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Hindawi Journal of Oncology Volume 2018, Article ID 3970169, 7 pages https://doi.org/10.1155/2018/3970169 Review Article Multiple Myeloma of the Central Nervous System: 13 Cases and Review of the Literature 1 2 2 2 3 Gergely Varga , Gábor Mikala, László Gopcsa, Zoltán Csukly, Sarolta Kollai, 4 5 1 1 1 György Balázs, Tímár Botond, Nikolett Wohner, Laura Horváth, Gergely Szombath, 1 1 Péter Farkas, and Tamás Masszi 3rd Department of Internal Medicine, Semmelweis University, Budapest, Hungary Department of Haematology and Stem Cell Transplantation, St. Istvan ´ and St. Las ´ zlo´ Hospital, Budapest, Hungary Department of Neurology, Semmelweis University, Budapest, Hungary Heart and Vascular Center, Division of Diagnostic Imaging, Semmelweis University, Budapest, Hungary 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary Correspondence should be addressed to Gergely Varga; email@example.com Received 27 November 2017; Accepted 18 March 2018; Published 23 April 2018 Academic Editor: Minesh P. Mehta Copyright © 2018 Gergely Varga et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Central nervous system involvement is a rare complication of multiple myeloma with extremely poor prognosis as it usually fails to respond to therapy. We present 13 cases diagnosed at two centers in Budapest and review the current literature. The majority of our cases presented with high-risk features initially; two had plasma cell leukemia. Repeated genetic tests showed clonal evolution in 3 cases. Treatments varied according to the era, and efficacy was poor as generally reported in the literature. Only one patient is currently alive, with 3-month follow-up, and the patient responded to daratumumab-based treatment. Recent case reports show promising effectivity of pomalidomide and marizomib. 1. Introduction features uncommon in historical cohorts. Normally myeloma cells need constant support from the bone marrow stromal Multiple myeloma (MM) typically presents with skeletal cells; however, evolution of the disease sometimes leads to symptoms (back pain, vertebral fractures, and lytic lesions), clones that can survive independently in extramedullary cytopenias (anemia, thrombocytopenia, and neutropenia), tissues. This is rare at presentation (7%) but becomes increas- renal failure, and infections related to immunoparesis . ingly common at subsequent relapses in the form of organ Extramedullary propagation is a rare event with poor prog- involvement, soft tissue tumors, plasma cell leukemia, and nosis due to frequent treatment failure. Within this group, rarely (less than 1%) CNS involvement, which is the focus of central nervous system (CNS) involvement is a particularly this paper . Due to its rarity, clinical trials are missing in problematic complication with an even worse prognosis. this field; therefore, most of our knowledge is derived from eTh treatment of MM developed a lot in recent years. case reports and retrospective reviews. As a consequence, we From the early 2000s, first thalidomide and its analogues do not have evidence-based treatment guidelines. and then bortezomib and newer proteasome inhibitors were Basedonareviewby Dispenzieri and Kyle, intracranial introduced, followed by anti-CD38 and anti-CS1 antibodies plasmacytomas or myelomas can be classified into four getting FDA and EMA approval most recently. As a result, the groups: (1) those extending from the skull pressing inward, expected survival of MM increased to 5–10 years in the major- (2) those growing from the dura mater or the leptomeninges, ity of patients . eTh longer survival corresponds to more (3) those arising from the mucous membranes of a nasopha- extensive disease evolution that sometimes results in previ- ryngeal plasmacytoma, and (4) intraparenchymal lesions ously unseen, more resistant, and more aggressive clones with without evidence of extension from any of these other three 2 Journal of Oncology (a) (b) Figure 1: CT and MRI images of meningeal myeloma. (a) Contrast-enhanced CT; arrows: abnormally enhancing, leptomeningeal nodular lesions in the right frontal sulci (patient 4); (b) T1-weighted brain MRI aer ft Gadolinium administration; arrows: abnormally enhancing dural lesion to be differentiated from subdural hemorrhage (patient 11). (a) (b) Figure 2: Gadolinium enhanced T1-weighted MRI images of leptomeningeal myeloma of the lumbosacral spine. (a) Axial and (b) sagittal image; arrows: contrast-enhanced myelomatous deposits (patient 11). sites . Leptomeningeal involvement is the most common 3. Imaging form, oen ft resulting in nerve root infiltration and cerebral In suspected CNS MM, the rst fi diagnostic step is usu- nerve palsies. ally contrast-enhanced MRI (head and/or whole spine). The sensitivity of MRI is over 90%: it can demonstrate 2. Symptoms bone-originated plasmacytomas, intraparenchymal tumor- ous lesions, or leptomeningeal contrast-enhanced deposits Specific symptoms depend on the underlying abnormality. (Figures 1 and 2). In a review, the latter was the most common Headache, confusion, cerebral nerve palsy, and radiculopathy form, present in 70% of the cases . CT can be diagnostic as are the most common general symptoms at presentation. In well but with lower sensitivity (80%), and iodinated contrast case of intraparenchymal lesions, focal neurologic symptoms can sometimes occur together with somnolence or seizures. material is oen ft contraindicated in myeloma . However, The diagnosis of CNS MM is based on imaging and/or the abnormalities are not necessarily specific; for example, cerebrospinal uid fl (CSF) analysis, with stereotaxic brain they can mimic subdural hemorrhage as in patient 11 in our biopsy, if applicable . series  (Figure 1(b)). Journal of Oncology 3 (a) (b) [Ungated] [Ungated] 3 3 2 2 10 10 10 10 0 1 2 3 0 1 2 3 10 10 10 10 10 10 10 10 CD38 ECD CD138 PE (c) (d) Figure 3: CSF analysis. (a) MGG stained cytospin preparation; (b) uo fl rescence in situ hybridization (FISH) with probes for 17p (normal); ((c) and (d)) flow cytometry: the plasma cells are CD38, 56, and 138 positive. 4. CSF Analysis this is usually dominantly sensory, while in case of thalido- mide, it is typically a sensomotor neuropathy. Both cause To cytologically conrfi m leptomeningeal disease, lumbar axonal degeneration, and the symptoms are only reversible puncture is necessary: in the previously cited review, it was in case of quick drug interruption/dose reduction; however, diagnostic in 90% of the cases . Liquor opening pressure is if treatment continues, they can become permanent . typically raised, and the liquor cell count is elevated. Plasma MM (and other M-protein secretory conditions from MGUS cells can be cytologically identified (Figure 3(a)). Flow cytom- to Waldenstrom ¨ ’s macroglobulinemia) can cause polyneu- etry can confirm monoclonality and aberrant protein expres- ropathy on their own right. M-protein is present in 10% sion (Figures 3(c) and 3(d)). CSF protein electrophoresis and of cryptogenic neuropathies, mostly IgM, and in 50% of free light chain analysis can indirectly confirm the CNS pres- the IgM cases the M-protein has an anti-myelin associated ence of the aberrant plasma cell clone. Fluorescence in situ glycoprotein (anti-MAG) activity . Another complication hybridization (FISH) on the cytospin preparation oen ft shows of the above-mentioned M-protein producing diseases is AL high-risk features, most commonly deletion 17p (TP53) amyloidosis. In case of clinical suspicion, tissue biopsy is (Figure 3(b)) . es Th e genetic aberrations contribute to the needed to confirm the diagnosis of amyloid deposition. eTh resistance to traditional chemotherapy and radiotherapy . most common biopsy targets are abdominal subcutaneous fat and either rectal mucosal or gingival biopsy. Other complications, common in MM, such as hyper- 5. Differential Diagnosis viscosity, renal failure, and hypercalcemia can also cause Naturally, there can be many other causes for nervous system CNS symptoms, most commonly disorientation and som- symptoms in myeloma patients, making the diagnosis of nolence. Given the average age of the MM population plus CNS propagation dicffi ult. Many of the established MM the prothrombotic properties of the IMiDs, vascular events drugs cause peripheral neuropathy. In case of bortezomib, (both ischemia and hemorrhage) can occur. Apart from CD56 APC CD19 PC5 4 Journal of Oncology fl fi fi fl Th Table 1: Patient characteristics. At diagnosis Prior treatment CNS presentation Survival (days) OS OS PFS Systemic New DG to Patient Age Sex ISS/PCL FISH/karyotype M-protein Lines al Bor Len ASCT Age Symptoms Diagnosis ISS Treatment Response from from from relapse FISH CNS CNS DG CNS EDAP, IT, LC 169 M 3 1qamp 1 1 1 0 0 69 Double vision CT, CSF flow yes 3 ND Mel-ASCT, Len PR 144 335 130 191 lambda maint VTD, Mel-ASCT, 2 65 M 1 1q amp LC kappa 1 0 1 0 0 65 Paraplegia CSF flow yes 1 ND PR 427 897 124 470 Len maint IgG 369 F 1 ND 2 1 1 0 0 74 Double vision CSF IFX no 1 ND LenDex NR 56 2025 0 1969 lambda Headache, Clinical (unspecific VRD-PACE, IT, LC hypoglossus, 441 F 3 1qamp 111 0 0 41 MRI yes 3 17p EDAP, IRD, PR 180 290 63 110 lambda and abducent abnormalities) Mel-Benda-ASCT paresis Thal + IT + Abducent craniocaudal irrad 552 M 3 del13q IgAkappa 3 1 1 0 Allo 55 paresis, unable CSF cytospin, MRI no 1 ND CR 134 1103 126 969 +discontinue to swallow GVHD prophylaxis Thal + 6 56 F 3 hyperd IgA kappa 3 1 1 0 1 60 Headache MRI no 1 ND craniocaudal irrad, PR 776 2191 104 1415 benda-VTD Oculomotor Clinical (MRI orbit 754 M 3 del13q IgAkappa 2 1 1 0 1 56 yes 3 1qamp VTD NR 93 1033 32 940 nerve paresis neg, CSF ND) complex, IgG Abducent Clinical (MRI neg, 853 M 3 31 1 0 2 57 yes 3 same PAD-Thal MR 213 1563 210 1350 hypodipl lambda paresis CSF ND) complex, del LC Paresis, cannot CSF cytospin, MRI: HD MTX, AraC, 9 43 M 3, PCL 1010 0 44 yes 3 same PD 44 140 0 96 13q lambda swallow tumors IT IgG Abducent 10 66 M 3 1q amp 21 1 0 0 67 MRI yes 3 same IRD PD 14 386 0 372 lambda paresis IgG Thio, Car, Thal, 11 34 M 2 t(4;14) 3 1 1 1 1 36 Left leg paresis MRI, CSF ow yes 1 same PR 38 557 38 519 lambda Dex VTD-PACE + ith 12 60 F 3, PCL t(11;14), del 17p IgG kappa 2 1 1 1 1 60 Seizures CSF cytospin yes 3 same triplet 4x, Mel-TBI PD 110 325 0 215 allo 13 72 M 2 normal LC kappa 4 1 1 1 0 73 Back pain CSF flow, CT yes ND 1qamp DVd + IT PR 60 695 60 675 7/13 Mean 56.5 8/12 HR 258.2 125 897 63 715 lambda Allo: allogeneic stem cell transplantation; amp: amplification; ASCT: auto logous stem cell transplantation; Bor: bortezomib; Car: carlzomib; CI : cranial irradiation; CSF: cerebrospinal uid; CTD: cyclophosphamide, thalidomide, and dexamethasone; CyBorDex: cyclophosphamide, bortezomib, and dexamethasone; Dara: daratumumab; del: deletion; DVd: daratumumab, bortezomib, and dexamethasone; flow: flow cytometry; hyperd: hyperdiploid; IFX: immunofixation; IRD: ixazomib, revlimid, and dexamethasone; IT: intrathecal chemotherapy; KTD: carlzomib, thalidom ide, and dexamethasone; LC: light chain; Len: lenalidomide; maint: maintenance; MPV: melphalan, prednisolone, and bortezomib; ND: not done; PACE: cisplatin, doxorubicin, cyclophosphamide, and etoposide; PAD: bortezomib, doxorubicin, and dexamethasone; PCL: plasma cell leukemia; PomD: pomalidomide and dexamethasone; RT: radiotherapy; T-CED: thalidomide, cyclophosphamide, etoposide, and dexamethasone; Thal: thalidomide; Thio: thiotepa; VAD: vincristine, doxorubicin, and dexamethasone; VTD: bortezomib, thalidomide, and dexamethasone. Journal of Oncology 5 Table 2: Largest recently published case series. Median OS 𝑛 Era Center(s) Reference (months, CI) Jurczyszyn et al. 172 1995–2014 3.7 (NA) Multicenter: 38 centers from 20 countries  Paludo et al. 29 1998–2014 3.4 (1–10) Mayo Clinic, Rochester  Schluterman et al. 23 1990–2003 3 (0.1–25) University of Arkansas, Little Rock  Chen et al. 37 1999–2010 4.6 (2.8–6.7) Princess Margaret Cancer Centre, Toronto  Abdallah et al. 35 1996–2012 4 (1–13) University of Arkansas, Little Rock  Majd et al. 9 1998–2012 3 (1–12) Mount Sinai Hospital, New York  GIMEMA (Gruppo Italiano Malattie EMatologiche Gozzetti et al. 50 2000–2010 6 (1–23)  dell’Adulto) multiple myeloma working party Dias et al. 21 2008–2016 5.8 (NA) Faculdade de Ciencias ˆ Medic ´ as da Santa Casa de Sao ˜ Paulo  CI: confidence interval; NA: not available. these, autoimmunity, paraneoplasia, and infections have to cytosine arabinoside, and dexamethasone (15 mg, 40 mg, and be considered (herpes and JC viruses) in these patients with 4 mg, resp.) is often applied continuously until liquor clear- compromised immune system. ance, usually in combination with high-dose chemotherapy, Most myeloma patients are taking multiple medications. using drugs with known CNS penetration (methotrexate, Among these, thalidomide has a sedative effect, but patients cytosine arabinoside, idarubicin, and thiotepa), together with taking thalidomide oeft n report vertigo, tremor, imbalance, high-dose dexamethasone, similar to what we normally do in and difficulty to walk too. es Th e tend to improve quickly CNS lymphoma. In case of a response to this strategy, ret- upon stopping thalidomide. Major analgesics (morphine and rospective data support the use of craniocaudal radiotherapy fentanyl) and adjuvant pain medications (gabapentin, pre- and possibly ASCT as consolidation . gabalin, tegretol, and tricyclic antidepressants) can blur the Recently, a case review reported the effectivity of poma- clinical picture further, especially if drug levels are unreliable lidomide in CNS MM . Pomalidomide is a drug of the duetoliverandkidneyfailure. IMiD class approved for lenalidomide refractory patients, which according to a subgroup analysis is more eeff ctive in high-risk cytogenetics, especially deletion 17p, than other 6. Treatment and Survival IMiDs and has good CNS penetration . Another drug that could have a role in this setting is marizomib, a potent eTh treatment of CNS MM is highly problematic. On one natural second-generation proteasome inhibitor produced by hand, this complication is more common in otherwise high- a marine bacterium, which was used successfully in two cases riskMM(bothclinicallyaggressiveand geneticallyhigh of CNS MM . risk), when chemotherapy is usually less eeff ctive. Another Based on these data, it is not surprising that the overall problemisthatdrugs tested andproveninrelapsedMM, survival in this condition is extremely poor. eTh survival such as the proteasome inhibitors (bortezomib, carfilzomib, data varies widely between studies but usually does not and ixazomib), cannot cross the blood-brain barrier, and exceed a couple of months from diagnosis (median survival: standard chemotherapy drugs used to treat CNS lymphoma 2–8 months, Table 2) [3, 5–11, 19]. It is significantly better, and brain cancer are not particularly effective in MM. The however, in those patients who had craniocaudal irradiation IMiDs (thalidomide, lenalidomide, and pomalidomide) do orASCT.Althoughthisdataisbiasedasthese areselected cross the blood-brain barrier; however, IMiD resistance is patients who responded to their initial treatment [3, 5], in not uncommon in this group of patients. eTh anti-CD38 more recent publications, nevertheless, there is a promising antibody daratumumab and anti-CS1 elotuzumab recently increase in survival . approved in relapsed MM were not prospectively tested in this particular group of patients; CNS involvement was an exclusion criterion in the registration trials. It is unknown 7. 13 Cases of CNS MM over 10 Years whether these antibodies can get through the blood-brain in Our 2 Centers barrier, and there is no published report about their intrathe- cal use, whatever tempting it would be theoretically. In one Outof548 MM casestreated over 10 yearsatthe 3rdDepart- case report of a CNS MM case, it was found that MM cells ment of Internal Medicine, Semmelweis University, and in the CSF shred their surface CD38 aer ft starting systemic the Department of Haematology and the Stem Cell Trans- daratumumab, which was interpreted as an indirect sign of plantation, St. Istvan ´ and St. Laszl ´ o´ Hospital, we identified CNS penetration of the drug . It has to be mentioned here retrospectively 13 cases of CNS MM. Patients’ characteristics that intrathecal injection of bortezomib can be fatal and is including symptoms, treatments, and survival are shown in therefore absolutely contraindicated! Table 1, treatment courses and responses to various treatment As asalvage,inanalogy to acutelymphoidleukemia, lines are depicted graphically in Figure 4, and progression- intrathecal combinational chemotherapy with methotrexate, free survival and overall survival given in Figure 5. 6 Journal of Oncology VTDx4, VTDCx1, HD-Cyclo EDAP, ASCT, Len PADx6, HD-Cyclo VTD, ASCT, Len maint VTDx6 CyBorDex ×2 LenDex VTDx3 VRD-PACE, IRD, ASCT VADx4 HD-Cyclo, MPV, ASCT PADx2, allo Thal, CI, IT VTD, MPVT, EDAP, ASCT RT, CTDx3 Thal, CI Benda-VTD CyBorDex, Thal maint 7 PAD, ASCT VTD VAD, ASCT T-CED, ASCT CyBorDex PAD-Thal PAD AraC, MTX CyBorDex MPVT IRD 11 VTDx4 VRD-PACE, ASCT IRD Thio-KTD, allo PAD VTD-PACE, Len maint VTD-PACE MPV CTD IRD PomD DVd, IT Years from diagnosis 12 3 4 5 SD CNS symptoms CR PD Death VGPR PR Figure 4: Treatments and responses. Allo: allogeneic stem cell transplantation; amp: amplification; ASCT: autologous stem cell trans- plantation; Bor: bortezomib; Car: carfilzomib; CI: cranial irradiation; CSF: cerebrospinal uid; fl CTD: cyclophosphamide, thalidomide, and dexamethasone; CyBorDex: cyclophosphamide, bortezomib, and dexamethasone; Dara: daratumumab; del: deletion; DVd: daratumumab, bortezomib, and dexamethasone; flow: flow cytometry; hyperd: hyperdiploid; IFX: immunofixation; IRD: ixazomib, revlimid, and dexamethasone; IT: intrathecal chemotherapy; KTD: carfilzomib, thalidomide, and dexamethasone; LC: light chain; Len: lenalidomide; maint: maintenance; MPV: melphalan, prednisolone, and bortezomib; ND: not done; PACE: cisplatin, doxorubicin, cyclophosphamide, and etoposide; PAD: bortezomib, doxorubicin, and dexamethasone; PCL: plasma cell leukemia; PomD: pomalidomide and dexamethasone; RT: radiotherapy; T-CED: thalidomide, cyclophosphamide, etoposide, and dexamethasone; Thal: thalidomide; Thio: thiotepa; VAD: vincristine, doxorubicin, and dexamethasone; VRD: bortezomib, lenalidomide, and dexamethasone; VTD: bortezomib, thalidomide, and dexamethasone. in terms of new FISH findings in 3 patients. Two patients 1,0 presented originally as primary plasma cell leukemia; in these cases, survival from the original diagnoses was only 5 and 12 0,8 months. The dominant symptoms were cranial nerve palsies (dou- ble vision and dysphagia) but patients also presented with 0,6 headache, seizures, paraparesis or paraplegia, and radicu- lopathy. The diagnosis was supported by imaging in 6 and by CSF analysis in 8 cases. 0,4 Treatment strategies varied according to the patients’ pre- senting symptoms, performance stage, and drug availability 0,2 at the time. Ten patients had treatment containing an IMiD (5 lenalidomide and 5 thalidomide), vfi e had high-dose salvage chemotherapy, four ASCT, two craniocaudal irradiation, and 0,0 six intrathecal chemotherapy. One very recent case (#13) presenting with CNS relapse in September 2017 showed ,00 200,00 400,00 600,00 800,00 a remarkable response to systemic daratumumab. Dara- (days) tumumab was combined with bortezomib and high-dose PFS 63 (0–185) days corticosteroids and the patient had 3 times intrathecal triplet OS 125 (84–165) days chemotherapy treatment as well. With 3-month follow-up, Figure 5: Progression-free survival (PFS) and overall survival (OS). he is alive and well, and his CSF that was previously full of plasma cells (Figure 3(a)) is now clear. In one case, CNS MM presented as an isolated relapse fol- CNS symptoms started in each case at the time of relapse, lowing allogeneic SCT, indicating that graft versus myeloma effect is less prominent in the CNS. In another case, aer ft on average 2 years from the initial diagnosis of MM (range: 3months–5.3years). eTh se patients wereyoungerthanthe combination chemotherapy for CNS MM, we attempted usual MM patients, with more IgA and LC secretory cases allogeneic SCT with total body irradiation (TBI) based than usually seen in MM. 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Published: Apr 23, 2018
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