Expression of B Cell Maturation Antigen (BCMA) and Transmembrane Activator and Caml Interactor (TACI) Are Correlated and Can be Targeted at Multiple Points during the Course of Multiple Myeloma

Therapies directed to specific antigens expressed on multiple myeloma [MM] cells are desirable given the high likelihood of relapse in patients [pts] and the toxicities associated with current treatment options. BCMA and TACI are surface proteins of interest as they promote the survival and proliferation of mature plasma cells. Given that their gene expression by RT-PCR is higher in MM cells compared to normal plasma cells [PCs], and the association of increasing serum BCMA levels with disease progression, we sought to assess if similar patterns were seen on PCs measured by flow cytometry. We specifically examined changes in BCMA/TACI expression (frequency and intensity) with progression of MM, whether expression of BCMA and TACI are correlated, and if levels of their expression correlates with PC burden as determined by IHC.

Flow cytometric data were collected using a validated multi-color panel used for clinical assessment of PC burden, with the addition of antibodies to BCMA and TACI, by the Flow Cytometry Clinical Laboratory at our Center. In total, 29 myeloma pts samples were analyzed, and a retrospective chart review of these individuals was performed under an IRB-approved protocol.

Pts were separated into 4 sets of groups based on their number of prior lines of therapy, status of disease, prior autologous stem cell transplant [ASCT], and early relapse post-ASCT. Frequency and intensity of BCMA/ TACI expression were examined across these groups by assessing the following variables within each set of groups: % BCMA⁺ total PCs, % TACI⁺ total PCs, as well as BCMA/TACI mean fluorescence intensity (MFI). Correlation analysis was performed to assess whether BCMA expression correlated to TACI expression (n=25). To evaluate the correlation of PC burden in BM aspirate with antigen expression, correlation analysis was performed between PC burden and the BCMA/TACI expression (frequency and intensity). Statistical analysis was performed using GraphPad Prism 7 Software. Statistical tests included 1 way ANOVA (comparison of ≥3 means), student t-test (comparison of 2 means), and Pearson correlation (correlation analysis).

The median patient age was 62, with 65.5% male and 34.5% female. IgG kappa (37.9%) was the most common type of MM. 17.2% were newly diagnosed, 27.6% had stable disease, 20.7% were in remission, and 39.5% had relapsed/refractory disease. A majority of pts (41.4%) received 1-3 prior lines of therapy. 51.7% underwent ASCT, 10% of which had relapsed, with 13.8% of relapses occurring ≤ 1 year post-ASCT.

Four of 29 pts were excluded from data analysis due to insufficient PCs as detected by flow cytometry. ≥Four lines of therapy (n=9), relapsed/refractory disease (n=8), relapse post-ASCT (n=7), and relapse ≤ 1 year post-ASCT (n=2), were all markers of disease progression. There were no significant differences in BCMA/ TACI expression (frequency and intensity) among these groups and their counterparts, but less variability of expression was observed in newly diagnosed pts.

There was a positive correlation between % BCMA⁺ total PCs with % TACI⁺ total PCs (r= 0.6051, p= 0.0014, n=25), and BCMA MFI with TACI MFI (r=0.5191, p=0.0078, n=25). A similar relationship was noted where aberrant PCs were identified (r=0.9199, p= 0.0094, n=6).

Of the patients without minimal residual disease, there was a negative correlation between PCs in BM aspirate with % TACI⁺ total PCs(r= -0.5211, p= 0.0320, n=17). There were no significant correlations with PCs in BM aspirate and % of BCMA⁺ total PCs, BCMA MFI, and TACI MFI. BCMA/TACI expression was spread across a broad range for pts with ≤ 10% clonal PCs in BM aspirate, and a narrower range in pts with > 10% clonal PCs in BM aspirate.

BCMA and TACI expression alone are not markers of progression of MM and should be used in conjunction with other antigens associated with progressive disease. However, the persistent and frequent expression of BCMA and TACI identified suggests that BCMA and TACI directed therapies can be used at multiple points during the course of disease. Since expression seems to be more uniform in newly diagnosed patients, patients treated at later time points may benefit from quantitative assessment of BCMA and/or TACI expression prior to receiving therapies targeting these molecules. Finally, expression of BCMA and TACI are correlated, but it remains to be seen if loss of one antigen could precipitate obligate loss of the other.