Morphology of Bone Marrow Plasma Cells (BMPC) and Its Relationship with Interphase Cytogenetics and Prognosis in Multiple Myeloma (MM).

BMPC number is important for diagnostic purposes in monoclonal gammopathies whereas BMPC morphology may be used as a prognostic factor in MM. So far, presence of plasmablasts or of BMPC displaying irregular nuclear outline have been related to adverse prognosis in MM. Interphase FISH demonstrates several cytogenetic changes (CG) in MM, and 17p deletion (del17p) and t(4;14) translocation have been recently shown as both major adverse prognostic factors. Up to 70% pts, however, lack both these CG changes, and prognostic parameters, easy-to-perform in routine practice, are needed for these patients. Our aim in this study was to ascertain whether BMPC morphology displayed prognosis in pts who did not demonstrate both adverse CG changes.

Methods. We performed a retrospective analysis of BMPC morphology from 245 patients with MM, uniformly treated within the IFM 99 trials based on presence or absence of high serum beta-2 microglobulin level and 13q- deletion, including IFM 99-02, 99-03, and 99-04. Interphase FISH was performed using previously published methods on sorted BMPC to look for del13q, t(11;14), del17p, and t(4;14) (one to four sets of probes tested in each pt, according to the number of PC sorted in each instance). BM smears were analyzed by at least two out of a group of five morphologists (from different University centers): in each case 100 BMPC were observed, analyzed, and computerized. Comparison between results from observers was performed next: in all instances, if discordance occurred, computerized images were observed by all five morphologists (meeting sessions and Email sessions) leading to consensus.

Median age was 55, and 38% of patients had ISS 2 and 3 in the overall cohort. 72.3%, 6.8% and 20.9% patients came from the 99-02, 99-03, and 99-04 trials, respectively. Pts were classified according to five morphological subgroups: Mature (>66% of PC displaying mature morphology) [n=74 (30.2%)], Small Plasmacytic (>15% of PC displaying mature morphology but high N/C ratio) [n=14 pts (5.7%)], Plasmablastic (>=1% plasmablasts) [n=48 (19.6%)], Irregular Nucleus (>5% PC displaying irregular nuclear outline, PCIN) [n=32 pts (30.2%)], Activated (one nucleolus in >33% PC and/or immature chromatin network in >10% PC) [n=76 (31%)]. Del13 was found in 125 pts (51%), t(11;14) in 43pts (17.6%), del17p in 16 pts (7.0%), and t(4;14) in 52 pts (21.2%). Del17p and t(4;14) were both absent in 181 pts (73.9%). This group had no clinic-biological difference with the overall population of the trials. The median follow up was 49 months (+/-se 0.74). Median Progression Free Survival (PFS) and Overall Survival (OS) were lower in the adverse CG group [displaying either del17p or t(4;14)] as compared to other pts: 21 vs 43 months (p<0.0001) and 42 months vs median not reached (p<0.0001), respectively.

33 pts (51.5%) with adverse CG changes displayed also adverse morphology [either plasmablastic or irregular nucleus]. Combination of adverse CG and adverse morphology led to dismal prognosis: median PFS were 20 months for pts with both adverse CG and morphology prognostic factors, and 36 months for pts with adverse morphology solely (p=0.0001), and median OS were 37 months and not reached (p=0.002), respectively.

For pts without adverse CG changes, presence of plasmablasts or/and of irregular nucleus was related to adverse prognosis [median PFS and OS for both subgroups were 36 months (p=0.034) and 49 months (p=0.039)]. In contrast, mature and activated MM groups both showed better prognosis (median PFS were 45 and 49 months and median OS were not reached).

Small plasmacytic MM group was peculiar, displaying t(11;14) in 85% cases but almost never del17p or t(4;14) (1.6% cases). This subgroup demonstrated here lower PFS and OS [34 months and 45 months, respectively] as compared to the Mature group, but also as compared to the whole t(11;14) population tested [43 months and median not reached, respectively].

Adverse morphological changes and adverse CG changes together lead to dismal prognosis. For pts who do not display del17p and t(4;14) we show here that plasmablasts and irregular nucleus are morphological changes which remain of adverse prognosis. T(11;14) is associated with high number of small PC and is related to intermediate prognosis, whereas quite good prognosis is associated with mature or activated BMPC. Modulation of therapy according to CG but also to BMPC morphology is stressed.

No relevant conflicts of interest to declare.