Concomitant Deletion of Short Arm (del 1p) and Amplification or Gain (1q21) of Chromosome 1 By Fluorescence in Situ Hybridization (FISH) Is Associated with Poor Clinical Outcome
Authors: Mohan Meera , Gong Zimu , Kendrick Samantha , Thanendrarajan Sharmilan , Schinke Carolina , Alapat Daisy , Tricot Guido , Zhan Fenghuang , van Rhee Frits , Sawyer Jeffery R. , Tian Erming , Zangari Maurizio 
Published: November 2021

Abstract
Introduction- Chromosome 1 abnormalities in multiple myeloma (MM) are increasingly recognized as high risk defined features. While there is robust data on 1q21 gain and amplification (amp), the clinical characteristics and outcome of patients with del 1p is less defined. Novel agents are incorporated into a backbone of multi-agent chemotherapy and tandem autologous stem cell transplantation (ASCT) in successive Total Therapy (TT) protocols for MM patients. We hereby report the prognostic value of del 1p by FISH at enrollment in subjects treated on TT protocols.
Methods: (FISH was performed on bone marrow obtained at the time of first visit to our institution or initial diagnosis. FISH probes were generated from specific BAC DNA clones for AHCYL1 gene locus (1p13.3) and CKS1B locus (1q21). MM cells were identified post-hybridization using isotype specific antibody conjugated with 7-amino-4-methylcoumarin-3-acetic acid (AMCA) to stain Ig-Kappa or Ig-Lambda light chain in cytoplasm (cIg) of myeloma tumor cells. The FISH signals in 100 myeloma cells were recorded. For this analysis, 3 copies of 1q21 are considered as 1q21 gain and ≥ 4 copies as 1q21 amp. A 20% cutoff point was used for detection of significant abnormalities, i.e. del 1p and 1q21 gain and amp. A multivariable logistic regression model was used to examine the combined effects of clinical variables on progression free (PFS) and overall survival (OS).
Results- A total of 1133 patients were included in this analysis. The median age was 60 (range 30.2-75), 434 (38.3%) patients were female and 106 (9.4%) were African Americans. ISS stage III disease accounted for 287 (25.3%). GEP70 high-risk was noted in 160/1133 (14.1%) of all patients. Of all patients, 1084 (95.7%) had at least one ASCT and 812 (71.7%) had tandem upfront ASCT. Metaphase cytogenetic abnormalities were noted in 548 (48.4%). While del 1p was detected in 220 (19.4%) patients, 1q21 gain or amplification were observed in 300 (26.5%) and 150 (13.2%) patients, respectively. Isolated 1q21 gain and amplification without del 1p were seen in 235 (20.7%) and 121 (10.7%) patients. Overall, there was enrichment of high-risk features such as ISS stage III disease (5.7% vs 10.9% p=0.049), GEP70 high-risk (8.4% vs 36.8%), GEP 70 subtypes such as MF (4.6% vs 8.2%), MS (10.5% vs 13.6%) and PR (11.3% vs 22.7%) and abnormal cytogenetic abnormalities (45.7% vs 59.5% p=&lt;0.01) in the group with del 1p . The median progression free survival (57 vs 39m; p= &lt;0.0004) and overall survival (131 vs 89 m; p=&lt;0.0013) were inferior in the subgroup with del 1p. On multivariate analysis, presence of ISS stage III disease, GEP high-risk, 1q21 gain and amplification were significant while presence of del 1p did not emerge as independent predictors of PFS or OS. Next, we looked at concomitant 1q21 gain and amp in the context of del 1p. del 1p with 1q21 gain or amp was observed in 65 (5.7%) and 29 (2.5%) patients, respectively. The PFS of the group with combined del 1p/1q21 gain and del 1p/1q21 amp were 25m and 35m respectively compared to 44 m with 1q21 gain and 37m with 1q21 amp alone. The OS of the group with both 1 del 1p/1q21 gain and del 1p/1q21 amp were dismal at 59m and 84 m respectively compared to 108 m with 1q21 gain and 76 m with 1q21 amp alone (Fig 1).
Conclusion: Deletion of short arm of chromosome 1p was observed in 19% of MM patients. Concomitant del 1p with 1q21 gain and /or amp was present in 8% of patients. The PFS and OS of patients with combined del1p/1q21gain abnormalities was significantly worse compared to del 1p alone and 1q21 gain alone and thus identifies a subset of patients with poor clinical outcome.
Figure 1 Figure 1.

Disclosures
Mohan: Medical College of Wisconsin: Current Employment.