Case study 55.1
A 59-year-old female is newly diagnosed with multiple myeloma (MM). Laboratory results show anemia, calcium and renal function that are normal, and an immunoglobulin A (IgA) kappa monoclonal protein that is 3.5 g/dl. The patient’s β2-microglobulin (β2 m) is 3.1 mg/l and the albumin is 2.2 g/dl, so she has International Staging System stage II myeloma.
1. What is the role of the International Staging System (ISS) in the era of new drugs in MM?
- It provides prognostic information
- It is necessary in making therapeutic choices
- It is considered to predict higher-risk disease
- A and C
Multiple myeloma is a heterogeneous disease with variable disease courses, responses to therapy, and survival outcomes that range from less than 1 year in patients with aggressive disease to more than 10 years in patients with indolent disease presentation. Many studies have focused on the description of prognostic factors capable of predicting this heterogeneity in survival. Analysis of prognostic factors is essential to compare outcomes within and between clinical trials.
The Durie–Salmon Staging System (DSS) is used in patients with newly diagnosed MM to determine tumor burden and estimate survival. However, there are significant shortcomings with this system, correlated with the introduction of high-dose therapy and novel agents that are able to better reduce tumor burden, hence the need to introduce a new system.
At the present, the most widely applied prognostic system in myeloma is the International Staging System, which stratifies patients into three groups based on serum albumin and β2 m levels: stage I with β2 m < 3.5 mg/l and serum albumin ≥3.5 g/dl (median survival: 62 months); stage II, which is neither stage I nor stage III (median survival: 44 months); and stage III with β2 m ≥5.5 mg/l (median survival: 29 months).
Compared with the DSS, the ISS is more reproducible and easier to compute, and it reflects both patient and tumor factors, with β2 m being a measure of tumor bulk and renal function, while albumin is associated with the general state of the patient.
For the most part, the ISS has now replaced the Durie–Salmon staging system as it does represent a better way to assess outcomes. However, the ISS has some important limitations. A recent study demonstrated that in patients who are aggressively treated using upfront autologous stem cell transplantation (auto-SCT), the ISS does not improve the prediction of posttransplant outcomes compared with the DSS. The use of ISS to determine choice of therapy for individual patients remains unproven, and its validity with combination novel agent therapy still needs to be confirmed. We think the ISS should be supplemented and not necessarily supplanted. There is a clear need and consensus to add other markers to the ISS for predicting patient outcome. Avet-Loiseau et al. (2012) recently demonstrated that the combination of immunofluorescent in situ hybridization (iFISH) data with ISS significantly improves risk assessment in myeloma, versus ISS staging alone. Boyd et al. (2012) showed that by integrating the ISS and FISH lesions associated with short survival, it is possible to better identify a group of patients with a very poor outcome.
For a biologically heterogeneous disease, it is unlikely that any one clinical staging system can fully accommodate the factors that affect the outcomes.
Prior to the initiation of therapy, risk stratification of the MM helps predict the clinical course, although its use to risk adapt therapy decisions remains less clear. To this end, most clinicians agree that patients should be treated with the best induction regimen, and in the modern era of myeloma therapy, this typically represents a three-drug regimen using an immunomodulatory agent, a proteasome inhibitor, or both. The concept of how to best use genetic material identified at the time of initial diagnosis likely plays a major factor when considering how to approach maintenance therapy as all patients (standard or high risk) can achieve a major response following effective induction therapy; however, the durability of that remission is what may be risk dependent. As such, our group has adopted a risk-adapted maintenance strategy to prolong duration of remission and survival based upon the genetic risk at the time of diagnosis (Kaufman et al. 2012).
The incorporation of host factors, disease characteristics, serum free light chains (sFLCs), and radiography has been explored as possible additions to ISS to refine risk stratification. Age, performance status and comorbidities are prognostic factors and impact therapeutic decision making. It has been recently shown that, despite being enriched for higher-risk genetic subtypes, younger patients live longer, presumptively as a consequence of their ability to better tolerate treatment. Because of the lack of uniform availability of the data for analysis, which led to proposal of the ISS, there are a number of individual factors that still may have a significant role in identifying high-risk patients, such as lactate dehydrogenase, which was found to have significant influence in identifying risk. Baseline sFLC concentration may also provide useful prognostic information. Usmani et al. (2012) showed that extramedullary disease is more prevalent in genomically defined high-risk MM and, such as in other studies, is associated with shorter progression-free survival, even in the era of novel agents. Other features considered significant as individual factors are IgA, renal failure, and plasma cell leukemia, but if these features are sometimes useful, their general applicability is unknown, and there is a consensus that no change in treatment approach is currently indicated based on such single higher-risk features.
Regarding imaging, fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) and magnetic resonance imaging (MRI) probably also contribute meaningfully to prognostication. A recent study has reported that the presence of more than three fluorodeoxyglucose-avid focal lesions is the leading independent parameter associated with inferior overall and event-free survival. Walker et al. (2007) showed that the presence of focal lesions on MRI independently affected survival and that achieving MRI-directed complete remission has prognostic significance. But none of the imaging studies or results is currently recommended for inclusion in risk stratification.
However, it is essential that new prognostic indicators continue to be evaluated in prospective clinical trials.
This patient’s initial diagnostic evaluation includes a unilateral bone marrow aspirate and biopsy evaluation with immunohistochemistry, cytogenetics, and fluorescence in situ hybridization (FISH).
2. What is the minimal FISH panel to stratify newly diagnosed MM patients?
- t(4;14), del17p, and del(13q14)
- t(4;14), t(14;16), and del17p
- t(4;14), del17p, +1q21, and t(11;14)
There is a consensus that both cytogenetics and FISH play important and independent roles in risk stratification. The general purpose of risk stratification is not to decide time of therapy, but to prognosticate, and so it is applicable to newly diagnosed patients. Most myeloma experts recommend that either FISH or conventional cytogenetics, or preferably both, should be done at diagnosis in all patients.
Among all newly diagnosed patients, 15% harbor t(11;14), and in most series tested, it seems to be associated with a favorable outcome, but this effect is not strong enough to be statistically significant, and it may relate to heterogeneity within patients with t(11;14). In fact, some cases of MM with t(11;14) manifest with an aggressive phenotype such as plasma cell leukemia. Then, the global effect of t(11;14) on prognosis remains neutral. Translocation (4;14) is noted in about 15% of MM patients and has been associated with adverse prognosis in a variety of clinical settings. It does appear from an analysis performed by an Italian group that the use of bortezomib and an immunomodulatory agent at the time of diagnosis and in the setting of consolidation therapy (VTD) is able to overcome what has traditionally been the poor risk set of patients with t(4 : 14). This was also noted in an analysis of the TT3 series from Barlogie et al. (2007), where, in a much more intense treatment approach, the poor risk features of t(4;14) also appear to be eliminated. The significance of t(14;16) has recently been questioned. The Intergroupe Francophone du Myelome (IFM) group did not correlate this translocation with adverse survival, but several groups have shown that t(14;16) is associated with poor prognosis. Del(17p) is considered to be the most important molecular cytogenetic factor for prognostication, and in all series tested, it confers a very negative effect on survival. The prognostic influence of deletion 13 by iFISH was shown to disappear in the IFM study when patients with simultaneous t(4,14) or del(17p) were excluded, indicating that the prognostic value of iFISH-detected deletion 13 was due to its frequent association with other known high-risk genetic abnormalities.
It is generally accepted that the t(4;14), t(14;16), and del 17p, demonstrated by FISH, confer an adverse outcome in myeloma. It has therefore been proposed that these abnormalities define “high-risk” myeloma, and at a bare minimum, a FISH panel for MM should include testing for t(4;14), t(14;16), and del 17p. There are some reports that the gain of 1q21 has been linked to adverse prognosis in a patient treated with tandem transplantation. However, its value as an independent FISH biomarker of adverse prognosis has not been validated by other groups. Recently, many studies have proposed that 1q analysis should be added to the diagnostic panel of FISH probes used in the routine assessment of prognosis in patients with MM. Boyd et al. (2012) demonstrated that t(4;14), t(14;16), t(14;20), +1q21 and del 17p can be used to define adverse prognosis in myeloma, and patients with the worst clinical outcome are identified by the cosegregation of more than one of these lesions. Another study recommended that the FISH testing panel should including testing for del 17p, chromosome 13 abnormalities, the five recurrent IgH translocations, and trisomy of any of the odd-numbered chromosomes; it was also showed that the presence of trisomies ameliorates the prognosis in patients with high-risk cytogenetics.
The expansion of a minimal panel to other probes may be desirable as it provides a more comprehensive assessment of the disease biology, clinical biology, clinical features, and likely outcome. Additionally, it is important that when FISH testing is performed, it is done using some method for identifying plasma cells in the mixed bone marrow aspirate. This can be done using light-chain staining to co-localize the FISH analysis on plasma cells, or using CD138 selection of plasma cells before performing FISH analysis. It is clear however, that if unselected FISH is performed, one runs the risk of incomplete staging as a negative result may be a false negative. The use of some plasma cell selection should be mandatory when assessing the risk status in a newly diagnosed myeloma patient.
Finally, recent reports suggested that novel approaches based on microarray technology should be used to achieve a more powerful prediction. Shaughnessy et al. (2007) have identified in 532 newly diagnosed myeloma patients, a set of 70 genes linked to shorter durations of complete remission, event-free survival, and overall survival. Decaux et al. (2008) also demonstrated in 182 patients that a set of 15 genes was able to identify the patients with the poorest prognosis. It is interesting to note that, although both these studies have included patients undergoing high-dose therapy, the 17 and 15 gene models do not share common genes. Novel gene expression profiling could be developed in the future, and it would be useful in risk stratification.
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