At first glance, the monitoring of multiple myeloma (MM) seems straightforward compared to other types of cancers. The tumor cells usually keep the innate ability of normal plasma cells (PC) to synthetize large quantities of monoclonal immunoglobulins and/or produce free immunoglobulin light chains (FLC), which are present in the serum of patients and can then be utilized to define the well-established International Myeloma Working Group (IMWG) response criteria (1, 2). However, approximately 3% of MM patients present without conventionally measurable serum markers. Several different etiologies can account for this occurrence. Defects in the immunoglobulin synthesis result in non-producer patients, in whom even the use of free light chain assay will not reveal measurable disease (3–7). Another subgroup of patients has defects in the secretion of immunoglobulins, leading to oligosecretory multiple myeloma. The defining criteria for these patients (serum M-protein of <10.0 g/L, urine M-protein of <200 mg/24 h, and free light chain of <100 mg/L) can make reliable measurements and therefore the monitoring of disease activity challenging. This is a particularly common problem in AL amyloidosis. The exact frequency of non- and oligosecretory myeloma is difficult to quantify, as with each subsequent relapse the tendency of clonal evolution into FLC only or true non-secretory myeloma increases. This often goes parallel with the development of other high risk features, such as genomic instability, extramedullary disease manifestations and drug resistance (8).

Oligo- and non-secretory myeloma patients present a problematic subgroup. Their diagnosis is frequently delayed; they do not meet the inclusion criteria of most clinical trials. To objectively measure response to treatment, FDG PET-CT and bone marrow biopsy are the only techniques currently being used, making the evaluation of the optimal timing to end or restart active therapy a challenge. The nature of these modalities also prevent them from being repeated on any regular basis.

B-cell maturation antigen (BCMA) is a member of the tumor necrosis factor receptor superfamily, present almost exclusively on the surface of mature B-cells and plasma cells. Recently it became a popular target for the development of cellular and non-cellular immunotherapies in MM, several of which are now licensed for treatment, such as belantamab mafodotin (9), ciltacabtagene autoleucel (10), idecabtagene vicleucel (11), and teclistamab (12).

BCMA is actively cleaved from the plasma cell surface by the ubiquitous multisubunit gamma-secretase complex, which then releases a soluble BCMA fragment (sBCMA) into the serum (13). Soluble BCMA was evaluated at first from the viewpoint of BCMA-targeted therapies: cleavage not only leads to the reduction of ligand density on tumor cells, sBCMA is capable of inhibiting CAR-T-cell function as well. Decreasing sBCMA levels can be a sign of biallelic loss of the BCMA target (14), whereas the reappearance of sBCMA can indicate the elimination of the anti-BCMA CAR-T-cell clone (15). The use of sBCMA as a prognostic and/or monitoring tool was suggested in non-BCMA targeted therapies as well. The levels of sBCMA not only positively correlate with disease stage, its increase was also reported through the progression from monoclonal gammopathy of unknown significance (MGUS) to active MM (16, 17). In another study, sBCMA levels were shown to correlate with the proportion of plasma cells found in bone marrow biopsies, the quality of response to therapy, and were prognostic towards progression free survival (PFS) and overall survival (OS) as well (18). Importantly, serum B-cell maturation antigen levels do not show any dependence on renal function, like free light chains do. Compared to M-protein, sBCMA has a drastically shorter plasma half-life (24–36 h), permitting rapid changes in measurable serum values, which could in turn reflect the ongoing changes in plasma cell burden, making it a potentially great monitoring tool (18).

The aim of our research was to evaluate sBCMA as a monitoring marker measured concurrent with the standard monitoring in MM patients at diagnosis, at relapse and during follow up, in order to establish its potential usefulness in oligo and non-secretory disease.

Soluble BCMA levels were then analyzed both as absolute values and also as percentage of the original reading to indicate response. We followed the way IMWG defined response categories based on the change from initial M-protein and FLC, i.e., as 50% and 90% drop from the original level to define sBCMA response categories sBCMA-SD, PR and VGPR.

The overall response rate was defined as the collective proportion of patients with complete response (CR), very good partial remission (VGPR), partial remission (PR), or stable disease (SD) as their best response (1). The primary endpoint for outcome was PFS which was measured from start of treatment to disease progression or death. Comparisons of dichotomous variables were performed by Fisher’s exact test. Continuous variables were compared using Mann-Whitney U test and Spearmann correlation analysis. PFS and OS were estimated by Kaplan–Meier analysis. The analyses were carried out using the SPSS (version 20.0; SPSS, Chicago, IL) software package.

The study was approved by the Institutional Review Board and informed consent was obtained in accordance with the Declaration of Helsinki.

Our results indicate the feasibility of using sBCMA for the monitoring of MM in conjunction with or—in the case of nonsecretory MM—instead of standard SPEP, UPEP and FLC measurements.

We successfully used the conventional 50% and 10% thresholds when segregating sBCMA response into SD, PR and VGPR groups, and found at least 100% rise from baseline in all cases of relapse. We think that sBCMA used this way could be a valuable addition to standard monitoring, especially in non- and oligosecretory disease. The problem with cases relapsing as oligo- or non-secretory is that lacking early biochemical warning signs, we are forced to wait until patients become outright symptomatic—often suffering serious consequences, such as skeletal fractures—until we may know they are truly relapsing. This is in part because mild variations in the M-protein and FLC levels are not uncommon, and moderate relapse symptoms such as anaemia, renal failure and bone pain may be related to other diseases or pre-existing conditions. In such situations, another layer of information could prove invaluable, giving a warning signal to prompt more frequent monitoring, bone marrow analysis or PET-CT.

Mass spectrometry was recently used in some of the leading laboratories to replace gel electrophoretic techniques (20, 21). Matrix-assisted laser desorption/ionization time of flight (MALDI TOF) mass spectrometry is several magnitudes more sensitive compared to the standard monitoring (i.e., SPEP, IFX, UPEP and FLC used together), reaching sensitivity similar to bone marrow based MRD techniques (22). Still, these promising techniques are only available in a handful of outstanding laboratories, and this situation is not expected to change in the near future. Possible limitations are the large initial cost of the installation of a mass spectrometer, and the lack of sufficient expertise in most laboratories. In addition to these, the current IMWG categories are established using gel techniques, and replacing them with mass spectrometry based measurements would require standardization as well as large scale validation.

Another potential candidate to improve myeloma monitoring is the Hevylite assay, developed by Binding Site, the same company that produced Freelite. For obvious reasons Hevylite will not be of help with light chain only oligosecretory disease, but can increase the sensitivity of monoclonal IgA and IgG detection at the point when SPEP and IFX cannot give a numerical value any longer due to the presence of polyclonal immunoglobulins (23). As a result Hevylite was included in the IMWG monitoring guideline in 2016, but so far did not get accepted generally in the routine clinical practice (24).

One important issue with FLC as a monitoring tool is that what we actually measure is the total FLC level and not the monoclonal fraction, and both kappa and lambda FLC levels are affected by renal clearance as well as immune activation. As renal failure is one of the important hallmarks of multiple myeloma, the abnormally elevated polyclonal FLC background very frequently makes FLC interpretation difficult, if not impossible. As Ghermezi et al. demonstrated, sBCMA levels are not dependent on renal function, and therefore can eliminate this important complication.

Another protein expressed on the surface of plasmacells similarly to BCMA is CD-138 (Syndecan) which is also shed into serum. This marker was suggested as independent prognostic parameter in multiple myeloma (25, 26), and the drop of serum level correlated with outcome in a cohort of patients (26, 27).

We did not include oligo and non-secretory patients in this analysis, and the benchmark we compared sBCMA response to, were the standard biomarkers IMWG suggests to use. We believe that our findings can still be generalized and utilized in oligo and non-secretory MM. Further studies enrolling oligo and non-secretory MM patients are warranted.

In conclusion, sBCMA is a cheap, noninvasive and easy to utilize ELISA measurement to monitor myeloma suggested to be used when the current monitoring strategy cannot give a reliable result.