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P.A. Egan et al.
BM microenvironment,47 or the inability to cross the blood-brain barrier (BBB).1 It has been suggested that, by preventing access of drugs to the brain, the BBB provides a safe haven for the tumor that only radiotherapy or IT administration can overcome.14 Therefore, when consider- ing systemic therapy, a prerequisite is that the chosen agent(s) have the potential to cross the BBB. Standard cytotoxic regimens lack efficacy in CNS-MM as they are either poor at penetrating the BBB (alkylating agents including melphalan and cyclophosphamide) or ineffec- tive against myeloma cells (high-dose methotrexate or cytarabine). Bendamustine is capable of permeating the BBB and has shown some efficacy in two cases of lep- tomeningeal relapse of myeloma in combination with thalidomide, dexamethasone and craniospinal irradia- tion.48 High-dose steroids are known to cross the BBB, although they are of limited benefit when used in isola- tion.
The retrospective analysis of 172 patients with CNS- MM published by Jurczyszyn et al. in 2016 highlighted the importance of incorporating systemic therapy into any planned treatment strategy.8 Ninety-seven percent of patients were treated, receiving systemic therapy (76%), radiotherapy (36%), and IT therapy (32%). The only group to have a significantly longer median OS than the untreated group received systemic treatment (OS 12 vs. 3 months), although the number of patients not given sys-
Figure 2. Detection and char- acterization of myeloma cells in cerebrospinal fluid by flow cytometry. Clonal plasma cells (blue) distinguished from other lymphocyte populations (red) and debris (black).
temic therapy was small. Furthermore, these data need to be interpreted with caution as it appears fair to assume that patients in whom systemic treatment could be con- sidered were in better condition to tolerate that treatment when CNS-MM was diagnosed. Hence, this is a potential source of bias in the interpretation of the OS data.
The IMiD thalidomide and lenalidomide have been reported to penetrate the BBB in non-human primates.49 In patients, thalidomide has been shown to cross the BBB in leptomeningeal CNS-MM;50 however, it is not certain whether it is sufficiently fast-acting to stabilize CNS-MM disease.8,51 A 2015 review of 31 Greek patients with CNS- MM showed no survival benefit from the use of novel agents (including thalidomide and lenalidomide) or radio- therapy, although it should be noted that they received no high-dose systemic therapy or SCT.52 Chen et al.'s 2013 study observed 6 of 9 long-term CNS-MM survivors when treated with IMiD-based therapy (5 thalidomide; 1 lenalidomide), with concomitant multi‐dosing IT therapy and cranial/spinal irradiation.15 The third-generation IMiD pomalidomide has demonstrated activity in EMD22 and good penetrance of the BBB in a murine model.53 Notably, a durable CSF emission has been reported using poma- lidomide-dexamethasone treatment.54
The current PI in regular clinical use (bortezomib, carfil- zomib and ixazomib) are not thought to cross the BBB. However, bortezomib has shown some efficacy when
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haematologica | 2020; 105(7)