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1716 Part XI: Malignant Lymphoid Diseases Chapter 105: Plasma Cell Neoplasms: General Considerations 1717

Serum β2m and albumin levels form the basis for the International while for the posttreatment samples a minimum of 500,000 events were
Staging System, which has major prognostic significance. 99 analyzed. In the transplantation group, absence of MRD at day 100 after
High-risk myeloma, defined by genetic abnormalities, is indepen- transplantation, observed in 62 percent of patients, was highly predic-
dent of the International Staging System and the latter had only signifi- tive of a favorable outcome (progression-free survival [PFS]: p <0.001;
cant prognostic value in patients with a low-risk gene expression profile overall survival [OS]: p = 0.018). This outcome advantage was seen
and normal metaphase cytogenetics. 155 irrespective of cytogenetic findings, but more clearly in patients with
adverse cytogenetics (p <0.001 vs. p = 0.014). There was no complete
Serum Lactic Dehydrogenase Levels agreement between immunofixation electrophoresis (IFE)-negative CR
The significance of high serum lactate dehydrogenase (LDH) levels in and absence of MRD by MPF. Approximately 15 percent of patients in
the absence of any other cause, such as liver disease or hemolytic ane- CR still had measurable disease by MPF, while 25 percent of MRD-
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mia, predicting poor prognosis has long been recognized in myeloma. negative patients failed to achieve a CR by IFE. The effect of thalidomide
Although rarely observed in the early phase of the disease, marked maintenance therapy after transplantation was also assessed. The best
elevations of LDH were detected in up to 20 percent of patients with outcomes were seen in patients who achieved MRD negativity and were
disease progressing after vincristine, Adriamycin, and dexamethasone maintained on thalidomide, while the outcome was worst in patients
chemotherapy. High LDH levels were associated with hypercalcemia, who failed to achieve MRD negativity and did not receive thalidomide
elevated serum β2m levels, extramedullary manifestations, plasmab- maintenance. In the MRD-positive group at day 100, 28 percent of those
lastic morphology, and short overall survival duration, despite marked receiving thalidomide became MRD-negative, while in those not receiv-
(usually very transient) antitumor responses to high-dose therapy. The ing thalidomide maintenance only 3 percent became MRD-negative
same poor prognosis was noted in patients with initially normal LDH (p = 0.025). Finally, MRD assessment at the end of induction therapy in
levels in who marked LDH increments were induced by treatment, pre- the nontransplantation group had no predictive value; only 15 percent
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sumably resulting from tumor lysis syndrome as an indicator of rapidly of such patients became MRD-negative. It should be noted that there
156
proliferative myeloma. Close correlations with plasma cell labeling is a large heterogeneity in assessing MRD by MPF in the United States in
162
index and plasmablastic morphology has been demonstrated. Ele- terms of events acquired and number of antibodies used. If outcomes
157
vated serum LDH levels at diagnosis also emerged as a significant of therapies are based on MPF, it is critical that this technique becomes
prognostic factor in an analysis of 155 newly diagnosed patients who standardized and suitable quality controls are in place.
received at least one course of high-dose therapy with autologous stem
cell transplantation (ASCT), irrespective of the deletion of chromo- Fluorescent Polymerase Chain Reaction
some 13. 158 F-PCR can detect one clonal cell in 10 normal cells and is thus less
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sensitive than ASO-PCR and MPF. However, F-PCR is rapid, affordable,
MINIMAL RESIDUAL DISEASE and easy to perform. High-molecular-weight DNA is isolated from 500
μL of marrow. Three different multiplex PCRs are used: IGH D-J, IGK
Methods to assess MRD include allele-specific oligonucleotide PCR V-J, and KDE rearrangements. The clonal population is identified at
(ASO-PCR), multiparameter flow cytometry (MPF), fluorescent-PCR diagnosis. Patient with a visible lack of a clonal peak identified at diag-
(F-PCR) and high-throughput sequencing-based MRD assessment. nosis were considered F-PCR–negative. MRD was assessed in 130 newly
diagnosed myeloma patients. The test was informative in 91.5 percent
Allele-Specific Oligonucleotide Polymerase Chain Reaction of patients. MPC was used in parallel with F-PCR. After induction, 64
ASO-PCR can detect one clonal cell in 10 normal cells. It remains a patients achieved a molecular response and 66 did not. Median PFS was
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costly and labor-intensive assay to perform because a specific probe 61 versus 36 months (p = 0.001). The corresponding PFS with MPC was
needs to be generated for each patient and it is unsuccessful in approxi- 67 versus 42 months for MPC− and MPC+ patients (p = 0.005). 163
mately 30 percent of patients. In a relatively small study of 40 patients
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who achieved either a CR or very good partial response after autolo- High-Throughput Sequencing-Based Minimal Residual
gous transplantation and who received consolidation with bortezomib, Disease Assessment
thalidomide, and dexamethasone (VTD), eight patients achieved a High-throughput sequencing-based MRD assessment relies on ampli-
molecular remission: two only in one sample and six had at least two fication and sequencing of immunoglobulin gene segments using con-
consecutive negative samples. With a median followup of 26 months sensus primers. It employs the IGH-VDJ , IGH-DJ , and IGK assays.
H
H
from study entry, no clinical relapses were seen in patients achieving a The assay can detect one clonal cell in 10 normal cells and is 1 log more
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molecular remission, although one molecular relapse was seen, while sensitive than ASO-PCR. The prognostic value of this test was assessed
eight clinical relapses occurred in patients not a achieving a molecular in 133 myeloma patients enrolled in the GEM myeloma trials and was
remission. Importantly, VTD consolidation decreased the tumor load compared to MPC and ASO-PCR. The test was informative in 91 per-
further after transplantation. In contrast to earlier held opinions that cent of patients. Concordance between deep sequencing and MPC or
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molecular remissions could only be obtained with allotransplantation, ASO-PCR was 83 percent and 85 percent, respectively. Patients who
this study showed that molecular remission were also seen after autolo- were MRD− by deep sequencing had a significantly longer time to pro-
gous transplants followed by consolidation therapy with VTD. gression (80 vs. 31 months; p <0.0001). In CR patients, the time to
progression remained significantly longer in MRD− patients (131 vs.
Multiparameter Flow Cytometry 35 months; p = 0.0009). 95
Multiparameter flow cytometry (MPC) has the advantage of being There is no doubt that assessment of MRD will receive more
readily available and short turn-around time. It requires sophisticated attention in the coming years to guide the clinicians in their treat-
analysis, but is automated. This technique can detect one clonal cell in ment decisions and to individualize patient care. However, it should
10 normal cells. In the MRC Myeloma 9 study, MRD was assessed by not be automatically concluded that MRD− obtained after continua-
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MPF in 397 patients who received an autotransplant and 245 patients tion of aggressive therapy to ultimately reach MRD− status which was
who were treated with a nontransplantation approach. A six-color panel not achieved after a standard aggressive approach will have the same
was applied. For pretreatment samples 100,000 events were acquired, prognostic significance as MRD− obtained with standard intensive

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