Impact of Additional Chromosome 1q Copies on Multiple Myeloma Survival Outcomes

Background:

Novel therapies have improved survival outcomes among Multiple Myeloma (MM) patients but a subset with high-risk cytogenetic features, like chromosome 1q abnormalities, continues to be associated with sub-optimal outcomes. Interphase fluorescent in situ hybridization (iFISH) is commonly used in detecting 1q abnormalities which has shown in prior studies to affect prognosis adversely. However, it is unclear if there is any difference between 1q gain (Gain1q, 3 copies of 1q) and amplifications (Amp1q, ≥4 copies of 1q) on survival outcomes within complex metaphase karyotypes as they both are treated in the same fashion with standard therapies. Our analysis aims to discern whether there are distinct survival differences between patients with Gain1q and Amp1q abnormalities in patients with complex and unstable “jumping 1q” aberrations identified in metaphase cytogenetic studies. This analysis should contribute to a deeper understanding of 1q instability and provide prognostic implications for MM management.

Methods:

We conducted a single center retrospective analysis in selected MM patients from 1999-2020 at the University of Arkansas Medical Center with complex G-band karyotypes that were subsequently probed for 1q12 and 1q21 abnormalities by locus specific metaphase FISH. A subset of patients had 1q abnormality discovered around initial diagnosis while others developed during disease progression. Data including patient demographics, type of 1q abnormality (Gain1q vs Amp1q), date of discovery of 1q, which is defined as the first time 1q was identified on FISH were retrospectively collected and univariate analysis of impact of 1q on survival was performed.

Results:

A total of 220 patients were analyzed. The median age at myeloma diagnosis was 59.2 years (30.3 – 84.0 years) and the median age at 1q discovery was 62.5 years (31.9 - 86.3 years). 42.7% (94/220) comprised of females. 80.9% (178/220) comprised of Caucasians. The most common isotype was IgG, and the most common free light chain was Lambda, comprising 53.1%(113/213) and 51.2% (109/213), respectively. Other isotypes comprised of 27.7% (59/213) of IgA, 0.9% (2/213) of IgM and 0.5% (1/213)of IgD. International staging system (ISS) stage was found to be Stage 1, 2 and 3 in 30% (36/120), 35% (42/120) and 35% (42/120) respectively. 33.2% (73/220) were discovered to have 1q abnormality within 1 year of myeloma diagnosis and the rest developed at various timelines during disease progression. 26.4% (58/220) of patients had concomitant IgH translocations. 79.5% (175/220) underwent auto transplant and 46.8% (103/220) underwent second auto transplant. The median follow-up duration in months from diagnosis to last follow-up was 42.5 months (0.05-352 months). At the time point of data collection 52 (23.6%) had Gain1q and 168 (76.4%) had Amp1q, respectively. Among Amp1q 92 (54.8%) had 4 copies and 76 (45.2%) had 5 and more copies. At a median follow-up of 42.5 months, the overall survival for 3, 4, 5+ copies, from MM diagnosis was 57, 50, 31 months and from date of 1q discovery is 11, 7, 7 months respectively. On comparison of OS, Amp 1q has worse survival than Gain 1q from date of discovery (p<0.0307).

Conclusion:

Our study suggests MM patients with Amp1q were noted to have worse prognosis than Gain1q. This distinction underscores the need for further exploration into the mechanisms in the gain of 1q and to improve outcomes in this high-risk subset of patients with amp1q and the jumping 1q instability phenotype.