Analysis of long-term outcomes in R-ISS stage 2 multiple myeloma with and without the presence of high-risk cytogenetics.
Authors: Joseph Nisha , Hofmeister Craig C. , Heffner Leonard T. , Gupta Vikas Anand , Boise Lawrence , Kaufman Jonathan L. , Dhodapkar Madhav V. , Lonial Sagar , Nooka Ajay K. 
Published: June 2022

8059 Background: The Revised International Staging System (R-ISS) is the current standard for risk-stratification of newly diagnosed myeloma (NDMM), incorporating albumin and β2M with high-risk cytogenetics and/or elevated LDH. (Palumbo et al, JCO 2015) R-ISS stage 2 represents a heterogeneous cohort including myeloma with and without high-risk cytogenetics, a known poor prognosticator. Here, we present a retrospective analysis on outcomes of R-ISS stage 2 NDMM utilizing our institutional database of patients treated at the Winship Cancer Institute of Emory University. Methods: From January 2007 to August 2016, 1,000 consecutive newly diagnosed myeloma patients treated with RVD induction therapy were identified. Demographics, clinical characteristics, and outcomes data for the patients were obtained from our institutional review board-approved myeloma database. Responses were evaluated per IMWG Uniform Response Criteria. Results: The median age of this cohort was 61 years (range 16-83). Other notable patient characteristics include: M/F 54.6%/45.4%, W/AA 61.8%/35.9%; ISS I/II/III 45.8%/30.8%/23.4%. R-ISS I/II/III 39.9%/48.7%/11.5%; Isotype IgG/IgA/FLC 59.2%/19.0%/15.7%; standard risk (SR)/high risk (HR) 71.2%/15.8%. ISS data was available for 75% of patients; R-ISS was available for 41% of patients. HR disease was defined as the presence of t(4;14), t(14;16), del(17p), and/or complex karyotype by conventional metaphase cytogenetics. Frequency of specific CTG abnormalities were 2.8% with t(14;16), 10% with del(17p), and 4.8% with t(4;14). With a median follow up of 88.4 months, the median PFS (mPFS) for the entire cohort was 68.7 months (95% CI 61.8-75.5) and the median OS was 128.9 months. The median PFS for HR vs SR patients was 42.4 months (95% CI 35.7-48.9) vs 80.3 months (95% CI 72.8-87.8). The median OS for SR patients was not reached, and for HR patients was 86.6 months (95% CI 70.1-103.1). The mPFS for R-ISS 1,2 and 3 was 95.4 months (95% CI 73.4-117.5), 56.6 months (95% CI 44.4-68.7), and 31.1 months (95% CI 16.3-45.9). When the R-ISS 2 cohort was divided into those without HR CTG and with HR CTG, the mPFS was 67.1 months (95% CI 53.3-80.8) versus 40.2 months (95% CI 30.1-50.3), respectively. The mOS for R-ISS I/II/III was NR, 122.7 months (95% CI 101.6-143.9), and 60.6 months (95% CI 11.6-109.5). For R-ISS 2 without and with HR CTG, the mOS was 129.1 months and 94.8 months (95% CI 61.3-128.3), respectively. Conclusions: The R-ISS is a validated risk model clearly defining three distinct groups in terms of long-term outcomes. However, these data suggest R-ISS stage 2 can further be characterized into two distinct groups based on the presence or absence of high risk cytogenetics. R-ISS 2 with HR-CTG portends both inferior mPFS and increased risk of death when compared to R-ISS 2 without HR-CTG (HR 2.63 versus HR 1.65), and behaves more similarly to R-ISS 3 disease.