Myelodysplasia-Associated Immunophenotypic Abnormalities of Bone Marrow (BM) Cells in Multiple Myeloma (MM): Are They Present At Diagnosis or Can Be Induced by Lenalidomide?
Authors: Matarraz Sergio , Paiva Bruno , Mateos Maria Victoria , Diez-Campelo María , Perez Estefania , Vidriales María-Belén , López-Corral Lucía , Giraldo Pilar , Hernandez Miguel T. , de Arriba Felipe , De La Rubia Javier , Bargay Joan , Leal da Costa Fernando , Esteves Graça , Lahuerta Juan José , Rosiñol Laura , Blade Joan , Miguel Jesus F. San , Orfao Alberto 
Published: October 2019

Abstract
Abstract 5066
Although secondary primary malignancies such as myelodysplastic syndromes (MDS) have been mostly associated with alkylating therapies in MM, a potential association with lenalidomide has also been recently reported. However, because of the high median age of MM patients, it could be hypothesized that dysplastic features may be already present in MM at diagnosis, but this remains largely unexplored.
Here, we used multiparameter flow cytometry (MFC) for detailed analysis of the distribution and immunophenotypic patterns of maturation of different BM hematopoietic cell compartments at diagnosis (baseline) in 33 MM patients (15 symptomatic and 18 high-risk smoldering MM; SMM). In addition, we analyzed the BM of 22 high-risk SMM patients after 9 courses of lenalidomide plus dexamethasone (LenDex), 8 of whom were from the baseline cohort (these patients were included in the QUIREDEX trial and received an induction phase of 9 four-week cycles of LenDex followed by maintenance with lenalidomide until disease progression).
Overall, multiple phenotypic abnormalities (>1 phenotypic abnormality in ≥1 cell lineages) were found at diagnosis in 4 of 15 (27%) symptomatic MM and 2 of 18 (11%) SMM patients, one of the latter two SMM cases also displaying morphological abnormalities consistent with MDS. In turn, a similar (p>.05) frequency of isolated phenotypic abnormalities (only 1 phenotypic abnormality in 1 lineage -unilineage-, or >1 lineages -multilineage-) was noted at baseline in symptomatic MM (6 of 15; 40%) and high-risk SMM (9 of 18; 50%) cases. Despite this, an imbalance (p=.03) in favor of isolated multilineage vs unilineage abnormalities was observed in symptomatic (67% vs 33%) compared to smoldering cases (22% vs 78%). Particularly, the frequency of phenotypically-altered monocytic cells was significantly higher in symptomatic vs. smoldering MM (80% vs 27%; p=.03), mainly due to aberrant CD56 expression (60% vs 9%; p=.02). Noteworthy, phenotypic abnormalities involving other minor BM cell compartments (e.g. basophils and eosinophils) were restricted to symptomatic MM.
Due to recent concerns about the potential risk for secondary MDS following lenalidomide treatment, we also analyzed the relative distribution and phenotypic patterns of the different BM cell compartments in SMM patients after 9 courses of LenDex. Except for a higher frequency of phenotypically altered erythroblasts (23% vs 0%; p=.03), no significant differences were noted between SMM patients after treatment vs the baseline cohort, concerning the frequency, extent and type of the phenotypic abnormalities detected. In order to further assess whether lenalidomide could either revert the phenotypic abnormalities present in SMM at baseline, or induce more abnormalities, we specifically focused our analysis in those 8 cases with paired studies performed at diagnosis and after 9 cycles of LenDex. Among these cases, three had no abnormalities at diagnosis: one remained without abnormalities after therapy while the two other developed isolated (unilineage and multilineage) abnormalities. Four cases presented isolated unilineage alterations at baseline; after induction one of these four patients reverted to a normal phenotype, two cases showed similar isolated unilineage alterations, and one patient developed multiple abnormalities. Similarly, one patient with isolated multilineage abnormalities at diagnosis, showed the same pattern after therapy.
Our results suggest that a significant proportion of MM and SMM patients already show altered MFC phenotypic features in different BM hematopoietic cell compartments at diagnosis, and do not support a clear association between LenDex therapy and MDS. However, whether or not the altered cells harbor a higher susceptibility for further multistep accumulation of genetic defects remains to be elucidated.

Disclosures:
Off Label Use: lenalidomide is not approved for smoldering myeloma. Paiva:Celgene: Honoraria; Janssen: Honoraria. Mateos:Celgene: Honoraria; Janssen: Honoraria. Lahuerta:Celgene: Honoraria; Janssen: Honoraria. Rosiñol:Celgene: Honoraria; Janssen: Honoraria. Blade:Celgene: Honoraria; Janssen: Honoraria. San Miguel:Celgene: Honoraria; Janssen-Cilag: Honoraria.