Received: 1 November 2023 Revised: 19 December 2023 Accepted: 8 January 2024

DOI: 10.1002/ajh.27225

TEST OF THE MONTH

Soluble B-cell maturation antigen in multiple myeloma

Bruno Almeida Costa 1,2 | Ricardo J. Ortiz 3 | Alexander M. Lesokhin 2,4,5 |

Joshua Richter 6
1
Department of Medicine, Mount Sinai Morningside and West, Icahn School of Medicine at Mount Sinai, New York, New York, USA
2
Department of Medicine, Cellular Therapy Service, Memorial Sloan Kettering Cancer Center, New York, New York, USA
3
Brookdale Department of Geriatrics and Palliative Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA
4
Department of Medicine, Myeloma Service, Memorial Sloan Kettering Cancer, New York, New York, USA
5
Department of Medicine, Weill Cornell Medicine, New York, New York, USA
6
Division of Hematology and Medical Oncology, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, New York, USA

Correspondence
Joshua Richter, Division of Hematology and
Medical Oncology, Tisch Cancer Institute,
Icahn School of Medicine at Mount Sinai,
1 Gustave L. Levy Place, Box 1185, New York,
NY, USA.
Email: joshua.richter@mountsinai.org
Funding information
American Society of Hematology
Abstract
B-cell maturation antigen (BCMA) has emerged as a promising immunotherapeutic
target in multiple myeloma (MM) management, with the successive approval of
antibody-drug conjugates, bispecific antibodies, and chimeric antigen receptor T-cell
therapies directed to this membrane receptor. Soluble BCMA (sBCMA), a truncated
version produced through gamma-secretase cleavage, can be quantified in serum/
plasma samples from patients with MM via electrochemiluminescence, fluorescence,
or enzyme-linked immunosorbent assays, as well as through mass spectrometry-
based proteomics. Besides its short serum half-life and independence from kidney
function, sBCMA represents a reliable and convenient tool for MM monitoring in
patients with nonsecretory or oligosecretory disease. Numerous studies have sug-
gested a potential utility of this bioanalyte in the risk stratification of premalignant
plasma cell disorders, diagnosis and prognostication of MM, and response evaluation
following anti-myeloma therapies. In short, sBCMA might be the “Swiss army knife”
of MM laboratory testing, but is it ready for prime time?

1 | I N T RO DU CT I O N autoleucel [cilta-cel]), and two bispecific antibodies (BsAbs; teclista-

mab and elranatamab) targeting BCMA for adults with relapsed
Since its gene was first described by Laabi et al. in the early 1990s, and/or refractory MM (RRMM) who received at least four prior lines
B-cell maturation antigen (BCMA)—a type III transmembrane glyco- of therapy (including a proteasome inhibitor, an immunomodulatory
protein member of the tumor necrosis factor receptor superfamily drug, and an anti-CD38 monoclonal antibody).3,4 Despite belanta-
(TNFRSF)—has progressively evolved into a central character of mab's withdrawal from the US market due to a lack of progression-
modern-day multiple myeloma (MM) management.1 The selective free survival (PFS) improvement in the DREAMM-3 trial, the practical
overexpression of this membrane-bound receptor on MM cells makes significance of other BCMA-directed agents has continued to rise.5
it an attractive therapeutic target, with numerous BCMA-directed Recent results from the KarMMa-3 and CARTITUDE-4 trials indicate
therapies in clinical development.2 that BCMA-targeting therapies might soon be applicable during the
Between 2020 and 2023, the US Food and Drug Administration initial stages of the disease.6,7 Several ongoing trials are further inves-
(FDA) has approved one antibody-drug conjugate (ADC; belantamab tigating the use of these agents earlier in MM natural history
mafodotin), two chimeric antigen receptor T-cell (CAR-T) (NCT04196491; NCT04923893; NCT05243797; NCT05317416;
products (idecabtagene vicleucel [ide-cel] and ciltacabtagene NCT05623020).3,4,8

Am J Hematol. 2024;1–12. wileyonlinelibrary.com/journal/ajh © 2024 Wiley Periodicals LLC. 1


2 COSTA ET AL.
In the context of contemporary precision medicine, soluble
BCMA (sBCMA) is emerging as a novel biomarker for MM and its pre-
malignant stages—monoclonal gammopathy of undetermined signifi-
cance (MGUS) and smoldering MM (SMM)—with several studies
demonstrating its usefulness for evaluating disease burden,
monitoring disease progression, and predicting clinical outcomes.9,10
The present “Test of the month” article is dedicated to providing an
up-to-date overview of the pathophysiologic rationale, available tech-
nologies, and practical applications for sBCMA measurement in mod-
ern MM care.
2 | MEMBRANE-BOUND RECEPTOR
Also known as CD269 or TNFRSF17, BCMA is encoded by a 2.92-kb
gene located on the short arm of chromosome 16 (16p13.1) and com-
posed of three exons separated by two introns.2 The functional pro-
tein consists of an extracellular domain (54 amino acids), a
transmembrane domain (23 amino acids), and an intracellular domain
(107 amino acids).1 During B cell development, BCMA is expressed in
normal PCs and their highly proliferative precursors, polyclonal plas-
mablasts.11 However, it is nearly absent in earlier stages such as
CD34+ hematopoietic stem cells and pro- or pre-B cells, as well
as memory and naive B cells.1,11 Other normal tissues have undetect-
able BCMA transcripts except for plasmacytoid dendritic cells, and
possibly keratinocytes and adipocytes.12,13
Figure 1 illustrates the molecular structure and function of
BCMA. When present on the cell surface, BCMA acts as a non-
tyrosine kinase receptor for B-cell activating factor (BAFF) and a
proliferation-inducing ligand (APRIL), two agonists mainly secreted in
a paracrine manner by bone marrow stromal cells, osteoclasts, and
macrophages.12,14 APRIL is a more specific ligand than BAFF, given its
stronger binding affinity to receptors on PCs but not other B- and
T-lineage cells.12 Upon ligand binding, receptor activation leads to a
multitude of downstream responses on normal and malignant PCs via
three main signaling cascades: MEK/ERK, PI3K/AKT, and NFκB
9,15
(including canonical and noncanonical pathways).
Physiologically, membrane-bound BCMA (mBCMA) regulates the
9
maturation and differentiation of B cells into normal PCs. It also sup-
ports the persistence of long-lived PCs in the bone marrow (BM),
which are key immune components for quick and effective responses
upon reexposure to pathogens.16 BCMA knockout mice have shown
an impaired survival of long-lived PCs, but no deficiencies in B-cell
development, short-term immunoglobulin (Ig) production, or early
humoral immune response.17
Besides a selective and universal expression by normal PCs,
BCMA is almost ubiquitously found on MM cells, where its expression
is often significantly increased. In MM cells, mBCMA activation stimu-
lates several survival and anti-apoptotic pathways, as well as genes
critical for cell adhesion, osteoclast activation, angiogenesis, metasta-
9,12
sis, and BM immunosuppression. Immunohistochemistry and flow
cytometry are commonly employed for detecting mBCMA in these
cells, with the former method typically revealing a membranous and
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Golgi staining pattern.18 Variable mBCMA expression (usually at
low-to-moderate levels) has also been detected across distinct malig-
nancies of precursor and late-stage B cells.19
3 | S O L U B LE TR U N C A T E D F O R M
Structurally, mBCMA is unlike other TNFRSF members due to its
extracellular domain comprising a single 6-cysteine-rich motif.18 Such
a short length facilitates the direct cleavage of this surface receptor at
or near its transmembrane domain by an integral membrane enzyme
called gamma-secretase (GS), leading to the release of a truncated
protein fragment (sBCMA) into the circulation.18,20 GS is a nearly
ubiquitous protease complex consisting of at least four subunits,
which are essential for its appropriate function: presenilin (PSEN1 or
PSEN2), nicastrin, Aph-1, and presenilin enhancer protein
(PSENEN).21 In physiologic conditions, the continuous activity of GS
effectively regulates normal B-cell maturation.22 In the pathophysiol-
ogy of MM, the proteolytic processing of mBCMA contributes to the
reduced polyclonal antibody (pAb) production and immune deficiency
associated with the condition.23
Among individuals with a normally functioning GS, the level of
sBCMA in BM aspirate supernatant or peripheral blood samples is
often proportional to the amount of mBCMA available for cleavage.22
As BCMA is prominently expressed by malignant PCs, serum/plasma
concentrations of its soluble form can reflect the PC burden in
patients with MM.10,24 Accordingly, median sBCMA levels were found
to be higher in newly diagnosed multiple myeloma (NDMM) patients
(505.9 ng/mL) when compared to SMM patients (88.9 ng/mL;
p < .001) and healthy controls (36.8 ng/mL; p < .001), with an optimal
threshold of 107.6 ng/mL being suggested to compare MM and non-
MM patients (93.2% sensitivity, 76.4% specificity).25
Notably, sBCMA can function as a potential drug sink, abrogating
the effectiveness of BCMA-directed therapies.24 In a RRMM cohort,
patients with serum levels of sBCMA ≥156 ng/mL showed decreased
binding of a BCMA-directed ADC to MM cells.26 In preclinical studies,
BCMA cleavage was found to interfere with CAR T-cell recognition of
tumor cells both by lowering surface density of the target antigen and
through binding of sBCMA to the CAR.20,27 Along these lines, sBCMA
concentrations as low as 50 ng/mL hindered in vitro binding of anti-
BCMA BsAbs to K562 cells transduced to stably express BCMA.28
4 | BIOANALYTICAL METHODS FOR
QUANTIFICATION
Serum/plasma concentrations of free sBCMA can be determined via
the following ligand-binding assays (LBAs): enzyme-linked immunosor-
bent assay (ELISA); electrochemiluminescence immunoassay; and
fluorescence immunoassay (including bead-based or microfluidic sand-
wich assays).10,29,30 To circumvent the drug interference and epitope
competition seen in LBAs, a peptide-level immunoaffinity liquid
chromatography-tandem mass spectrometry assay was developed for
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COSTA ET AL. 3

F I G U R E 1 B-cell maturation antigen (BCMA)—Throughout B-cell development, BCMA is predominantly expressed in plasmablasts and plasma
cells (especially long-lived bone marrow plasma cells). Membrane-bound BCMA facilitates normal plasma cell development and survival via BAFF and
APRIL binding, which activates critical signaling pathways (including MEK/ERK, PI3K/AKT, and NFκB). This process is regulated through the
receptor's cleavage by an intramembrane, multisubunit protease called gamma-secretase, culminating in the release of soluble BCMA into the
circulation. BCMA expression is significantly heightened in myeloma cells, promoting tumor growth and immune evasion. Among individuals with
multiple myeloma, soluble BCMA can disrupt immune responses by sequestering BAFF/APRIL and act as a sink for BCMA-targeted therapies. AP1:
Activator protein 1; APRIL: a proliferation-inducing ligand; BAFF: B-cell activating factor; BCMA: B-cell maturation antigen; BMSC: bone marrow
stromal cell; ERK: extracellular signal-regulated kinase; GC: germinal center; IKKα: IκB kinase alpha; IKKβ: IκB kinase beta; mBCMA: membrane-bound
BCMA; MEK: mitogen-activated protein kinase/ERK kinase; MEKK: MEK kinase; MM: multiple myeloma; mTORC1: mammalian target of rapamycin
complex 1; NEMO: NFκB essential modulator; NFκB: nuclear factor kappa B; NIK: NFκB-inducing kinase; PI3K: phosphoinositide 3-kinase; PC: plasma
cell; PS1/2: presenilin 1/2; Rheb: Ras homolog enriched in brain; sBCMA: soluble BCMA; TAK1: transforming growth factor beta-activated kinase 1;
TRAF: tumor necrosis factor receptor-associated factor; TSC1/2: tuberous sclerosis protein 1/2.

4 COSTA ET AL.
total sBCMA quantification, being successfully adapted for use with
human samples in preparation for translation into the clinic.30
Although the available techniques have not yet been formally
compared in terms of accuracy and precision, a sandwich ELISA using
capture/primary pAbs and detection/secondary pAbs has been more
often employed, given its relative convenience and lower price com-
10,29
pared to other diagnostic approaches. This method requires only
a small amount of serum (approximately 4 μL) and has minimal cross-
reactivity with high concentrations of human IgG (1000 ng/mL is
associated with a sBCMA readout as low as 0.015 ng/mL).10,31 Using
ELISA (R&D Systems; Minneapolis, MN, USA; catalogue #DY193E), a
universal reference interval of <82.59 ng/mL has been proposed as
a normal range for sBCMA levels among healthy individuals, but stan-
dardized cutoffs for other protocols/techniques remain to be fully
10,32
established.
5 | ADVANTAGES AS A BIOMARKER
Serum/urine protein electrophoresis (PEP) and/or serum free light
chain (sFLC) assays cannot be universally employed for MM monitor-
ing, as up to 12% of affected individuals present with oligosecretory
or nonsecretory disease at diagnosis.33 The proportion of patients fall-
ing into this category becomes even higher during subsequent lines of
treatment, culminating in a more frequent need for positron emission
tomography (PET) scans and BM biopsies to adequately track disease
progression, despite the high costs of the former and invasiveness of
34,35
the latter. On top of that, oligo/nonsecretory MM can also be
associated with diagnostic delays and clinical trial ineligibility.35
Hence, a more reliable and convenient biomarker is imperatively
needed for this patient population, with a promising candidate being
sBCMA.10
When International Myeloma Working Group (IMWG)-defined
thresholds for monoclonal protein (M-protein; ≥1 g/dL in serum
or ≥ 200 mg/24 h in urine) are not reached, sFLC levels are often
employed as a proxy marker of disease.36 One particularly useful
property of sFLCs is their short serum half-life (kappa, 2–4 h; lambda,
3–6 h) when compared to intact Ig molecules (IgG, 21–25 days; IgA,
7–14 days).34 This provides an opportunity for real-time monitoring
of disease progression and response to treatment, especially among
37
patients with high-risk MM. Yet, sFLC assays can only perform such
a valuable role if the involved and uninvolved sFLCs show both an
appropriate difference (≥10 mg/dL) and abnormal ratio (<0.26 or
>1.65).36 When such IMWG parameters are not fulfilled, periodic
assessments of sBCMA levels in peripheral blood samples could alter-
natively allow for a rapid identification of nonresponders, given the
relatively short serum half-life of this bioanalyte (24–36 h).10,34
Bujarski et al. illustrated the above concept in a retrospective
cohort of patients starting a new therapy for RRMM.34,38 In the sub-
group that could not be followed by either sFLC or M-protein levels,
individuals who experienced a ≥25% increase in sBCMA at any point
during cycle 1 showed a shorter median PFS than those who did not
(1.6 vs. 19.3 months; p = .015).38 Furthermore, in the whole cohort, a
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≥25% increase in sBCMA occurred prior to fulfillment of IMWG
criteria for progressive disease (PD) in 67.5% of patients. As specu-
lated by the authors, a possible explanation is that BCMA is shed
more rapidly from PCs than Ig fragments, although this theory is still
under investigation.34
Even in secretory MM, routine markers of patient prognosis and
disease burden may exhibit potential limitations.39 For instance, serum
beta-2-microglobulin (B2M) levels are subject to variations in esti-
mated glomerular filtration rate (eGFR), while several MM-unrelated
factors affect serum albumin levels.34 The plasma clearance of sFLCs
(generally more efficient for the kappa isotype than the lambda iso-
type) can also be influenced by renal function, with lower eGFR values
leading to increased sFLC levels and kappa/lambda ratios.39 This com-
plicates laboratory interpretation in patients with MM and renal dys-
function, especially if there is light chain-only disease (where
M-protein cannot be used for tracking progression).38,39 In contrast,
serum concentrations of sBCMA have been found to be largely inde-
pendent of eGFR. Similarly, sBCMA did not show significant variability
when tested against other known prognostic indicators (e.g., age,
hemoglobin, or bone disease status).25
6 | CLINICAL APPLICATIONS
Table 1 compiles published studies supporting the clinical utility of
sBCMA for diagnosing, risk-stratifying, and monitoring MM or its pre-
cursor stages (MGUS and SMM).25,26,31,32,34,40–44 Serum/plasma con-
centrations of sBCMA have prognostic value among patients with
premalignant PC disorders, as those with higher levels often experi-
ence poorer clinical outcomes than those with lower values.34,40,43,44
Compared to non-progressors, baseline sBCMA levels were signifi-
cantly increased in MGUS and SMM patients progressing to MM dur-
ing clinical follow-up ( p < .001). When stratified according to the
median baseline sBCMA level for each cohort, higher serum concen-
trations were associated with a shorter PFS for either MGUS or SMM
(p < .001).40
In MM cohorts, sBCMA has been shown to correlate with serum
B2M, M-protein, and involved light chain levels.25,41 Among individ-
uals with nonsecretory disease, sBCMA has been shown to correlate
with BM PC percentages and findings from PET scans.25 In a pooled
analysis of MagnetisMM trials, baseline sBCMA was higher in partici-
pants with Revised International Staging System (R-ISS)
Stage 3 compared to those with stage 1 or 2 (p < .001). Additionally, a
trend for association with the presence of extramedullary disease
(p = .047) was observed, though sBCMA levels were comparable
between participants with high versus standard risk cytogenetics
(p = .29).45 An inverse correlation between baseline sBCMA and
future response to anti-myeloma therapy has also been reported, but
this relationship was not consistently replicated across previous
cohorts.9,42,44
Notably, sBCMA levels showed significant reductions across
IMWG response categories.25,41 For instance, Ghermezi et al.
reported lower median sBCMA levels in patients with complete
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COSTA ET AL. 5

T A B L E 1 Key published studies (n ≥ 100) assessing the clinical utility of soluble B-cell maturation antigen (sBCMA) quantification in patients
with newly diagnosed multiple myeloma (NDMM), relapsed and/or refractory MM, smoldering MM, or monoclonal gammopathy of undetermined
significance.

Reference Study population Summary of study findings

Sanchez et al., MM, 209; MGUS, 23; • Median sBCMA levels were higher in NDMM patients (13.87) when compared to MGUS patients
2012a31 HCs, 40 (5.30; p = .016) and HCs (2.57; p < .001).
• MM patients with a treatment response ≥PR had lower median sBCMA levels (4.06) than those
who experienced PD (19.76; p = .004).
• MM patients with sBCMA levels above the median (10.85) showed a shortened OS (p = .001). The
difference was more pronounced for those in the highest quartile (≥24.56; p < .001).
Ghermezi et al., MM, 243; SMM, 46; • Median sBCMA levels were higher in NDMM patients (505.9) when compared to SMM patients
2017b25 HCs, 43 (88.9; p < .001) and HCs (36.8; p < .001).
• ROC curve indicated an optimal sBCMA threshold of 107.6 to compare MM and non-MM patients
(93.2% sensitivity, 76.4% specificity).
• sBCMA levels correlated with M-protein and sFLC levels in secretory MM, as well as with PET-CT
changes and BMPC% in nonsecretory MM.
• When grouped based on IMWG-URC, MM patients with CR had a lower median sBCMA (38.6)
than those with PR (81.7; p = .037), stable disease (100.6; p < .001) and PD (301.4; p < .001).
• MM patients with sBCMA levels above the median (326.4) showed a shortened PFS ( p = .001).
The difference was more pronounced for those in the highest quartile (>971.0; p < .001).
Chen et al., RRMM, 379; HCs, 104 • Median sBCMA was higher in RRMM patients (176.0) compared to HCs (36.0; p < .001).
2019b26 • Through immunofluorescence staining, sBCMA levels ≥156 ng/mL were demonstrated to block
anti-BCMA antibody binding to MM cells in a concentration-dependent manner.
Jew et al., NDMM, 116; RRMM, • A nonparametric method using the median ± 2 SDs suggested a universal reference interval of
2021b32 90; HCs, 196 <82.59 for serum concentrations of sBCMA measured by ELISA.
• MM patients with normal pretreatment sBCMA levels had a higher median PFS (32.6 vs.
12.7 months; p = .04) and OS (NR vs. 98.3 months; p = .021) than those with pretreatment
sBCMA ≥82.59. Among the latter, achieving normal sBCMA levels after treatment predicted an
improved ORR (90% vs. 34%; p < .001) and median OS (NR vs. 98.1 months; p = .008) compared
to non-normalization, independently of the specific therapy administered.
• sBCMA levels ultimately normalized in all MM patients who reached CR, with a shorter time to
normalization than time to CR per IMWG-URC (0.9 vs. 5.0 months; p = .004).
Visram et al., SMM, 184; MGUS, 99 • Baseline sBCMA levels were higher in MGUS patients who developed MM during follow-up
2021b40 (106.5) compared to those who did not (43.7; p < .001).
• For MGUS patients with MM progression, sBCMA levels increased by a median of 312 ng/mL
(IQR, 150–775; p < .001) or 2.7 fold (IQR, 0.9–7.4).
• Baseline sBCMA levels were higher in SMM patients who developed MM during follow-up (162.7)
compared to those who did not (101.7; p < .001).
• For SMM patients with MM progression, sBCMA levels increased by a median of 303 ng/mL (IQR
58–657; p < .001) or 1.3 fold (IQR 0.7–2.9).
• For each cohort, baseline sBCMA above the respective median levels correlated with reduced PFS
in MGUS patients (HR 3.44 comparing sBCMA ≥77 vs. <77; p < .001) and SMM patients (HR 2.0
comparing sBCMA ≥128 vs <128; p < .001), even after adjusting for baseline MGUS or SMM risk
stratification.
Bujarski et al., RRMM, 81; SMM, 65 • ROC curve indicated an optimal sBCMA threshold of 137.5 to distinguish between SMM patients
2021b34 developing MM within 5 years from those without progression (specificity 84.2% and
sensitivity 62.5%).
• RRMM patients with baseline sBCMA above the median (305.5) had reduced PFS (median, 2.6 vs.
8.0 months; p = .008) and those in the highest quartile (≥594.8) had reduced OS (median, 9.8 vs.
22.5 months; p = .002) compared to those with lower levels.
• Longer PFS after initiating salvage therapy was predicted by a decrease in sBCMA levels ≥50% at
week 4 (p = .005), week 8 ( p = .029), and anytime through week 12 ( p = .006).
• Shorter PFS after initiating salvage therapy was predicted by a rise in sBCMA levels ≥25% at week
4 ( p = .001), week 8 ( p < .001), and anytime through week 12 ( p < .001). In 67.5% of patients,
a ≥25% increase in sBCMA levels occurred before progression per IMWG-URC.
Wiedemann MM, 126; HCs, 16 • Median sBCMA levels were higher in patients with NDMM (676) or RRMM (264) when compared
et al., 2023b41 to HCs (20.8; p < .001). Among MM patients, sBCMA had a positive correlation with BMPC%
(r = 0.52; p = .005) and serum B2M (r = 0.364; p = .01).
• Median sBCMA levels showed statistically significant reductions across response categories,
including CR (9.5), VGPR (19.3), PR (59.5), and stable disease (104.5).
• Among NDMM patients who achieved ≥PR per IMWG-URC, 33/37 (89%) had a ≥50% drop in
sBCMA levels (sBCMA-PR) by treatment week 4. Such patients had a prolonged median PFS
compared to those not reaching sBCMA-PR (NR vs. 5 months; p < .001).

(Continues)
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6 COSTA ET AL.

TABLE 1 (Continued)

Reference Study population Summary of study findings

Jew et al., NDMM, 161 • At baseline, NDMM patients had a median sBCMA level of 320.3 (range, 2.8–3800.4), with 13%
2023b42 showing values within the normal range (≤82.59).
• Patients in the lowest quartile group (≤136.2) showed a longer PFS compared with patients in the
three upper quartile groups (median, 42.2 vs. 21.1 months; p = .026).
• Compared to patients with baseline sBCMA above the median, those with levels ≤320.3 showed a
numerically higher OS (median, 173.5 vs. 93.5 months) but this did not reach statistical
significance ( p = .293).
Tan et al., MGUS/SMM, 150 • Median baseline sBCMA levels were lower in patients with MGUS compared to those with SMM
2023b43 (44.4 vs. 59.4; p = .006).
• Longitudinal analysis showed that MGUS progressors to SMM (n = 4) and SMM progressors to
MM (n = 13) had increasing sBCMA levels over time.
Terpos et al., MM, 122; SMM, 44 • Mean baseline sBCMA levels were lower in SMM patients (19.4; SD, 169) and MM patients
2023c44 without documented disease progression (103; SD, 107) compared with MM patients who had one
(200; SD, 194) or two (198; SD, 185) disease progressions during the follow-up period.
• No significant association between baseline sBCMA and best response during first-line therapy.
• Based on median baseline sBCMA, patients were categorized as low expressors (<113) or high
expressors (≥113). The latter group had lower median PFS (24.7 vs. 53.7 months; HR, 1.67;
p = .031) and OS (58.4 months vs. NR; HR, 2.05; p = .039).
• In a subgroup analysis of high versus low expressors according to ISS, a significant association
became evident only for patients with ISS 3 (HR, 2.24; 95% CI, 1.12–4.48; p = .023).

Note: Serum levels were uniformly represented in ng/mL.

Abbreviations: B2M, beta-2-macroglobulin; BCMA, B-cell maturation antigen; BMPC, bone marrow plasma cell; CR, complete response; ELISA, enzyme-
linked immunosorbent assay; HCs, healthy controls; HR, hazard ratio; IMWG-URC, International Myeloma Working Group Uniform Response Criteria; IQR,
interquartile range; ISS, International Staging System; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; M-protein,
monoclonal protein; NDMM, newly diagnosed multiple myeloma; NR, not reached; OS, overall survival; PD, progressive disease; PET-CT, positron emission
tomography–computed tomography; PFS, progression-free survival; PR, partial response; ROC, receiver operating characteristic; RRMM, relapsed and/or
refractory multiple myeloma; sBCMA, soluble B-cell maturation antigen; SD, standard deviation; sFLC, serum free light chain; SMM, smoldering multiple
myeloma; VGPR, very good partial response.
a
After serum samples were diluted 1:50, sBCMA measurement was performed via a sandwich ELISA using a polyclonal anti-BCMA antibody
(R&D Systems; Minneapolis, MN).
b
After serum samples were diluted 1:500, sBCMA measurement was performed via a sandwich ELISA using a polyclonal anti-BCMA antibody
(R&D Systems; Minneapolis, MN).
c
Serum concentrations of sBCMA were determined using Elecsys® electrochemiluminescence immunoassay (Roche Diagnostics International Ltd,
Rotkreuz, Switzerland). Patients with sBCMA values outside of measuring range (1.2–900 ng/mL) were excluded.

response (CR; 38.6 ng/mL) when compared to those with partial
response (81.7 ng/mL; p = .037), stable disease (100.6; p < .001), or
PD (301.4 ng/mL; p < .001). While a drop of 50% or more in sBCMA
levels has been associated with prolonged PFS, sBCMA increases of
more than 25% have been predictive of disease progression according
to IMWG response criteria. 25
Given such encouraging findings, numerous trials of anti-myeloma
therapies have employed sBCMA as a diagnostic tool for response
evaluation and disease surveillance.10 In the KarMMA trial, early
sBCMA clearance at post-infusion month 2 was associated with dura-
ble responses, while levels <20 ng/mL were suggested as an indirect
measure of ongoing CAR T-cell functional persistence.46 At a cutoff
of approximately 70 ng/mL, sBCMA also showed good sensitivity
(87.5%) and specificity (88.5%) for identifying relapse of MM after
cilta-cel treatment.47 Table 2 displays MM trials where sBCMA levels
were prospectively assessed among patients receiving BCMA-
targeted agents.6,46–58
Recent studies have underscored this biomarker's utility for
response monitoring even among patients undergoing non-BCMA
therapies. In a post-hoc analysis of the KarMMa-3 study, lower
baseline sBCMA levels predicted a higher overall response rate (ORR)
in the standard-regimen group ( p = .039).50 In a phase 1 trial (n = 38)
of ruxolitinib/lenalidomide/methylprednisolone for RRMM, partici-
pants with baseline sBCMA below the median (142 ng/mL) achieved
a longer PFS ( p = .023), while those with a ≥25% increase in sBCMA
levels through their first cycle had a shorter PFS ( p = .002).59 In a
post-hoc analysis of the MonumenTAL-1 study, 49/50 patients (98%)
who responded to talquetamab—a G protein–coupled receptor,
family C, group 5, member D (GPRC5D)  CD3 BsAb—had a reduc-
tion in sBCMA from baseline to C3D1.56 In an early-phase trial of
another GPRC5D-targeted BsAb (forimtamig; NCT04557150),
sBCMA levels correlated with parameters of pharmacodynamic
activity, ORR, and minimal residual disease (MRD) negativity.60
7 | C U R R E N T L I M I T A T I O N S A N D C LI N I C A L
PITFALLS
Given its multitude of clinical uses, sBCMA may be regarded as a
“Swiss army knife” of MM laboratory testing. However, some
 10968652, 0, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/ajh.27225 by Universidad Nacional Autonoma De Mexico, Wiley Online Library on [25/01/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
COSTA ET AL. 7

T A B L E 2 Clinical trials of B cell maturation antigen (BCMA)-targeted therapies integrating soluble BCMA as a composite biomarker for
response evaluation and disease monitoring in patients with relapsed and/or refractory multiple myeloma.

Trial (Phase) Anti-BCMA therapy (n) Method of sBCMA quantification Summary of study findings
DREAMM-1/2 Belantamab mafodotin ECLIA (MesoScale Discovery; Rockville, • Lower sBCMA levels were observed in
(Phase 1/2)48 (234) MD) responders compared to nonresponders at any
given time after belantamab initiation.
• However, no threshold of baseline sBCMA
identified to delineate responders versus
nonresponders.
• Following correction for survivorship effect,
reduction in sBCMA over time remained, but
there was not complete loss.
• sBCMA levels returned to near baseline upon
progression.
CRB-401 (Phase 1)49 Ide-cel (62) Bead-based FIA (Luminex; Austin, TX) • Both the depth and duration of sBCMA
reduction were associated with improved
DOR. Patients with DOR > 18 months
maintained sBCMA levels below the median
nadir (4.692) for the longest duration.
• Among patients experiencing PD, sBCMA
levels were almost universally elevated at the
time of relapse (one had values around the
median nadir due to BCMA loss).
KarMMa (Phase Ide-cel (128) Bead-based FIA (Luminex; Austin, TX) • Following ide-cel infusion, baseline sBCMA
2)46,50 decreased rapidly among responders, with
nadir values achieved within 3 months.
• The rates of undetectable sBCMA increased as
the depth of response improved, with MVA
subsequently identifying high baseline sBCMA
as a negative correlate of CR/sCR (OR,
0.637; p = .011).
• Duration of undetectable sBCMA correlated
with DOR, while sBCMA clearance at month 2
was associated with longer PFS ( p < .001).
KarMMa-3 (Phase Ide-cel (254) Bead-based FIA (Luminex; Austin, TX) • Lower baseline sBCMA was associated with
3)6,51 higher ORR (p = .022) and CRR ( p = .0038).
• Lower baseline sBCMA was associated with
lower grades of CRS ( p = .002) or
neurotoxicity ( p = .011).
• Median PFS was longer for patients with
undetectable versus detectable sBCMA at
2 months post-infusion (16.3 vs. 5.2 months;
HR, 0.26) or at 6 months post-infusion (16.8
vs. 9.6 months; HR, 0.62).
LEGEND-2 (Phase Cilta-cel (57) ELISA (R&D Systems; Minneapolis, MN) • Median baseline sBCMA (142) dropped by
1)47,52 94% following infusion, with nadir levels
reached at a median of 155 days.
• Patients with > 80% reduction in sBCMA had
a longer PFS ( p = .01) and OS ( p < .001) than
those with a mild decrease.
• At a cutoff of 69.3, sBCMA showed high
sensitivity (87.5%) and specificity (88.5%) for
identifying disease relapse.
CARTITUDE-2a Cilta-cel (20) ECLIA (MesoScale Discovery; Rockville, • Serum BCMA decreased after infusion,
(Phase 2)53 MD) reaching nadir levels near the lower limit of
quantification around day 100.
• All patients who experienced PD had sBCMA
levels at the time of relapse similar to baseline
before cilta-cel treatment.
• No correlation between baseline sBCMA and
clinical response.

(Continues)
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8 COSTA ET AL.

TABLE 2 (Continued)

Trial (Phase) Anti-BCMA therapy (n) Method of sBCMA quantification Summary of study findings
EVOLVE (Phase Orva-cel (115) ECLIA (MesoScale Discovery; Rockville, • Baseline sBCMA (median, 480) correlated with
1/2)54 MD) BMPC% and serum levels of M-protein, FLCs,
B2M, LDH, and ferritin.
• Patients with higher baseline sBCMA levels
were also more likely to experience AEs,
including CRS and neurotoxicity ( p < .05).
• sBCMA levels at nadir were significantly
associated with ORR, CRR, and Month 6
response rate ( p < .05).
• sBCMA levels within the first month
postinfusion allowed for stratification of
Month 6 responders versus nonresponders.
NCT03502577 FCARH143b (18) ELISA (R&D Systems; Minneapolis, MN) • Among participants who had an increase in
(Phase 1)55 mBCMA density with the GSI, a median
decrease of 317 (IQR 117–604) in sBCMA
levels was observed over the 5-day run-in.
• sBCMA concentration at day 60 was
significantly associated with PFS (HR, 24.08;
p = .002) and OS (HR, 11.71; p = .013).
MajesTEC-1 Teclistamab (165) ECLIA (MesoScale Discovery; Rockville, • During the first 4 cycles, reductions in sBCMA
(Phase 1/2)56 MD) levels occurred in 63/72 evaluable patients
(88%) who had a PR or better, with greater
reductions in patients with a deeper response.
MagnetisMM-1 Elranatamab (55) Immunoaffinity LC–MS/MSc • Elranatamab-induced changes in sBCMA were
(Phase 1)57 observed, with progressively lower levels over
time among responders.
MagnetisMM-3 Elranatamab (75) Immunoaffinity LC–MS/MSc • There was a ≥50% reduction in free sBCMA
(Phase 2)45 levels in >90% of responders, and an increase
from baseline (or lack of decline) in >90% of
nonresponders. Free sBCMA declined in
the majority of responding participants within
2–3 cycles.
• Total sBCMA increased in nonresponders and
declined in responders. However, the decline
was observed at later timepoints (as total
sBCMA levels were affected by elranatamab
half-life).
LINKER-MM1 Linvoseltamab (117) Sandwich ELISA • ORRs according to tertiles of baseline sBCMA
(Phase 1/2)58 were as follows: 91.7% (≤210); 70.6%
(210–607); 55.9% (607–4460).

Note: Serum levels were uniformly represented in ng/mL.

Abbreviations: AE, adverse event; B2M, beta-2-macroglobulin; BCMA, B-cell maturation antigen; BMPC, bone marrow plasma cell; Cilta-cel, ciltacabtagene
autoleucel; CR, complete response; CRR, complete response rate; CRS, cytokine release syndrome; DOR, duration of response; ECLIA,
electrochemiluminescence immunoassay; ELISA, enzyme-linked immunosorbent assay; EMD, extramedullary disease; FIA, fluorescence immunoassay; GSI,
gamma-secretase inhibitor; HR, hazard ratio; Ide-cel, idecabtagene vicleucel; IQR, interquartile range; LC–MS/MS, liquid chromatography–tandem mass
spectrometry assay; LDH, lactate dehydrogenase; mBCMA, membrane-bound B-cell maturation antigen; MM, multiple myeloma; M-protein, monoclonal
protein; MVA, multivariate analysis; OR, odds ratio; ORR, overall response rate; Orva-cel, orvacabtagene autoleucel; OS, overall survival; OS, overall survival;
PD, progressive disease; PFS, progression-free survival; PR, partial response; R-ISS, Revised International Staging System; sBCMA, soluble B-cell maturation
antigen; sCR, stringent complete response; sFLC, serum free light chain.
a
Correspond to preliminary results from cohort C, which enrolled quadruple-class exposed patients with relapsed/refractory disease who had prior
exposure to noncellular BCMA-directed agents.
b
All participants received crenigacestat, an oral gamma-secretase inhibitor, at 25 mg every other day for three doses in a pretreatment run-in phase.
Starting on the day of CAR T-cell infusion, crenigacestat administration was then scheduled as 25 mg three times a week starting for a total of nine doses.
c
To minimize drug interference, sBCMA was captured with biotinylated polyclonal anti-BCMA antibodies, which were immunoprecipitated using
streptavidin-coated magnetic beads. Beads were washed, bound sBCMA was eluted, and eluates were processed to generate tryptic peptides that were
analyzed by LC-MS/MS.

COSTA ET AL.
practical limitations should be highlighted. Among the quantification
methods available, standardized cutoffs for sBCMA levels remain
undefined, leading to variable reference values for interpretation
(as showcased in Table 1). Coupled with this, the magnitude of
sBCMA interference may vary with different anti-BCMA therapies,
warranting a more nuanced performance evaluation of the various
30,32
bioanalytical strategies for each specific drug.
Noteworthy, much of the evidence supporting the utility of
sBCMA testing in MM care is based on early correlative analyses.
Despite providing a solid foundation for optimistic speculation about
the future potential of sBCMA, current data are not sufficiently robust
to confirm cause-and-effect relationships across diverse clinicopatho-
logic and therapeutic settings.10 While studies have linked sBCMA
dynamics with PFS, sBCMA serves as a “surrogate measure” for a
“surrogate endpoint.” As such, it may not fully reflect clinical efficacy
or safety. The BELLINI trial's lessons remind us of the need for cau-
tious reliance on surrogate endpoints, especially in complex treatment
strategies like those in MM care.61 With all these aspects considered,
the available techniques for sBCMA quantification still lack FDA
approval for routine use in healthcare settings, complicating applica-
tion outside of academic centers or clinical trials. Furthermore, insur-
ance coverage remains deterred by the absence of specific indications
for sBCMA testing in current consensus guidelines from medical
societies.40,41,47
The clinical utility of this biomarker may also be compromised by
genetic alterations in the BCMA and GS pathways. In a KarMMa trial
participant with undetectable sBCMA levels at relapse, Da Vià et al.
identified the selection of an MM clone with homozygous TNFRSF17
deletion as the underlying mechanism of immune escape.62 Similarly,
Samur et al. documented a case where biallelic BCMA loss (acquired
by deletion of one allele and nonsense mutation of the second allele)
generated lower sBCMA levels discordant with tumor burden.63 In
another five relapsed cases, Lee et al. found that missense mutations
or in-frame deletions in the BCMA ectodomain could negate the effi-
cacies of T-cell-redirecting therapies, while having the potential to
interfere with GS-mediated cleavage.64 Monoallelic deletions of the
BCMA locus, which theoretically constitute a risk factor for biallelic
loss after BCMA-directed therapy, were common in a combined
cohort of 2458 newly diagnosed patients, with an incidence of 8.58%
even without treatment pressure.65
As illustrated by recent case reports, mutational events in GS-
related genes (e.g., PSEN1 and PSENEN) should be additionally consid-
ered for patients presenting with low levels of sBCMA despite high sur-
face expression of mBCMA.21,66 In preclinical studies, mBCMA
shedding has also been reversibly blocked using GS inhibitors
(e.g., crenigacestat), increasing mBCMA density and reducing sBCMA
20,24
concentration. This process boosts CAR-T activity by enhancing
tumor recognition. Such a strategy has been investigated in clinical tri-
als, with preliminary evidence showing positive results.55 With the fore-
seen translation of GS inhibitors into clinical practice, their expanding
use may add another layer of complexity to sBCMA testing, as the intri-
cate effects of these small molecules on sBCMA dynamics could further
challenge diagnostic reliability and result interpretability.67
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9
8 | FU T U R E P E R S P E C T I V E S
Besides establishing optimal reference ranges across diverse clinical
contexts, ongoing and future studies hold the potential to provide
more precise insights into how sBCMA levels can be strategically inte-
grated into the MM clinic to achieve the following objectives: (1) assist
in informed decisions regarding the initiation, modification, sequenc-
ing, or dosage adjustments of various therapies; (2) enable early
response assessment in diverse patient subgroups, including those
with distinct disease subtypes, molecular profiles, or underlying
comorbidities; (3) enhance the prognostic accuracy of current staging
systems, risk scores, and response criteria when integrated with tradi-
tional diagnostic tools (e.g., BM pathology, PET scans, and M-protein/
sFLC levels); (4) curtail the regular need for invasive BM aspiration/
biopsies in RRMM through its integration as a backbone of MRD test-
ing (an ambitious goal which will require careful and sequential valida-
tion before it can be realized).9,10,30,67
In conclusion, sBCMA constitutes a peripherally accessible and
composite biomarker of disease burden, clinical prognosis, and thera-
peutic responses in MM. Its utility is particularly evident for patients
with oligo- or nonsecretory disease (in whom serum/urine PEP and/or
sFLC assays do not adequately follow disease progression) and mod-
erate/severe renal impairment (given the marked independency of
sBCMA from CrCl when compared to traditional markers). As research
continues, the MM community can be optimistic about the future,
with BCMA-based diagnostics and therapeutics leading to more effec-
tive and personalized care for patients.
AUTHOR CONTRIBU TIONS
All authors substantially contributed to study conceptualization, data
acquisition and interpretation, manuscript drafting, critical revision for
important intellectual content, and final approval of the version to be
published.
ACKNOWLEDG MENTS
Our figure was created using BioRender.com. We thank Damodara
Rao Mendu, PhD, DABCC, from the Department of Pathology at the
Icahn School of Medicine at Mount Sinai (New York, NY) for his
expert guidance during the development of this work.
FUNDING INF ORMATI ON
This work was supported by the “Hematology Opportunities for the
Next Generation of Research Scientists” (HONORS) Award to
B.A.C. from the American Society of Hematology.
CONFLIC T OF INTER E ST STATEMENT
J.R. has received consulting fees and served on the speakers' bureau
for Janssen, Sanofi and Adaptive Biotechnologies; advisory board fees
from Celgene/BMS, Janssen, Karyopharm, Sanofi, Adaptive Biotech-
nologies; consultancy fees from Celgene/BMS, and Takeda.
A.M.L. has received consulting fees from Trillium Therapeutics, Pfizer,
Iteos, Sanofi, Genmab, and Janssen; grant funding from Pfizer and
Bristol Myers Squibb; payment for lectures and educational

10
presentations from Janssen and COR2Ed; and royalties from Serame-
trix, Inc. All other authors have no conflicts of interest to disclose.
DATA AVAI LAB ILITY S TATEMENT
Data sharing is not applicable to this article as no new data were cre-
ated or analyzed in this study.
ORCID
Bruno Almeida Costa https://orcid.org/0000-0002-1816-4498
Ricardo J. Ortiz https://orcid.org/0000-0002-2789-8311
Alexander M. Lesokhin https://orcid.org/0000-0001-9321-702X
Joshua Richter https://orcid.org/0000-0002-0274-0585
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How to cite this article: Costa BA, Ortiz RJ, Lesokhin AM,
Richter J. Soluble B-cell maturation antigen in multiple
myeloma. Am J Hematol. 2024;1‐12. doi:10.1002/ajh.27225