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1714 Part XI: Malignant Lymphoid Diseases Chapter 105: Plasma Cell Neoplasms: General Considerations 1715

subpopulation of memory B-cell–like cells with the CD138−/CD19+/ are ineffective producers of immunoglobulins and produce 10 to 100
CD27+ phenotype was identified and termed myeloma stem cells. 134,135 times less immunoglobulin per cell per day than a normal plasma cell.
The CD138− cell population derived from myeloma cell lines contains In addition, the more immature and more proliferative myeloma cells
significantly higher levels of ALDH, a marker for stem cells. In con- are, the less immunoglobulin per cell per day they secrete. In myeloma,
trast to the CD138+ cells, the CD138− cells were not affected by the there is an imbalance of heavy chains and light chains in favor of the
drugs we typically use in myeloma, such as lenalidomide, bortezomib, light chains. In general, the more aggressive the myeloma, the more
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dexamethasone, and cyclophosphamide. In an earlier study, human pronounced the imbalance in favor of excess light-chain secretion. The
CD34+/CD45 clonotypic myeloma cells were shown to cause lytic excess light chains cannot bind to heavy chains and can pass freely
low
bone lesions in a xenograft mouse model, and these CD34+ progen- though the renal glomeruli. Monomeric FLC, characteristic κ, are
itors included approximately one-third of DNA aneuploid cells. 135,136 cleared from the serum in 2 to 4 hours at 40 percent of the glomeru-
Mature CD138+ myeloma cell dedifferentiation to myeloma stem cells lar filtration rate (GFR), while dimeric FLC, typically , are cleared
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with a CD34+/CD138+/B7−/H1+ phenotype has been reported, in 3 to 6 hours at 20 percent of GFR. Removal may take 2 to 3 days
showing that myeloma cells have the plasticity to replenish the in patients with complete renal failure. This is in contrast to IgG, which
stem cell compartment if required, and that we should not think has a plasma half-life of 21 days.
of stem cells as a static, but as a dynamic concept. CD38++/CD45− Although it has long been possible to measure the total amount
plasma cells proliferated successfully within an engrafted human fetal (free plus bound to heavy chains) of light chains in the urine, our ability
bone using the severe combined immune deficiency (SCID)-hu mouse to measure serum FLCs became a reality early in the 21st century. This
model. 138,139 This could have been because of dedifferentiation of these test is not only of high affinity and allows measurement of low con-
more mature myeloma cells. It also has been demonstrated that the SP centrations of FLC, but it is also of high specificity and only measures
cells from different myeloma cell lines are able to generate more colo- unbound light chains. Serum FLC are several orders of magnitude lower
nies than mature plasma cells. However, this SP cell population lacked than serum light chains bound to intact immunoglobulin and the test
correlation with CD138 expression. 132,133 To isolate multiple myeloma is based on an antibody that exclusively binds to an epitope of the FLC
stem cells (MMSCs) from primary samples, we have relied on a func- that is hidden if the light-chain molecule is bound to a heavy chain.
tional characteristic of cancer stem cells, the ability to pump out the Because the half-life of serum FLCs is much shorter than that of the
Hoechst dye, rather than on membrane markers, which are more likely intact immunoglobulin, serial serum FLCs allow assessment of success
to change with changing environmental conditions. To this functional of therapy much earlier than serial M-protein levels. Patients with high-
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marker, we have added a myeloma specific marker, either surface κ or est amount of light chains have the worst outcome. The serum FLC
λ light chain, based on the specific M-protein. Because drug-resistant ratio is an independent prognostic factor for progression of myeloma
myeloma cells are enriched in patients relapsing early after tandem in monoclonal gammopathy and SMM. Incorporation of serum FLCs
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autologous transplants, we compared GEPs at baseline and at relapse into a staging system also improves risk stratification for patients with
in 51 patients. The gene most differentially expressed at relapse was AL and levels of serum FLCs correlate with tumor burden in mac-
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the retinoic receptor α (RARα). This receptor has two splice variants: roglobulinemia.. The serum FLC assay is also an early indicator of
α and α . RARα is present on all myeloma cells; RARα expression relapse in myeloma. As explained above, both serum κ and concen-
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2
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is only present in one-third of newly diagnosed patients. The latter trations increase with deteriorating renal function, but the ratio only
patients have a significantly inferior survival after tandem autotrans- changes slightly; with increasing renal failure the κ: ratio gradually
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plants. In a subsequent study, we were able to show that increased increases. Diseases associated with generalized increased B-cell activa-
RARα expression conferred stem cell features to myeloma cells, such tion frequently have high concentrations of polyclonal immunoglob-
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as increased drug resistance, increased clonogenic potential, activa- ulins and high polyclonal FLC, but the κ: ratios will remain within
tion of pathways typically found in a cancer stem cell (CSC) such as normal range.
the Wnt and Hedgehog pathways, increased SP and ALDH levels, and In addition to a SPEP and serum FLCs, it is important perform
increased expression of embryonic stem cell genes, such as Nanog, a serum immunofixation electrophoresis (sIFE) to identify the nature
Oct4, and Sox2. These same characteristics were found in the SP+ and of the M-protein, and to measure the quantitative immunoglobulins.
surface light-chain–restricted cells of primary myeloma samples. We Many of the IgA and some of the IgG myelomas have their M-spike in
also found that RARα expressing CD138+ myeloma cells have a much the β-globulin region, where the M-protein level is less reliable because
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higher expression of Oct4, Sox2, Nanog, TCF1, CCND1, and ABCC3. there is comigration of many other proteins. If an M-protein is identi-
This indicates that RARα -positive myeloma cells show stem cell fea- fied on SPEP and sIFE does not identify the heavy chain, quantitative
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tures and, therefore, have a worse outcome. 141 analysis of IgD and IgE should be performed. Most IgD myelomas are
associated with lambda light chains.
DIAGNOSIS OF PLASMA CELL TESTS OF URINE
NEOPLASM A typical myeloma workup will have a 24-hour urine collection for total
protein, urine protein electrophoresis (UPEP), urine M-protein, and
TESTS OF SERUM urine immunofixation electrophoresis (uIFE). In contrast to the serum
Because PCNs are B-cell malignancies derived from antibody-producing FLCs, the role of urine FLCs is much less clear and is generally not used.
plasma cells in the marrow, which continue to secrete in the vast major- In the era of serum FLC assays, some experts believe that urine analysis
ity, an M-protein will be found in serum and/or urine in the majority can be eliminated. In a study by the Mayo Clinic of 428 patients, there
of patients. The monoclonal protein is either an intact immunoglobu- were only two cases where a urinary monoclonal protein was missed by
lin or a component of the immunoglobulin. The most common types omitting urine analysis (0.5 percent). These two cases did not require
in myeloma are IgG and IgA; in Waldenström macroglobulinemia, it any medical intervention. When patients have a large amount of albu-
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is IgM. The most common screening test to identify a serum M-pro- minuria in the presence of PCN with or without urine M-protein, the
tein is the serum protein electrophoresis (SPEP). While the quantity of possibility of AL should be entertained, either primary AL or AL in the
M-protein is often considered a marker of tumor load, myeloma cells context of myeloma.

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