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P.A. Egan et al.
liferation. t(11;14) cases in MM are predicted to be BCL-2- dependent resulting in upregulation of anti-apoptotic pro- teins and thereby making BCL-2 a potential target in this subtype of myeloma.68 Venetoclax is a BCL-2 inhibitor and promotes apoptosis via a TP53 mutation-independent pathway and is of proven efficacy in patients with chronic lymphocytic leukemia (CLL) with del(17p) and/or TP53 mutation.69 It has also been demonstrated to cross the BBB in CLL and is therefore of potential efficacy in CNS-MM.70 Several phase III trials are currently underway using vene- toclax in patients with RRMM.
The BRAF gene encodes protein kinases which regulate the intracellular MAP/ERK signaling pathway involved in cell proliferation and survival. Somatic mutations arising in this gene can lead to oncogenesis. The BRAFV600E muta- tion is seen in up to 10% of MM patients at diagnosis and up to 20% at relapse.71,72 Inhibition of this pathway using selective inhibitors of BRAFV600E kinase such as vemu- rafenib, has shown some efficacy in RRMM.73 Other agents targeting this pathway are currently the subject of prospective clinical trials in Europe (clinicaltrials.gov identifi- er: NCT02834364) and in the United States (clinicaltrials.gov identifier: NCT03091257). There is evidence such agents may cross the BBB74 and at least one case report of a patient with BRAFV600E positive CNS-MM relapse respond- ing clinically and radiologically to BRAF-MEK inhibitors.75
Chimeric antigen receptor-modified T-cell (CAR-T) therapy is in preclinical stages of development for patients with RRMM. The CAR-T construct targets the B-cell mat- uration antigen (BCMA) which is highly expressed on malignant plasma cells. Soluble BCMA levels are signifi- cantly increased in CSF in primary CNS lymphoma.76 There is an assumption that CAR-T products cross the BBB given that neurotoxicity is a frequent but generally temporary side effect of this therapy. Its use in treating patients diagnosed with CNS-MM might be impeded by the fact that currently the time from patient leukapheresis to re-infusion with the CAR-T product is approximately four weeks. However, development of ‘off-the-shelf’ CAR-T products may overcome this obstacle in the future.77 Other immunotherapy modalities that target the BCMA include bispecific antibody constructs, including BiTE® (bispecific T-cell engager) immuno-oncology thera- pies, and antibody-drug conjugates (ADC). These prod- ucts, like CAR-T, have shown efficacy in RRMM.78 However, unlike CAR-T, they have the advantage of not requiring ex vivo manipulation of patients’ cells, therefore conferring a significantly faster time-to-treatment follow- ing diagnosis. Studies have suggested sBCMA is not just a
suitable target for drug therapy but that it may also have an important role in MM as a biomarker at diagnosis for its prognostic value, in assessment of response to therapy, and in minimal residual disease monitoring.78-81
Conclusions
Prevention of CNS-MM and improved outcomes face significant challenges due to the rarity of the condition, and its rapid progression. Sensitive detection of mono- clonal immunoprotein and plasma cells in CSF enables efficient diagnosis and monitoring of treatment response.13,82 This, together with new drugs, such as the next generation of PI, mAb and molecularly targeted and immune-oncological therapies, potentially offers improved risk stratification and treatment options. However, there remains a paucity of data to provide a clear evidence base on whether novel agents offer improved therapy for these patients, especially at relapse.52,83,84 Furthermore, myelosuppression is a side- effect of myeloma drug treatment, including some of the most recent novel agents such as pomalidomide,85 although modern radiotherapy may allow targeting of CNS-MM to avoid the BM and resultant damage to hematopoiesis.59
The difficulties in recruiting adequate numbers of patients with CNS-MM to clinical trials is acknowledged. Thus, these innovative treatment approaches may best be achieved through worldwide group efforts to determine optimum diagnostics and treatments, and offer the best evidence-based potential to improve outcomes. We there- fore recommend the establishment of an International Registry of such cases as the best way to produce a data- base to underpin best practice recommendations for both diagnosis and treatment. The design of a ‘proforma’ to be submitted with each dataset registered will be of para- mount importance to enable capture of this information. This approach has been used successfully in, for example, light chain (AL) amyloidosis and POEMS syndrome.
Finally, in EMD, there is evidence that poor prognosis is not linked to advanced disease alone, or to treatment received, but to tumor biology.2 Therefore, an improved understanding of this would enable identification of MM cases at risk of CNS relapse. This, in turn, would allow consideration of prophylaxis in patients thus identified, as, for example, in high grade B-cell lymphoma.16 However, at present, CNS-MM confers a bleak outlook and urgently requires an innovative approach to treatment.
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