Plasma Cell Proliferation Using Ki67 Antigen Expression Defines Subgroups Related to Short Survival in Multiple Myeloma Especially with Low Beta-2 Microglobulin.
Authors: Gastinne Thomas , Leleu Xavier , Moreau Anne-Sophie , Andrieux Joris , Lai Jean-Luc , Coiteux Valérie , Yakoub-Agha Ibrahim , Bauters Francis , Moreau Philippe , Harousseau Jean-Luc , Facon Thierry , Zandecki Marc 
Published: April 2020

Abstract
Background: The current most powerful prognosis model in Multiple Myeloma (MM) combines beta-2 microglobulin (b2m) with albumin, corresponding to the International Staging System (ISS). However, the prognosis of patients within the group I of ISS (high albumin and low b2m) may vary. Proliferative activity of plasma cells has been previously related to prognosis in MM, but methods proposed so far are difficult to apply in routine practice. Ki-67 is a nuclear protein associated with cell proliferation, and its expression is reported as a powerful prognosis marker in solid tumours and several hematological malignancies. We retrospectively evaluated the % of bone marrow plasma cells (BMPC) expressing Ki-67 antigen (Ki67 index) in a series of 174 untreated patients with MM at diagnosis and we looked for its prognostic value on survival in MM.
Method: Ki-67 index was determined after double immunocytochemistry on PC from BM cytospins (ABC peroxidase to identify cells expressing Ki-67, and alkaline phosphatase to identify PC expressing either Kappa or Lambda light chain). Conventional cytogenetic study and interphase FISH (research of Rb1 gene deletion) were performed in 114 and in 128 pts respectively.
Results: Median survival (± se; months) for pts with stage III, II, and stage I of ISS score were 20 (± 3), 41 (± 3), 51 (± 3) months, respectively (p&lt;0.001). Median Ki-67 index (± se) was of 3.0% (± 1.2), 6.1% (± 1.2), and 6.5% (± 1.4) in ISS stage I, stage II, and stage III patients, respectively (p&lt; 0.004). Independently of the ISS staging system, Ki-67 index ≥ 4% was highly predictive of adverse prognosis, with a median survival of 26 ± 4 months and of 49 ± 10 months over and under that value, respectively (p &lt; 0.0001). B2m (threshold at 3 mg/L) gave identical results than Ki-67 index (p &lt; 0.001), whereas chromosome 13 deletion (del 13) was less powerful (p&lt; 0.02). Ki-67 index correlated well with several markers of intrinsic malignancy, with markers of tumour burden, but it was unrelated to age, serum creatinine and b2m. There was a strong relationship between hypodiploidy and BMPC proliferation: within the group of pts displaying Ki-67 index ≥ 4%, 93% pts were found hypodiploid (p &lt; 0.0001). Within ISS stage I, median survival [± se; RR of death (95%CI)] was of 31 ± 4 months [2.65 (1.5–4.6)] and of 67 ± 6 months in patients with Ki-67 index ≥ 4% and &lt; 4%, respectively (p &lt; 0.001). Chromosome 13 deletion also delineated two groups within ISS stage I pts, but the difference did not reach statistical significance (p = 0.243). Finally, the combination of Ki-67 to b2m produced an efficient prognostic model that appeared the most effective in our series compared to known models such as b2m/chr 13 deletion and ISS. The -2Log (likelihood) scores calculated on 155 patients were 1107.885, 1113.256 and 1116.829 for Ki-67/b2m model, ISS model and b2m/del13 model, respectively.
Conclusion: Ki-67 index is easy to perform in routine practice, and is a good prognostic marker, which provides additional survival prognostic information to b2m into the ISS model.