Changes in Serum B-Cell Maturation Antigen Levels Rapidly Indicate Changes in Clinical Status Among Multiple Myeloma Patients Undergoing New Treatments

Introduction : B-cell maturation antigen (BCMA) is a protein that is expressed on the plasma cells from patients (pts) with multiple myeloma (MM). Our group has previously shown that MM pts have higher levels of serum (s) BCMA than healthy subjects and that sBCMA levels can be used to monitor the disease course of MM pts. Notably, we have shown that the half-life of soluble BCMA is only 24-36 hours which is much shorter than sM-protein, and its levels are independent of renal function. With the expanding therapeutic options for the treatment (Tx) of MM, there is a need for more rapid and accurate ways to assess the efficacy of new therapies. To this end, we compared changes in levels of sBCMA with sM-protein among MM patients undergoing new treatments.

Methods : Serum was obtained at least weekly during each pt's first cycle of a new therapy (C1) and the first day of their second cycle (C2D1) and at least monthly thereafter from all MM pts receiving a new Tx regimen (n=83) at a single clinic from March 2015 to July 2017. sM-protein levels were measured, and sBCMA levels were determined using an enzyme-linked immunosorbent assay (R&D Systems; Minneapolis, MN). Percentage changes in sBCMA and sM-protein throughout Tx were determined relative to levels measured at their start of treatment (C1D1). Kaplan-Meier analysis was used to assess differences in time on therapy (TOT) based on the percentage changes in sBCMA levels at cycle 1 day 8 (C1D8) and day 15 (C1D15) of the pt's new Tx. All patient samples were obtained following proper informed consent in accordance with the Declaration of Helsinki.

Results : Forty-nine MM pts (IgG [n=37], IgA [n=12]) receiving 83 Tx regimens were analyzed. Regimens that resulted in a > 25% increase in sBCMA by C1D8 (n=10) had a shorter median TOT than all other regimens (n=71; median TOT: 1.73 months vs. 5.76 months; P=.0037). Regimens that showed a > 25% decrease in sBCMA levels on C1D8 (n=27) had a longer TOT (median TOT: 6.91 months) when compared with all other regimens (median TOT: 2.89 months). In contrast, sM-protein levels did not show > 25% changes at these early time points.

For those patients who achieved at least a minimal response (MR) using IMWG criteria (n=30), the time to achieve at least a 25% decrease in sBCMA was much shorter (median 7 days) than the time for sM-protein (median 21 days; P=.0004). For those that progressed during the first cycle (n=5), the time to achieve at least a 25% increase in sBCMA was similarly much shorter (median 7 days) than the time for sM-protein (median 21 days).

Because the half-life of IgG is long (approximately 3-4 weeks), we studied the 64 regimens among the 37 pts with IgG MM. Twenty-four (38%) achieved at least an MR. Among these pts, sBCMA levels reduced by an average of 31% on C1D8, whereas sM-protein decreased by an average of only 7.6%.The regimens that resulted in a > 25% decrease on C1D8 (n=23) had a longer TOT than regimens that did not reach this reduction (n=41; median TOT: 7.8 months vs. 2.8 months, P=.023). Those regimens with a confirmed > 25% increase in sBCMA levels (n=6) at C1D15 had a shorter TOT than those with a confirmed > 25% decrease in sBCMA levels (n=22) at C1D15 (median 0.9 months vs. 6.9 months, P <.0001), and had a shorter TOT than all other Tx regimens (n=75; median 0.9 months vs. 5.8 months, P <.0001).

There were six regimens for which pts did not achieve a response during the first cycle but did so during subsequent cycles. At C1D8, sBCMA levels decreased > 25% in four pts and 24% in another pt. During the second week of therapy, sBCMA levels continued to decrease in these five pts. In contrast, sM-protein did not show a response (> 25% decrease) in any of these regimens during C1 and decreased by an average of only 9.7% and 13.3% on days 8 and 15, respectively.

Conclusions: We have shown that relative changes in sBCMA levels from baseline can much more rapidly determine changes in clinical status than the standard sM-protein biomarker among MM pts starting new treatments. By C1D8, sBCMA establishes changes in clinical status whereas sM-protein takes much longer to show the effect of treatment on response status. In addition, a > 25% increase or decrease in sBCMA levels at C1D8 indicates a much shorter or longer TOT, respectively for these pts. Thus, relative changes in sBCMA levels among MM pts on new therapies allows more rapid determination of changes in their clinical status, and these early changes predict the length of time on those treatments.