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CNS-MM
The recent study of 50 patients with intracranial myelo- ma by Gozzetti et al. illustrates the distinction of osteodur- al myeloma from CNS-MM, with osteodural myeloma patients showing a median OS more than three times that of patients whose CNS-MM was defined by the presence of plasma cells in CSF.26 Dias et al. studied 20 patients with CNS infiltration, 17 of whom had only osteodural myelo- ma without leptomeningeal involvement and median OS of 40.3 months from the start of CNS involvement, com- pared to 5.8 months with leptomeningeal involvement.27 Our overall analysis of CNS-MM survival data from stud- ies cited in this review (4.5 months) (Table 2) is in accor- dance with these figures.
Cytogenetics
The cytogenetic risk factors of MM have been estab- lished as prognostic indicators of poor OS in CNS-MM patients. Jurczyszyn et al. found del(13q) (39%) and del(17p) (23%) to be the most common.8 del(13q) is detected at a similar frequency in CNS-MM to MM, and therefore this study concurs with an older review by Nieuwenhuizen and Biesma which found no association between CNS-MM and del(13q).1,8 Jurczyszyn et al. also observed the frequency of del(17p) in CNS-MM to be sim- ilar to that in MM.8 Smaller studies, however, have shown higher rates of del(13q)24 and del(17p) in CNS-MM.18 A similar pattern of cytogenetic abnormalities is seen in EMD and BM-MM, apart from the t(4;14) FGFR3/IgH translocation and del(17p), which showed a higher fre- quency in EMD.7 A small study using immunostaining to compare EMD with BM-MM showed higher aberrant expression of p53 in EMD.20 We advocate caution in the interpretation of some data providing apparently convinc- ing evidence of association between specific acquired cytogenetic aberrations such as del17p,18 published well over a decade ago when methodologies and iFISH probe quality were questionable. In our own experience, we have failed to detect any significant association between BM iFISH results at diagnosis and co-existing or subse- quent development of CNS-MM. Also, we have refined our iFISH technique during the past 15 years, including preselection of CD138 positive plasma cells, and switched to alternative iFISH probes giving clearer signals, so would include our own earlier results in this ‘questionable’ cate- gory.
Other associations
Associations between CNS-MM and several further parameters have been suggested, although some evidence comes from small studies. IgA myeloma represented 27% of CNS-MM cases in the multi-center study by Jurczyszyn et al. compared to 21% of the 1,027 newly-diagnosed MM (ND-MM) cases studied by Kyle et al.8,28 The figure of 27% is very similar to that of 26% in the summary analysis of data referenced in this review (Table 2). The review by Nieuwenhuizen and Biesma shows a higher proportion of cases of λ than k light chain expression in CNS-MM patients, to that observed in MM.1 Jurczyszyn et al. report 52% of cases expressing k, 42% λ and 5% both k and λ, also suggesting a higher frequency of λ-expressing myelo- ma in CNS-MM than in MM.8 Nieuwenhuizen and Biesma also observed 8.3% of CNS-MM cases expressing IgD and 7.3% showing biclonal immunoglobulin expres- sion,1 both of which are around 2% in ND-MM.28 Other studies suggest a higher likelihood of IgD and light chain
myeloma in CNS-MM.25,29 According to Jurczyszyn et al., however, 2% of CNS-MM cases were IgD and 1% had biclonal immunoglobulins; the proportions of cases with light chain myeloma and IgG myeloma were also similar to those seen in ND-MM.8,28 Data from studies of EMD in general show a higher prevalence of IgD myeloma among EMD at relapse than in MM;21 and cases with EMD at MM diagnosis are more likely to be IgD, λ or non-secretory myeloma.5 Our summary analysis of studies referenced in this review identified 4% of cases expressed IgD, and 5% showed biclonal immunoglobulin expression. Overall, however, there is no consensus for associations between light chain restriction, or Ig class, and CNS-MM.
The phenomenon that CNS-MM might be seen more often in autologous SCT (ASCT)-receiving patients might be: a) by chance; b) because specifically those patients may show longer survival and may, with prolonged sur- vival, develop extramedullary site (EM)-MM; and/or c) because EM/CNS-MM specifically homes to sites other than the BM, as has been observed after intensive thera- pies, such as ASCT and allogeneic-SCT.30,31
Other associations seen in CNS-MM suggest features of late disease or, alternatively, distinct biology. In Nieuwenhuizen and Biesma’s 2008 review, 41.3% of CNS-MM were stage 3 disease by the Durie-Salmon stag- ing system.1 The later study by Jurczystyn et al. found only 27% to be stage 3, using the International Staging System (ISS), although 47% showed elevation of lactate dehydro- genase (LDH), one of the parameters of late-stage MM used in the ISS.8 The 18 cases studied by Fassas et al. sug- gest an association between CNS-MM and tumor mass, other EMD, PCL and plasmablastic morphology.32 Nieuwenhuizen and Biesma observed circulating plasma cells (cPC) in 20% of CNS-MM and postulated an associ- ation, although the Kyle et al. study reported cPC in the majority of ND-MM.28 Some groups propose loss of the cellular adhesion molecule CD56 from the surface of malignant plasma cells as a mechanism of extramedullary spread and, hence, CNS infiltration.33 Although our own data suggested a higher incidence of CD56 loss in CNS- MM than in ND-MM, data from some other studies do not support this or the presence of a CNS-specific immunophenotype.29,34-37 Studies of EMD in general have revealed a putative biological signature which includes increased LDH,7,38 along with evidence of a reduction in CD56 expression.20,39 We found no difference in features such as cytogenetics, cytology and histopathology between CNS-MM diagnosed at the time of MM diagno- sis and those diagnosed at relapse. A summary of studies considered in this review is given in Table 3.
Diagnosis
Multiple myeloma with CNS involvement is difficult to diagnose as it can produce heterogeneous symptoms relat- ed to either spinal, cranial or meningeal infiltration, which can be confounded by neurological symptoms caused by the hypercalcemia, uremia, paraproteinemia and bone damage typical in MM,8 as well as side-effects of drug therapy and, in some cases, amyloid protein.32 In addition, clinical and laboratory findings of CNS-MM are not always MM-specific; for example, they can be similar to those of leptomeningeal metastases from other hemato- logic malignancies.40 CNS-MM patients can present with impairments to sight, speech, motor and sensory func- tions, radicular pain, headache, confusion, dizziness and,
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