Impact of Revised International Staging System 2 (R2-ISS) Risk Stratification on Outcomes of Patients with Multiple Myeloma Receiving Autologous Hematopoietic Stem Cell Transplantation
Authors: Alzahrani Kamal , Pasvolsky Oren , Wang Zhongya , Milton Denái R. , Tanner Mark R. , Bashir Qaiser , Srour Samer A. , Saini Neeraj Y. , Lin Paul , Ramdial Jeremy , Nieto Yago , Lee Hans C. , Patel Krina K. , Manasanch Elisabet E. , Kebriaei Partow , Thomas Sheeba K. , Weber Donna M. , Orlowski Robert Z. , Shpall Elizabeth J. , Champlin Richard E. , Qazilbash Muzaffar H. 
Published: December 2023

Background: The second revision of the International Staging System (R2-ISS) is a new and simple tool to risk stratify newly diagnosed multiple myeloma (NDMM) patients. Our aim in this study was to evaluate the utility of R2-ISS in NDMM patients who received upfront autologous hematopoietic stem cell transplantation (auto-HCT).

Methods: We conducted a retrospective analysis of all NDMM patients who underwent upfront auto-HCT between 1988 and 2021 at MD Anderson Cancer Center and had available data for calculation of R2-ISS, including albumin, β-2 microglobulin, LDH, and fluorescence in-situ hybridization (FISH) analysis at diagnosis. High-risk cytogenetic abnormalities (HRCA) were t(4;14), del(17p), and 1q21 gain or amplification, as detected by FISH. The primary endpoints were progression-free survival (PFS) and overall survival (OS), and the secondary endpoint was hematological response after auto-HCT.

Results: A total of 1291 patients were included, with a median age of 62 years (range 29 - 83) and 60% were male. Four hundred-and-nineteen patients (32%) had HRCA. Most patients received either bortezomib, lenalidomide, and dexamethasone (VRD) (34%) or carfilzomib, lenalidomide, and dexamethasone (KRD) (25%) induction regimens, and most patients (95%) received melphalan based conditioning. The distribution of R2-ISS stages in our cohort was as follows: 123 (10%) stage I, 471 (36%) stage II, 566 (44%) stage III, and 131 (10%) stage IV. A total of 1027 (80%) patients received post auto-HCT maintenance, mostly lenalidomide with or without dexamethasone (n = 785, 61%) (Table 1).

With a median follow-up of 42.2 months (range 0.3 - 181.0) for the entire cohort, the median PFS was 73.0, 65.2, 44.0, and 24.8 months ( P &lt; .001) and the median OS was 130.8, 128.5, 94.2, and 61.4 months ( P &lt; .001) for patients with R2-ISS stages I, II, III, and IV, respectively (Figure 1). On multivariable analysis (MVA) for PFS, using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (hazard ratio [95% CI], 1.11 [0.76-1.63]; P = .59), but there was a significant worsening in PFS for R2-ISS stage III (1.55 [1.05-2.29]; P = .028) and R2-ISS stage IV (2.04 [1.24-3.36]; P = .005). On MVA for OS, again using R2-ISS stage I as the reference group, there was no significant difference for R2-ISS stage II (1.33 [0.74-2.40]; P = .34) or R2-ISS stage III (1.75 [0.97-3.17]; P = .06), but there was a significant worsening in OS for R2-ISS stage IV (2.43 [1.18-5.01]; P = .017).

On MVA, other measures significantly associated with worsening PFS were year of auto-HCT &lt; 2010, lambda light chain disease subtype, presence of HRCA, prior MRD/response other than negative/≥CR, and not achieving MRD negative/≥ CR post auto-HCT. For OS, other measures significantly associated with worsening survival on MVA were presence of HRCA, HCT-CI &gt; 3, having at least one bone lesion, not achieving CR at best response, and not receiving post auto-HCT maintenance therapy.

Conclusion: Our study demonstrates that R2-ISS is a reliable prognostic tool for NDMM in a large cohort of patients who received standard anti-myeloma treatment, including modern induction regimens, upfront auto-HCT, and post-transplant maintenance.