Pb2096 high plasma cell proliferative index is associated with a dominant expansion of a single immunophenotypic subclone and predicts response to lenalidomide/dexamethasone in relapsed multiple mieloma

Background: Plasma cell proliferative index (PCPI) is an easily available prognostic parameter as well as a reliable progression indicator in multiple myeloma (MM). Despite this, there are no data regarding the utility of PCPI as a routine indicator to predict the response to second‐line lenalidomide based treatments. Aims: Study of theprognostic value of PCPI in patients with relapsed MM treated with lenalidomide/dexamethasone (len/dex) compared to other available indicators (International Staging System disease stage, high risk cytogenetics, serum albumin, LDH, β 2 ‐microglobulin, depth and duration of the previous response) as well as to immunophenotypic features. Methods Study design: Observational retrospective study in a cohort of 108 patients with relapsed MM treated with len/dex (Jun 2014‐Dec 2018). The median age was 69.7 years (range, 44 to 90) with 55 males and 53 females. Study variables: Immunophenotype, PCPI and genetics using fluorescent in situ hibridation were performed in bone marrow specimens before the start of len/dex. Responses to len/dex were evaluated after 6 cycles, also recording time to progression. The primary efficacy endpoint was the progression‐free survival (PFS), and secondary efficacy endpoints included overall response rate (ORR) and rates of very good partial response or better (CR + VGPR). Flow‐cytometry: Flow cytometer FACSCanto II, BD CA was used. Study of PCPI (percentage of plasma cells in S‐phase) was performed using a single propidium iodide/CD138 BV421 double‐staining technique (fig 1‐A). Plasma cell subclones were identified using two specifically designed 8‐color combinations as previously described. Statistical methodology: χ 2 and U Mann‐Whitney tests were used to estimate statistically significant differences. Survival curves were plotted using the Kaplan‐Meier method, and differences were assessed with the log‐rank test. For multivariate analysis, stepwise Cox proportional hazard and logistic regressions were performed with SPSS Version 15.0 software. Results: A cut‐off PCPI value of 8% discriminates between two different groups of patients according to the detected subclones (mean of 1.14 subclones in PCPI> 8% versus 1.96 in PCPI≤8%, p < 0.05%). PCPI value was not significantly correlated with the other studied variables such as R‐ISS or genetics. Univariate analysis demonstrated that only PCPI and R‐ISS staging system were significantly associated with ORR and PFS. Overall responses (71.9%) were lower in MM > 8% (57.2% vs 79.3%; P < .05). The rates of best responses (CR + VPGR: 29.5%) were also lower in MM > 8% group (8.3% vs 39.3%; P < .01). PFS (median 24.2 months) were shorter in MM > 8% (11.1 months, vs 38.2 months p <. 001, see figure 1). In the multivariable analysis only PCPI > 8% is associated with PFS (Hazard Ratio 8.1‐ IC95% 7.2‐9.0) and predicts the duration of the response independently from R‐ISS, genetics, number of subclones detected and the other studied variables. Summary/Conclusion: Plasma cell proliferation measurement using PCPI is an easy technique that provides prognostic information in relapsed MM patients independently of the other risk factors. The expansion of a single subclone seems to reflect a loss of intraclonal equilibrium and may be an important factor related to the kinetics of disease progression. The perceived impact of the PCPI in the efficacy of len/dex combination must be better studied in order to understand if subsequent modifications in lenalidomide containing regimens should be considered in selected patients. image