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CNS-MM
used in combination with other agents and treatment modalities in CNS-MM.26 This benefit may be due to pathological changes such as inflammation and angiogen- esis increasing the permeability of the BBB, thus allowing passage of the drug. Marizomib, a newer PI which can cross the BBB, can be detected in the CNS upon systemic therapy, and has shown potential efficacy in relapsed refractory MM (RRMM), malignant glioma, and a small number of CNS-MM patients.16,55
Intrathecal therapy
The typical intrathecal therapy (IT) therapy regimen administered in CNS-MM is the triplet of IT hydrocorti- sone, methotrexate and/or cytarabine. This is repeated until clearance of plasma cells and free light chains from the CSF. Its use is controversial as myeloma cells are not thought to be particularly susceptible to methotrexate or cytarabine and it is unlikely to penetrate parenchymal CNS lesions. In two 2013 studies, one of 17 CNS-MM cases showed longer median OS in patients given IT ther- apy (methotrexate and/or dexamethasone) compared to those who had not,12 and a study of 37 patients identified a subgroup treated with radiotherapy, IMiD and IT thera- py (hydrocortisone, methotrexate and/or cytarabine) who had longer median OS.15 Since patients were not randomly grouped, the effect of bias cannot be ruled out in these studies. No such positive effect was observed in a 2014 study of eight patients where IT therapy was associated with a median OS of 0.9 months,24 consistent with other studies that have only shown a modest benefit of IT ther- apy.25 Intrathecal use of rituximab [a humanized anti- CD20 monoclonal antibody (mAb)] has been shown to be safe for this method of administration in the setting of CNS lymphoma56 which might suggest a future role for other mAb with anti-myeloma activity being adminis- tered by this route.
Cranial or cranial-spinal irradiation
Malignant plasma cells are known to be sensitive to radiotherapy and this treatment modality is the corner- stone of treatment for solitary plasmacytomas of bone and EM plasmacytomas.57 Cranial irradiation was reported in one review to show statistically significant benefit in improving survival (median 3 vs. 0.81 months) compared to those not receiving this treatment modality.1 Targeted radiotherapy can alleviate focal symptoms such as muscle weakness caused by intramedullary spinal cord lesions.58 There is evidence that modern radiotherapy techniques can deliver impressive responses in parenchymal CNS- MM lesions without significant myelotoxic sequelae.59
Stem cell transplantation
Stem cell transplantation can overcome the poor prog- nosis of EMD when detected at MM diagnosis,60,61 and can have a similar effect in extramedullary relapse as in BM relapse, contradicting the theory that EMD has its own immunological environment that will not support a graft- versus-myeloma response.2 In a study of 18 CNS-MM patients, the longest survivor (25 months) had received an allo-SCT after the diagnosis of CNS-MM and had no evi- dence of CNS-MM relapse at the time of death, suggesting a graft-versus-myeloma effect in the CNS.32 However, unlike in EMD, SCT is not currently considered a standard salvage treatment option in most cases of CNS-MM due to their short survival time.
Current approach
Important factors in the approach to treatment of CNS- MM include the following.
• Accurate diagnosis with a clear understanding of which part of the CNS is involved in order to help target therapy and penetrate site of disease.
• Patient factors, including: a) current BM function and likelihood of being able to tolerate further systemic thera- py; b) practicalities of delivering frequent IT therapy; c) potential toxicities of CNS irradiation.
• Acknowledgment of prior lines of systemic therapy, to avoid use of likely disease-resistant agent(s). However, drug resistance in the primary site of the tumor (BM) may not necessarily be replicated in the CNS due to the absence of BM mesenchymal stromal cells which may provide protection to the tumor cells in the BM environ- ment.
• Constraints of treatment options in resource-poor countries.
• Choice of agents known to cross the BBB and with evidence of efficacy in CNS-MM.
Given the limited therapeutic evidence-base described, our current approach to patients with suspected CNS-MM is as follows: accurate diagnosis (as summarized in Figure 1) employing MRI of brain and whole spine, analysis of CSF including serum free light chain (FLC) analysis and multi-color flow cytometry to demonstrate presence of MM cells, and, less commonly, stereotactic brain biopsy as indicated; a backbone of systemic therapy incorporating IMiD and high-dose steroid, and anti-CD38 mAb (see below) depending on local funding directives; and appro- priate site-directed CNS irradiation. We would acknowl- edge that, whilst IT therapy is controversial, it remains part of the standard of care in most centers.
Future direction
Several newer agents have demonstrated activity in B- cell neoplasms including CNS-MM. Monoclonal antibod- ies are of considerable interest and may play an important part in improving outcomes in CNS-MM. Daratumumab is a humanized mAb specific for CD38 and there is evi- dence it can cross the intact BBB, being measurable in CSF.62 It has shown significant activity in parenchymal CNS-MM in combination with IT therapy and radiother- apy (XRT).63 Also, in a study of relapsed / refractory MM (RRMM) with CNS involvement, a patient treated sys- temically with daratumumab achieved a response, clear- ing the CSF of plasma cells, although there was concomi- tant use of IT therapy.6 Isatuximab, another anti-CD38 mAb, has shown efficacy in heavily pre-treated MM patients64 and is currently being evaluated in phase III studies in combination with steroid and novel agents.65 Elotuzumab is a humanized mAb directed against SLAMF7, also called CS1. SLAMF7 is expressed on most myeloma and natural killer cells, but not on normal tis- sues. More than 95% of BM myeloma cells have been demonstrated to express SLAMF7. Elotuzumab has been shown to have activity in RRMM in combination with IMiD and steroid.66,67 However, there are no current data on its use in CNS-MM.
Translocations involving chromosome 14 are a recurrent finding in MM and approximately 15% of patients demon- strate a t(11;14) (q13;q32) involving the CCND1/IGH genes. This juxtaposition results in CCND1 being over- expressed, leading to kinase activation and tumor cell pro-
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