Page 1784 - Williams Hematology ( PDFDrive )

1758 Part XI: Malignant Lymphoid Diseases Chapter 107: Myeloma 1759

in the loss of previously secreted intact immunoglobulin and a switch thalidomide. Finally, circulating proteasome levels are an indepen-
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to secretion of light-chains only (“Bence Jones escape”) or entire loss of dent prognostic factor for survival. 585
immunoglobulin-secretory capacity, often associated with extramed- Many of these factors are interrelated and, therefore, of limited
ullary spread, best signified by increased LDH levels and lesions found independent value. Using multivariate analysis, several groups have
on PET-CT examination. Occasionally, unexplained anemia or pan- found that the best combination of variables to predict outcome was
cytopenia accompanies the disappearance of myeloma protein mark- serum β M, reflecting both the tumor burden and the renal function;
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ers, necessitating prompt marrow examination to detect fulminant and the proliferative activity of plasma cells, evaluated by the LI or num-
relapse. ber of tumor cells in S-phase. Age and performance status also improves
Many induction regimens currently affect tumor cytoreduction the prognostic assessment. 586,587
rapidly, so that monoclonal immunoglobulin reduction of 50 percent or Cytogenetic findings associated with poor outcome include hypo-
more is apparent within a few months of therapy. Thus, at least monthly diploidy and deletion 17p13, the locus of the tumor-suppressor gene
myeloma protein evaluations should be performed during induction. TP53. 308,309,372,588 Gains of chromosome 1q arm and loss of 1p occur in
After two to four induction cycles and prior to high-dose melpha- tandem duplications and jumping translocations of chromosome 1, and
lan-based auto-HSCT, the disease is restaged, to include marrow exami- signify more aggressive and more advanced myeloma. 59,589–591 Combin-
nation with cytogenetics and MRI and/or PET-CT of indicator lesions ing hypodiploidy and high β M has also been used to identify patient
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in order to assess whether intramedullary or EMD has been reduced. populations with a poor outcome. 588,592 In contrast, hyperdiploidy, which
Disease monitoring should be performed at least every month for the accounts for almost half of the patients with abnormal cytogenetics and
first year and at a minimum every other month thereafter. Marrow involves nonrandom gains of chromosomes 3, 5, 7, 9, 11, 15, 19, and
biopsy, including cytogenetic examinations, should be performed at the 21, is associated with chemosensitive disease and better OS. Translo-
time of progression or change in therapy. Imaging should be performed cation t(11;14) also confers a better outcome. Chromosome 13 dele-
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annually or in the presence of new symptoms. tions are present in more than 50 percent of patients with myeloma and
are associated with poor prognosis; however, these deletions are also
PROGNOSIS associated with MG, 83,89,307 and their role in transformation to myeloma
is undefined at present. Chromosome 13 deletion is not prognostic for
The prognosis of myeloma is determined by three factors: (1) the host, response to bortezomib, highlighting the importance of prognostic fac-
(2) tumor biology and disease burden, and (3) the type of therapy tors for particular therapies. 593
applied. Host parameters, such as comorbidities, advanced age, frailty, Interphase FISH does not depend on cycling cells and increases
and poor performance status, negatively impact overall outcome and the detection of abnormal cells to 80 to 90 percent. Interphase FISH
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increase treatment-related morbidity and mortality. With the advent of can also detect cytogenetically silent translocations, for example, t(4;14),
new drugs, used in combination or incorporated into high-dose mel- t(14;16), and t(14;20), and can be performed on stored material. The
phalan-based auto-HSCT approaches, some poor prognostic factors above data suggest that analysis of metaphase cytogenetic abnormalities
can be overcome (see “Management of Newly Diagnosed Myeloma” and FISH can identify patients who do not do well with auto-HSCT or
above). standard therapies. Individual prognostication remains highly variable
Advances in cytogenetics, gene-expression profiling, and imaging despite the application of these more sophisticated cytogenetic tech-
(MRI and PET-CT) have greatly increased our understanding of tumor niques. The Total Therapy 2 patient data set revealed that standard prog-
biology and burden. Furthermore, such variables are more powerful nostic variables and metaphase cytogenetic had limited ability to account
prognostic indicators than standard prognostic variables. for outcome variability with hazard ratios not exceeding 2.0. 64,595,596
Numerous individual parameters have been examined for their Gene-expression profiling on newly diagnosed patients has
value as prognostic features. Higher labeling indices, serum IL-6 allowed for the interpretation of outcome in the context of whole
receptor levels, increased RAS mutations, more aggressive disease, and human genomic data. Gene-expression profiling not only has the ability
shortened survival has been reported in patients with plasmablastic to define disease pathogenesis, but also to identify both novel prognos-
morphology. Serum β M represents the light chain of the MHC com- tic factors and potential therapeutic targets. 597,598 Using tumor cells from
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plex of the cell membrane. Increased serum β M results from secretion 532 newly diagnosed patients, Shaughnessy and colleagues defined a
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by tumors with a high growth fraction and rapid cell turnover rates. In 70-gene model and a 17-gene subset that have the ability to identify high-
patients with myeloma and normal renal function, rising serum β M risk disease. In a study by the IFM, gene-expression profiles were gen-
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predicts for progression. The labeling index (LI), a measure of DNA erated for 250 newly diagnosed patients. The 15 most stable genes were
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synthesis by myeloma cells, predicts for survival. It is usually low (<1 used to construct a survival model. The 15-gene model demonstrated
percent) at diagnosis, higher at relapse, and lower in MG and indolent an improved ability to predict survival in newly diagnosed patients with
myeloma. 576 myeloma treated with high-dose therapy. Specifically, this work demon-
Serum IL-6 levels appear to correlate both with stage of disease strated that high-risk patients have a 6.8-fold hazard ratio (95 percent
and survival. 577,578 IL-6 stimulates hepatocytes to produce acute phase confidence interval, 3.92 to 11.73; P <0.001) of death compared with
proteins, such as C-reactive protein (CRP); CRP, therefore, may reflect low-risk patients. IFM 15-gene and University of Arkansas for Medical
the IL-6 level and proliferative status of marrow plasma cells. Indeed, Sciences (UAMS) 17-gene models, when applied to their respective data
CRP levels are significantly lower in patients with MG than in those sets, are powerful prognostic tools that can enhance the ISS for the iden-
with MM, and survival can be correlated with serum CRP level. High tification of high-risk disease. The HOVON group developed a 92 gene
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serum levels of soluble IL-6 receptor (sIL-6R), hepatocyte growth fac- signature which predicts for differential outcome. These gene signa-
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tor, and syndecan-1, as well as low serum levels of hyaluronate, tures are, however, not yet generalizable, as they have not been studied
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are independent prognostic factors predicting poor outcome. prospectively. Moreover, an analysis of signatures defined in Arkansas,
The percentage of circulating plasma cells in the blood and their IFM, Millennium, and HOVON studies shows that these signatures are
labeling indices are independent prognostic factors for survival in mye- not broadly useful in myeloma. 129
loma after both conventional and high-dose therapy. 294,583 Circulating These gene-expression profiling studies also identify mechanisms
endothelial cells also correlate with disease course and response to of sensitivity versus resistance to conventional and novel myeloma

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