Relative Clone Size By FISH of Both Del(13q) and Del(17p) Independently Impact Overall Survival
Authors: Culver Soluman , Williams Nita , Sharma Nidhi , Efebera Yvonne A , Rosko Ashley E , Benson Don M , Hofmeister Craig C 
Published: October 2019

Abstract
Introduction: Interphase FISH is used in the risk stratification of newly diagnosed multiple myeloma. The presence of high-risk cytogenetics is a key component of the Revised International Staging System (R-ISS), despite the fact that precise cutoffs for positivity have yet to be standardized and usage differs between institutions and reference labs. For deletion 17p, Avet-Loiseau et al (2007) used a 60% cutoff and An et al (2015) used 50% as a positive cutoff. For del(13q), Avet-Loiseau used del(13q14) 74% and An et al used 10%.
Methods: Since 2011, consecutive patients in Ohio State University's myeloma clinic were consented to participate in the Ohio Myeloma Initiative (NCT01408225), an observational registry. We identified patients with multiple myeloma who had a bone marrow biopsy performed within six months of diagnosis. All FISH was performed after CD138 magnetic separation. We assessed the impact of del17p (P53) and del13q (RB1) on overall survival (OS).
Results: 1,029 myeloma patient were identified, 767 patients with a FISH study within 6 months of diagnosis with an age range of 26-91. 39% of patients had an ISS 1, 34% had ISS 2, and 27% had ISS 3 disease. The median duration of follow-up for these patients was 3.17 years. 82.7% of patients had data regarding del13q, 82.5% had data regarding del17p, and 78.4% had data regarding both del13q and 17p.
Using iterative survival analysis we calculated a maximal effect of del17p on OS occurring at 50% positivity on interphase FISH. Additionally, our data suggests that positivity for del13q is maximal at 40% positivity and a predictor of moderately decreased overall survival independent of 17p status. Moreover, our data suggests that intermediate FISH positivity for 17p does have a dose-dependent effect on OS with the presence of even non-dominant del17p clones exerting a measurable influence similar in effect size to del13q.
Analyzing those patients with del13q >40% that were negative for del(17p) and t(4;14) (n=27), these patients suffered an inferior overall survival when compared to patients that were negative for del13q, del17p, and t(4;14) (n=116), p=0.0042.
Conclusions: These findings suggest that specific cutoffs for both the del(13q) and del(17p) clones at diagnosis independently have statistically significant effects on overall survival. At the meeting, additional analyses will demonstrate the percentages of del(13q) that impact similarly on overall survival to those patients with del(17p) alone. A scoring system will be created to estimate hazard ratios for relative clone size % of del(13q) and del(17p) separately and when combined.
Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures
Hofmeister: Arno Therapeutics, Inc.: Research Funding; Signal Genetics, Inc.: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Janssen: Pharmaceutical Companies of Johnson & Johnson: Research Funding; Karyopharm Therapeutics: Research Funding; Incyte, Corp: Membership on an entity's Board of Directors or advisory committees; Takeda Pharmaceutical Company: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees.