: (i) stage II vs. I (HR 2.21, p = 0.005), (ii) stage III vs. I (HR 4.57, p &lt; 0.001), and (iii) stage IV vs. I (HR 9.48, p &lt; 0.001).
Conclusion
The new R-ISS/PET had a remarkable prognostic power for estimating the survival outcomes of patients with NDMM. This system helps discriminate patients with a good prognosis from those with a poor prognosis more precisely. Thus, R-ISS/PET is applicable for identifying heterogeneous manifestation of clinical MM.
Figure 1 Figure 1.

Disclosures
No relevant conflicts of interest to declare.