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J. Caers et al.
Table 4. The Revised-International Staging System is one of the best stratification methods; it is based on routinely available cytogenetic and biochem- istry tests (Palumbo et al.).56
R-ISS definitions
R-ISS stage I
R-ISS stage II R-ISS stage III
Determinants
ISS stage I, no high-risk CA, and normal LDH
Other combinations
ISS stage III plus high-risk
CA or high LDH
Number
871 (28%)
1894 (62%)
295 (10%)
OS (5 years)
82%
62%
40%
Median OS
NR
83 months
43 months
PFS (5 years)
55%
36%
24%
Median PFS
66 months
42 months
29 months
R-ISS Revised- International Staging System; ISS: International Staging System; OS: overall survival; PFS: progression free survival; CA; cytogenetic abnormalities; LDH: lactate dehy- drogenase; NR: not reported.
2005. Other biomarkers have been identified and include markers of tumor cell proliferation, cytokines, pro-angio- genic factors, indicators of bone remodeling, circulating (exosomal) miRNA and imaging abnormalities. Another promising biomarker is the serum level of shed B-cell mat- uration antigen, which correlates well with BM PC infil- tration and declines according to tumor response.57 Follow-up of serum B-cell maturation antigen levels seems of interest in patients with non-secretory disease, for whom we lack reliable parameters in the blood; future studies are therefore warranted.
Apart from the often still reported Salmon & Durie stag- ing system, the ISS and revised (R)-ISS are frequently used as staging systems; in the latter systems, the β2- microglobulin and albumin levels reflect patients' tumor burden, turnover rate, presence of renal impairment, and nutritional and performance status.58 In order to improve the prognostic performance of the ISS score, the IMWG updated it, adding high-risk cytogenetics [t(4;14), t(14;16), and del17p determined by interphase fluorescence in situ hybridization] and elevated serum lactate dehydrogenase (Table 4).59 These factors had been previously identified as relevant risk factors for early progression after autologous transplantation.60 Of note, the ISS and R-ISS give prognos- tic information at diagnosis, but have not been validated in relapsed/refractory MM.
Frailty and co-morbidities
Once a treatment has started, adherence to the estab- lished protocol remains a major clinical concern in elderly and frail patients. This requires an individualized approach in which therapeutic decisions should be driven by both disease features and the patient’s characteristics. As in other malignancies, comprehensive geriatric assess- ments have been evaluated to assess patients’ functional, cognitive and mental status, comorbidities, nutrition and presence of geriatric symptoms. Palumbo and co-workers developed a retrospective simplified geriatric assessment, named the IMWG-Frailty Index, in which age, the Charlson Comorbidity Index, activities of daily living and instrumental activities of daily living were used to dis- criminate between fit, intermediate-fit and frail patients, showing different incidences of severe adverse events, progression-free survival and overall survival.61 Expectedly, more severe adverse events and treatment discontinua- tions were reported in frail patients. The most extensive retrospective and prospective tests and validation analyses were performed within the German study group, who prospectively assessed the IMWG-Frailty Index with the revised Myeloma Comorbidity Index (R-MCI) and other comorbidity indices.62 A second prospective German
study including 801 MM patients determined that impaired renal and pulmonary function, poorer Karnofsky performance status, frailty and age were independent, multivariate risk factors for overall survival. Addition of cytogentic abnormalities resulted in the weighted revised Myeloma Comorbidity Index, which is able to assess patients' physical condition accurately and is simple to apply in the clinic.63 Although not yet proven via random- ized treatment algorithms, there is circumstantial evi- dence that limited induction therapy, careful dose modifi- cations and reductions, sensible use of supportive care and watchful surveillance of unfit and frail patients may improve patients’ outcome further.64 The EMN insists on developing trials, specifically designed for frail patients, for further refinement of frailty-related diagnostics and best treatment selection.65
Drug-related biomarkers
While prognostic factors regarding disease evaluation are listed above, drug-related biomarkers are being assessed to predict response to treatment and, possibly, to facilitate optimal treatment while avoiding ineffective therapies and unnecessary toxicity. Recent pharmacogenomic studies revealed gene signatures that could predict the clinical out- come after treatments based on immunomodulatory drugs66 or bortezomib.67 The expression of cereblon, an intracellular binding partner of immunomodulatory drugs has been intensively studied as a biomarker and initial studies corre- lated cereblon levels with the outcome of MM patients receiving treatment with such drugs.68-71 These studies used quantitative real time PCR analysis, gene expression profil- ing or immunohistochemistry to quantify cereblon expres- sion and showed that loss of cereblon expression was asso- ciated with resistance to immunomodulatory drugs. Further investigations revealed limitations of these assays, because both splice variants of cereblon and point mutations were described.72,73 When exploring predictors for tumor respons- es to daratumumab, higher CD38 expression was found on MM cells of responsive patients. However, good responses were also seen in patients with lower CD38 expression, an observation confirmed in a second study that showed that CD38 expression level was not necessarily predictive of response in advanced MM; nevertheless attempts to assess agents that keep CD38 upregulation increased, e.g., all-trans retinoic acid and histone deacetylase inhibitors, are being pursued pre-clinically and clinically.74,75
Finally, expression of anti-apoptotic proteins, BCL-2, BCL-XL or MCL-1, measured by quantitative real-time PCR, predict pharmacological responses to the bcl-2 inhibitor venetoclax, which is mostly active in patients harboring t(11,14) translocations.76
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