primary plasma cell leukemia ( ppcl ) is a very aggressive form of plasma cell disorder . ppcl is very rare , reported in only 4 - 6% of patients with multiple myeloma ( mm ) . ppcl is defined as the presence of more than 20% plasma cells in the peripheral blood and an absolute plasma cell count greater than 2  10/l , without previous evidence of mm . consistent with the high tumor burden , extramedullary involvement , such as hepatosplenomegaly , lymphadenopathy , soft - tissue plasmacytomas , or leptomeningeal infiltration , is more frequent in ppcl than in mm .   despite the development of new agents , such as proteasome inhibitors or immunomodulatory drugs ( imids ) , for plasma cell disorders , the median overall survival of ppcl although ppcl is difficult to treat , high - dose melphalan followed by autologous stem cell transplantation ( auto - sct ) and/or allogeneic stem cell transplantation ( allo - sct ) seems to improve outcomes in younger selected patients . however , patients with ppcl who had central nervous system ( cns ) relapse after auto- and/or allo - sct were refractory to various treatments , and had an extremely poor prognosis . we herein present a ppcl patient with cns relapse after allo - sct who underwent concurrent intrathecal therapy ( it ) and radiotherapy ( rt ) followed by maintenance therapy with pomalidomide and low - dose dexamethasone ( pd ) . a 46-year - old man without a previous significant medical history was referred to our hospital with complaints of anorexia and generalized fatigue . laboratory findings revealed significant abnormalities , including a white blood cell ( wbc ) count of 19.710/l with 45% plasma cells , a hemoglobin level of 11.6 g / dl , a platelet count of 7.010/l , a creatinine level of 7.63 mg / dl , and a ldh level of 301 iu / l ( table 1 ) . on a peripheral blood smear , the plasma cells were medium - sized , with round nuclei , basophilic cytoplasm , and occasional cytoplasmic vacuoles ( figure 1a ) . g / l , and the serum free light chain ( flc ) k/ ratio was 161.11 ( table 1 ) . in this case , a m - component of the igg - k type was identified by serum protein electrophoresis . moreover , flow cytometry on the peripheral blood showed that these plasma cells were positive for cd38 , cd49e , cd54 , cd138 and cytoplasmic kappa light chain . t(11;14)(q13;q32 ) in 9 metaphase cells ( figure 1b ) and 46,xy in 11 metaphase cells , and a fluorescent in situ hybridization analysis revealed ccnd1/igh gene fusion rearrangement . the patient was admitted to an intensive care unit ( icu ) for continuous hemodiafiltration ( chdf ) . on the same day , we started induction therapy with lenalidomide ( 15 mg / day orally on days 1 - 14 ) , bortezomib ( 1.3 mg / m subcutaneously on days 1 , 4 , 8 , and 11 ) , and low - dose dexamethasone ( 20 mg / day orally on days 1 , 2 , 4 , 5 , 8 , 9 , 11 , and 12 ) , also known as rvd induction therapy , each for a 21-day cycle . eight days after starting the induction therapy , the circulating plasma cells in the peripheral blood disappeared , and he was transferred from the icu after withdrawal of chdf . after a total of 3 cycles of chemotherapy , the laboratory abnormalities markedly subsided , consistent with a very good partial response ( vgpr ) , because serum immunofixation was positive . he and his family consented to undergo allo - sct . at our outpatient department , because of grade 2 peripheral neuropathy , he continued induction therapy with lenalidomide ( 25 mg / day orally on days 1 - 14 ) , bortezomib ( 1.3 mg / m subcutaneously on days 1 and 8) , and dexamethasone ( 20 mg / day orally on days 1 and 8) in each 21-day cycle . after a total of 6 courses , allo - sct was performed with the bone marrow from an unrelated donor ( hla - a one allele mismatch ) . the conditioning regimen consisted of fludarabine 120 mg / m ( 30mg / m on day -5 , -4 , -3 , and -2 ) , melphalan 180 mg / m ( 90mg / m on day-4 and -3 ) , and rabbit anti - thymocyte globulin 2.5 mg / m ( 1.25mg / m on day -2 and -1 ) . for the prevention of graft - versus - host - disease ( gvhd ) , tacrolimus was started from day -1 , and methotrexate was given on days 1 , 3 , and 6 . complete donor chimerism was detected in the bone marrow on day 29 . during this admission , however , serum immunofixation was positive despite normal igg and flc levels ; therefore , he was still considered to have a vgpr . two months after discharge , the patient developed cervical , mediastinal , and axillary lymphadenopathy . he was therefore diagnosed with ebv - associated lymphoproliferative disease and was immediately treated with 2 cycles of rituximab monotherapy , resulting in a complete response . tacrolimus was discontinued on day 180 , and there was no evidence of chronic gvhd . however , 6 months after allo - sct , he had marked cytomegalovirus ( cmv ) antigenemia . the protein level in the cerebrospinal fluid was 53 mg / dl , and the glucose level was 55 mg / dl ; 17 monocytes per microliter were detected . cytological examination revealed that some of these cells resembled plasma cells ( figure 2a ) . magnetic resonance imaging ( mri ) with gadolinium ( gd ) enhancement revealed a small , enhanced nodule in the lateral medulla oblongata ( figure 2b , arrowhead ) . enhanced computed tomography ( ct ) showed no extramedullary tumors . moreover , we still observed complete donor chimerism , without leukemic plasma cells , in his bone marrow . the patient underwent 4 courses of weekly it , consisting of methotrexate 15 mg , cytarabine 20 mg , and prednisolone 40 mg in combination with local cranial rt ( 5 fractions of 2 gy for a total dose of 10 gy ) . after this combined treatment , his neurological symptoms resolved and the plasma cells in the cerebrospinal fluid disappeared . to prevent cns recurrence , we administered pomalidomide 4 mg / day on days 121 , with 20 mg of dexamethasone weekly for each 28-day cycle . subsequently , a reduced dose of 2 mg was administered for 2 cycles , but grade 4 neutropenia occurred again . he resumed pomalidomide at 1 mg and continued the low dose without severe hematological abnormalities . twelve months after the cns relapse , both enhanced ct and brain mri with gd enhancement revealed no extramedullary tumors . in our outpatient follow - up , he maintained vgpr without major complications for more than 18 months after the diagnosis of cns relapse . the prognosis of plasma cell disorder has improved following the introduction of new agents and the development of sct , but a cure remains elusive . the long - term survival rate of ppcl is low due to the aggressive nature of the disease that comprises high tumor burden and extramedullary involvement . in the us , upfront allo - sct is still one of the treatment options for young ppcl patients without major complications . in our study , we performed upfront allo - sct with a myeloablative - conditioning regimen for our young patients without major complications . the center for international blood and marrow transplant research ( cibmtr ) conducted a retrospective sct study in ppcl , and demonstrated high survival rates in an autologous group compared with those in an allogeneic group . in the cibmtr study , non - relapse mortality in the allogeneic group was much higher at 3 years ( 42% vs. 5% ) , despite this group possessing a lower relapse rate ( 39% vs. 61% ) . our patient survived for more than 2 years after allo - sct , although he unfortunately suffered from cns relapse on day 350 . consolidation and maintenance therapy after auto- and/or allo - sct in plasma cell disorder is still controversial . however , some clinical trials have recently shown that lenalidomide maintenance after auto - sct for mm significantly prolonged progression - free survival ( pfs ) and overall survival . moreover , a prospective clinical trial by the intergroupe francophone du mylome group showed that a bortezomibbased regimen followed by auto - sct and subsequent maintenance therapy with lenalidomide , bortezomib , and dexamethasone for ppcl significantly improved pfs compared with those who received a reduced intensity conditioning allograft . in the future , auto - sct and maintenance therapy combined with novel agents may be a treatment option for young ppcl patients . the prognosis of plasma cell disorders with cns involvement is extremely poor . in a retrospective study on cns myeloma conducted in 12 greek institutions , there was no significant difference in median survival of cns myeloma ( called post cns - mm ) between novel drug - treated patients and those given other treatments ( 4 months vs. 2 months ) . by multivariable analysis , extramedullary lesions , prior to treatment with novel drugs , and high ldh levels at myeloma diagnosis were statistically independent predictors of post cns - mm survival . these findings corroborate our observations that our patient with cns relapse of ppcl had an extremely short - term outcome . it has been reported that 19% of post cns - mm patients met the criteria for ppcl . furthermore , some of these ppcl patients developed isolated cns relapse during systemic remission after auto - sct . in a prospective study by royer et al . , 2 ppcl patients experienced neuromeningeal relapse after autologous- and allo - sct , respectively , and both patients soon died despite intrathecal chemotherapy . in the present case , although vgpr was maintained by rvd induction therapy followed by allo - sct , isolated cns relapse occurred within 1 year . several drugs used in multiple myeloma , including bortezomib and lenalidomide , do not efficiently cross the blood of note , bbb penetration of lenalidomide was 11% in a rhesus monkey model , whereas that of thalidomide was 42% . in a murine model , pomalidomide displayed 39% bbb penetration and high anti - tumor activity in the cns . to the best of our knowledge , the anti - tumor effect of thalidomide is inferior to that of pomalidomide . additionally , pomalidomide is more effective in ameliorating extramedullary involvement . in our case , concurrent it and rt followed by pd was initiated after the diagnosis of isolated cns involvement after allo - sct . in addition , maintenance therapy by pd might prolong survival to prevent systemic recurrence , including cns involvement , for more than 18 months . the role of pomalidomide for ppcl patients with cns involvement should be further explored in clinical trials . our ppcl patient received rvd induction therapy followed by up - front allo - sct . however , concurrent it and rt followed by pomalidomide - based maintenance therapy well controlled his cns recurrence and prolonged his survival . to find an optimal treatment for this rare but aggressive ppcl , prospective clinical trials for this disorder should take into account the importance of myeloma drug penetration across the bbb in order to enhance the treatment of cns recurrence
primary plasma cell leukemia ( ppcl ) is a rare aggressive variant of plasma cell disorder and frequently presents with extramedullary disease . 
 central nervous system ( cns ) involvement with ppcl has an extremely poor prognosis . 
 we describe a 46-year - old man with ppcl treated with a combination of lenalidomide , bortezomib , and dexamethasone as induction therapy following upfront allogeneic stem cell transplantation ( allo - sct ) . despite achieving a very good partial response 
 , the patient suffered from an isolated cns relapse 12 months after allo - sct . 
 he was immediately started on concurrent intrathecal chemotherapy ( it ) and cranial irradiation ( rt ) . 
 subsequently , pomalidomide and low - dose dexamethasone ( pd ) were given as maintenance therapy . 
 he has been without cns recurrence for more than 18 months . 
 our case suggests that concurrent it and rt followed by pd maintenance therapy may be an effective option to control cns relapse of ppcl after allo - sct .